Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([C@H:28]([CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[C:29]([O:31]CC4C=CC=CC=4)=[O:30])[CH2:18]3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CO>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([C@H:28]([CH:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[C:29]([OH:31])=[O:30])[CH2:18]3)[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OCc1ccccc1)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Yield: 99.5 %

Procedure:
A solution of 37 mg (0.062 mmol) of 2-(R)-(3-(S)-((4-(3-phenylpropyl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 71, Step A) and 19 mg (0.093 mmol) of 10% palladium on carbon in 4 mL of MeOH was hydrogenated (40 psi) on a Parr shaker for 1 h. The reaction mixture was filtered through a 0.45 micron nylon membrane polypropylene filter and concentrated to give 31 mg (100%) of the title compound: 1H NM (500 MHz) δ 0.85-4.11 (35H), 7.11-7.39 (10H); NH3-CI-MS 503 (M+H).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]12[C@:11]([OH:14])([C:12]#[CH:13])[CH2:10][CH2:9][C@H:8]1[C@@H:7]1[CH2:15][CH2:16][C:17]3[C@@H:23]([C@H:6]1[CH2:5][CH2:4]2)[CH2:22][CH2:21][C:19](=O)[CH:18]=3.C([C@]12CC[C@@H]3C4CC=C(OC)CC=4CC[C@H]3[C@@H]1CC[C@@H]2O)C.[Cl-].O[NH3+].C([C@]12CC[C@@H]3[C@@H]4C(CC[C@H]3[C@@H]1CC[C@@H]2O)=CC(=[N:68][OH:69])CC4)C>N1C=CC=CC=1>[CH3:1][CH2:2][C@@:3]12[C@:11]([OH:14])([C:12]#[CH:13])[CH2:10][CH2:9][C@H:8]1[C@@H:7]1[CH2:15][CH2:16][C:17]3[C@@H:23]([C@H:6]1[CH2:5][CH2:4]2)[CH2:22][CH2:21]/[C:19](=[N:68]\[OH:69])/[CH:18]=3
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=NO)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Agent: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: [Cl-]
Agent: [NH3+]O
Solvent: c1ccncc1
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=C/C(=N/O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
Hungarian Patent No. 165356 describes the synthesis of dl- as well as d-norgestrel. The starting material of the synthesis is the racemic or the optically active 13-ethyl-3-methoxygona-2,5(10)-diene-17β-ol, which is reacted with hydroxylammonium chloride in pyridine at 100° C. Then the obtained 13-ethyl-3-(hydroxyimino)-gon-4-ene-17β-ol is oxidized at position 17, followed by ethinylation of the oxo group at position 17, to give the dl-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-oxime, or norelgestromin. Although the synthesis of the intermediates, the dl-(17α)-13-ethyl-17-hydroxy-18,19-dinorpregn-4-ene-20-yn-3-one-oxime and norelgestromin, are described, the identification and the purity (the quality requirements) as well as the pharmacological activity of these compounds are not provided.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[CH:8]=[C:7]([O:20]S(C(F)(F)F)(=O)=O)[C:6]=2[CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>[Cl-].[NH4+]>[OH:20][C:7]1[C:6]2[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:11]=2[CH:10]=[C:9]([O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:15])=[O:14])[CH:8]=1
Reactant: O=C1CCCc2c(OS(=O)(=O)C(F)(F)F)cc(OS(=O)(=O)C(F)(F)F)cc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: COCCOC
Product: O=C1CCCc2c(O)cc(OS(=O)(=O)C(F)(F)F)cc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 47.7 %

