Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>O1CCOCC1>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[CH:15][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:11])[F:10])[N:3]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:21]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(C(F)(F)F)n1
Solvent: C1COCCO1
Product: CCOC(=O)C(=CNc1cccc(C(F)(F)F)n1)C(=O)OCC
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of 2-amino-6-trifluoromethylpyridine (15.0 g, 92.5 mmol) and diethyl ethoxymethylenemalonate (18.5 mL, 20.0 g, 92.5 mmol) in 1,4-dioxane (30 mL) was stirred at 100° C. for 48 h. Upon cooling to room temperature, 2-[(6-trifluoromethylpyridin-2-ylamino)methylene]malonic acid diethyl ester precipitated from solution, which was separated by filtration, washed with diethyl ether and air-dried (27.2 g, 89%): δH (400 MHz, CDCl3) 1.35 (3H, t, J 7.2), 1.39 (3H, t, J 7.0), 4.28 (2H, q, J 7.2), 4.33 (2H, q, J 7.2), 7.03 (1H, d, J 8.2), 7.38 (1H, d, J 7.4), 7.82 (1H, t, J 8.1), 9.12 (1H, d, J 12.9), 11.20 (1H, d, J 12.5). m/z (ES+) 333 [MH]+, 287 [M-EtO]+
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][CH:4]=1)[CH3:2].C1C(=O)N([Br:20])C(=O)C1>>[Br:20][C:4]1[N:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:7][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc(CC)[nH]1
Product: CCOC(=O)c1nc(Br)c(CC)[nH]1
Yield: 69 %

Procedure:
The same operation as in Example (1c) was performed using ethyl 5-ethyl-1H-imidazole-2-carboxylate obtained by the method described in Example (1b) (0.29 g, 1.30 mmol) and NBS (0.28 g, 1.28 mmol), to obtain 0.22 g of the title compound as a white solid (69%).
Reaction SMILES: [H-].[Li+].[CH2:3]([C:5]1[N:6]=[C:7]([CH2:10][C:11]#[N:12])[S:8][CH:9]=1)[CH3:4].[Cl:13][C:14]1[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=1>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]([C:10](=[C:7]2[NH:6][C:5]([CH2:3][CH3:4])=[CH:9][S:8]2)[C:11]#[N:12])[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCc1csc(CC#N)n1
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1=CSC(=C(C#N)c2ccnc(Cl)n2)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a suspension of LiH (699 mg, 87.90 mmol) in anhydrous THF was added dropwise a suspension of (4-ethyl-1,3-thiazol-2-yl)acetonitrile (6.69 g, 43.95 mmol) in THF (60 mL) and the suspension was stirred for 1 h at 0° C. A suspension of 2,4-dichloropyrimidine (7.2 g, 48.34 mmol) in THF (60 mL) was added dropwise to the pale red suspension at 0° C. and the resulting mixture was stirred at rt for 7 h. The reaction was quenched by addition water (10 mL) at 0° C. then the solution obtained was left overnight under stirring. The THF was removed under reduced pressure then 80 mL of water were added and the suspension was acidified with 1N HCl. The precipitate formed was filtered off and washed with water until neutral pH to afford 9.96 g of the title compound as a beige powder (Y=85.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](Cl)=[O:37]>>[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)=[O:37]
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4ccc5ccccc5c4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and 2-naphthoyl chloride (57 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a free base.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)CC1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1-methylpiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-methylpiperazine-1-carbonyl)benzamide. MS (Q1) 469 (M)+.
Reaction SMILES: [Na].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)(O)=[O:3].C(Cl)(=O)C([Cl:20])=O>O1CCCC1.CCOCC>[Cl:20][C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:16])[CH2:13][CH2:14][CH:15]=1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCCCC1=CCCC1=O
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cl)CCCCCCC1=CCCC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 1.94 g (0.08 mol) of sodium hydric in 100 ml of tetrahydrofuran is added with stirring under argo dropwise a solution of 17 g (0.08 mol) of 2-(6-carboxyhexyl)-cyclopent-2-en-1-one in 160 ml of tetrahydrofuran. After the addition is complete, the mixture is stirred for 1 hour 15 minutes. The mixture is cooled to 0° C. and 13 ml of oxalyl chloride is added. The mixture is stirred at 0° C. for 30 minutes and at room temperature for 30 minutes. The solution is diluted with 500 ml of ether and filtered through Celite. The solvent is removed from the filtrate and the residue is extracted with hot hexane twice. The hexane is removed to give 16.0 g of the title compound.
Reaction SMILES: N[C@H](C(O)=O)CCCNC(=N)N.[NH2:13][C@H:14]([C:25]([OH:27])=[O:26])[CH2:15][C:16]1[C:24]2C(=CC=CC=2)N[CH:17]=1>>[NH2:13][C@H:14]([C:25]([OH:27])=[O:26])[CH2:15][CH:16]([CH3:24])[CH3:17]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
His; 1.04 (1), Arg; 2.05 (2), Trp; 0.88 (1)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2].C(N(CC)CC)C.S([NH:47][N:48]=[CH:49][CH:50](Cl)Cl)(C1C=CC(C)=CC=1)(=O)=O>CO.O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH:50]=[CH:49][N:48]=[N:47]3)=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)NN=CC(Cl)Cl)cc1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(N)cc2)n1-c1ccc(C(N)=O)cc1C
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(-c2ccc(-n3ccnn3)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 51.2 %

