Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:15][CH2:14][CH2:13][O:12]1.[H-].[Na+].Cl.Cl[CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][CH2:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:26][CH2:27]1)[C:6](=[O:11])[C:5]12[O:12][CH2:13][CH2:14][O:15]1
Reactant: ClCCC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc2c(c1)C1(OCCO1)C(=O)N2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C1(OCCO1)C(=O)N2CCC1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
5'-Methyl-spiro[1,3-dioxolane-2,3'-[3H]indol]-2'(1'H)-one (1 equivalent) in dry DMF (5 ml) was added dropwise to sodium hydride (3 equivalents) in dry DMF (2 ml) at 0° C. After 20 minutes, a solution of 4-(2-chloroethyl)-1-(phenylmethyl)piperidine hydrochloride (1.5 equivalents) in dry DMF (15 ml) was slowly added. The mixture was heated to 80° C., stirred at this temperature for 3 hours, and then left at RT overnight. The mixture was evaporated to dryness under reduced pressure and the residue purified by flash chromatography to yield the title compound (53%).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH:32]([O:34][CH3:35])[CH3:33])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]=1[C:10]([O:12]C)=[O:11])([CH3:4])[CH3:3].[OH-].[Na+]>>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH:32]([O:34][CH3:35])[CH3:33])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]=1[C:10]([OH:12])=[O:11])([CH3:3])[CH3:4]
Reactant: COC(=O)c1c(C(C)(C)O)nc(C(C)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COC(C)c1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
A solution of 331 m9 of methyl 4-(1-hydroxy-1-methylethyl)-2-(1-methoxyethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 94(b)] in 3 ml of a 1N aqueous solution of sodium hydroxide was stirred at room temperature for 2.5 hours. At the end of this time, insoluble matter was filtered off and 3 ml of 1N aqueous hydrochloric acid was added to the filtrate. The amorphous powder which precipitated was collected by filtration, to give 209 mg of the title compound, melting at 174°-185° C. (with softening).
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([O:13][CH3:14])(=[O:12])[C:8]([O:10]C)=O.[C:15]([C:18]1[C:19](=[O:39])[N:20]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21](=[O:31])[N:22]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=1)(=[O:17])[CH3:16]>C1COCC1>[CH2:24]([N:22]1[CH:23]=[C:18]([C:15](=[O:17])[CH:16]=[C:8]([OH:10])[C:7]([O:13][CH3:14])=[O:12])[C:19](=[O:39])[N:20]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:21]1=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Reactant: COC(=O)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(O)=CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.2 %

Procedure:
To a stirred solution of sodium t-butoxide (577 mg, 6 mmol) in anhydrous THF (15 ml) at room temperature was added, dropwise, dimethyl oxalate (472 mg, 4 mmol) in THF (7 ml) followed by 5-acetyl-1,3-dibenzyluracil (2a) (669 mg, 2 mmol) in THF (8 ml). The resulting mixture was stirred at room temperature for 4 h and then was acidified to pH=2. THF was evaporated. The residue in CH2Cl2 (100 ml) washed with brine (20 ml) and purified by column chromatography (hexane:ethyl acetate, 2:1). The appropriate fraction was concentrated and crystallized from ethanol to give 254 mg of a yellow solid. Yield was 29.1%. Mp. 158-159° C. 1HNMR (CDCl3): 15.04 (s, br, 1H), 8.36 (s, 1H), 7.72 (s, 1H), 7.29-7.49 (m, 10H), 5.18 (s, 2H), 5.05 (s, 2H), 3.92 (s, 3H). 13CNMR (CDCl3): 185.7, 168.8, 162.4, 159.7, 150.5, 148.5, 136.0, 134.0, 129.4, 129.1, 129.0, 128.5, 128.3, 127.9, 109.0, 101.6, 53.7, 53.2, 45.0. FAB-HRMS: [M+H]+ Calcd. for C23H21N2O6 421.1400. Found 421.1418.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cc(Cl)ccc1N1CCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A 100 mL round-bottom flask was charged with 5-chloro-2-fluorobenzaldehyde (2.00 g, 12.6 mmol, 1.00 equiv), pyrrolidine (1.34 g, 18.8 mmol, 1.49 equiv), potassium carbonate (4.34 g, 31.4 mmol, 1.92 equiv), and dimethyl sulfoxide (10 mL). The resulting solution was stirred overnight at 100° C. in an oil bath and diluted with H2O (20 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/10) to yield 1.80 g (68% yield) of 5-chloro-2-(pyrrolidin-1-yl)benzaldehyde as brown oil. 1H NMR 300 MHz (CDCl3) δ 10.05 (s, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.267-7.31 (m, 1H), 6.76 (d, J=9.0 Hz, 1H), 3.29-3.37 (m, 4H), 1.95-2.04 (m, 4H). LCMS (ESI, m/z): 210 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH2:20][CH:19]3[C:31](=[O:33])[NH2:32])=[O:17])=[C:11]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[CH:10]=2)[CH2:4][CH2:3]1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:40][S:41]([N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH2:20][CH:19]3[C:31](=[O:33])[NH2:32])=[O:17])=[C:11]([O:34][CH2:35][C:36]([F:37])([F:38])[F:39])[CH:10]=2)[CH2:4][CH2:3]1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1N1CCN(C(=O)Cc2ccc(OC3CCNCC3)cc2OCC(F)(F)F)C(C(N)=O)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(C(=O)Cc2ccc(OC3CCN(S(C)(=O)=O)CC3)cc2OCC(F)(F)F)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine hydrochloride (0.20 g, 0.35 mmol) from Example 1 in CH2Cl2 (20 mL) was added methanesulfonoyl chloride (0.045 g, 0.39 mmol) and DIEA (0.14 mL, 0.80 mmol). The solution was stirred at ambient temperature for 6 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 0.25 M aqueous citric acid (25 mL), H2O (25 mL), and saturated aqueous NaHCO3 (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 97:3 CH2Cl2 :MeOH. The product-containing fractions were combined and the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 :hexane, and evaporation of this solution under reduced pressure gave the title compound as an amorphous solid.
