Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH2:3][CH2:4][CH3:5].C1CCC(NC2CCCCC2)CC1.[NH2:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33].Cl.C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)(Cl)Cl>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OC
Reaction time: 8 h
Yield: 75 %

Procedure:
BOC-Nva-OH, liberated from 8.0 g (20 mmoles) of the DCHA salt as described in Step 1 of Example 4, and 3.82 g (21 mmoles) of H-Leu-OMe.HCl are dissolved in 60 ml of chloroform, and 2.94 ml (21 mmoles) of triethylamine are added. The solution is cooled with ice, and a solution of 4.33 g (21 mmoles) of DCC in 40 ml of chloroform is added with stirring. The reaction mixture is allowed to stand at 5° C. overnight, the separated DCU is removed by filtration, the filtrate is washed thrice with 30 ml of n hydrochloric acid, each, thrice with 30 ml of n sodium hydrocarbonate solution, each, and finally with 30 ml of water, dried over anhydrous sodium sulfate, and then evaporated. The crystalline residue is triturated with n-hexane, filtered off, and the resulting 6.65 g of crude product is recrystallized from a mixture of 5 ml of ethyl acetate and 20 ml of petroleum ether. 5.20 g (75%) of BOC-Nva-Leu-OMe are obtained; m.p.: 100°-101° C., Rf2 =0.84, [α]D25 =-47.5° (c=1%, in methanol).
Reaction SMILES: [CH3:1][S:2]SC.C(P(CCCC)CCCC)CCC.[F:18][C:19]([F:53])([F:52])[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]2[O:29][CH:30]=[C:31]([CH2:33][O:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][N:45]4[CH:49]=[CH:48][N:47]=[C:46]4[CH2:50]O)=[CH:37][CH:36]=3)[N:32]=2)=[CH:22][CH:21]=1.[OH-].[Na+]>ClCCl.N1C=CC=CC=1>[CH3:1][S:2][CH2:50][C:46]1[N:45]([CH2:44][CH2:43][CH2:42][CH2:41][C:38]2[CH:39]=[CH:40][C:35]([O:34][CH2:33][C:31]3[N:32]=[C:28](/[CH:27]=[CH:26]/[C:23]4[CH:24]=[CH:25][C:20]([C:19]([F:53])([F:52])[F:18])=[CH:21][CH:22]=4)[O:29][CH:30]=3)=[CH:36][CH:37]=2)[CH:49]=[CH:48][N:47]=1
Reactant: OCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Reactant: CSSC
Agent: CCCCP(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Pyridine (0.600 ml), dimethyl disulfide (0.217 ml) and tributylphosphine (0.600 ml) were added to a solution of [1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]methanol (400 mg) in dichloromethane (8 ml) at room temperature, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was combined with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to ethyl acetate), and recrystallized from ethyl acetate-diethyl ether-hexane to give the titled compound (213 mg) as a colorless crystal powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:30]([F:36])=[CH:31][CH:32]=[CH:33][C:34]=3[F:35])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCNCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-piperazinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.50 g, 0.734 mmol) in DCM (10 mL) was treated with methanesulfonyl chloride (0.074 mL, 0.954 mmol) and stirred at rt for 3 h. Silica was added and concentrated. The residue was column chromatographed with EtOAc/DCM to give title compound of Step C (0.38 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 8.32 (d, J=5.5 Hz, 1H), 7.64-7.74 (m, 1H), 7.42-7.50 (m, 1H), 7.39 (t, J=6.1 Hz, 1H), 7.29-7.35 (m, 1H), 7.25 (t, J=9.1 Hz, 2H), 6.49 (d, J=5.4 Hz, 1H), 3.63-3.76 (m, 4H), 3.27 (t, J=4.7 Hz, 4H), 2.93 (s, 3H). m/z (ES+): 646 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH:12]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13]1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([C:16]1[NH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=1)=[O:5]
Reactant: COC(=O)c1cc[nH]c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: COC(=O)c1c[nH]c(C(=O)c2ccc(Cl)cc2Cl)c1

Procedure:
By the procedure of Example 64, 2,4-dichlorobenzoyl chloride (4.18 g., 20 mmoles) and methyl pyrrole-3-carboxylate were reacted to form methyl 5-(2,4-dichlorobenzoyl)pyrrole-3-carboxylate (3.0 g., gummy solid, Rf 0.5 on silica gel thin layer chromatography with ethyl acetate-1/hexane-1 as eluant).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[C:19]([CH3:42])=[N:20][N:21](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:22]=4)[CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[ClH:43]>>[ClH:43].[ClH:43].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[C:19]([CH3:42])=[N:20][NH:21][CH:22]=4)[CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C)CC3)c2c1
Agent: Cl
Product: Cc1n[nH]cc1-c1ccc2nccc(N3CCN(C)CC3)c2c1