Procedure:
Under a nitrogen atmosphere, 3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (11A, see Scheme 11) (103 mg, 0.26 mmol) was dissolved in methanol (5 mL). Triethylamine (0.07 mL, 0.48 mmol) was added. The mixture was cooled to 0° C. 2,2-dichloroacetaldehyde tosylhydrazone (15A) (62 mg, 0.22 mmol), dissolved in methanol (1.5 mL) was added slowly. The reaction was stirred at 0° C. for 5 min, and then heated to 40° C. for 3 hrs, then cooled to room temperature for 16 hrs. 2,2-dichloroacetaldehyde tosylhydrazone (15A) (62 mg) was added and stirred an additional 4 hr. The reaction was diluted with water (5 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative TLC plate (1500 microns, 10% IPA/CH2Cl2). The desired band (RF=0.3) was isolated and dried under high vacuum to yield 3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,3]triazol-1-yl-phenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (15B) (50 mg, 43%, light tan powder).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33](O)=O)[CH:18]=1>>[F:37][C:16]([F:15])([F:36])[C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=2)[N:20]=[C:19]([C:33]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=3)[N:14]=2)[CH:18]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)n1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)n2)c1

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.230 g, 1.06 mmol) and 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example D.12) (0.30 g, 1.00 mmol) according to the general procedure V. Obtained as a white solid (0.100 g, 22%). MS (ISP) 513.2 [(M+H)+]; mp 211° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:14]4[C:18]([C:19](=[O:20])[C:7]([C:8]=23)=[CH:6][N:5]=1)=[CH:17][CH:16]=[CH:15]4)[CH3:2].O.[N+:22]([O-])([OH:24])=[O:23]>>[CH2:1]([O:3][C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:14]4[C:18]([C:19](=[O:20])[C:7]([C:8]=23)=[CH:6][N:5]=1)=[CH:17][CH:16]=[C:15]4[N+:22]([O-:24])=[O:23])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ncc2c(=O)c3cccn3c3cccc1c23
Solvent: O
Product: CCOc1ncc2c(=O)c3ccc([N+](=O)[O-])n3c3cccc1c23
Reaction time: 0.25 h

