Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:22])[C:10]([F:21])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH3:24][O-:25].[Na+].[CH:27](OCC)=[O:28]>ClCCl>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:22])[C:10]([F:21])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH:27]=[O:28])[CH:16]([CH3:20])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[CH:6]([CH:24]=[O:25])[CH2:5]2)[CH2:2][CH2:3]1
Reactant: CCOC=O
Reactant: C[O-]
Reactant: Cc1c(F)c(N2CCNC(C)C2)cc2c1C(=O)CCN2C1CC1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(F)c(N2CCN(C=O)C(C)C2)cc2c1C(=O)C(C=O)CN2C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
1-Cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)5-methyl-4-oxo-1,2,3,4-tetrahydroquinoline (5.7 g) is dissolved in dichloromethane (200 ml) and thereto is added gradually sodium methylate (6.8 g) and further added dropwise a solution of ethyl formate (9.3 g) in dichloromethane (100 ml). The mixture is stirred at room temperature for one hour and then refluxed for one hour. After cooling, the reaction mixture is washed with water (200 ml) and dilute aqueous sodium hydroxide solution (200 ml) and extracted. The aqueous layer is taken and is made weakly acidic with diluted hydrochloric acid and extracted with dichloromethane. The extract is washed with water, dried and then dichloromethane is distilled off. The resulting residue is purified by silica gel column chromatography (eluent, chloroform) and recrystallized from diethyl ether - isopropanol to give 1-cyclopropyl-6-fluoro-7-(4-formyl-3-methyl-1-piperazinyl)-5-methyl-4-oxo-3-formyl1,2,3,4-tetrahydroquinoline (4.4 g) as yellow powdery crystals, m.p. 148°-150° C.
Reaction SMILES: [OH:1][C@@H:2]([C:27]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:3]([NH:5][C@@H:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([N:9]([CH3:22])[C@@H:10]([CH:19]([CH3:21])[CH3:20])/[CH:11]=[C:12](\[CH3:18])/[C:13]([O:15]CC)=[O:14])=[O:8])=[O:4].O[C@H](C(C)(C1C=CC=CC=1)C)C(N[C@@H](C(C)(C)C)C(N(C)[C@@H](C(C)C)/C=C(\C)/C(OCC)=O)=O)=O.O.O.[OH-].[Li+]>CO.O1CCCC1>[OH:1][C@H:2]([C:27]([CH3:35])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH3:28])[C:3]([NH:5][C@H:6]([C:7]([N:9]([CH3:22])[C@@H:10]([CH:19]([CH3:21])[CH3:20])/[CH:11]=[C:12](\[CH3:18])/[C:13]([OH:15])=[O:14])=[O:8])[C:23]([CH3:24])([CH3:25])[CH3:26])=[O:4]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](O)C(C)(C)c1ccccc1)C(C)(C)C
Agent: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](O)C(C)(C)c1ccccc1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C/C(=C\[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](O)C(C)(C)c1ccccc1)C(C)(C)C)C(=O)O
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A 1:1 mixture of ethyl (E,4S)-4-[((2S)-2-{[(2S)-2-hydroxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate and ethyl (E,4S)-4-[((2S)-2-{[(2R)-2-hydroxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate (0.34 g, 0.70 mmol, from Reference Example 41) is dissolved in methanol (3.2 mL) and tetrahydrofuran (3.2 mL). To this solution is added water (1.6 mL) and lithium hydroxide monohydrate (64 mg, 1.5 mmol), and the resulting mixture is stirred at 65° C. for 16 hours. Solvents are removed in vacuo and the residue is then dissolved in water. The solution is acidified to pH 1 with 2 M aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a white foam. A sample of this crude material (200 mg) is subjected to HPLC purification (Prodigy OS3 column, acetonitrile/water/TFA) to give (E,4S)-4-[{N-[(2R)-2-hydroxy-3-methyl-3-phenylbutanoyl]-3-methyl-L-valyl}(methyl)amino]-2,5-dimethyl-2-hexenoic acid as a white foam, which is crushed to a powder (50 mg). MS (ES+): (M+H)=461.0
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[F:16][CH:15]([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([NH:18][C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)=[N:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Nc1cccc(O)c1
Reactant: FC(F)Oc1ccc(-c2cnc(Cl)nc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Oc1cccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)c1
Temperature: 100 °C

Procedure:
To a mixture of 2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 30 (3.2 mmol) and 3-aminophenol (6.42 mmol) in 1,4-dioxane (5 mL) is added p-TSA (5.4 mmol). The reaction mixture is heated at 100° C. for 12 h. After this time, the reaction is diluted with a 2M solution of Na2CO3 and extracted with DCM (3×50 mL). The organic layer is washed with brine, dried over Na2SO4, and concentrated. Purification by short SiO2 chromatography using a DCM:EtOAc=7:3 as eluant affords (3-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenol 39. MS (m/z) (M+1)+: 330.1.
Reaction SMILES: Cl.[CH:2]1([N:8]([CH2:10][C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:15]([Cl:25])[CH:14]=2)[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(OCC)(=O)C.CO.[Pd]>[ClH:25].[CH:2]1([N:8]([CH2:10]/[CH:11]=[CH:12]\[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:15]([Cl:25])[CH:14]=2)[CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CN(CC#Cc1ccc(C2CCCCC2)c(Cl)c1)C1CCCCC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C/C=C\c1ccc(C2CCCCC2)c(Cl)c1)C1CCCCC1
Yield: 85 %

Procedure:
A solution containing 13.1 g of the compound prepared in Example 1, in the form of the base, and 1.2 g of 5% palladium on barium sulfate in 100 ml of ethyl acetate and 5 ml of methanol is hydrogenated at normal temperature and pressure. The volume of hydrogen absorbed is 650 ml. After filtration and concentration of the solution, the residue is taken up in ethyl ether and the hydrochloride is precipitated by bubbling hydrogen chloride. 5.6 g of the expected compound are obtained after recrystallization from acetonitrile. Yield: 43%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([NH:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Nc1nc(NCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91 %

Procedure:
2-Amino-6-benzylamino-3-nitropyridine was prepared from 2-amino-6-chloro-3-nitropyridine as follows: 2-Amino-6-chloro-3-nitropyridine (17.35 g, 0.10 mol), benzyl amine (Fluka) (10.72 g, 0.10 mol) and powdered potassium carbonate (10.4 g, 0.035 mol) in n-butanol (100 mL) were heated under reflux for 2 hours. The suspension was filtered and after cooling to room temperature the solid was collected by filtration, washed with butanol, and dried at 50 C in vacuo to give 2-amino-6-benzylamino-3-nitropyridine (22.2 g, 91%, m.p. 145-146 C).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[CH3:14][O:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCCc2ccc(O)cc21
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)CCCC2
Temperature: 52.5 °C
Reaction time: 7 h
Yield: 72.4 %

Procedure:
A mixture of 3-hydroxy-6,7,8,9-tetrahydrobenzocyclohepten-5-one (7.02 g), potassium carbonate (8.25 g) and iodomethane (7.4 ml) in N,N-dimethylformamide (70 ml) was stirred at 50-55° C. for 7 hours. The resulting mixture was diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to afford 3-methoxy-6,7,8,9-tetrahydrobenzocyclohepten-5-one (5.49 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:15][CH2:16][CH2:17][C@H:18]([N:26](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:19]([O:21]C(C)(C)C)=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6]C=C[CH:3]=1.Cl.C(O[CH2:58][CH3:59])C>CCOC(C)=O>[C:2]([C@@:18]([NH2:26])([CH2:17][CH2:16][CH2:15][N:14]([CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:59]=[CH:58][CH:3]=1)=[O:10])[CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45])[C:19]([OH:21])=[O:20])([CH3:7])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)[C@H](CCCN(CCNC(=O)OCc1ccccc1)CCNC(=O)OCc1ccccc1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCOCC
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)[C@@](N)(CCCN(CCNC(=O)OCc1ccccc1)CCNC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a solution of tert-butyl (2S)-5-[bis(2-{[(benzyloxy)carbonyl]amino}ethyl)amino]-2-{bis[(tert-butoxy)carbonyl]amino}pentanoate XXII (3.00 g, 4.04 mmol) in EtOAc (20 mL) was added HCl (3.5 M solution in EtOAc, 20 mL). The reaction mixture was stirred for 30 min at room temperature before adding ethyl ether (about 50 mL). The precipitate was filtered and washed with ether to give tert-butyl (2S)-5-[bis(2-{[(benzyloxy)carbonyl]amino}ethyl)amino]-2-aminopentanoic acid as a white crystalline solid (1.82 g, 3.14 mmol, 78% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:16][C:7]=2[C:6]([C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1)[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3.[C:20]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O.O>CC(C)=O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3([O:16][C:7]=2[C:6]([C:17]([O:19][CH3:20])=[O:18])=[CH:5][CH:4]=1)[CH2:11][CH2:12][S:13][CH2:14][CH2:15]3
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)O)c2c1OC1(CCSCC1)O2
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(OC)c2c1OC1(CCSCC1)O2
Temperature: 50 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A suspension of 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylic acid (570 mg, 2.02 mmol), K2CO3 (558 mg, 4.04 mmol) and dimethyl sulphate (0.25 mL, 2.62 mmol) in acetone (14 mL) was stirred at 50° C. overnight. At room temperature water (30 mL) was added. The aqueous phase was extracted with dichloromethane (3×15 mL). The combined organic phase was dried over MgSO4 and evaporated to dryness under reduced pressure. Standard silica gel column chromatography afforded methyl 7-methoxy-2′,3′,5′,6′-tetrahydro-spiro[1,3-benzodioxole-2,4′-(4H)-thiopyran]-4-carboxylate (407 mg, 68%). 13C NMR (DMSO) δ 163.8, 148.1, 146.9, 134.6, 123.4, 118.3, 107.1, 105.9, 56.1, 51.6, 35.9, 25.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[NH:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17].[C:25]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)(=[O:27])[CH3:26]>>[OH2:11].[C:25]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)[C:5]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])([NH:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[C:6]3=[O:11])(=[O:38])=[O:39])=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)(=[O:27])[CH3:26].[C:25]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=4)[C:5]([NH:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17])([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:24])[C:6]3=[O:11])(=[O:38])=[O:39])=[CH:34][CH:35]=2)[CH2:30][CH2:29]1)(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Reactant: COCCCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Product: COCCCNC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc3c(c2)CCN3C(C)=O)c2ccc(Cl)cc21
Product: O
Yield: 84.5 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 222 from 1 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[(3-methoxypropyl)amino]indol-2-one and 0.711 g of 1-acetylindoline-5-sulfonyl chloride. 0.921 g of the expected product is obtained after crystallization from a DCM/iso ether mixture. M.p=158°-162° C.
Reaction SMILES: [CH2:1](O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:23][CH2:24][C:25]1([CH3:44])[O:29][N:28]=[C:27]([S:30][CH2:31][C:32]2[C:33]([C:40]([F:43])([F:42])[F:41])=[N:34][N:35]([CH2:38][CH3:39])[C:36]=2[OH:37])[CH2:26]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C.O>[Cl:23][CH2:24][C:25]1([CH3:44])[O:29][N:28]=[C:27]([S:30][CH2:31][C:32]2[C:33]([C:40]([F:43])([F:42])[F:41])=[N:34][N:35]([CH2:38][CH3:39])[C:36]=2[O:37][CH2:1][CH3:2])[CH2:26]1
Reactant: CCO
Reactant: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1c(CSC2=NOC(C)(CCl)C2)c(C(F)(F)F)nn1CC
Reaction time: 1 h
Yield: 86.4 %

Procedure:
0.3 g (5.4 mmoles) of ethanol and 1.4 g (5.4 mmoles) of triphenylphosphine were added, at room temperature, into a solution of 1.6 g (4.5 mmoles) of 5-chloromethyl-3-(1-ethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-meth-yl-2-isoxazoline dissolved in 20 ml of tetrahydrofuran. Thereto was added, with ice-cooling, 1.1 g (5.4 mmoles) of diisopropyl azodicarboxylate. The mixture was stirred for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.5 g (yield: 86.8%) of 5-chloromethyl-3-(5-ethoxy-1-ethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=O)[CH:11]=[C:10]2[CH3:18]>N>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([Cl:3])[CH:11]=[C:10]2[CH3:18]
Reactant: Cc1cc(=O)[nH]c2ccc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: Cc1cc(Cl)nc2ccc(Br)cc12

Procedure:
25 mL of phosphorus oxychloride was added to 2.7 g (11.34 mmol) of 6-bromo-4-methyl-1H-quinolin-2-one (Example 1b) and the reaction mixture was refluxed for 2 hours. After cooling, the mixture was added batchwise to 250 mL of 10% NH3 solution, and the precipitate formed was filtered off, washed with water, and dried in the circulating air dryer at 30° C. Yield: 2.7 g (93% of theoretical); C10H7BrClN (M=256.526); calc.: molpeak (M+H)+: 256/258/260 (BrCl); found: molpeak (M+H)+: 256/258/260 (BrCl); Rf value: 0.95 (silica gel, DCM/MeOH 9:1).
Reaction SMILES: [N:1]([CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15](=[O:32])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][CH:17]=2)[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-].[H][H]>C(O)C>[NH2:1][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15](=[O:32])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][CH:17]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N=[N+]=[N-])c3ccccc32)cc1
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Yield: 57.5 %

Procedure:
5-Azido-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.63 g) is dissolved in ethanol and thereto is added 10% Pd--C (0.1 g). The mixture is subjected to catalytic hydrogenation at room temperature under 1 atm. of hydrogen. Pd--C is removed by filtration and the filtrate is evaporated. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from diethyl ether to give 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.34 g) as white powder, m.p. 198.5°-199.5° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[C:12]([O:16][C:17](=[O:22])[C:18]([NH2:21])([CH3:20])[CH3:19])([CH3:15])([CH3:14])[CH3:13].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[C:12]([O:16][C:17](=[O:22])[C:18]([CH3:20])([NH:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:19])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(C)(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 85 °C
Yield: 49.6 %

Procedure:
To a mixture of 1-fluoro-2-nitrobenzene (485 μL, 4.6 mmol) and 2-amino-2-methyl-propionic acid tert-butyl ester hydrochloride (1.0 g, 5.1 mmol) in DMF (5 mL) was added Et3N (1.3 mL, 9.3 mmol). The mixture was heated at 85° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL) and washed with H2O (50 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 10% EtOAc in Hexane as the eluent to afford the desired 2-methyl-2-(2-nitro-phenylamino)-propionic acid tert-butyl ester (640 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CC1C2C(=CC=CC=2)C=CC=1.[C-]#N.[Na+].[CH3:28][N:29]1C=CN=C1>[Cu]I.O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:28]#[N:29])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: Cn1ccnc1
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc2ccccc12
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL, three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (5.0 g, 0.02 mol, 99.1% purity) and 1-methylnaphthalene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature and sodium cyanide (ground to a powder just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57 g, 0.003 mol, 98% purity) and 1-methyl-1H-imidazole (1.40 g, 0.017 mol, 99%) were added. The mixture was heated to between 160 and 165° C. for 6 h and then transferred to a 200-mL flask and allowed to cool overnight. Water (20 mL) was added dropwise to the reaction mixture over 5 minutes while stirring. After stirring for an additional 2 h, the reaction mixture was filtered and the collected solid was washed with water (3×10 mL) and xylenes (10 mL) and dried to a constant weight in a vacuum-oven at 80° C. to give the title compound as a light brown solid (3.85 g).
Reaction SMILES: CI.C([I:5])C.[CH2:6]([N:8]1[CH2:17][CH:16]2[C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:14]3[C:15]2=[C:10]([C:11]([O:28][CH3:29])=[C:12]([O:26][CH3:27])[CH:13]=3)[CH2:9]1)[CH3:7]>>[I-:5].[CH2:6]([N+:8]1[CH2:17][CH:16]2[C:18]3[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=3[CH2:20][CH2:21][C:14]3[C:15]2=[C:10]([C:11]([O:28][CH3:29])=[C:12]([O:26][CH3:27])[CH:13]=3)[CH:9]=1)[CH3:7]
Reactant: CCI
Reactant: CCN1Cc2c(OC)c(OC)cc3c2C(C1)c1ccccc1CC3
Solvent: CI
Product: CC[N+]1=Cc2c(OC)c(OC)cc3c2C(C1)c1ccccc1CC3
Product: [I-]

