Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.F[C:12]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:13]=1[CH:14]=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)CCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:12]3[C:13](=[CH:16][C:17]([I:20])=[CH:18][CH:19]=3)[CH:14]=[N:10]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=Cc1cc(I)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2ncc3cc(I)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-chlorophenylhydrazine hydrochloride (5.24 g, 29.27 mmol), 2-fluoro-5-iodobenzaldehyde (7.5 g, 30.00 mmol) and cesium carbonate (22.8 g, 69.98 mmol) was suspended in NMP (120 mL) and stirred at ambient temperature for 45 min. The temperature was raised to +160° C. and the reaction mixture was stirred for 1 h, the now black suspension was allowed to reach r.t. Water was added, the slurry was extracted with EtOAc (500 mL. The organic phase was washed with brine (2×). The brine fractions and waterphase was combined and back extracted once with EtOAc. This second EtOAc phase was washed with brine (2×) before combined with the previous EtOAc phase. The organic phases were dried over Na2SO4, filtered and evaporated. The black residue were dissolved in DCM/Heptane (=1/1) and filtered through a silica column, and the column was then further eluted with DCM/Heptane (=1/1) solvent mixture. The fractions containing product was evaporated, residue was dissolved in EtOAc and Heptane was added, evaporation and diluting with Heptane afforded a slurry, the solid material was collected by filtration and washed with Heptane. Yield 2.82 g (27%)
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][NH:4]1)[CH3:2].[CH3:12][N:13]=[C:14]=[S:15]>C(#N)C.C(O)C>[CH2:1]([CH:3]1[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH2:6][CH2:5][N:4]1[C:14](=[S:15])[NH:13][CH3:12])[CH3:2]
Reactant: CN=C=S
Reactant: CCC1NCCc2[nH]cnc21
Solvent: CC#N
Solvent: CCO
Product: CCC1c2nc[nH]c2CCN1C(=S)NC
Yield: 69.7 %

Procedure:
A solution of 2.9 g of 4-ethyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine (Farmaco, Ed. Sci. 1967, 22, 821) and 3 g of methyl isothiocyanate in 32 ml of acetonitrile and 8 ml of ethanol is refluxed for 8 h. The solution is evaporated in vacuo, and the residue crystallized from diethyl ether to give 3 g of 4-ethyl-5-(N-methyl-thiocarbamoyl)-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine, m.p. 230°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[CH:3][CH:2]=1.C(C1C=CN=CC=1)(=O)C.[NH2:25][C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31]#[N:32]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:27]3[CH:28]=[N:29][C:30]([C:31]#[N:32])=[C:26]3[N:25]=2)=[CH:3][CH:2]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccncc1
Agent: CC(=O)c1ccncc1
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccncc3)nc12
Yield: 26.6 %

Procedure:
Reaction of 1-pyridin-4-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0 mmol), prepared from commercially available 4-acetylpyridine according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (77 mg, 27%). MS (ISP) 289.8 [(M+H)+]; mp 254° C.
Reaction SMILES: B([O:8][CH2:9][CH3:10])(OCC)OCC.C([C:14]1[C:19]2[N:20]=[N:21][S:22][C:18]=2C=[CH:16][CH:15]=1)(O)=O.CO>O1CCCC1>[OH:8][CH2:9][C:10]1[C:18]2[S:22][N:21]=[N:20][C:19]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CCOB(OCC)OCC
Reactant: O=C(O)c1cccc2snnc12
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cccc2nnsc12
Reaction time: 1 h