Procedure:
247 mg 4-(4-methylpiperazin-1-yl)-6-(3-methyl-1-trityl-1H-4-pyrazolyl)quinoline obtained in Example 168 and 3.4 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 163, to give 147 mg of the title compound as yellow crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+:20]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:14][CH2:15][C:16]([O-:18])=[O:17])[CH2:11][CH2:12][CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[Na+:20]
Reactant: CCCC(SCC(=O)O)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(SCC(=O)[O-])c1ccc2c(c1)OCO2

Procedure:
100 g of [{1-(1,3-benzodioxol-5-yl)butyl}thio]acetic acid was dissolved in 500 ml of ethanol. 372 ml of 1N-aqueous sodium hydroxide solution was added thereto. Ethanol and water were removed from the reaction mixture by azeotropic distillation and then ether was added to the residue to solidify it. A precipitate thus formed was recovered by filtration and dried to obtain 102 g of the intended compound in the form of a white powder.
Reaction SMILES: C(O[C:4](=[O:20])[C:5](=[N:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[O:18][CH3:19])[C:6](=O)[CH3:7])C.Cl.[CH3:22][C:23]1[CH:24]=[C:25]([NH:30][NH2:31])[CH:26]=[CH:27][C:28]=1[CH3:29].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[C:4](=[O:20])[C:5](=[N:9][NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=3[O:18][CH3:19])[C:6]([CH3:7])=[N:31]2)[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: CCOC(=O)C(=NNc1cccc(Br)c1OC)C(C)=O
Reactant: Cc1ccc(NN)cc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(Br)cccc1NN=C1C(=O)N(c2ccc(C)c(C)c2)N=C1C

Procedure:
A solution of ethyl-2-[(3-bromo-2-methoxyphenyl)hydrazono]-3-oxobutanoate (5 g) prepared as in Example 1, and 3,4-dimethylphenylhydrazine hydrochloride (2.48 g) and sodium acetate (1.4 g) in glacial acetic acid (100 mL) was stirred and heated to reflux for about 3 hours. The mixture was cooled to about room temperature and stirred for about 1 hour. It was filtered, washed with water (25 mL) and dried in an oven at about 55° C. to about 60° C. for about 12 hours to obtain an orange solid product. Yield: 4.15 g; Melting point: 197.4-198.2° C.; Purity (HPLC): 99.33%
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([N+:27]([O-])=O)[CH:21]=2)[CH2:11][CH2:10]1.[Cl-].[NH4+]>CCO.O.[Fe]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH:21]=2)[NH2:27])[CH2:13][CH2:14]1
Reactant: Cc1ccc(OCCCCN2CCN(c3cccc(Cl)c3Cl)CC2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(OCCCCN2CCN(c3cccc(Cl)c3Cl)CC2)cc1N
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A mixture of intermediate 62 (180 mg, 0.41 mmol), Fe (70 mg, 1.23 mmol) and ammonium chloride (25 mg, 0.41 mmol) was dissolved in EtOH and H2O, and the solution was heated to reflux and stirred overnight. The solution was filtered, diluted with water, and then extracted with DCM. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-methylaniline (intermediate 63) (150 mg, 90%) as a yellow solid. HPLC: 99%, RT 3.197 min. MS (ESI) m/z 407.9 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:9]([C:11]3[CH2:12][CH2:13][N:14]([C:17]([O-:19])=[O:18])[CH2:15][CH:16]=3)=[CH:10][C:3]=12.[CH2:29]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[C:33]([C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=2)=[N:32]1)[CH3:30]>>[CH2:29]([N:31]1[CH:35]=[C:34]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)(=[O:22])=[O:21])[C:9]([C:11]4[CH2:12][CH2:13][N:14]([C:17]([O:19][C:3]([CH3:10])([CH3:4])[CH3:2])=[O:18])[CH2:15][CH:16]=4)=[CH:10][C:3]=23)[C:33]([C:45]2[CH:46]=[CH:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=2)=[N:32]1)[CH3:30]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: O=C([O-])N1CC=C(c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)CC1
Product: CCn1cc(-c2ccnc3c2cc(C2=CCN(C(=O)OC(C)(C)C)CC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 11 with 4-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydro-1(2H)-pyridinecarboxylate and 1-ethyl-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave the title compound. ESMS [M+H]+: 655.4
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[ClH:22].O1CCOCC1>ClCCl>[ClH:22].[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]2=[O:21])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2)C(=O)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1CNCCN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To the solution of tert-butyl 4-(4-fluorophenyl)-3-oxopiperazine-1-carboxylate (2 g, 6.80 mmol) in dichloromethane (5 ml) was added slowly hydrogenchloride in 1,4-dioxane (16.99 ml, 68.0 mmol) at 0° C. and reaction was stirred for 3 h at 25° C. After completion of the reaction, the solvent was evaporated under reduced pressure to obtained salt was triturated with diethyl ether (2×10 ml) decanted it and dried to give 1-(4-fluorophenyl)piperazin-2-one hydrochloride (1.2 g, 5.20 mmol, 77%)
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:23][CH2:24]COS(C2C=CC=CC=2)(=O)=O)[CH:12]([F:13])[C:11](=[O:14])[N:10]([C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][Si](C)(C)[N-][Si](C)(C)C.[K+].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]12[CH2:23][CH2:24][CH2:36][C@:12]1([F:13])[C:11](=[O:14])[N:10]([C@@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH2:9]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCCOS(=O)(=O)c2ccccc2)(C(=O)OC(C)(C)C)C(F)C1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CCC[C@]2(F)C1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
(3S)-3-(3-benzenesulfonyloxy-1-propyl)-4-Fluoro-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (10.9 g) was dissolved in tetrahydrofuran (350 mL), and the atmosphere was replaced with argon. Then, potassium hexamethyldisilazide (0.5 M solution in toluene) (86.5 mL) was added dropwise at −15° C., and the mixture was stirred at 0° C. for 1.5 hours. After cooling to −10° C., saturated aqueous ammonium chloride (100 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with a 10% citric acid solution and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. Thereafter, the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=9:1→7:1) to give 4.36 g of the title compound as a pale yellow solid.
Reaction SMILES: C([NH:14][CH:15]([P:20]([OH:22])[OH:21])[CH2:16][CH:17]([CH3:19])[CH3:18])(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][CH:15]([P:20]([OH:22])[OH:21])[CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CC(NC(c1ccccc1)c1ccccc1)P(O)O
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: CC(C)CC(N)P(O)O

Procedure:
The procedure described in Example 1C was repeated using DL-1-benzhydrylamino-3-methylbutanephosphonous acid as starting material instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-amino-3-methyl-butanephosphonous acid of melting point 222° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][NH:27][CH2:28][CH:29]3[CH2:33][CH2:32][C:31](=[O:34])[O:30]3)[N:9]=2)[CH:7]=1.C=O.[BH3-][C:42]#N.[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH2:26][N:27]([CH3:42])[CH2:28][CH:29]3[CH2:33][CH2:32][C:31](=[O:34])[O:30]3)[N:9]=2)[CH:7]=1
Reactant: O=C1CCC(CNCCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)O1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(CCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1)CC1CCC(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(5-oxooxolan-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (140 mg, 0.26 mmol) in MeOH (20 mL) was added 37% formaldehyde in water (23 mg), followed by NaBH3CN (24.6 mg, 0.39 mmol). The resulting solution was stirred at room temperature for 3 h. The resulting mixture was concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 8% MeOH in DCM. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 0.05% FA and MeCN (18.0% MeCN up to 36.0% in 8 min); Detector, 254/220. This resulted in 22.4 mg of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[methyl[(5-oxooxolan-2-yl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 28) [M+H]+=560.2, RT=0.94 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.38 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.60 (d, 1H, J=2.4 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.0, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 4.59-4.55 (m, 1H), 4.30-4.27 (m, 2H), 2.94-2.88 (m, 2H), 2.62 (d, 2H, J=5.6 Hz), 2.44-2.41 (m, 2H), 2.32 (s, 3H), 2.14-2.11 (m, 1H), 1.83-1.77 (m, 1H).
Reaction SMILES: [CH2:1]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]3[N:25]=[CH:24][C:23]([OH:26])=[CH:22][N:21]=3)[CH:17]=2)[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1(C)C=CC(S(O[CH2:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)(=O)=O)=CC=1.[OH-].[K+].O>C(O)C>[CH2:1]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]3[N:25]=[CH:24][C:23]([O:26][CH2:37][CH2:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:22][N:21]=3)[CH:17]=2)[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCC1Cc2ccc(-c3ncc(OCCCc4ccccc4)cn3)cc2C1
Yield: 56.3 %