Procedure:
A mixture (150.4 cc) of equal volumes of about 50% by weight nitric acid (density 1.33) and about 97% by weight nitric acid (density 1.52) is added dropwise to a suspension, stirred and maintained between 5° and 10° C., of 4-ethoxy-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (30 g) in nitric acid (density 1.33; l34 cc). The addition takes 15 minutes. The mixture is stirred for a further 15 minutes, whilst allowing the red solution to return to ambient temperature. This solution is poured into water (1.7 liter) and the orange solid which precipitates is filtered off. The residue is washed with water (5 × 50 cc) and then dried under reduced pressure (1 mm Hg) at 50° C. Crude 4-ethoxy-10-nitro-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (31 g) is thus obtained. After recrystallisation from acetonitrile, the pure product melts at 192° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[F:12]>[Ni].C(O)C.N.CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][C:5]=1[F:12]
Reactant: COC(=O)c1ccc(C#N)cc1F
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CCO
Product: COC(=O)c1ccc(CN)cc1F
Temperature: 25 °C

Procedure:
Add a slurry of Raney nickel in ethanol (1.2 g, 1.2 ml) to 4-cyano-2-fluoro-benzoic acid methyl ester (5.8 g, 30.0 mmol) in 2N ammonia in methanol (580 mL). Purge with nitrogen gas (3×), purge with hydrogen gas (3×), and pressurize with hydrogen gas to 419 KPa. Heat the reaction at 40° C. for 18 hrs. Allow to cool to room temperature and filter the reaction mixture. Concentrate the filtrate to the crude title compound (6.9 g, 99%). MS (m/z): 184 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:32]([C:34]1[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][C:35]=1B(O)O)#[N:33]>>[C:32]([C:34]1[CH:39]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:37]=[CH:36][C:35]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1)#[N:33]
Reactant: N#Cc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C#N)nccc3c2)c(OC)c1

Procedure:
The titled compound was prepared in an analogous manner to that of INTERMEDIATE DD, except that 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate OOO) and (2-cyano-4-(trifluoromethyl)phenyl)boronic acid were used as the coupling partners. The material was purified via silica gel column chromatography (12 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 1-(2-cyano-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. m/z (ESI) 629.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].Cl[C:31]1[S:35][N:34]=[C:33]([CH3:36])[N:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:20][CH2:21][N:22]([C:31]4[S:35][N:34]=[C:33]([CH3:36])[N:32]=4)[CH2:23][CH2:24]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: Cc1nsc(Cl)n1
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CC2)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nsc(N2CCC(N(C)C(=O)c3ccc4c(c3)[C@H](NC(=O)c3ccccc3Cl)CC4)CC2)n1
Temperature: 80 °C
Yield: 59 %

Procedure:
A mixture of (R)-3-(2-chlorobenzamido)-N-methyl-N-(piperidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide (see stage 2 illustrative compound H-214) (230 mg, 0.559 mmol, 1 eq), 5-chloro-3-methyl-1,2,4-thiadiazole (83 mg, 0.615 mmol, 1.1 eq) and Cs2CO3 (363 mg, 1.118 mmol, 2 eq) in dioxane (10 ml) was heated for 2 h at 80° C. When the reaction was complete according to TLC monitoring, the reaction mixture was concentrated under reduced pressure. The residue was taken up in dichloromethane (50 ml), washed with water (30 ml) and saturated sodium chloride solution (30 ml) and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure and the crude product was purified by column chromatography (Alox, 0.5% methanol/dichloromethane). The desired product was in the form of a white solid. Yield: 59% (170 mg, 0.333 mmol)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:10][C@@H:9]1[C@H:19]1[O:23][C:22]([CH3:25])([CH3:24])[N:21]([C:26](=[O:28])[CH3:27])[C@H:20]1[CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:10][C@@H:9]1[C@H:19]1[O:23][C:22]([CH3:24])([CH3:25])[N:21]([C:26](=[O:28])[CH3:27])[C@H:20]1[CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCC=C(C)C)CN2C(=O)OC(C)(C)C)OC1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](OCCC(C)C)CN2C(=O)OC(C)(C)C)OC1(C)C
Yield: 76 %

Procedure:
Stir a solution of (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-(3-methyl-but-2-enyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester and 10% palladium on carbon (0.02 g) in methanol (5 mL) under one atmosphere of hydrogen gas for 18 hours. Filter and evaporate to give the desired compound as a foam (0.081 g, 76%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.[NH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1>C(O)C>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH:12]1[NH:11][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12
Reactant: NC1Cc2ccccc2C1
Reactant: Clc1nc[nH]c2nccc1-2
Solvent: CCO
Product: c1ccc2c(c1)CC(Nc1nc[nH]c3nccc1-3)C2
Yield: 37 %

Procedure:
4-chloropyrrolo[2,3-d]pyrimidine (83 mg, 0.54 mmol) (see J. Chem. Soc., 131 (1960), J. Org. Chem., 26, 3809 (1961)) and 2-aminoindan (220 mg, 1.6 mmol) in dry ethanol (5 ml) were heated to reflux under an argon atmosphere for 1 hour. The solvent was distilled off under reduced pressure and the residue obtained was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (38 mg, 0.20 mmol) having the following physical properties:
Reaction SMILES: C1O[C:4]([CH3:19])([CH2:5][N:6]2[C:10](=[S:11])[NH:9][N:8]=[C:7]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:3]C1.Cl>C(O)C>[CH2:12]([C:7]1[N:6]([CH2:5][C:4](=[O:3])[CH3:19])[C:10](=[S:11])[NH:9][N:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1(Cn2c(Cc3ccccc3)n[nH]c2=S)OCCO1
Agent: Cl
Solvent: CCO
Product: CC(=O)Cn1c(Cc2ccccc2)n[nH]c1=S

Procedure:
To 10 ml of ethanol was added 1.1 g of the 1-(3-benzyl-1,5-dihydro-5-thioxo-4H-1,2,4-triazol-4-yl)-2-propanone ethylenacetal obtained in Reference Example 5, followed by addition of 5.0 ml of 2N-hydrochloric acid. The mixture was refluxed for 40 minutes and, then, concentrated to half the original volume. To the concentrate was added water and the resultant precipitate was recovered by filtration. This procedure provided 1-(3-benzyl-1,5-dihydro-5-thioxo-4H-1,2,4-triazol-4-yl)-2-propanone as crystals. Recrystallization from ethyl acetate gave colorless needles melting at 163°-165° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([NH2:10])=O)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1.C(Cl)Cl.O>[CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:10][C:25](=[O:26])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:4][CH2:3]1
Reactant: C=C1CCC(C(N)=O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C1CCC(CNC(=O)OCc2ccccc2)CC1
Yield: 35.7 %

Procedure:
Compound 8-3 (9.5 g, 0.068 mol) was dissolved in 300 mL of THF, and lithium aluminium hydride (2.62 g, 0.069 mol) was added slowly at −10° C. After the addition, reacted at room temperature for 2 hours, and added 5 mL of water after completion of the reaction of raw materials, suction filtered through Celite and the filtrate was concentrated to give an oil. The obtained oil and triethylamine (10.7 mL, 0.075 mol) were dissolved in 100 mL of DCM, and added dropwise benzyl chloroformate (11.6 g, 0.068 mol) slowly at −10° C., then further reacted for 2 hours at room temperature after the addition was completed. The reaction mixture was washed with 100 mL of water and 100 mL of saturated brine once respectively, dried and concentrated and purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give Compound 8-4 as a white solid (6.3 g, yield 35.7%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>ClC1C=CC=CC=1Cl>[CH:18]1([C:14]2[N:13]3[C:3]4[C:2]([NH:1][C:23](=[O:24])[C:17]3=[CH:16][N:15]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:12])[CH:4]=4)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1cc(N)c(-n2ccnc2C2CCCC2)cc1C
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cc2[nH]c(=O)c3cnc(C4CCCC4)n3c2cc1C
Temperature: 190 °C
Reaction time: 3 h
Yield: 46.8 %

Procedure:
A mixture of 1.79 g of methyl 5-amino-4-(2-cyclopentyl-1H-imidazol-1-yl)-2-methylbenzoate, 1.04 g of 1,1′-carbonyldiimidazole, and 18 mL of 1,2-dichlorobenzene was stirred at 190° C. for 3 hours. After air-cooling, the reaction mixture was purified by silica gel column chromatography (chloroform/methanol) to obtain 0.91 g of methyl 1-cyclopentyl-8-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([F:15])[F:14])[CH:11]=1)S[CH2:7][CH2:6][C@@:5]2([C:17]([OH:19])=[O:18])[OH:16].O.O[O:22][S:23]([O-:25])=O.[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([F:14])[F:15])[CH:11]=1)[S:23](=[O:25])(=[O:22])[CH2:7][CH2:6][C@@:5]2([C:17]([OH:19])=[O:18])[OH:16]
Reactant: O=S([O-])OO
Reactant: O=C(O)[C@@]1(O)CCSc2c(OC(F)F)cc(Cl)cc21
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)[C@@]1(O)CCS(=O)(=O)c2c(OC(F)F)cc(Cl)cc21
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of (R)-6-chloro-8-difluoromethoxy-4-hydroxythiochromane-4-yl-carboxylic acid (0.50 g, 1.6 mmol; from step (vi) above), wet alumina (prepared by adding H2O (1 mL) to alumina (5.0 g) and shaking until a free flowing powder was obtained, ca. 0.82 g, 8.0 mmol), and Oxone® (4.9 g, 8.0 mmol) in CHCl3 (19 mL) was heated to 40-45° C. for 20 h. The reaction was cooled to room temperature, filtered through a Buichner funnel with EtOAc (50 mL), and concentrated in vacuo to afford 0.54 g (98%) of the sub-title compound as a brown foam which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[CH2:21][NH2:22])[N:14](CC3C=CC(OC)=CC=3)[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[CH2:21][NH2:22])[NH:14][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2CC3(CCN(Cc4ccccc4)C3)c3c(CN)cccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc2c1C1(CCN(Cc3ccccc3)C1)CN2
Yield: 72 %

Procedure:
A solution of (1′-benzyl-1-(4-methoxybenzyl)spiro[indoline-3,3′-pyrrolidine]-4-yl)methanamine (0.500 g, 1.21 mmol) in TFA (7.00 mL) was heated at 85° C. for 24 hours. The solvent was evaporated to give (1′-benzylspiro[indoline-3,3′-pyrrolidine]-4-yl)methanamine trifluoroacetic acid salt (0.355 g, 0.872 mmol, 72%). LCMS (APCI+) M+H+294 (100%); Rt=2.06 min.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[CH3:6][N:7]1[CH2:24][CH:23]2[CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[O:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=32)[CH2:8]1>C(O)C>[CH3:6][N:7]1[CH2:24][CH:23]2[CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[O:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=32)[CH2:8]1.[P:1]([O-:5])([O-:4])([O-:3])=[O:2]
Reactant: O=P(O)(O)O
Agent: CN1CC2c3ccccc3Oc3ccc(Cl)cc3C2C1
Solvent: CCO
Product: O=P([O-])([O-])[O-]
Temperature: 50 °C

Procedure:
0.69 Kg of asenapine maleate (1.69 moles) with a purity of 98% (HPLC) is loaded into a reactor. Toluene (7.2 L) is added, and the suspension is stirred at 25° C. A 9% solution of sodium bicarbonate (7.2 L) is added by dripping. The solution is left under stirring at 25° C. for 30 minutes. The lower aqueous phase is eliminated. The organic phase is washed with water (2×3.6 L). The solvent is evaporated under vacuum, obtaining asenapine base (0.50 Kg) in the form of oil. 4.6 L of ethanol is added. The solution is stirred, heating to 50° C. An 85% solution of phosphoric acid (0.12 L, 1.69 moles) in ethanol (0.68 L) is dripped into the solution of asenapine base at 50° C. in 10 minutes. The solution is stirred for 30 minutes at 50° C. The solution is cooled to 25° C. in approx. 2 hours. The solution is left under stirring at 25° C. for 2 hours. The product is isolated by filtration, washing with ethanol (0.75 L). The product is dried under vacuum at 25° C. for 20 hours. 0.614 Kg of asenapine phosphate is obtained (yield=94.0%). Purity >99.5% (HPLC).