Procedure:
To a mixture of trifluoro-methanesulfonic acid 8-oxo-4-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-2-yl ester (XXVII, 542 mg, 1.23 mmol) and cesium carbonate (599 mg, 1.84 mmol) was added dimethoxyethane (11 mL) at room temperature. The resulting brown suspension was then heated at 80° C. and stirred for 3 h. The reaction mixture was cooled to room temperature and diluted with saturated ammonium chloride solution (50 mL), and then extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude product was dissolved in dichloromethane (15 mL) and diluted with hexanes (100 mL), then heated to remove the dichloromethane. The cloudy solution was then stored in the refrigerator for 15 h. The resulting solids were collected by filtration and washed with hexanes. After drying in the air, trifluoro-methanesulfonic acid 4-hydroxy-8-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (182 mg, 51%) was obtained as a dark brown solid: ES(−)-HRMS m/e calcd. for C11H9F3O5S (M−H)− 309.0050, obsd. 309.0049.
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>O1CCCC1.CCCCCC>[C:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][CH:22]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CCc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
tert-Butyl acetoacetate (23.8 ml) was added dropwise over 15 minutes to a stirred suspension of sodium hydride (8.9 mg) in tetrahydrofuran at 0° C. under nitrogen atmosphere. After stirring for 20 minutes n-butyl lithium in hexane (111 ml) was added then stirring continued for a further ten minutes. The resulting solution was treated dropwise with a solution of 4-bromobenzyl bromide (14.19 g) in tetrahydrofuran (100 ml) and then warmed to room temperature. The reaction was stirred for 40 minutes at room temperature and then quenched with HCl (6M, 5 ml). The resulting mixture was extracted with diethyl ether. The organic phases were combined, washed with brine and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure. The residue was thus obtained was purified via flash chromatography using 5% ethyl acetate in hexane as eluant to furnish the title compound (37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][N:15]=1>>[Cl:13][C:14]1[N:15]=[CH:16][C:17]([C:18]([NH:6][C:5]2[C:4]([CH3:12])=[CH:3][C:2]([Cl:1])=[CH:8][C:7]=2[N+:9]([O-:11])=[O:10])=[O:19])=[CH:21][CH:22]=1
Reactant: Cc1cc(Cl)cc([N+](=O)[O-])c1N
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: Cc1cc(Cl)cc([N+](=O)[O-])c1NC(=O)c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-6-nitroaniline (204 mg, 1.09 mmol) and 6-chloronicotinoyl chloride (192 mg, 1.09 mmol) and obtained as a light yellow solid as described in Example 62. 1H NMR (CDCl3): 9.13 (s, 1H), 8.96 (dd, J=0.6, 2.4 Hz, 1H), 8.20 (dd, J=2.7, 8.4 Hz, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.51 (dd, J=0.6, 8.1 Hz, 1H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:31])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.Cl[CH:34]([F:36])[F:35]>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:34]([F:36])[F:35])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)C(C)C)cc1
Reactant: FC(F)Cl
Product: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)C(C)C)cc1

Procedure:
The title compound was prepared by the method of Preparation 10c using [8-chloro-2-ethyl-3-(4-isobutyrylbenzyl)-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].C(B(CC)[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)C.[O-]CC.[Na+].[Br-].C([NH3+])CCC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: CCB(CC)c1ccncc1
Agent: [Pd]
Agent: CCCC[NH3+]
Agent: CC[O-]
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(-c3ccncc3)cc12