Procedure:
By following the two step procedure of example 4, but replacing methyl iodide with an equivalent amount of ethyl iodide, 2-ethyl-4,5-dimethoxy-1,2,3,7,8,12b-hexahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinoline; mp 105°-106° C.; NMR (CDCl3) δ 1.29 (t, J=7 Hz, 3H), 2.65 (t,J=7 Hz, 2H), 3.69 & 3.73 (2s, 6H), 4.55 (t, J=4 Hz, 1H), 6.41 (s, 1H), 7.10 (m, 3H), 7.35 (m, 1H); Anal Calcd for C21H25NO2 : C, 77.98% H, 7.79% N, 4.33%; Found: C, 78.17% H, 8.21% N, 4.33%, was obtained via the quaternary Schiff base, 2-ethyl-4,5-dimethoxy-1,7,8,12b-tetrahydrobenzo[6,7]cyclohepta[1,2,3-de]isoquinolinium iodide, mp 179°-181° C.; NMR (CDCl3) δ 1.78 (t, 3H), 3.84 & 3.92 (2s, 6H), 5.25 (m, 1H), 6.9-7.4 (m, 4H), 7.8 (s, 1H), 10.0 (s, 1H); IR (CHCl3) 1660 cm-1.
Reaction SMILES: [OH-:1].[Na+:2].[C:3](=[O:5])=[O:4]>>[C:3]([O-:1])([O-:5])=[O:4].[Na+:2].[Na+:2].[C:3]([O-:1])([OH:5])=[O:4].[Na+:2]
Reactant: O=C=O
Reactant: [OH-]
Agent: [Na+]
Product: O=C([O-])O
Product: O=C([O-])[O-]

Procedure:
subjecting a NaOH solution to CO2 present in air, resulting in production of Na2CO3 and NaHCO3 ;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]2[CH2:14][CH2:13][N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.OC1C=CC(C(O)=O)=CC=1.Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1
Agent: Br
Agent: O=C(O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.8 %

Procedure:
370 g (0.839 mole) of levorotatory (-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine (prepared in Example 3.A1) and 405 g of 4-hydroxybenzoic acid are added to 1 liter of a 30% solution of hydrobromic acid in acetic acid. The suspension is stirred for 17 hours at 25° C. 2 liters of water are then added thereto and the suspension is cooled in an ice bath. The precipitate which forms is filtered and washed with 750 ml of water. 2 liters of toluene and 0.9 liters of a 50% aqueous solution of sodium hydroxide are then added to the filtrate. The organic phase is decanted off and washed with 100 ml of water and then once again with 1 liter of a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and the solvent evaporated off under reduced pressure. The residue is recrystallized from 600 ml of boiling hexane. The solution is filtered while hot, so as to remove any slightly insoluble material and the filtrate is then allowed to crystallize, first at ambient temperature, and then for 24 hours in an ice bath. The crystals are filtered off, washed with hexane and dried under vacuum at 40° C. 204.15 g of levorotatory (-)-1-[(4-chlorophenyl)phenylmethyl]piperazine are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.[C:32]1([CH2:38][CH2:39][SH:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=[C:10]2[CH2:12][S:40][CH2:39][CH2:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: SCCc1ccccc1
Reactant: OB(O)c1ccccc1F
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)C=C(CSCCc2ccccc2)c2cc(-c3ccccc3F)ccc2N1

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 2-fluorophenyl boronic acid. Bromination and coupling reaction with 2-phenylethanethiol gave 72 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:6]=1.O.[NH2:20][NH2:21]>CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([NH:20][NH2:21])=[O:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:6]=1
Reactant: COC(=O)c1ccc(-n2cnc(Cl)c2)c(OC)c1
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)NN)ccc1-n1cnc(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxybenzoate (25.5 mg) in methanol (1 mL) was added hydrazine monohydrate (0.019 mL) at room temperature, the mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (12.7 mg).