Procedure:
0.443 g of 2-(2-decylindan-5-yl)pyrimidine-5-ol, 0.343 g of phenylpropyl p-toluenesulfonate and 0.1 g of potassium hydroxide were dissolved in 2 ml of ethanol, followed by heat-refluxing for 4 hours. After the reaction, the reaction mixture was poured into water and subjected to extraction with toluene. The resultant organic layer was washed with water and dried with anhydrous sodium sulfate, followed by distilling-off of the solvent and purification by silica gel column chromatography to obtain 0.313 g of an objective product (Yield: 53.2%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(CN)CCCCC1.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:43](=[O:44])[C:42]1[CH:46]=[CH:47][C:39]([CH2:38][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3([CH2:30][O:29][C:28]4[CH:31]=[C:32]5[C:36](=[CH:37][C:27]3=4)[CH2:35][CH2:34][O:33]5)[C:18]2=[O:17])=[CH:40][CH:41]=1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: Nc1ccccc1F
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1ccccc1F)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2-fluoroaniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2-fluorophenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (75%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.42 (ddd, J=8.1, 8.1, 1.2 Hz, 1H), 8.16-7.99 (m, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.25-7.01 (m, 6H), 6.77 (d, J=7.7 Hz, 1H), 6.49 (s, 1H), 6.43 (s, 1H), 5.03 (ABq, 2H), 4.86 (ABq, 2H), 4.55 (t, J=8.6 Hz, 2H), 3.10-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 164.8, 161.8, 161.3, 152.7 (d, J=243.1 Hz), 141.7, 140.1, 134.0, 132.6, 128.7, 127.7 (2C), 126.3 (d, J=9.8 Hz, 2C), 124.7, 124.6 (d, J=3.9 Hz), 124.0, 123.6, 121.8, 119.9 (2C), 118.7, 114.8 (d, J=19.2 Hz, 2C), 109.0, 93.2, 80.6, 72.3, 57.7, 43.7, 29.0; MS (ES+) m/z 507.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[CH3:2].[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][S:36]([C:33]3[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=3)(=[O:37])=[O:38])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(O)cc2)cc1)OCC
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(=O)(=O)c3ccc([N+](=O)[O-])cc3)cc2)cc1)OCC

Procedure:
2-Ethoxy-3-{4-[2-(4-hydroxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 26b) was esterified with 4-nitrobenzenesulfonyl chloride using the same method as in Example 26 (c) to give 2-ethoxy-3-(4-{2-[4-(4-nitrobenzenesulfonyloxy)phenyl]-ethoxy}phenyl)propanoic acid ethyl ester.
Reaction SMILES: [CH2:1]([OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:24]([OH:32])(=[O:31])[C:25]([CH2:27][C:28]([OH:30])=O)=[CH2:26]>C1(C)C(C)=CC=CC=1>[C:24]([O:32][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:31])[C:25]([CH2:27][C:28]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:30])=[CH2:26]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Solvent: Cc1ccccc1C
Product: C=C(CC(=O)OCCCCCCCCCCCCCCCCCCCCCC)C(=O)OCCCCCCCCCCCCCCCCCCCCCC

Procedure:
In 800 g of xylene, 1641 g (2.2 moles) of dibehenyl itaconate of the formula, C22H45OCOCH2C(═CH2)COOC22H45, obtained by a reaction between behenyl alcohol and itaconic acid, and 875 g (1.0 mole) of the organopolysiloxane having mercapto groups at both terminals represented by the following formula were reacted in the presence of 1 g of triphenylphosphine as a catalyst at 130° C. for 5 hours. 2440 g, corresponding to a yield of 97%, of Silicone wax (H) was obtained by stripping the solvent.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].Cl[S:21]([C:24]1[CH:39]=[CH:38][C:27]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41])(=[O:23])=[O:22]>C(Cl)Cl.CCOC(C)=O>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:21]([C:24]2[CH:39]=[CH:38][C:27]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])=[CH:26][C:25]=2[O:40][CH3:41])(=[O:23])=[O:22])[C:3]1=[O:12]
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OCc2ccccc2)ccc1S(=O)(=O)N1C(=O)C(N)(c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 78.7 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 1 from 0.860 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 1 g of benzyl 4-chlorosulfonyl-3-methoxybenzoate. Chromatography on silica using a DCM/AcOEt mixture (99/1; v/v) as the eluent gives 1.38 g of the expected product, which is used as such in the next step.