Procedure:
5-Bromo-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1H-indole (see Preparation 36) and diethyl (4-pyridyl)borane (see Preparation 50) were reacted together in the presence of sodium ethoxide, n-butylammonium bromide and tetrakis(triphenylphosphine)palladium(O) using a procedure similar to that in Example 56. This gave the title compound. Found: C,75.77; H,7.16; N,13.78%; C19H21N3.1/8CH2Cl2 requires: C,76.06; H,7.09; N,13.91%.
Reaction SMILES: [Na].O=C1O[C@H]([C@H](CO)O)C(O)=C1O.[CH2:14]([N:18]([CH2:26][C:27]([N:29]1[CH2:48][CH2:47][C:32]2[N:33]=[C:34]([NH:37][CH:38]3[CH2:46][C:45]4[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH2:39]3)[N:35]=[CH:36][C:31]=2[CH2:30]1)=[O:28])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15][C:16]#[CH:17].C1(C)C=CC=CC=1.[N:56]([Si](C)(C)C)=[N+:57]=[N-:58]>CN(C)C=O.O.C(OCC)(=O)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:46][CH:38]1[NH:37][C:34]1[N:35]=[CH:36][C:31]2[CH2:30][N:29]([C:27](=[O:28])[CH2:26][N:18]([CH2:14][CH2:15][C:16]3[N:56]=[N:57][NH:58][CH:17]=3)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:48][CH2:47][C:32]=2[N:33]=1
Reactant: C#CCCN(CC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N(CCc1c[nH]nn1)CC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
Add copper(II)sulfate pentahydrate (0.026 g; 0.2 equiv; 0.106 mmoles) and L-ascorbic acid sodium salt (0.21 g; 2.0 equiv; 1.06 mmoles) to a deoxygenated solution of tert-butyl N-but-3-ynyl-N-[2-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-2-oxo-ethyl]carbamate (0.252 g; 1.0 equiv; 0.53 mmoles) in dimethylformamide (6 mL) and water (3 mL) (including toluene (0.05 mL) as an internal standard). Heat the reaction vessel to 90° C. and then add azidotrimethylsilane (0.565 mL; 8 equiv; 4.24 mmoles) slowly. Stir at 90° C. for 4 hours, then dilute the reaction mixture with water (100 mL) and ethyl acetate (50 mL), and extract 3×50 mL ethyl acetate. Wash the combined organic extracts with brine, dry over magnesium sulfate, filter, and concentrate. Purify the crude product by column chromatography (0 to 10% methanol in ethyl acetate) to give tert-butyl {2-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-2-oxoethyl}[2-(1H-1,2,3-triazol-4-yl)-ethyl]carbamate (0.174 g; 63%) as a colorless foam: MS (m/z): 519 (M+1).
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[CH:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:29][C:28]([C:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:31][CH:30]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1)([CH3:20])[CH3:19]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OC(C)C)cc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(OC(C)C)cc1
Yield: 19.8 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-isopropoxyphenyl)-3-oxopropionate (15.0 g) and 4-nitrobenzylamine (11.2 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-isopropoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate (4.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([NH:16][CH3:17])=[O:15])[C:4]=1[C:5](NC)=[O:6].[OH-].[Na+].C(O)(=O)C>O.C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:6])[N:16]([CH3:17])[C:14](=[O:15])[NH:13]2
Reactant: CNC(=O)Nc1cccc(OC)c1C(=O)NC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc2[nH]c(=O)n(C)c(=O)c12
Yield: 96.6 %

Procedure:
A mixture of 2-Methoxy-N-methyl-6-[[(methylamino)carbonyl]amino]benzamide (200 mg, 0.843 mmol), 5% sodium hydroxide solution in water (8 ml) and ethanol (4 ml) was refluxed for 1 h. The solution was allowed to cool and then acidified with acetic acid. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under vacuum to afford 168 mg (97%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:8]=[CH:9][N:10]3[C:19]4[C:14](=[C:15](C(F)(F)F)[CH:16]=[CH:17][CH:18]=4)[C:13](=[O:24])[N:12]([CH3:25])[C:11]=23)[N:3]=1.[CH3:26][C:27]1ON=C(C[N+]#[C-])N=1>>[CH:1]1([C:2]2[O:6][N:5]=[C:4]([C:7]3[N:8]=[CH:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13](=[O:24])[N:12]([CH3:25])[C:11]=34)[N:3]=2)[CH2:27][CH2:26]1
Reactant: [C-]#[N+]Cc1noc(C)n1
Reactant: Cc1nc(-c2ncn3c4cccc(C(F)(F)F)c4c(=O)n(C)c23)no1
Product: Cn1c(=O)c2ccccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
3-(5-methyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-methyl-5-oxo-6-trifluoromethyl-imidazo(1,5-a)quinazoline, M.p. 251.5°-251.9° C., by reaction between 3-methyl-5-trifluoromethyl 1 2,3,4-tetrahydro-2,4-dioxo-quinazoline and 5-methyl-3-isocyanomethyl-1,2,4-oxadiazole.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:25]=[CH:24][C:19]3[NH:20][C:21](=[O:23])[NH:22][C:18]=3[CH:17]=2)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:25]=[CH:24][C:19]3[NH:20][C:21](=[O:23])[NH:22][C:18]=3[CH:17]=2)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2[nH]c(=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2[nH]c(=O)[nH]c2c1
Yield: 13.8 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-phenylpyrimidin-5-yl)pentanoate (0.180 g; 0.432 mmol), sodium hydroxide 10N (0.432 mL; 4.32 mmol) in methanol (4.3 mL). Purification by preparative HPLC (HPLC method 2) furnished 0.024 g (13%) of the title compound as a white solid.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]([OH:12])=[O:11])[CH:4]=1.[CH3:13][NH:14][CH3:15]>C(O)CCC>[CH3:13][N:14]([CH3:15])[C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]([OH:12])=[O:11])[CH:4]=1
Reactant: CNC
Reactant: Cc1cc(Br)cc(C(=O)O)n1
Agent: Cl
Solvent: CCCCO
Product: Cc1cc(N(C)C)cc(C(=O)O)n1
Yield: 142.9 %