Reaction SMILES: [C:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[CH2:14]1[O:42][C:41]2[CH:40]=[CH:39][C:18]([C:19]([N:21]3[C:30]4[C:25](=[CH:26][C:27]([C:31]5[CH:36]([CH3:37])[S:35][C:34](=[O:38])[NH:33][N:32]=5)=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:17][C:16]=2[O:15]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([N:33]1[N:32]=[C:31]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:21]([C:19](=[O:20])[C:18]2[CH:39]=[CH:40][C:41]4[O:42][CH2:14][O:15][C:16]=4[CH:17]=2)[CH2:22][CH2:23][CH2:24]3)[CH:36]([CH3:37])[S:35][C:34]1=[O:38])=[O:11]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CCCN2C(=O)c1ccc2c(c1)OCO2
Reactant: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1SC(=O)N(C(=O)C2CC3CCC2(C)C3(C)C)N=C1c1ccc2c(c1)CCCN2C(=O)c1ccc2c(c1)OCO2
Reaction time: 4 h

Procedure:
A solution of 26 g of (-)-camphanic acid chloride in 100 ml of methylene chloride is added dropwise at 0°, with stirring, to a suspension of 48 g of 5-[1- (3,4-methylenedioxybenzoyl)-1,2,3, 4-tetrahydroquinol-6- yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in 800 ml of methylene chloride to which 20 ml of triethylamine have been added, and the reaction mixture is stirred for 4 hours. It is then washed with dilute hydrochloric acid and subsequently with bicarbonate solution. The organic phase is separated off and worked up in conventional manner to give 3-[(-)-camphanoyl]-5-[1-(3,4-methylenedioxybenzoyl)-1,2,3, 4- tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4- thiadiazin-2-one as a mixture of diastereoisomers, m.p. 216°-217° .
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[O:15]=[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]([C:26]([Cl:28])=[O:27])[CH2:18][CH2:17]1.[OH-].[Na+]>>[ClH:28].[O:15]=[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]([C:26]([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[CH2:8][N:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)=[O:27])[CH2:18][CH2:17]1
Reactant: C1CCC(CN2CCCC2)NC1
Reactant: O=C1CCC(C(=O)Cl)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CCC(C(=O)N2CCCCC2CN2CCCC2)c2ccccc21
Yield: 76.7 %

Procedure:
From 3.48 g of 2-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride, 4.44 g of 1,2,3,4-tetrahydro-4-oxo-1-naphthoyl chloride and 63.9 ml of 1N aqueous sodium hydroxide solution. 4.17 g of the title compound was obtained, melting at 239°-242° C. (dec). using a procedure similar to that in Example 1.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:19]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:20]>>[CH2:22]([N:21]([CH2:19][CH3:20])[C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=1)=[O:16])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: CCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)c1cnoc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and N-ethylbenzylamine (8.1 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (10.7 mg). Calcd for C20H17F3N2O2: 374.1242, found 374.1243.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[F:18])=[CH:8][C:7]([CH2:19]O)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:23])=O>C(Cl)Cl>[Cl:23][CH2:19][C:7]1[CH:8]=[C:9]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[F:18])[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(F)c(-c2cc(CO)ccc2C2CC2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(F)c(-c2cc(CCl)ccc2C2CC2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
To a dry, round bottom flask containing 13.4 (0.24 g, 0.88 mmol) under an argon atmosphere was added dry DCM (5 mL). The resulting homogeneous solution was cooled to 0° C. After 15 minutes, thionyl chloride (0.20 mL, 2.74 mmol) was added dropwise at 0° C. Upon complete addition of thionyl chloride, the mixture was allowed to warm to room temperature and for 16 hours. After 19 hours, the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (SiO2 gel 60, eluted with 0 to 15% EtOAc in hexanes) to yield a colorless oil 13.5 (0.13 g, 49% yield.) 1H NMR (400 MHz, CDCl3) δ ppm 7.36 (2H, dd, J=8.2, 2.0 Hz), 7.13 (1H, m), 6.98 (1H, d, J=8.2 Hz), 6.93 (2H, m), 4.62 (2H, s), 3.84 (3H, s), 1.87 (1H, m), 0.91 (2H, m), 0.7 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][S:32](Cl)(=[O:34])=[O:33]>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)=[CH:6][CH:7]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: Nc1ccc(C2=NCC(=O)Nc3c2ccc2ccccc32)cc1
