Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH2:25][CH2:26][C:27](=[O:30])[NH:28][N:29]=4)=[CH:20][CH:19]=3)=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]=O.[OH-].[K+]>C(O)C>[C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:25]=[C:26]([CH3:31])[C:27](=[O:30])[NH:28][N:29]=4)=[CH:22][CH:23]=3)=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=O
Reactant: O=C1CCC(c2ccc(NC(=O)CCN3CCC(c4ccccc4)CC3)cc2)=NN1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2ccc(NC(=O)CCN3CCC(c4ccccc4)CC3)cc2)n[nH]c1=O

Procedure:
4.0 g (10 millimoles) of 6-[p-(3-(4-phenylpiperid--1-yl)-propionylamino)-phenyl]-4,5-dihydro-3(2H)-pyridazinone in 15 ml of ethanol were refluxed with 1.5 ml of 37% strength formalin solution and 40 ml of 4% strength ethanolic KOH for 3 hours. Insoluble material was filtered off under suction, after which the mother liquor was evaporated down and the product was recrystallized from isopropanol. 2.2 g of 6-[p-(3-(4-phenylpiperid-1-yl)-propionylamino)-phenyl]-4-methyl-3(2H)-pyridazinone were obtained as pale beige crystals of melting point 239°-240° C.
Reaction SMILES: [C:1]([N:4]([CH3:26])[C:5]1[CH:6]=[CH:7][C:8]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:9]([NH:11][C:12](=O)[C:13]([F:16])([F:15])[CH3:14])[CH:10]=1)(=[O:3])[CH3:2]>C(O)(=O)C>[F:15][C:13]([C:12]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:8]2[CH:7]=[CH:6][C:5]([N:4]([CH3:26])[C:1](=[O:3])[CH3:2])=[CH:10][C:9]=2[N:11]=1)([F:16])[CH3:14]
Reactant: CC(=O)N(C)c1ccc(NCC2CCOCC2)c(NC(=O)C(C)(F)F)c1
Solvent: CC(=O)O
Product: CC(=O)N(C)c1ccc2c(c1)nc(C(C)(F)F)n2CC1CCOCC1

Procedure:
N-{5-[Acetyl(methyl)amino]-2-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-2,2-difluoropropanamide (1.00 g, 2.70 mmol) was heated to 90° C. overnight in acetic acid (20 mL). The solvent was concentrated. The crude product was purified by flash chromatography on silica gel, using MeOH 3.5% and acetone 8% in DCM as eluent, giving the title compound. Yield: 0.48 g (50%); MS (ESI) (M+H)+: 352.0.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].N1C=CC=C(C)C=1.[CH2:26]([NH:28][CH2:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)[CH3:27]>[OH-].[NH4+]>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:32]3[CH2:33][CH2:34][CH:30]([CH2:29][NH:28][CH2:26][CH3:27])[CH2:31]3)[CH:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CCNCC1CCNC1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1cccnc1
Product: CCNCC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CC)C1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of 2.70 g (10.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 60 ml of β-picoline and 3.85 g (30.0 mmole) of N-ethyl-3-pyrrolidinemethanamine were refluxed overnight. Reaction mixture was cooled to room temperature, 100 ml concentrated ammonium hydroxide added, and the solvents removed at reduced pressure. A solution of 200 ml dichloromethane/ether (1:3) was added. The resulting precipitate was filtered, washed with ethanol/ether (1:3) and finally with ether until dry to give 1.87 g of 1-ethyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 248°-252° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]=[CH:6][CH2:5][C@H:4]([NH:9]C(=O)OC(C)(C)C)[C:3]1=[O:17].Cl>C(Cl)Cl>[NH2:9][C@H:4]1[CH2:5][CH:6]=[CH:7][CH2:8][N:2]([CH3:1])[C:3]1=[O:17]
Reactant: CN1CC=CC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: ClCCl
Product: CN1CC=CC[C@H](N)C1=O
Reaction time: 12 h

Procedure:
To a solution of 1,1-dimethylethyl [(3S)-1-methyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-yl]carbamate (0.6 g, 2.5 mmol) in DCM (4 mL) was added HCl (6.2 mL, 25 mmol, 4M in dioxane) and the resulting mixture was stirred for 12 hours. Removal of the solvents under reduced pressure yielded (3S)-3-amino-1-methyl-1,3,4,7-tetrahydro-2H-azepin-2-one.HCl (500 mg, quantitative). LCMS: (M+H)+: not detected.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:17]=1[CH2:18][S:19][C:20]1[N:25]=[C:24]([NH:26][S:27]([N:30]2[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH:23]=[C:22]([O:37][CH3:38])[N:21]=1.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.[OH-].[Na+].Cl>C(Cl)Cl.C(O)(=O)C>[F:15][C:16]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:17]=1[CH2:18][S:19][C:20]1[N:25]=[C:24]([NH:26][S:27]([N:30]2[CH2:31][CH2:32][CH:33]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH2:34][CH2:35]2)(=[O:29])=[O:28])[CH:23]=[C:22]([O:37][CH3:38])[N:21]=1
Reactant: C1COCCN1
Reactant: COc1cc(NS(=O)(=O)N2CCC(=O)CC2)nc(SCc2cccc(F)c2F)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)N2CCC(N3CCOCC3)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium triacetoxyborohydride (0.48 g) was added to a solution of N-{2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}-4-oxopiperidine-1-sulfonamide (the product of step iii) (0.249 g), morpholine (0.2 mL) and 2M aqueous acetic acid (0.5 mL) in DCM (12 mL). The mixture was stirred at room temperature for 18 h then 2M aqueous sodium hydroxide (10 mL) added to the residue. The mixture was shaken vigorously then acidified to pH 8 with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica using a 3:7 to 1:0 mixture of ethyl acetate and iso-hexane as eluent then precipitated slowly from methanol, filtered and washed with further methanol to afford the title compound as a pale yellow solid. Yield: 53 mg
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH:7]=[C:6]([C:11]([O-:13])=[O:12])[C:5]=2[CH:4]=[N:3]1.[BH4-].[Na+].[CH3:16]O>Cl[Ni]Cl>[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:11]([O:13][CH3:16])=[O:12])[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1CCC=C2C(=O)[O-]
Reactant: CO
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)C1CCCc2c1cnn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 1-methyl-6,7-dihydro-1H-indazole-4-carboxylate (7.5 g, 38.7 mmol) and NiCl2 (4.9 g, 38.7 mmol) in MeOH (250 mL) was added NaBH4 (14 g, 387 mmol) in portions at 0° C. The resulting mixture was stirred at room temperature for further 1 hour. The solvent was removed and the residue was purified by column chromatography on silica gel (PE/THF=5/1 v/v %) to afford methyl 1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxylate (7 g, 94%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1[OH:4].CC1C=CC(O)=C(C)C=1C.CC1C(C)=CC(C)=CC=1O.CC1C(C)=CC=C(C)C=1O.O=O>CN(C)C=O.[Co]>[CH3:1][C:2]1[C:3](=[O:4])[CH:5]=[C:6]([CH3:11])[C:7](=[O:10])[C:8]=1[CH3:9]
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: [Co]
Agent: Cc1cc(C)c(C)c(O)c1
Agent: Cc1ccc(C)c(O)c1C
Solvent: CN(C)C=O
Product: CC1=CC(=O)C(C)=C(C)C1=O

Procedure:
In the process for the preparation of 2,3,5-trimethylhydroquinone by (a) catalytic oxidation of a trimethylphenol starting material selected from the class consisting of 2,3,5-trimethylphenol, 2,3,6-trimethylphenol and mixtures thereof by reaction with oxygen in the presence of a cobalt chelate complex in a dimethylformamide solvent to afford 2,3,5-trimethyl-p-benzoquinone followed by (b) catalytic hydrogenation of the 2,3,5-trimethyl-p-benzoquinone thus formed by reaction with hydrogen in the presence of a noble metal catalyst, the improvement which comprises; (1) mixing the 2,3,5-trimethyl-p-benzoquinone containing reaction mixture from step (a) with di-n-butyl ether and water to form a di-n-butyl ether phase containing 2,3,5-trimethyl-p-benzoquinone, a precipitate comprising the cobalt catalyst and an aqueous phase containing the dimethylformamide reaction solvent, (2) separating the di-n-butyl ether phase from the precipitate and aqueous phase, and (3) subjecting the separated di-n-butyl ether phase to catalytic hydrogenation according to reaction step (b), said di-n-butyl ether functioning as the reaction solvent.
Reaction SMILES: [Br:1][C:2]1[C:7](F)=[CH:6][N:5]=[C:4]([C:9]2[CH2:13][CH2:12][C@:11]3([CH2:17][CH2:16][N:15]([CH3:18])[C:14]3=[O:19])[N:10]=2)[CH:3]=1.[CH3:20][O-:21].[Na+].CO>C1COCC1>[Br:1][C:2]1[C:7]([O:21][CH3:20])=[CH:6][N:5]=[C:4]([C:9]2[CH2:13][CH2:12][C@:11]3([CH2:17][CH2:16][N:15]([CH3:18])[C:14]3=[O:19])[N:10]=2)[CH:3]=1
Reactant: C[O-]
Reactant: CN1CC[C@]2(CCC(c3cc(Br)c(F)cn3)=N2)C1=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cnc(C2=N[C@]3(CC2)CCN(C)C3=O)cc1Br
Reaction time: 0.17 h

Procedure:
To a solution of (5R)-2-(4-bromo-5-fluoro-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 35) (50 mg, 0.1500 mmol) in THF (2 mL) was added 30% wt. sodium methoxide in methanol (27.6 mg, 0.1500 mmol). The solution was stirred for 10 mins. A further 2 portions of 30% wt. sodium methoxide in methanol (27.6 mg, 0.1500 mmol) were added and the mixture stirred at room temperature for a further 10 mins. A further portion of 30% wt. sodium methoxide in methanol (27.6 mg, 0.1500 mmol) was added and the mixture stirred for 10 mins. The mixture was concentrated and the residues partitioned between water and DCM. The layers were separated with a hydrophobic frit and the organic filtrate evaporated to give (5R)-2-(4-bromo-5-methoxy-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (D56) as a cream solid (47 mg);
Reaction SMILES: FC1C=[C:4](C=CC=1F)[CH2:5][N:6]1C=CC=C(C(NCC2C=C(C3C4C(=NC=C(C(N)=O)C=4)NC=3)C=CC=2)=O)C1=O.[F:39][C:40]1[CH:41]=[C:42]([CH:72]=[CH:73][C:74]=1[F:75])[CH2:43][N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([NH:52][CH2:53][C:54]2[S:58][C:57]([C:59]3[C:67]4[C:62](=[N:63][CH:64]=[C:65]([C:68]([OH:70])=O)[CH:66]=4)[NH:61][CH:60]=3)=[CH:56][CH:55]=2)=[O:51])[C:45]1=[O:71].Cl.C(N)C>>[CH2:5]([NH:6][C:68]([C:65]1[CH:66]=[C:67]2[C:59]([C:57]3[S:58][C:54]([CH2:53][NH:52][C:50]([C:46]4[C:45](=[O:71])[N:44]([CH2:43][C:42]5[CH:72]=[CH:73][C:74]([F:75])=[C:40]([F:39])[CH:41]=5)[CH:49]=[CH:48][CH:47]=4)=[O:51])=[CH:55][CH:56]=3)=[CH:60][NH:61][C:62]2=[N:63][CH:64]=1)=[O:70])[CH3:4]
Reactant: NC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Reactant: O=C(O)c1cnc2[nH]cc(-c3ccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)s3)c2c1
Agent: CCN
Agent: Cl
Product: CCNC(=O)c1cnc2[nH]cc(-c3ccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)s3)c2c1

Procedure:
Except where indicated, 3-[5-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-thiophen-2-yl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethylamide was synthesized as per Example 81, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid amide using 3-[5-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-thiophen-2-yl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (43 mg, 0.000083 mol) as carboxylic acid and ethylamine hydrochloride (17 mg, 0.00021 mol; Aldrich) as amine, to yield the product. 1H NMR (400 MHz, DMSO-d6) d ppm 12.161 (s, 1H) 10.066 (t, J=5.6 Hz, 1H) 8.760 (s, 1H) 8.634 (s, 1H) 8.606 (m, 1H) 8.404 (d, J=7.4 Hz, 1H) 8.237 (d, J=6.5 Hz, 1H) 7.855 (s, 1H) 7.479-7.347 (m, 2H) 7.272 (d, J=3.0 Hz, 1H) 7.187-7.129 (m, 1H) 7.055 (d, J=3.0 Hz, 1H) 6.597 (t, J=7.1 Hz, 1H) 5.195 (s, 2H) 4.686 (d, J=5.9 Hz, 2H) 3.324 (qd, J=6.5 Hz, 6.5 Hz, 2H) 1.147 (t, J=6.8 Hz, 3H); MS m/z=548.19 M+H.