Procedure:
To a solution of 4-bromo-6-methyl-pyridine-2-carboxylic acid hydrochloride (100 mg, 0.396 mmol) in butanol (6 mL), dimethylamine (162 mg, 1.19 mmol) is added and the mixture is refluxed for 2 days. The solvent is removed in vacuo and the residue is dried under HV to give 4-dimethylamino-6-methyl-pyridine-2-carboxylic acid (102 mg) as dimethylammonium salt in form of a yellow oil; LC-MS: tR=0.48 min, [M+1]+=181.07. This material is dissolved in DCM (5 mL), methanol (0.5 mL) and triethylamine (5 mL). The solution is stirred for 5 min at rt before it is concentrated and dried under HV to give the title compound (125 mg) as triethylammonium salt in form of a pale yellow oil. 1H NMR (D6-DMSO): δ 1.20 (t, J=7.3 Hz, 18H), 3.08 (q, J=7.0 Hz, 12H), 3.17 (s, 6H), 6.80 (s, 1H), 7.14 (s, 1H), 9.75 (s br, 2H).
Reaction SMILES: Cl[CH:2]([CH2:15][CH3:16])[CH2:3][CH2:4][C:5]#[C:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[C-:17]#[N:18].[Na+].O>CS(C)=O>[C:17]([CH:2]([CH2:15][CH3:16])[CH2:3][CH2:4][C:5]#[C:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)#[N:18]
Reactant: CCC(Cl)CCC#CCOC1CCCCO1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C#N)CCC#CCOC1CCCCO1
Reaction time: 65 h
Yield: 65.8 %

Procedure:
A solution of chloride 35 (20.0 g, 92.3 mmol) in dry DMSO (75 mL) was added to a solution of NaCN (6.0 g, 122.0 mmol) in dry DMSO (100 mL). The reaction mixture was stirred at 50°-60° C. for 65 h. The dark brown mixture was cooled, poured into water (200 mL), and extracted with five 100-mL portions of CH2Cl2. The combined organic extracts were washed with water (3×150 mL), dried over Na2SO4, and concentrated by rotary evaporation. The black oil was dissolved in Et2O (200 mL) and filtered through a pad of silica gel (60-200 mesh, Baker Chemical Co.) to yield 36 as a yellow oil (14.3 g, 75%): IR (neat) 2940 (s), 2870, 2280 (w), 2250, 1440, 1345, 1200, 1130, 1115 (s), 1075, 1020 (s), 900, 865, 810 cm-1 ; 1H NMR (CDCl3)δ 4.80 (m, 1H), 4.23 (t, J=2 Hz, 2H), 3.66 (m, 2H), (m, 4H), 1.67 (m, 8H). Nitrile 36 was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=1.Cl.CN(C)CCCN=C=NCC.N1(C2C=CN=CC=2)CCCC1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:17][C:13]1[N:12]=[C:11]([NH:10][C@H:8]([C:4]2[CH:3]=[C:2]([NH:1][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([CH3:18])=[N:20][CH:21]=3)[CH:7]=[CH:6][CH:5]=2)[CH3:9])[CH:16]=[N:15][CH:14]=1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1cccc(N)c1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2cccc([C@H](C)Nc3cncc(Cl)n3)c2)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.1 %