Product: O=C1CN=C(c2ccc(NS(=O)(=O)Cc3ccccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 40.8 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-e][1,4]diazepin-2(3H)-one (30 mg, 0.1 mmol) obtained in Example 64, (1), and (2-chlorophenyl)methanesulfonyl chloride (34 mg, 0.15 mmol), the title compound (20 mg, yield 27%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[C:10]2[N:16]=[C:17]([S:21][CH3:22])[N:18]=[C:19](Cl)[C:9]=2[C:8]1=[O:23].[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1OB(O)O>>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[C:10]2[N:16]=[C:17]([S:21][CH3:22])[N:18]=[C:19]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])[C:9]=2[C:8]1=[O:23]
Reactant: CSc1nc(Cl)c2c(n1)N(C)CCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Reactant: Cc1ccccc1OB(O)O
Product: CSc1nc(-c2ccccc2C)c2c(n1)N(C)CCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Yield: 100 %

Procedure:
In a similar manner to Reference Example 10, 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-10-methyl-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 9; 1.25 g) was reacted with 2-methylphenylboric acid (410 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (1.39 g, 100%).
Reaction SMILES: [OH:1][CH:2]=[C:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.[BH4-].[Na+]>CO>[OH:1][CH2:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: O=c1[nH]c2c3ccccc3c(=CO)c2n2ccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c2c(n3ccnc13)C(CO)c1ccccc1-2
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
To a suspension of 3 g of 10-hydroxymethylene-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one (mixture of the Z and E forms) in 240 ml of methanol is added 1 g of sodium borohydride portionwise over 10 minutes with stirring, and the stirring is continued at a temperature in the region of 20° C. for 1 hour 30 minutes. A further 1 g of sodium borohydride is added portionwise and the stirring is continued for 30 minutes. The reaction mixture is then filtered and the filter is rinsed with twice 30 ml of methanol. The insoluble material is taken up with 50 ml of water and 4 ml of 1N hydrochloric acid, filtered again, washed with water until neutral and air-dried. The crude product (1 g) is purified by dissolution while hot in 65 ml of dimethylformamide, filtration, addition to the still hot filtrate of 80 ml of methanol and crystallization in an ice-water bath. The crystals obtained are filtered off, washed with twice 15 ml of methanol and dried at 80° C. 0.66 g of 10-hydroxymethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, in the form of a white solid melting above 260° C. (Analysis % calculated C: 66.40, H: 4.38, N: 16.59, O: 12.63, % found C: 66.4, H: 4.3, N: 16.6, O: 12.1).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[C:13]2I)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C([Mg]Cl)(C)C.[CH2:27]([Sn:31]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:33][CH2:34][CH2:35][CH3:36])Cl)[CH2:28][CH2:29][CH3:30]>C1COCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:19])([CH3:18])[C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[C:13]2[Sn:31]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:27][CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc2c(I)n[nH]c12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2c(C(C)(C)O[SiH2]C(C)(C)C)cccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a round-bottomed flask, 7-(tert-butyl-dimethyl-silanyloxymethyl)-3-iodo-1H-indazole (200 mg, 0.52 mmol) was dissolved in THF (2.8 ml) and sodium hydride (60% in mineral oil, 25 mg, 0.63 mmol) was added. The reaction mixture was stirred at room temperature for 10 min then cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.36 ml, 0.72 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 30 min then tributylchlorostannane (0.16 ml, 0.59 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 2.5 h then quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 7-(tert-butyl-dimethyl-silanyloxymethyl)-3-tributylstannanyl-1H-indazole as a yellow oil which was used without further purification.