Procedure:
110 ml of triethyl borate are added dropwise to a suspension of 54 g of carboxybenzo-1,2,3-thiadiazole in 420 ml of tetrahydrofuran at room temperature under a nitrogen atmosphere, while stirring, stirring is continued for 1 hour and 45.6 ml of borane-dimethyl sulfide complex in 60 ml of tetrahydrofuran are then added dropwise, with gentle cooling, vigorous evolution of gas being observed. After the mixture has been stirred overnight and left to stand at room temperature, it is cooled again to 5°-10° C. and 200 ml of methanol are added dropwise, while stirring and cooling thoroughly, vigorous evolution of gas again occurring. The mixture is then evaporated in vacuo, a further 300 ml of methanol are added and the mixture is evaporated again. The residue is purified on silica gel (solvent: ethyl acetate/hexane) and the resulting product is recrystallized from ethyl acetate/hexane. The resulting title compound melts at 79°-81° C.
Reaction SMILES: C(N(C1CCCCC1)C(=O)C1C=C([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)C=CC=1F)C=C.[CH3:41][C:42]1[CH:50]=[CH:49][C:48]([N+]([O-])=O)=[CH:47][C:43]=1[C:44]([OH:46])=O.[CH3:54][NH:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>>[CH:56]1([N:55]([CH3:54])[C:44](=[O:46])[C:43]2[CH:47]=[C:48]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:14][CH2:13]3)[CH:49]=[CH:50][C:42]=2[CH3:41])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: C=CCN(C(=O)c1cc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)ccc1F)C1CCCCC1
Reactant: CNC1CCCCC1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Product: Cc1ccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1C(=O)N(C)C1CCCCC1

Procedure:
Steps (a) and (b) of Example 59 were repeated, except that 2-methyl-5-nitrobenzoic acid was used instead of 2-fluoro-5-nitrobenzoic acid. Step (c) of Example 59 was then repeated, except that N-methylcyclohexylamine was used instead of N-allylcyclohexylamine. Thus, the title compound was prepared.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.C([Li])(C)(C)C.[CH2:19]([O:26][C:27]1[C:32]([CH:33]=[O:34])=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:19]([O:26][C:27]1[C:32]([CH:33]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][O:4][CH2:3][O:2][CH3:1])=[CH:8][CH:9]=2)[OH:34])=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc(C)c(C=O)c(OCc2ccccc2)n1
Reactant: COCOCCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOCCc1ccc(C(O)c2c(C)cc(C)nc2OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a solution of 4-(2-methoxymethyloxyethyl) bromobenzene (0.60 g) in tetrahydrofuran (6 mL) was added tert-butyllithium (1.5 mol/L solution in hexane, 2.0 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. Then, a solution of 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.49 g) in tetrahydrofuran (5 mL) was added to the reaction mixture, and the mixture was stirred for 3 hours at 0° C. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with dimethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 2-benzyloxy-4,6-dimethylpyridin-3-yl 4-(2-methoxymethyloxyethyl)phenyl methanol (0.74 g). To a solution of the obtained 2-benzyloxy-4,6-dimethylpyridin-3-yl 4-(2-methoxymethyloxyethyl)phenyl methanol (0.11 g) in ethanol (5.3 mL) was added 10% palladium carbon powder (0.065 g), and the mixture was stirred for 11 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloro-methane/methanol=10/1) to give 3-[4-(2-methoxymethyloxy-ethyl)benzyl]-4,6-dimethyl-1H-pyridin-2-one (0.074 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[OH-].[Na+].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:20]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1ccc(CN)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(CNC(=O)CCCCCBr)cc1
Yield: 65 %

Procedure:
A cooled solution of (4-methoxyphenyl) methanamine (0.55 g, 4.0 mmol) in CH2Cl2 was stirred vigorously with 2% aqueous NaOH (9.6 mL, 4.8 mmol) while 6-bromohexanoyl chloride (4.8 mmol) in CH2Cl2 was added dropwise. The same NaOH solution was then used to maintain pH at 9, and at costant pH the layers were separated. The organic phase was washed with 3 N HCl, with H2O, and then dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (CHCl3/AcOEt, 1:1, as eluent) to afford pure compound in 65% yield. 1R NMR (CDCl3): δ 1.43-1.53 (m, 2H), 1.65-1.73 (m, 2H), 1.83-1.92 (m, 2H), 2.26 (app. t, 2H), 3.41 (t, 2H, J=6.6 Hz), 3.81 (s, 3H), 4.49 (d, 2H, J=6.05 Hz), 5.93 (br t, 1H, D2O exchanged), 7.37 (d, 2H, J=8.5 Hz), 7.59-7.63 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[CH2:13](I)[CH3:14].[Cl-].[Na+]>C(O)C.O>[CH2:13]([S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:14]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCSc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
16.56 g (106.72 mmol) of 4-nitrothiophenol was added, while cooling with water, to a solution of 4.27 g (106.76 mmol) sodium hydroxide in 320 ml ethanol and it was stirred for 15 minutes at room temperature. Then, while cooling with water, 8.63 ml (106.79 mmol) of ethyl iodide was added and the mixture was stirred overnight at room temperature. The mixture was added to saturated sodium chloride solution and was extracted with ethyl acetate (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. Then it was dissolved in DCM and filtered again and evaporated to dryness. 16.86 g (92.02 mmol) of the raw product was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[CH3:37])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[CH3:37])[CH2:23][C:24]([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[O:25])=[CH:18][CH:17]=1
Reactant: COc1ccc(Br)cn1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccc(Cl)cc1C
Agent: [Li]CCCC
Product: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccc(Cl)cc2C)cn1

Procedure:
In analogy to example 151, step 1, 5-bromo-2-methoxypyridine was reacted first with n-butyllithium and later with 3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)-N-methoxy-N-methylpropanamide (example 138, step 3) to give the title compound as a light yellow oil, MS (ESI+): m/z=446.03 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-:13].[K+].[K+].[CH3:18][C:19]([CH3:21])=[O:20]>>[OH:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][C@@H:19]([OH:20])[CH2:21][OH:13])=[CH:7][CH:6]=1
Reactant: CC(C)=O
Reactant: O=C([O-])[O-]
Reactant: OCCCc1ccc(O)cc1
Agent: [K+]
Product: OCCCc1ccc(OC[C@@H](O)CO)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-hydroxyphenyl)-1-propanol (15.0 g, 99 mmol) in acetone (300 mL) is added S-(−)-glycidol (10.0 g, 105 mmol) and potassium carbonate (20.0 g, 145 mmol) and the reaction mixture is heated at reflux for 24 h. The resulting mixture is allowed to cool to RT, filtered and the filtrate is concentrated in vacuo. Purification by column chromatography (SiO2, 0-4% MeOH in DCM) affords the product as a white solid. [M+H]+ 227.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[C:7]=2[C:6]=1[CH3:29])=[O:4].CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:28][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][C@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:23]3)[C:7]=2[C:6]=1[CH3:29])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCNC3)c2c1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(S(C)(=O)=O)C3)c2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[4-fluoro-2-((S)-piperidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (110 mg) in dichloromethane (3 ml) at 0° C. was added DIPEA (55 μl) followed by methanesulfonyl chloride (25 μl) and the reaction was allowed to warm to room temperature and stirred for 2 h.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:31][C:32](=[O:36])[C:33]([OH:35])=[O:34])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[N:6]([CH2:31][CH:32]([OH:36])[C:33]([OH:35])=[O:34])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CC(=O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CC(O)C(=O)O
Temperature: 25 °C

Procedure:
To a solution of 3-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-1-yl)-2-oxopropanoic acid (50 mg, 0.10 mmol) in MeOH (1 mL) was added NaBH4 (19 mg, 0.50 mmol) at 0° C. The mixture was stirred at room temperature for 15 mm. The resulting mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc twice and the combined organic layers were washed with brine and dried over anhydrous MgSO4. After the removal of the solvent, the residue was taken up in DMSO and purified by preparative LC/MS to give 3-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-1-yl)-2-hydroxypropanoic acid. 1H NMR (400 MHz, CDCl3) δ 7.36 (s), 7.27-7.23 (m, 2H), 7.15-7.11 (m, 2H), 6.94 (d, J=8.5 Hz, 1H), 6.23 (s, 1H), 4.71 (s, 3H), 4.59 (q, J=10.3 Hz, 1H), 4.40-4.33 (m, 2H), 1.70 (d, J=1.9 Hz, 2H), 1.15 (q, J=4.0 Hz, 2H). 13C NMR (400 MHz, CDCl3) δ 173.6, 173.1, 150.7, 144.1, 143.6, 136.2, 135.4, 134.3, 131.7, 129.2, 129.0, 127.6, 126.7, 116.6, 114.2, 112.4, 110.4, 110.1, 99.7, 70.3, 48.5, 32.6, 30.9, 30.7, 16.8. MS (ESI) m/e (M+H+) 501.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([Cl:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[ClH:41].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:38]([C:35]3[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=3)(=[O:40])=[O:39])=[C:3]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCCNCC3)cc2NS(=O)(=O)c2ccccc2)cc1
Product: Cl