Reaction SMILES: [F:1][C:2]([F:15])([CH:6]([O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].C1CCC(N=C=NC2CCCCC2)CC1.[F:31][C:32]([F:36])([F:35])[CH2:33]O.Cl>ClCCl.CN(C1C=CN=CC=1)C>[F:31][C:32]([F:36])([F:35])[CH2:33][O:4][C:3](=[O:5])[C:2]([F:15])([F:1])[CH:6]([O:9][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])[CH2:7][CH3:8]
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)O
Reactant: OCC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OCC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
After a reaction vessel which had been sufficiently dried inside by vacuum heating was replaced with dry nitrogen, 100 mL of a solution of 22.22 g (0.1 mol) of 2,2-difluoro-3-(methacryloyloxy)pentanoic acid in dichloromethane was added into the reaction vessel, and the mixture was cooled to an ice temperature. Thereto was added 100 mL of a solution of 22.70 g (0.11 mol) of DCC in dichloromethane over 10 min, and 0.61 g (5 mmol) of DMAP and 10.40 g (0.105 mol) of 2,2,2-trifluoroethanol were further added. Thereafter, the temperature of the reaction vessel was elevated to the room temperature, followed by stirring the mixture for 2 hrs, and 300 g of 1 N aqueous hydrochloric acid was added while intimately stirring. Subsequently, dichloromethane was separated by a separatory funnel, and the aqueous layer was extracted again with dichloromethane to obtain an extraction liquid. After the extraction liquid was combined with the dichloromethane layer and washed with 1 N aqueous hydrochloric acid, the solvent of the dichloromethane layer was distilled off with an evaporator, followed by purification by column chromatography to give 21.60 g of 2,2,2-trifluoroethyl-2,2-difluoro-3-(methacryloyloxy)pentanoate (M-5) (yield: 71%).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:7]=1)[CH2:3][CH2:4][OH:5].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.CCOC(C)=O>C(Cl)Cl>[CH:15]1([O:14][C:8]2[CH:7]=[C:6]([CH:2]([N:1]3[C:23](=[O:24])[C:22]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]4[C:20]3=[O:25])[CH2:3][CH2:4][OH:5])[CH:11]=[CH:10][C:9]=2[O:12][CH3:13])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COc1ccc(C(N)CCO)cc1OC1CCCC1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(CCO)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 77 %

Procedure:
A mixture of 3-amino-3-(3'-cyclopentyloxy-4'methoxyphenyl)-1-propanol (4.31 grams, 16.24 mmol) and phthalic anhydride (2.41 grams, 16.27 mmol) was melted with a heat gun for 6 minutes. The mixture was allowed to cool to room temperature. Chromatography (silica gel 100 grams, 1:5 EtOAc:CH2Cl2) gave 3-(3'-cyclopentyloxy-4'-methoxyphenyl)-3-phthalimido-1-propanol as solid, (4.97 grams, 77% yield): mp, 59.0°-61.0° C.; 1H NMR (CDCl3)δ1.56-1.98 (m, 9H, OH, C5H8), 2.48-2.59 (m, 1H, CHH), 2.71-2.83 (m, 1H, CHH), 3.66-3.74 (m, 2H, OCH2), 3.80 (s, 3H, CH3), 4.74-4.80 (m, 1H, CH), 5.51 (dd, J=6.5, 9.4 Hz, 1H, NCH), 6.78 (J=8.3 Hz, 1H, Ar), 7.05-7.09 (m, 1H, Ar), 7.16-7.17 (m, 1H, Ar), 7.64-7.70 (m, 2H, Ar), 7.75-7.81 (m, 2H, Ar); 13C NMR (CDCl3)δ24.02, 32.71, 38.84, 51.44, 55.94, 59.75, 80.35, 111.58, 115.06, 120.54, 123.12, 131.60, 131.80, 133.86, 147.48, 149.55, 168.43; Anal Calcd for C23H25NO5 : C, 69.86; H, 6.37; N, 3.54. Found: C, 69.51; H, 6.41; N, 3.54.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C@@H:8]12[C:17](=[O:18])[O:16][C:14](=[O:15])[C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2>O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:17]([C@@H:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[C:14]([OH:16])=[O:15])=[O:18])[CH2:4][CH2:3]1
Reactant: O=C1OC(=O)[C@H]2CCCC[C@H]12
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: CN1CCN(C(=O)[C@@H]2CCCC[C@H]2C(=O)O)CC1
Reaction time: 1.25 h

Procedure:
0.37 cm3 of N-methylpiperazine in solution in 5 cm3 of dioxane is added, under an argon atmosphere, to 0.50 g of (−)-trans-1,2-cyclohexanedicarboxylic anhydride in solution at −15° C. in 20 cm3 of dioxane. After 1.25 hours at 20° C., the reaction mixture is filtered, the solid is washed with 20 cm3 of diethyl ether, drained, and then dried under reduced pressure (2,7 kPa) at 20° C., to give 0.65 g of (1R, 2R)-2-[(4-methylpiperazin-1-yl)carbonyl]-1-cyclohexanecarboxylic acid in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[Na+].O1CCCC1>C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1[nH]c2c(NS(=O)(=O)c3cccs3)cccc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(=O)O)[nH]c2c(NS(=O)(=O)c3cccs3)cccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of ethyl 3-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (1.33 g), 8N aqueous sodium hydroxide solution (2.0 mL), tetrahydrofuran (5 mL) and ethanol (10 mL) was stirred at 60° C. for 3 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (1.15 g, yield 94%) as colorless crystals. melting point>263° C. (decomposition).
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][C:35]5[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=5[F:42])=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:43]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[O:44])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:53])=[N+]=[N-].N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O.CO>[NH2:1][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][CH2:33][O:34][C:35]5[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=5[F:42])=[CH:28][CH:29]=4)[CH2:22][CH2:21][N:20]([C:43]([O:45][CH2:46][C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)=[O:44])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:53]
Reactant: [N-]=[N+]=NCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOc4cc(F)ccc4F)cc3)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.660 g of benzyl 3-[4-(2-azidoethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[3-(2,5-difluorophenoxy)propoxy]phenyl}piperidine-1-carboxylate in 2.5 ml of tetrahydrofuran and 0.55 ml of water is admixed at room temperature with a solution of 0.55 ml of 25% conc. ammonia in 2.4 ml of methanol. After 0.357 g of triphenylphosphine has been added, the reaction mixture is stirred at room temperature over 16 hours. The reaction mixture is poured onto water (40 ml) and extracted with tert-butyl methyl ether (3×40 ml). The organic phases are washed with brine (20 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.31 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.01.
Reaction SMILES: ClC1C=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.[S:83]1C=CC=C1B(O)O>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[CH:9]=[C:8]([O:39][CH3:40])[CH:7]=[CH:6][C:5]=2[C:4]2[S:83][CH:43]=[CH:42][CH:41]=2)[CH:20]=[CH:19]3)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: OB(O)c1cccs1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2cccs2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 27 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 2-thiopheneboronic acid (34 mg, 0.2625 mmol) to produce the title compound (26 mg, 27% yield).
Reaction SMILES: BrCCBr.[Mg].Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH2:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])=[CH:9][CH:8]=1.[CH2:21]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH:30]([CH2:35][O:36][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([N:28]1[CH2:33][CH2:32][C:31]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][O:14][CH2:15][C@@H:16]([CH3:20])[CH2:17][O:18][CH3:19])=[CH:9][CH:8]=2)([OH:34])[CH:30]([CH2:35][O:36][C:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC[C@H](C)COCc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COC[C@H](C)COCc1ccc(C2(O)CCN(Cc3ccccc3)CC2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.32 mmol of 1,2-dibromoethane are added to a suspension of 156.518 mmol of magnesium in 20 ml of tetrahydrofuran under argon at room temperature. The reaction mixture is warmed until the magnesium starts to react and then 3 ml of a solution of 151.509 mmol of 1-bromo-4-((S)-3-methoxy-2-methyl-propoxymethyl)-benzene in 170 ml of tetrahydrofuran, followed by the rest of the solution, is added while maintaining a gentle reflux. After 2 hours, the reaction mixture is cooled to room temperature and then a solution of 125.214 mmol of 1-benzyl-3-trityloxymethyl -piperidin-4-one [234757-27-8] in 170 ml of tetrahydrofuran is slowly added, taking care to keep the internal reaction temperature under 40° C. After overnight stirring at room temperature, the reaction mixture is quenched with saturated aqueous ammonium chloride solution. Ethyl acetate is added to the reaction mixture and the phases separated—the organic phase is washed successively with water and brine. The combined aqueous phases are back-extracted with ethyl acetate—the combined organic phases are dried with sodium sulfate and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound as a yellow oil. Rf=0.30 (EtOAc-heptane-25% ammonia conc. 100:100:1); Rt=5.43 (gradient I).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][C:4]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1)#[N:2].OO.C(=O)([O-])[O-:30].[K+].[K+].[OH-].[K+].Cl>CS(C)=O.O.CO>[NH2:2][C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[NH:14][C@H:15]1[CH2:16][CH2:17][C@H:18]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:19][CH2:20]1)=[O:30]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(C#N)c(N[C@H]2CC[C@H](N3CCCCC3)CC2)c1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: NC(=O)c1ccc(C(=O)O)cc1N[C@H]1CC[C@H](N2CCCCC2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 4-cyano-3-[(trans-4-piperidin-1-ylcyclohexyl)amino]benzoate (0.145 g, 0.41 mmol) in DMSO (0.5 mL) was added a 30% hydrogen peroxide solution (0.078 mL, 0.81 mmol) and potassium carbonate (0.014 g, 0.10 mmol). The reaction mixture was stirred at 50° C. for 3 h. A mixture of methanol (1.5 mL) and water (0.5 mL) was then added followed by potassium hydroxide (0.046 g, 0.81 mmol), and the solution was stirred at 55° C. for 2 h. The mixture was acidified to pH 5 by addition of 1N aqueous hydrochloric acid and lyophilized to afford crude 4-(aminocarbonyl)-3-(trans-4-(piperidin-1-yl)cyclohexylamino]benzoic acid which was used without further purification. MS (EI) for C19H27N3O3: 346 (MH+).