Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18](O)=[O:19])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:18](=[O:19])[CH2:17][S:16][C:13]2[S:12][C:11]([NH:10][C:8](=[O:9])[C@@H:7]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[N:15][CH:14]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CSc2cnc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)s2)CC1

Procedure:
(R)-4-(2-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-acetyl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from (R)-{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-acetic acid and tert-butyl-1-piperazinecarboxylate as described in Example 12. 1H-NMR (CDCl3): δ 7.87 (d, 2H), 7.54 (d, 2H), 7.44 (s, 1H), 3.87 (t, 1H), 3.66 (s, 2H), 3.61-3.46 (m, 8H), 3.05 (s, 3H), 2.24 (m, 1H), 1.89 (m, 1H), 1.79-1.54 (m, 5H), 1.48 (m, 11H), 1.14 (m, 2H); HPLC-MS: m/z: 637 (M+1), 582 (M+1-C(CH3)3)
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH3:24])[CH:22]=2)[CH:3]=1.[Br-].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Zn+]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[CH:3][C:4]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH3:24])[CH:22]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: [Zn+]c1ccccn1
Reactant: CCNC(=O)Nc1nc2cc(-c3cncc(OC)c3)cc(Br)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cncc(OC)c3)cc(-c3ccccn3)c2s1
Temperature: 60 °C
Yield: 28 %

Procedure:
To a stirred solution of 1-[7-Bromo-5-(5-methoxy-pyridin-3-yl)-benzothiazol-2-yl]-3-ethyl-urea (90 mg, 0.22 mmol), and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.015 mmol), in tetrahydrofuran (4 ml), was added 2-pyridylzinc bromide (3.1 ml, 1.5 mmol, 0.5 M solution in THF). The reaction was purged with nitrogen then heated at 60° C. for 16 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution followed by brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by preparative HPLC to give 1-Ethyl-3-[5-(5-methoxy-pyridin-3-yl)-7-pyridin-2-yl-benzothiazol-2-yl]-urea as a white solid (25 mg, 27%)
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.[H-].[Na+].Cl[C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1>CN(C=O)C.C1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([S:7][C:11]2[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=2)=[N:4][N:3]=1
Reactant: N#Cc1nccnc1Cl
Reactant: Cc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: Cc1nnc(Sc2nccnc2C#N)s1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The title compound was prepared according to Example 1 by using 5-methyl-1,3,4-thiadiazole-2-thiol (264 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 6 hr.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]4[CH2:20][CH2:19]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>>[CH:18]1([C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:22])[C:2]([C:32]#[C:31][C:29]([OH:33])([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=5)[CH3:30])=[CH:21][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH2:20][CH2:19]1
Reactant: NC(=O)c1nc2n(c1C1CC1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(O)c1ccccn1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C1CC1)c1ccccn1
Yield: 16 %

Procedure:
10-bromo-3-cyclopropyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(pyridin-2-yl)but-3-yn-2-ol via General Procedure E to yield 9.5 mg (16%) of (±)-3-cyclopropyl-9-fluoro-10-[3-hydroxy-3-(2-pyridyl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]([N:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCCC1>[CH2:24]([N:31]1[CH2:37][CH2:36][CH2:35][N:34]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(CN2CCCNCC2)cc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCN(Cc3ccccc3)CC2)nc1-c1ccc(C)cc1
Yield: 59.8 %

Procedure:
This compound was prepared according to the method C from methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.095 g; 0.285 mmol), 1-benzyl-1,4-diazepane (0.178 g, 0.937 mmol) and triethyl amine (0.200 mL; 1.43 mmol) in tetrahydrofuran (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.083 g (54%) of the titled compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccccc2C)c(C)c1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 93.4 %

Procedure:
A mixture of methyl 4-bromo-3-methylbenzoate (25.0 g, 110 mmol), o-tolylboronic acid (16.5 g, 120 mmol) and potassium carbonate (50 g, 360 mmol) in dioxane:water (300 mL: 200 mL) was purged with nitrogen for 1 hour. [1,1′bis(Diphenylphosphino)ferrocene]dichloropalladium[II] (4.5 g, 5.5 mmol) was added and the reaction mixture was heated to 100° C. with vigorous stirring for 3.5 hours. The cooled reaction mixture was filtered through Celite and the cake washed with ethyl acetate (500 mL). The organic phase was separated, washed with 1 M sodium hydroxide (500 mL) and brine (500 mL), dried over anhydrous potassium carbonate and concentrated in vacuo to give the crude product as a dark oil (28.6 g). Purification by flash chromatography using a solvent gradient of 2% ethyl acetate in hexane afforded the title compound (24.7 g, 93%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[CH:4]=[N:5][OH:6].ClN1C(=O)[CH2:16][CH2:15][C:14]1=O.CC[C:22]([O:24][C:25]([CH:27]([CH3:29])C)=[O:26])=O.C[O-].[Na+].ClC1C=CC=C(Cl)C=1C(Cl)=NO>CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]1[C:27]([C:25]([O:24][CH3:22])=[O:26])=[C:29]([CH:15]([CH3:16])[CH3:14])[O:6][N:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1c(Cl)cccc1Cl
Reactant: CCC(=O)OC(=O)C(C)C
Agent: C[O-]
Agent: ON=C(Cl)c1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C(C)C

Procedure:
A solution of 2,6-dichlorobenzaldehyde oxime (19.8 g, 0.104 mol) in N,N-dimethyl formamide (80 mL) was placed in an ambient temperature water bath and was treated with N-chlorosuccinimide (13.9 g, 0.104 mole). Following dissolution, an exotherm was observed along with a color change to dark yellow. The reaction was stirred an additional hour then the contents were then poured into water (200 mL) and the product extracted with diethyl ether (300 mL). The ethereal layer was washed with water (3×100 mL) and brine (50 mL), then dried over anhydrous magnesium sulfate. After filtering, the solvent was removed in vacuo to yield a yellow oil which was used in the next step without further purification. Separately, a solution of methyl isobutyryl acetate (18 g, 0.125 mol) in tetrahydrofuran (25 mL) at 0° C. was treated with a solution of sodium methoxide (250 mL, 0.5 M in methanol). A solution of the above crude 2,6-dichloro-N-hydroxybenzenecarboximidoyl chloride in tetrahydrofuran (80 mL) was then added dropwise. After stirring at ambient temperature for 16 h the solvent was removed in vacuo. The residue was triturated with water (250 mL) and the resulting solids filtered and washed with water. Yield=22.7 g. (69%) of methyl 3-(2,6-dichlorophenyl)-5-isopropylisoxazole-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH:11]([CH3:14])[CH:12]=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.[OH:16][CH:17]([C:25]1[CH:34]=[CH:33][C:28]2[C:29](=[O:32])[O:30][CH2:31][C:27]=2[C:26]=1[CH3:35])[CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl>[OH:16][CH:17]([C:25]1[CH:34]=[CH:33][C:28]2[C:29](=[O:32])[O:30][CH2:31][C:27]=2[C:26]=1[CH3:35])[CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:12][CH:11]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=2)[CH3:14])[CH2:21][CH2:20]1
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Reactant: COc1cc(C(C)C=O)ccc1C#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C(C)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2-methoxy-4-(1-oxopropan-2-yl)benzonitrile (0.020 g, 0.106 mmol) were added dichloromethane (15 mL) and 5-[1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride [(0.037 g, 0.116 mmol), in dichloromethane (2 mL), and triethylamine (0.029 mL, 0.211 mmol)], and the mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (0.112 g, 0.529 mmol) was added, and the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched with water (5 mL), and the organics were extracted with EtOAc (2×40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL) and dried (MgSO4). Filtration followed by concentration afforded an oily residue, which was purified via mass-directed reverse-phase HPLC followed by evaporation and drying of the pure fraction obtained which then converted to HCl salt by triturating in 1M HCl in diethyl ether (0.50 mL, 2 h). Evaporation and dried under vacuum provided 4-(2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-methylethyl)-2-(methyloxy)benzonitrile.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3([CH2:39][OH:40])[CH2:38][CH2:37][CH2:36]3)=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[N:41]1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.[C:64]([O:67]CC)(=[O:66])C>ClCCl>[CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3([CH2:39][OH:40])[CH2:36][CH2:37][CH2:38]3)=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:41][C:64](=[O:66])[O:67][N:26]=3)=[CH:17][CH:18]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OC3(CO)CCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(C)=O
Reactant: Cc1cccc(C)n1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc(CC)n(-c2ccc(OC3(CO)CCC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-{[1-(hydroxymethyl)cyclobutyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.5 g) and 2,6-lutidine (0.17 mL) in dichloromethane (5 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.34 mL) at 0° C., and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A mixture of the residue, hydroxylammonium chloride (0.67 g), sodium hydrogen carbonate (0.97 g) and dimethyl sulfoxide (5 mL) was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.23 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 30 min. Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 1.9 mL) was added, and the mixture was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.43 g, 76%) as an amorphous solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]1[CH2:12][CH2:11][C:10]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21]Br>C(Cl)(Cl)Cl>[BrH:21].[CH2:14]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]1[CH2:12][CH:11]([Br:21])[C:10]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrBr
Reactant: O=C1CCC1N(Cc1ccccc1)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Br
Product: O=C1C(Br)CC1N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
2-(Dibenzylamino)cyclobutanone is dissolved in CHCl3 (1 molar conc.) and treated dropwise with one equivalent of bromine dissolved in CHCl3 (1 molar conc.) at 0° C. After stirring the mixture for 30 minutes, evaporate the solution to obtain the desired product of this step.
Reaction SMILES: [CH3:1][C@:2]([N+:8]([O-])=O)([C@@H:5]([OH:7])[CH3:6])[CH2:3][OH:4].[C:11]([OH:14])(=[O:13])[CH3:12].N[C@@](C)([C@H](O)C)CO>>[C:11]([OH:14])(=[O:13])[CH3:12].[NH2:8][C@@:2]([CH3:1])([C@@H:5]([OH:7])[CH3:6])[CH2:3][OH:4]
Reactant: C[C@H](O)[C@@](C)(CO)[N+](=O)[O-]
Agent: C[C@@H](O)[C@](C)(N)CO
Solvent: CC(=O)O
Product: C[C@H](O)[C@](C)(N)CO

Procedure:
Prepared from (+-)(2R*,3S*)-2-methyl-2-nitro-1,3-butanediol (7A) as described for 7E (93%) (C,H,N) mp 163°-165° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].C=O.[C:15](OCC)(=O)C.Cl>C(O)(C)C>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:9](=[O:11])(=[O:10])[NH:12][CH2:15]1
Reactant: CNc1ccncc1S(N)(=O)=O
Reactant: CCOC(C)=O
Agent: C=O
Agent: Cl
Solvent: CC(C)O
Product: CN1CNS(=O)(=O)c2cnccc21

Procedure:
A mixture of 1 g of 4-methylaminopyridine-3- sulfonamide (Preparation 6) and 1 g of paraformaldehyde (excess) in 10 cm3 of isopropanol to which 4 cm3 of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 10 hours. After this lapse of time, the solvent is removed under partial vacuum (rotary evaporator) and the residue is redissolved in methanol. A possible insoluble material is filtered and the filtrate, to which 2 volumes of diethyl ether have been added, is left to precipitate the title compound in the form of crystals. The crystals are collected on a filter, washed with diethyl ether and dried. Yd. : 60-65% M.p. (hydrochloride): 291-294° C.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)=[C:14]([C:26]([O:28][CH3:29])=[O:27])[N:15]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:16]2=[O:19])=[CH:11][C:10]=1[O:42][CH3:43])C1C=CC=CC=1.CO>[C].[Pd].CN(C)C=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)=[C:14]([C:26]([O:28][CH3:29])=[O:27])[N:15]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:16]2=[O:19])=[CH:11][C:10]=1[O:42][CH3:43]
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OCc3ccccc3)cc2c(=O)n1N1CCOCC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
To the compound obtained in Example 1 (2.8 g) are added methanol (100 ml), dimethylformamide (100 ml) and palladium-carbon (100 mg), and the mixture is stirred under hydrogen atmosphere (1 atm) at room temperature for 1.5 hour. The catalyst is removed by filtration, and the filtrate is concentrated. The precipitated crystals are collected by filtration, and washed with diethyl ether to give 7-hydroxy-6-methoxy-3-methoxycarbonyl-2-morpholino-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (2.26 g) as listed in Table 1.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:18])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)[N:7]=2)[CH2:3][CH2:2]1.[F:19][C:20]([F:35])([F:34])[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=O.C(N(CC)CC)C.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.[Ti](Cl)(Cl)(Cl)Cl>[CH:1]1([NH:4][C:5]([C:6]2[N:7]=[C:8]([C:12]3[CH2:13][CH2:14][N:15]([CH:21]([C:23]4[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=4)[C:20]([F:35])([F:34])[F:19])[CH2:16][CH:17]=3)[CH:9]=[CH:10][CH:11]=2)=[O:18])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1cccc(C2=CCNCC2)n1
Reactant: O=C(c1ccc(OC(F)(F)F)cc1)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1CC1)c1cccc(C2=CCN(C(c3ccc(OC(F)(F)F)cc3)C(F)(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.3 %

Procedure:
Titanium (IV) chloride (0.098 ml, 0.887 mmol) was added to a solution of N-cyclopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)picolinamide free base (5b) (432 mg, 1.77 mmol), 2,2,2-trifluoro-1-(4-trifluoromethoxyphenyl)ethanone (63) (458 mg, 1.77 mmol) and triethylamine (0.492 ml, 3.55 mmol) in CH2Cl2 (12 ml) and stirred at room temperature for 18 hours. Sodium cyanoborohydride (334 mg, 5.32 mmol) in methanol (4 ml) was added to the reaction mixture and stirred for 19 hours. The reaction was quenched with aqueous NaOH solution (2 N), extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 67/33) to give 1′-[2,2,2-trifluoro-1-(4-trifluoromethoxyphenyl)ethyl]-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-carboxylic acid cyclopropylamide (64) (226 mg, yield 26%) as a pale orange oil. 1H NMR (400 MHz, CDCl1): S 8.04 (m, 1H), 8.00 (brs, 1H), 7.77 (t, J=7.8 Hz, 1H), 7.47 (m, 3H), 7.26 (m, 2H), 6.58 (m, 1H), 4.21 (q, J=7.9 Hz, 1H), 3.45 (m, 2H), 2.97 (m, 1H), 2.90 (m, 1H), 2.80 (m, 1H), 2.66 (m, 2H), 0.88 (m, 2H), 0.65 (m, 2H); MS: 486 (M+H+).
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:9][CH2:8][CH2:7][C@@H:6]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:5]1.I[C:24]1[NH:25][C:26](C)([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[O:27][C:28]=1[CH3:29].[C:41](OC)(C)(C)C>CN(C)C=O>[CH3:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:12]([CH2:11][O:10][C@@H:6]2[CH2:7][CH2:8][CH2:9][C@H:4]([O:3][CH2:41][C:24]3[N:25]=[C:26]([C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=4)[O:27][C:28]=3[CH3:29])[CH2:5]2)[C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CC1=C(I)NC(C)(c2ccc3ccccc3c2)O1
Reactant: COC(C)(C)C
Reactant: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cccc1CO[C@@H]1CCC[C@H](OCc2nc(-c3ccc4ccccc4c3)oc2C)C1
Reaction time: 1 h

Procedure:
At room temperature, 50 mg of a 60% strength suspension of sodium hydride are added to a solution of 200 mg of methyl 2-((1R,3S)-3-hydroxycyclohexyloxy-methyl)-6-methylbenzoate in 5 ml of dimethylformamide, and 380 mg of 4-iodo-methyl-5-methyl-2-naphthalen-2-yloxazole are then added. After one hour, methyl tert-butyl ether is added and the mixture is extracted with water. The organic phase is dried over magnesium sulfate, the solvents are removed under reduced pressure and the residue is purified by RP-HPLC. This gives 94 mg of methyl 2-methyl-6-[(1R,3S)3-(5-methyl-2-naphthalen-2-yloxazol-4-ylmethoxy)cyclohexyl-oxymethyl]benzoate as a light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].CC(=C)C.Cl([O-])=[O:33].[Na+].O>C(O)(C)(C)C.CCOC(C)=O>[Cl:21][C:19]1[CH:20]=[C:15]([N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:24]([F:26])([F:25])[F:27])[CH:4]=2)(=[O:10])=[O:9])[CH2:12][O:13][CH3:14])[C:16]([C:22]([OH:33])=[O:23])=[N:17][CH:18]=1
Reactant: COCN(c1cc(Cl)cnc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: [O-][Cl+][O-]
Agent: C=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (590 mg, 1.33 mmol) in tert-butanol (26 mL) was added isobutylene (5 mL), sodium chlorite (751 mg, 6.66 mmol) sodium dihydrogen phosphate (919 mg, 6.66 mmol) and water (26 mL). After the solution was stirred at room temperature for 3 h, EtOAc (10 mL) was added and the layers were separated. The organic layer was washed with saturated sodium bicarbonate (2×10 mL) and brine (1×10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]([C:6]1[CH:24]=[CH:23][C:9]([CH2:10][C:11]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[O:13]CC(O)CO)=[CH:8][CH:7]=1)=[O:5])[CH3:2].I([O-])(=O)(=O)=O.[Na+].[O:33]1CCO[CH2:35][CH2:34]1>O>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:24]=[CH:23][C:9]([CH2:10][C:11]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[O:13][C:34](=[O:33])[CH3:35])=[CH:8][CH:7]=1)=[O:5])[CH3:26]
Reactant: C1COCCO1
Reactant: CCN(CC)C(=O)c1ccc(Cc2ccccc2OCC(O)CO)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CCN(CC)C(=O)c1ccc(Cc2ccccc2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1-[2-(4-Diethylcarbamoylbenzyl)phenoxy]-2,3-dihydroxypropane (263 mg) was dissolved in a mixed solution of dioxane (2.6 ml) and water (2.6 ml), added with sodium periodate (362 mg) and stirred at room temperature for 1 hour. The reaction mixture was added with water (10 ml) and extracted twice with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 239 mg of the title compound. Yield: 100%.