Reaction SMILES: Cl.[CH3:2][N:3]1C[CH2:6][CH:5]([O:8][C:9]2[C:14]([C:15]([O-:17])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:4]1.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]([Cl:42])(Cl)(Cl)[Cl:39]>C(Cl)(Cl)Cl.C(O)C>[ClH:39].[Cl:42][CH2:38][CH2:6][CH:5]1[CH2:4][N:3]([CH3:2])[C:15](=[O:17])[C:14]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=2[O:8]1
Reactant: CN1CCC(Oc2ncccc2C(=O)[O-])C1
Reactant: ClC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CN1CC(CCCl)Oc2ncccc2C1=O

Procedure:
Hydrogen chloride gas was bubbled into a suspension of 150 g (0.61 mole) of sodium 2-[(1-methyl-3-pyrrolidinyl)oxy]-3-pyridinecarboxylate in 1 liter of chloroform until a pH of 6 was reached. To the stirred mixture was added 350 g (1.34 mole) of triphenylphosphine and 350 g (2.3 mole) of carbon tetrachloride and the resulting cloudy solution was stirred at reflux for 1.5 hr. About 100 ml of ethanol was added and the heat removed. The solution was stirred for 1 hour while cooling and 200 ml of isooctane was added. The solution was extracted 4 times with a total of 800 ml of dilute hydrochloric acid. The acid extracts were combined, made basic with sodium hydroxide and extracted with chloroform. The chloroform layer was separated and dried over sodium sulfate and concentrated. The residue was dissolved in a mixture of 500 ml each of isopropyl alcohol and isopropyl ether and acidified with ethereal hydrogen chloride. The resulting crystals weighed 82 g (49%). A portion was recrystallized from isopropyl alcohol, m.p. 149°-153° C.
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)=[O:18])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:40]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1CCN(CCCC(C2C=CC(C(C)(C)C(OCC)=O)=CC=2)=O)CC1>>[ClH:1].[OH:40][C:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH:17]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([CH3:31])([CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=2)[OH:18])[CH2:13][CH2:14]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Product: CCOC(=O)C(C)(C)c1ccc(C(O)CCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
When in the procedure of Example 2 an appropriate amount of ethyl 4-[3-[4-(diphenylmethylene)-1-piperidinyl]-1-oxopropyl]-α,α-dimethylbenzene acetate hydrochloride is substituted for ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride, ethyl 4-[3-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxypropyl]-α,α- dimethylbenzeneacetate hydrochloride is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@@H]3CCCC[C@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@@H]1CCCC[C@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 87.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 122c by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (23.3 g, 37.8 mmol) prepared in Example 142b, triethylsilane (28.3 mL, 177 mmol), trifluoroacetic acid (50 mL) and dichloromethane (500 mL), to yield the title compound (15.4 g, 88%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=O)=[CH:11][CH:10]=1)[CH3:8].O=S(Cl)Cl.[OH-].[Na+]>C(Cl)Cl>[CH2:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13]2[O:4][CH2:3][C:2]([CH3:6])([CH3:5])[N:1]=2)=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(N)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCc1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a 3-neck, 2 L round bottom flask was added 173.71 g (1.0 mol, 97%) of 2-amino-2-methyl-1-propanol in 300 mL of dry methylene chloride. The flask was equipped with a magnetic stir bar and thermometer and was placed into a dry ice/acetone bath and cooled to 0° C. From a separatory funnel, a solution of 4-ethylbenzoyl chloride (168.5 g, 1.0 mol), dissolved in about 300 mL of methylene chloride was slowly added, while maintaining the reaction temperature below 5° C. The mixture was allowed to stir at room temperature overnight. Solid propanol amine-HCl was filtered off and the filter cake was washed with methylene chloride. The combined methylene chloride extracts were concentrated partially on a rotary evaporator and used directly in the next step. The intermediate amide solution generated in the first step was cooled in an ice bath and DMF (0.5 mL) was added. 125 g (1.04 mol) of SOCl2 in 50 mL of methylene chloride from a separatory funnel was added drop-wise at a controlled rate, keeping the reaction temperature at 0-5° C. The reaction was stirred at room temperature for an additional 2-3 hours. The reaction mixture was cooled in an ice bath and 25% NaOH was added to make the aqueous layer basic (pH=11-12). The mixture was transferred to a large separatory funnel, the methylene chloride layer was separated, and the aqueous layer was extracted twice with chloroform. The combined organic phases were dried an evaporated to yield 201 g of 2-(4-ethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole as a yellow viscous oil. 1H NMR(CDCl3, 300 MHz), δ (ppm): 7.8 (d, 2H), 7.2 (d, 2H), 4.088 (s, 2H), 2.68 (q, 2H), 1.375 (s, 6H), 1.24 (t, 3H).