Procedure:
A mixture of N-[(1S)-1-(3-aminophenyl)ethyl]-6-chloropyrazin-2-amine (300 mg, 1.2 mmol), 6-methylnicotinic acid (182 mg, 1.32 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (277 mg, 1.45 mmol), 4-pyrrolidinopyridine (36 mg, 0.24 mmol) and triethylamine (0.34 mL, 2.4 mmol) in dichloromethane (6 mL) was stirred at room temperature for 72 hours. After this time the mixture was diluted with ethyl acetate (20 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×15 mL) and brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure to give a yellow oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give N-(3-{(1S)-1-[(6-chloropyrazin-2-yl)amino]ethyl}phenyl)-6-methylnicotinamide (380 mg, 86%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([O:25]CC2C=CC=CC=2)=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)(C)(C)C>CO>[NH2:7][C@@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2ccc3c(OCc4ccccc4)nccc3c2)CC1
Solvent: CO
Product: N[C@H]1CC[C@@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1

Procedure:
The title compound was prepared by stirring cis-[4-(1-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (27) at room temperature in methanol/2 N HCl (1:1). After complete conversion, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC. The obtained trifluoroacetate was converted to the corresponding hydrochloride by dissolving the compound in 2 N HCl and evaporation of the solvent. After dissolving the residue in water and lyophilisation, the desired product (HCl-salt) was isolated as a colourless solid. Rt=0.75 min (Method B). Detected mass: 259,2 (M+H+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[C:8]([CH2:10][NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:6][CH:5]=1.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C=O)C.C(OCC)(=O)C>[CH2:22]([O:21][C:19]([N:11]([CH2:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:3])[N:9]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CNCc1cccc(Br)n1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
Sodium hydride (88 mg, 2.20 mmol) was suspended in DMF (2.93 mL) and cooled to 0° C. Ethyl N-[(6-bromopyridin-2-yl)methyl]glycinate (200 mg, 0.73 mmol) was added and the solution was stirred for thirty minutes at 0° C. Benzyl chloroformate (0.11 mL, 0.73 mmol) was added and the solution was heated at 50° C. and allowed to stir until completion. The reaction was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5].[CH:13](Br)([CH3:15])[CH3:14]>>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([O:1][CH:13]([CH3:15])[CH3:14])[C:3]=1[C:4]#[N:5])([O-:12])=[O:11]
Reactant: N#Cc1c(O)cccc1[N+](=O)[O-]
Reactant: CC(C)Br
Product: CC(C)Oc1cccc([N+](=O)[O-])c1C#N
Yield: 64 %

Procedure:
Prepared in a similar manner as Example 115c from 2-hydroxy-6-nitrobenzonitrile (Example 115d) and isopropyl bromide to provide 2-nitro-6-isopropoxybenzonitrile (324 mg, 64%). 1H NMR (400 MHz, MeOD) δ 1.43 (d, J=6.2 Hz, 6H), 4.89 (sept, J=6.2 Hz, 1H), 7.61 (dd, J=8.0, 1.0 Hz, 1H), 7.80 (t, J=8.2 Hz, 1H), 7.85 (dd, J=8.2, 1.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC(F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=O)[CH2:19][CH2:18]2)[CH:3]=1.Cl[C:31]1C=C(Cl)C2C(=CC=C(C)C=2)N=1.S1(=O)C2C=CC=CC=2CNCC1.NC1(CNC2C3C(=CC=C(C)C=3)N=C(N3CC4C=CC=CC=4S(=O)CC3)C=2)COC1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:31])[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])[CH2:19][CH2:18]2)[CH:3]=1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Reactant: Cc1ccc2nc(Cl)cc(Cl)c2c1
Agent: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(NCC3(N)COC3)c2c1
Agent: O=S1CCNCc2ccccc21
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)cc(Cl)c2c1

Procedure:
The title compound was prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1 in Scheme 6 by using 2,4-dichloro-6-methylquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide. N-[(3-Aminooxetan-3-yl)methyl]-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine