Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[C@H:12]2[CH2:17][C@@H:9]1[C@H:10]([OH:18])[CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[C:24]([NH2:26])=[O:25].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl.O>[NH2:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:14]([C@@H:13]1[C@H:12]2[CH2:17][C@H:9]([C@H:10]([OH:18])[CH2:11]2)[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])=[O:25]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)O
Reactant: NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)N1CCC[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.3 %

Procedure:
To a suspension of (1R,3S,4S,6R)-2-(tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid obtained in Example 42-6 (45 g) in chloroform (450 mL), were added (2S)-2-pyrrolidinecarboxamide (21 g), 1-hydroxybenzotriazole hydrate (29.5 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (36.9 g) and diisopropylethylamine (45.3 g) in water bath. The mixture was stirred at room temperature for 5 hrs. The precipitate collected by vacuum filtration and washed with ethyl acetate to give the target compound as a solid (51.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[C:16]([CH3:23])([CH3:22])[CH2:15]1.O1[CH2:29][CH2:28]OCC1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:22][C:16]1([CH3:23])[CH2:15][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:29]4[CH:28]=[CH:9][CH:10]=[CH:2][CH:3]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:19][CH2:18][S:17]1(=[O:21])=[O:20]
Reactant: C1COCCO1
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CCS1(=O)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CCS1(=O)=O
Temperature: 100 °C
Yield: 18 %

Procedure:
5-Bromo-3-(2,2-dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (104 mg, 0.26 mmol) was placed in a microwave vial and dissolved with 1,4-dioxane (6 mL) and water (3 mL). 3-Phenylboronic acid (64 mg, 0.52 mmol) and K2CO3 (108 mg, 0.78 mmol) were added. Argon was bubbled in the mixture for 10 min with stirring. PdCl2(dppf) (10 mg, 0.02 mmol) was added, and argon was bubbled another 10 min. The vial is sealed and heated in a microwave for 5 min at 100° C. on high absorption. The reaction was evaporated to remove most of the dioxane. The residue was partitioned between ethyl acetate and water. The layers were separated, the organic layer was dried (MgSO4), and the solvent was removed under vacuum. The residue was dissolved in DMSO (3 mL), and was purified on a Gilson HPLC. The desired fractions were concentrated, giving 20 mg (18%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)=[CH:4][C:3]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=2)[S:31]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:41][CH2:42][C:43]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([CH3:19])([CH3:17])[CH3:18])[CH:10]=4)=[CH:4][C:3]=3[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:44])=[CH:46][CH:47]=2)[S:31]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)c(C(C)(C)C)c2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(O)c(C(C)(C)C)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 93.8 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-t-butyl-4-hydroxyphenoxy)phenyl]-N-methylcarbamate (1.11 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.89 g), diethyl cyanophosphonate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (1.75 g).
Reaction SMILES: ClN1C(=O)C[CH2:4][C:3]1=O.[Br:9][C:10]1[C:11]([CH3:23])=[C:12]([C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1)[CH:13]=[N:14][OH:15].C=C.C(N(CC)CC)C>CN(C)C=O>[Br:9][C:10]1[C:11]([CH3:23])=[C:12]([C:13]2[CH2:4][CH2:3][O:15][N:14]=2)[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: Cc1c(Br)ccc(S(C)(=O)=O)c1C=NO
Reactant: O=C1CCC(=O)N1Cl
Agent: C=C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(Br)ccc(S(C)(=O)=O)c1C1=NOCC1
Reaction time: 0.5 h

Procedure:
At 60° C., a small amount of N-chlorosuccinimide is added to a solution of 50 g (171 mmol) of 3-bromo-2-methyl-6-methylsulfonylbenzaldoxime in 200 ml of dimethylformamide. Once the reaction has started, a total of 23.3 g (171 mmol) of N-chlorosuccinimide are metered in at 40-50° C. The reaction mixture is stirred for another 30 minutes, until conversion is complete according to HPLC. The reaction mixture is then poured onto ice-water and the solid is filtered off with suction, washed three times with water and twice with n-pentane. The hydroxamic acid chloride is used moist and without further purification for the next reaction. The solid is dissolved in 250 ml of dichloromethane, and ethylene is passed through the solution. With continued introduction of ethylene, 20.3 q (200 mmol) of triethylamine are added dropwise. The reaction mixture is stirred at room temperature for about 72 hours, with repeated introduction of more gaseous ethylene.
Reaction SMILES: [NH:1]1[C:40](=[O:41])[C@H:36](C(C)C)[N:35]([CH3:42])[C:33](=[O:34])[C@@H:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:24][C:22](=[O:23])[C@H:17]([CH2:18][C:19](=[O:21])[OH:20])[NH:16][C:14](=[O:15])[CH2:13][NH:12][C:10](=[O:11])[C@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C(O)(C(F)(F)F)=O>>[NH:1]1[C:40](=[O:41])[CH2:36][N:35]([CH3:42])[C:33](=[O:34])[C@@H:25]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:24][C:22](=[O:23])[C@H:17]([CH2:18][C:19](=[O:20])[OH:21])[NH:16][C:14](=[O:15])[CH2:13][NH:12][C:10](=[O:11])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CC(C)[C@H]1C(=O)N[C@H](CCCNC(=N)N)C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](Cc2ccccc2)C(=O)N1C
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(=O)N[C@@H](CCCNC(=N)N)C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](Cc2ccccc2)C1=O

Procedure:
Cyclo-(DArg-Gly-Asp-DPhe-NMeVal)×TFA; RT=18.7; FAB-MS(M+H): 589;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](=O)[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)=[CH:7][C:6]=1[F:26])[CH3:2].ClCCl.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.C([BH3-])#N.[Na+]>CCCCCC.C(OCC)(=O)C.C(O)(=O)C.C(#N)C>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[CH:19]([NH:34][CH:31]4[CH2:33][CH2:32]4)[CH2:18][CH2:17][C:16]([CH3:24])([CH3:25])[C:15]=3[CH:14]=2)=[CH:7][C:6]=1[F:26])[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3NC2CC2)cc1F

Procedure:
Following general procedure G and using 2-fluoro-4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-benzoic acid ethyl ester (Compound 9, 0.132 g, 0.3 mmol), dichloromethane (4 mL), acetonitrile (2 mL), cyclopropyl amine (1 mL, 14.45 mmol), acetic acid (1 mL) and sodium cyanoborohydride (0.18 g, 2.86 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 16-20% ethyl acetate in hexane as the eluent, the title compound was obtained as a pale yellow oil (0.1 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[C:21]([NH:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccccn2)cn(-c2ccccc2)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
30 mg of 3-amino-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 1 ml of methylene chloride and 1 ml of pyridine, to which 19 mg of benzoyl chloride was added with cooling with ice, and the mixture was stirred at room temperature for a night. The reaction mixture was concentrated, diluted with ethyl acetate, and washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried by magnesium sulfate, and refined by NH silica gel chromatography (ethyl acetate). The solvent was concentrated, and the resultant crude crystal was washed with ethyl acetate/hexane, to obtain 35 mg of the subject compound.
Reaction SMILES: [CH2:1]([CH:3]1[O:8][C:7]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:6][NH:5][CH2:4]1)[CH3:2].Cl[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.CC(C)([O-])C.[Na+].C(OCC)(=O)C.CCCCCC>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([CH:3]1[O:8][C:7]2([CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:12][CH2:13]2)[CH2:6][N:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:4]1)[CH3:2]
Reactant: CCC1CNCC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reactant: Clc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC1CN(c2ccccn2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 40 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
A solution of rac-BINAP (43.8 mg, 0.070 mmol) and Pd2(dba)3 (32.2 mg, 0.0352 mmol) in toluene (1 mL) was stirred under nitrogen atmosphere in a sealed vial at 90° C. for 10 min, then cooled to 40° C. and cannulated into a stirring solution of tert-butyl 4-ethyl-5-oxa-2,9-diazaspiro[5.5]undecane-9-carboxylate (500 mg, 1.76 mmol) and 2-chloropyridine (200 mg, 165 μL, 1.76 mmol) in toluene (6 mL). The solution was treated with sodium tert-butoxide (275 mg, 2.87 mmol), flushed with nitrogen and stirred for 3 h at 90° C. The reaction mixture was cooled, diluted with ethyl acetate (100 mL), filtered through Celite and concentrated in vacuo. Silica gel chromatography (120 g silica, 10-70% ethyl acetate/hexane) provided tert-butyl 10-ethyl-8-(2-pyridyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (486 mg, 1.34 mmol, 76%) as an orange-colored oil. ESI-MS m/z calc. 361.2. Found 362.3 (M+1)+; Retention time: 1.25 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 8.08 (dd, J=4.9, 1.4 Hz, 1H), 7.51 (ddd, J=8.8, 7.1, 2.0 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 6.61 (dd, J=6.7, 4.9 Hz, 1H), 4.24 (d, J=12.0 Hz, 1H), 4.11 (d, J=12.9 Hz, 1H), 3.75-3.51 (m, 3H), 3.15 (br s, 1H), 2.91 (br s, 1H), 2.59 (d, J=13.0 Hz, 1H), 2.40 (dd, J=12.6, 10.9 Hz, 1H), 2.02 (d, J=13.3 Hz, 1H), 1.60-1.42 (m, 4H), 1.39 (s, 9H), 1.36-1.26 (m, 1H), 0.95 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[BH4-].[Na+].Cl>C(O)C.O>[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][CH:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: N#CCC#N
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(C#N)Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a mixture of malononitrile (2.64 g, 40 mmol) in 95% Ethanol (50 mL) was added 2,3-dichlorobenzaldehyde (7.00 g, 40.0 mmol). The reaction was stirred at rt for 18 h. EtOH (20 mL) was added and the mixture was stirred at rt for 20 min and cooled to 0° C. in an ice bath. Sodium borohydride (0.424 g, 11.20 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (40 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 87%). To a solution of [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 34.9 mmol) in Ethanol (80 mL) was added hydrazine hydrate (2.57 mL, 52.4 mmol). The mixture is heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (MeOH/DCM: 0˜10%) to give the product (4.2 g, 47%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.77 (s, 2H) 7.09 (m, 1H) 7.19 (t, J=7.96 Hz, 1H) 7.38 (m, 1H); LC/MS: MS (ES+) m/e 257.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[C:15](=[O:17])[CH3:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[C:19]([OH:23])(=[O:22])[CH:20]=O>C(O)(=O)C.O>[O:17]=[C:15](/[CH:14]=[CH:13]/[C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH:16]=[CH:20]/[C:19]([OH:23])=[O:22]
Reactant: O=CC(=O)O
Reactant: COc1cc(/C=C/C(C)=O)cc(OC)c1OC
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(/C=C/C(=O)/C=C/C(=O)O)cc(OC)c1OC

Procedure:
A solution of 5 g (21 mmol) of (E)-4-(3,4,5-trimethoxyphenyl)but-3-en-2-one and 2 g (21.7 mmol) of glyoxylic acid monohydrate in 5.2 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether yielded (E,E)-4-oxo-6-(3,4,5-trimethoxyphenyl)-2,5-hexadienoic acid of melting point 152°-154°.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[C:6]([CH3:38])=[C:7]([CH:34]=[CH:35][C:36]=1[Cl:37])[O:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C@@H:22]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:23]([O:25]C)=[O:24])[CH2:18][CH2:17]2)[CH2:11][CH2:10]1.C([O-])(=O)C.[NH4+].C(OC)(C)(C)C>O.CO.C1COCC1>[Cl:4][C:5]1[C:6]([CH3:38])=[C:7]([CH:34]=[CH:35][C:36]=1[Cl:37])[O:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([C@@H:22]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:23]([OH:25])=[O:24])[CH2:20][CH2:21]2)[CH2:13][CH2:14]1
Reactant: COC(=O)[C@H](Cc1ccccc1)N1CCC(CN2CCC(Oc3ccc(Cl)c(Cl)c3C)CC2)CC1
Agent: CC(=O)[O-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CO
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1c(OC2CCN(CC3CCN([C@@H](Cc4ccccc4)C(=O)O)CC3)CC2)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of lithium hydroxide monohydrate (30.5 g) in water (180 mL) was added dropwise to an ice cooled solution of methyl (2S)-2-(4-{[4-(3,4-dichloro-2-methylphenoxy)piperidin-1-yl]methyl}piperidin-1-yl)-3-phenylpropanoate (from step A) in methanol (115 mL) and THF (450 mL). The mixture was stirred at room temperature overnight. A solution of ammonium acetate (165 g) in water (300 mL) was added to the reaction mixture, followed by tert-butylmethyl ether (300 mL). The two phase mixture was stirred rapidly for 2 h. The solid was collected, washed with water (3×300 mL) and diethyl ether (3×200 mL). The solid was added to diethyl ether and stirred for 1 h then filtered. Fresh diethyl ether was added and the stirring, filtering procedure was repeated. The solid obtained was dried under vacuum at 50° C. overnight to give the title compound (33 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]([OH:15])=O)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=[O:4].C(Cl)(=O)C(Cl)=O.[CH3:22][N:23](C=O)C.CN>C(Cl)Cl>[CH3:22][NH:23][C:13]([C:8]12[CH2:11][CH2:12][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH2:10][CH2:9]1)[CH2:6][CH2:7]2)=[O:15]
Reactant: CN(C)C=O
Reactant: COC(=O)C12CCC(C(=O)O)(CC1)CC2
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CNC(=O)C12CCC(C(=O)OC)(CC1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid 1-A (Chapman, N. B. et al. J. Org. Chem., 1970, 35, 917) (4.0 g, 18.9 mmol) was dissolved in 12 mL of anhydrous methylene chloride under nitrogen atmosphere, treated with oxalyl chloride (2M in methylene chloride, 28 mL, 56 mmol) and subsequently with 0.5 ml of DMF. The reaction was stirred at room temperature under nitrogen atmosphere for 90 min, then evaporated and placed under vacuum for 20 min. The acid chloride was dissolved in anhydrous methylene chloride (75 mL), cooled in an ice-bath, and then treated dropwise with a solution of methylamine (2M in THF, 57 mL, 113 mmol). Upon addition of the amine, the cooling bath was removed and the reaction stirred at ambient temperature for 30 min. The mixture was diluted with 1000 mL of methylene chloride and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. Product was purified by flash silica gel chromatography, eluting with 0-5% MeOH/CH2Cl2 gradient to yield methyl 4-[(methylamino)carbonyl]bicyclo[2.2.2]octane-1-carboxylate 1-B as a white solid. MS (ESI+)=226.2 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[C:20]([NH:23][CH2:24][CH2:25][NH2:26])(=[O:22])[CH3:21].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:20]([NH:23][CH2:24][CH2:25][NH:26][S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17])(=[O:22])[CH3:21]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CC(=O)NCCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCNS(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Reaction time: 3 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (110 mg; 0.33 mmol; 1 eq), is dissolved in a mixture of DCM/DMF(1/1, 10 ml). N-acetylethylene diamine (168 mg; 1.65 mmol; 5 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After 3 hours, the solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is dissolved in DCM (3 ml) and title compound precipitates with diethyl ether, affording after filtration, Compound (13) as a yellow powder (14 mg; 11%).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([OH:19])[CH:13]=2)O)[O:6][C:5](=[O:20])[CH:4]=1.O1CCCC1.C1(C)C=CC=CC=1.C(OCC)=O.CO>C(O)=O>[OH:19][C:14]1[CH:13]=[C:12]([CH:10]=[CH:9][C:7]2[O:6][C:5](=[O:20])[CH:4]=[C:3]([OH:2])[CH:8]=2)[CH:17]=[CH:16][C:15]=1[OH:18]
Reactant: O=c1cc(O)cc(CC(O)c2ccc(O)c(O)c2)o1
Agent: Cl
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: CO
Product: O=c1cc(O)cc(C=Cc2ccc(O)c(O)c2)o1

Procedure:
2 ml 3N HCl was added to a suspension of 8.0 g (30 mmol) 4-hydroxy-6-[2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-2H-pyran-2-one VII and 300 ml tetrahydrofuran. The resulting clear solution was heated for 2-3 hours under reflux until it was no longer possible to detect starting material. (TLC control, mobile solvent: toluene/ethyl formate/methanol 5:4:1, 0.5% formic acid). After drying over sodium sulphate the solution was strongly evaporated (residual volume ca. 50 ml) and it was crystallized by admixing with ether. Yield 4.7 g (63%) hispidine II, melting point 232°-234° C. (decomp.) or melting point 253° C. (decomp; bunch of needles from toluene/ethyl formate).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:42]2[N:43]=[CH:44]C=CC=2N=N1.C(N(CC)C(C)C)(C)C.CNC>CN(C)C=O.C(#N)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([N:43]([CH3:44])[CH3:42])=[O:19])=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(=O)N1c2ccc(-c3cccc(C(=O)O)c3)cc2[C@H](Nc2cccnc2)C[C@@H]1C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cccc(C(=O)N(C)C)c3)cc2[C@H](Nc2cccnc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.92 h
Yield: 59.3 %

Procedure:
A solution of 3-[(2S,4R)-1-acetyl-2-methyl-4-(3-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoic acid (for a preparation see Example 174) (9.0 mg, 0.022 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (43.6 mg, 0.115 mmol) in N,N-dimethylformamide (DMF) (0.5 ml) was treated with N,N-diisopropylethylamine (DIPEA) (0.023 ml, 0.135 mmol) and dimethylamine (2.0M solution in THF, 0.112 ml, 0.224 mmol). The resulting mixture was stirred at room temperature for 55 min then was reduced in volume under a stream of nitrogen, diluted with acetonitrile and directly purified by MDAP to give 3-[(2S,4R)-1-acetyl-2-methyl-4-(3-pyridinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-N,N-dimethylbenzamide (5.7 mg, 0.013 mmol, 59.3% yield) as a orange gum.