Procedure:
The compound was synthesized from of N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)- phenyl}benzenesulfonamide and p-toluenesulfonylchloride (51 mg, 0.27 mmol) to give 22 mg as purple solid. M+1 501.3 Calcd 501.15; 1HNMR δ 7.77-7.26 (m, 9H), 6.54 (d, 1H), 6.50 (d, 1H), 6.40 (dd, 1H), 3.63 (app t, 2H), 3.42 (app t, 2H), 3.25 (app t, 2H), 3.16 (app t, 2H), 2.38 (s, 3H), 2.11-2.03 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C@@:6]12[CH2:24][C@H:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[N:13]1[C@@H:9]([CH2:10][C@@H:11]([O:34][C:35]([N:37]3[CH2:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH2:38]3)=[O:36])[CH2:12]1)[C:8](=[O:46])[NH:7]2)=[O:5])C.O[Li].O>C(Cl)Cl.CO>[C:29]([O:28][C:26]([NH:25][C@@H:15]1[C:14](=[O:33])[N:13]2[C@@H:9]([CH2:10][C@@H:11]([O:34][C:35]([N:37]3[CH2:38][C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:45]3)=[O:36])[CH2:12]2)[C:8](=[O:46])[NH:7][C@@:6]2([C:4]([OH:5])=[O:3])[C@@H:23]([CH2:24]2)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4ccccc4C3)C[C@H]1C(=O)N2
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4ccccc4C3)CN2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
The macrocyclic ester 11 (60 mg, 0.092 mmol) was dissolved in 0.9 mL of a mixed solvent (THF/MeOH/H2O 2:1:1), followed by addition of LiOH—H2O (23 mg, 6 equiv). The mixture was stirred at rt for overnight. After 18 h, TLC (DCM/MeOH 9:1) showed a clean new spot with a lower Rf. The reaction was concentrated down to almost dryness and partitioned between 1N aq. HCl (15 mL) and DCM (20 mL). The aqueous layer was extracted with DCM (2×10 mL). The organic layers were combined, dried over Na2SO4 and concentrated down, giving the desired compound as a light brownish foamy powder (50 mg, 87%). 1H NMR (CDCl3, 500 MHz) 1.21-1.44 (m, 8H), 1.32 (s, 9H), 1.54-1.62 (m, 2H), 1.78-1.88 (m, 2H), 2.04-2.13 (m, 1H), 2.16-2.23 (m, 1H), 2.24-2.36 (m, 2H), 2.66-2.74 (m, 1H), 3.87-3.90 (m, 1H), 4.15 (d, J=11.0 Hz, 1H), 4.37-4.43 (m, 1H), 4.61-4.77 (m, 5H), 5.18 (t, J=10.3 Hz, 1H), 5.24-5.31 (m, 1H), 5.40-5.45 (m, 1H), 5.58-5.66 (m, 1H), 7.11-7.30 (m, 4H). MS m/e 611.0 (M++1).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[C:15]([Cl:33])[C:16]3[C:17](=[O:32])[N:18]([O:28]CC=C)[C:19](=[O:27])[C:20]4[C:25]=3[C:24]=2[C:23]([Cl:26])=[CH:22][CH:21]=4)[CH2:9]1)(C)(C)C>FC(F)(F)C(O)=O>[ClH:26].[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[C:15]([Cl:33])[C:16]3[C:17](=[O:32])[N:18]([OH:28])[C:19](=[O:27])[C:20]4[C:25]=3[C:24]=2[C:23]([Cl:26])=[CH:22][CH:21]=4)[CH2:9]1
Reactant: C=CCON1C(=O)c2ccc(Cl)c3c(N4CC[C@H](NC(=O)OC(C)(C)C)C4)cc(Cl)c(c23)C1=O
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@H]1CCN(c2cc(Cl)c3c4c(ccc(Cl)c24)C(=O)N(O)C3=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (S)-[1-(2-allyloxy-4,7-dichloro-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (0.3 g, 0.6 mmol, from Example K4) in 10 mL of trifluoroacetic acid was treated with boron tristrifluoroacetate (4 mL, 4.0 mmol, 1.0 M in trifluoroacetic acid). The reaction was stirred at room temperature for 2 hours and the solvent evaporated in vacuo. The residue was chased with dichloromethane and redissolved in methanol which was also evaporated. The residue was triturated with ether, the solid removed by filtration and dried in vacuo to give 0.27 g, mp 210-212° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH:18]2[CH:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=32)[CH2:3]1.[P:21](=[O:25])([OH:24])([OH:23])[OH:22]>C(O)C>[CH3:1][N:2]1[CH2:19][CH:18]2[CH:4]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[O:11][C:12]3[CH:13]=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=32)[CH2:3]1.[P:21]([O-:25])([O-:24])([O-:23])=[O:22]
Reactant: O=P(O)(O)O
Agent: CN1CC2c3ccccc3Oc3ccc(Cl)cc3C2C1
Solvent: CCO
Product: O=P([O-])([O-])[O-]
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
0.71 Kg of crude asenapine base (2.48 moles) and 6.7 L of ethanol are loaded into a reactor and dissolved by heating at 50° C. An 85% solution of phosphoric acid (0.17 L, 2.48 moles) in ethanol (1.0 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 (1.1 L). The product is dried under vacuum at 25° C. for 20 hours. 1 Kg of asenapine phosphate is obtained (yield=94.0%). Purity >99.5% (HPLC). The IR spectrum, the DSC thermogram and the XRPD spectrum of asenapine phosphate are shown in FIGS. 1, 2 and 3 respectively. Table 1 shows the Bragg 2-theta angles (2θ), interplanar distances d and the relative intensities expressed as a percentage of the most intense diffraction peak. Table 3 shows the improvement in the quality of the product, expressed as HPLC area %, obtained in the conversion from asenapine base to asenapine phosphate. In Table 3, RRT indicates the relative retention time of the impurities present in the product obtained, compared with the retention time of asenapine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[C:3]=1[OH:9].[CH3:10][O-:11].[Na+].BrC1C=C(C(C)(C)C)C=C(Br)[C:15]=1[OH:25]>CO.CN(C)C=O>[CH3:10][O:11][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:25][CH3:15])[C:3]=1[OH:9]
Reactant: CC(C)(C)c1cc(Br)c(O)c(Br)c1
Reactant: Oc1c(Br)cccc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cccc(OC)c1O

Procedure:
2,6-Dibromophenol (14.5 g, 0.058 mole) was treated with sodium methoxide (from 10.3 g sodium, 0.45 g atom) in methanol (100 ml) and dimethylformamide (100 ml) in the presence of cuprous iodide (2 g) in the same way as described in detail for 2,6-dibromo-4-t-butylphenol in Example 9. The crude yield of title product was 5.4 g (60%), m.p. 53°-6° C. (literature gives 55°-6° C.). The lower yield may be explained by incomplete extraction, 2,6-dimethoxyphenol being to some extent water soluble.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C([O-])(=O)C.[Na+].[H][H]>[Pd].C(O)C.O>[ClH:22].[N:19]1[CH:20]=[CH:21][C:16]([NH:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccnc(Cl)n2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cl
Product: c1cc(NCC2CCNCC2)ncn1
Reaction time: 24 h
Yield: 99 %

Procedure:
A suspension of 1-t-butoxycarbonyl-4-[(2-chloropyrimidin-4-ylamino)methyl]piperidine (8.40 g, 25.7 mmol), sodium acetate (4.22 g, 51.4 mmol) and 5% palladium on activated carbon (5.47 g, 2.57 mmol) in ethanol (205 mL) and water (51 mL) is stirred rapidly under 1 atmosphere of hydrogen for 24 hours. After the atmosphere of hydrogen is replaced with argon the mixture is filtered through a bed of Celite™ and the mixture is concentrated in vacuo. Chloroform, water and saturated sodium bicarbonate are added, the phases are separated and the aqueous phase is extracted into chloroform (×3). The combined organic extracts are dried (sodium sulfate), filtered and concentrated in vacuo. The residue is taken into methanol (750 mL) and hydrogen chloride gas is passed through the solution maintaining the temperature at less than 20° C. The mixture is kept at this temperature for 24 hours before it is concentrated in vacuo and freeze-dried from water, providing 4-[(pyrimidin-4-ylamino)methyl]piperidine hydrochloride (5.82 g, 99%).