Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][C:4]([CH:9]([CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[C:10](=O)[CH2:11][CH2:12][C:13]([C:15]2[S:16][C:17]([CH2:20][O:21]C3CCCCO3)=[CH:18][N:19]=2)=O)=[N:3]1.C([O-])(=O)C.[NH4+:40].[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][C:4]([CH:9]([C:10]2[NH:40][C:13]([C:15]3[S:16][C:17]([CH2:20][OH:21])=[CH:18][N:19]=3)=[CH:12][CH:11]=2)[CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:3]1
Reactant: CSc1cc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)nn1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CSc1cc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)nn1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A mixture of 5-[1-methyl-5-(methylsulfanyl)-1H-pyrazol-3-yl]-6-(tetrahydro-2H-pyran-4-yl)-1-{5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-2-yl}hexane-1,4-dione (0.65 g), ammonium acetate (0.46 g) and acetic acid (6 mL) was stirred at 100° C. for 1 hr. The reaction mixture was neutralized with 8N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.40 g, yield 80%) as a yellow amorphous solid from the fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). MS: 419 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:10]=1[CH2:11][N:12]1[C:16]([CH3:17])=[CH:15][C:14]([CH:18]=O)=[N:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]([CH:29]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:28]>C1COCC1.CCOC(C)=O>[CH3:25][O:26][C:27](=[O:28])/[CH:29]=[CH:18]/[C:14]1[CH:15]=[C:16]([CH3:17])[N:12]([CH2:11][C:10]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C=O)nn1Cc1cc(Cl)ccc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cc(C)n(Cc2cc(Cl)ccc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 70 h
Yield: 99 %

Procedure:
To a stirred solution of aldehyde 13, (1 g, 2.9 mmol) in THF was added (methoxycarbonylmethylene)triphenylphosphorane, 2 g (6 mmol). The mixture was stirred at room temperature for 70 hours. The mixture was diluted with EtOAc and the organic phase was washed with 2M HCl, saturated NaHCO3 and brine, dried over MgSO4 and evaporated in vacuo. The crude unsaturated ester 14 was purified on silica to yield 1.2 g as a white solid (99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:20])[CH3:21])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[C:8]([NH2:38])=[N:9][C:10]=2[CH:11]=1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCOC(C)C
Temperature: 5 °C
Reaction time: 1 h

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline (20 g) was dissolved in chloroform (400 mL). 3-Chloroperoxybenzoic acid (60% pure, 17.1 g) was added in 2 g portions over a 5 minute period and the reaction was stirred for 1 hour. Ammonium hydroxide (300 mL) was added and the mixture was cooled to 5° C. with an ice/water bath. p-Toluenesulfonyl chloride (9.4 g) was added at the rate of 1 g/min to minimize gas evolution. After stirring for 16 hours, the layers were separated and the aqueous fraction was extracted with chloroform. The combined organic fractions were sequentially washed with 5% aqueous sodium bicarbonate, water and brine; dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel. The polar component of the eluent was chloroform:methanol:ammonium hydroxide 80:18:2 (CMA). The purification was carried out eluting with chloroform:CMA in a gradient from 98:2 to 88:12. The material recovered from the column was recrystallized from acetonitrile to yield 7.0 g of 7-bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tan granular powder.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.[C:25]([CH2:27]P(=O)(OCC)OCC)#[N:26]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH:27][C:25]#[N:26])=[CH:19][CH:18]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCCOc1ccc(C=O)cc1
Product: Cc1oc(-c2ccccc2)nc1CCCOc1ccc(C=CC#N)cc1

Procedure:
According to the method described for Reference Example 35, 4-[3-(5-methyl-2-phenyl-4-oxazolyl)propoxy]benzaldehyde was allowed to react with diethyl cyanomethylphosphonate to give 4-[3-(5-methyl-2-phenyl-4-oxazolyl)propoxy]cinnamonitrile. Recrystallization from ethyl acetate--isopropyl ether--hexane gave colorless prisms, m.p.97°-98° C.
Reaction SMILES: [BH4-].[Na+].[Si:3]([N:10]1[C@@H:13]([S:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([CH:34]=[O:35])[C:11]1=[O:36])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>O1CCCC1.C(OCC)(=O)C>[Si:3]([N:10]1[C@@H:13]([S:14][C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:12]([CH2:34][OH:35])[C:11]1=[O:36])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](C=O)[C@@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CO)[C@@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To a cold (ice bath) suspension of NaBH4 (227 mg, 6 mmol) in tetrahydrofuran (20 ml) was added dropwise a solution of trans 1-(t-butyldimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone (2.0 g, 4.1 mmol) in tetrahydrofuran (5 ml). The reaction mixture was stirred at room temperature for 30 min, then diluted with ethyl acetate and washed successively with cold 1N HCl and brine. The organic layer was dried (MgSO4) and evaporated in vacuo to give the title compound (2.0 g) (quantitative) as an amorphous solid. It was used in the next step without further purification. ir νmax (CDCl3): 1740 cm-1. 1Hmr (CDCl3)δ: 7.25 (15H, m), 4.30 (1H, d, J=2, H-4), 3.28 (1H, dd, J=11, J=3, H-1'), 3.0 (1H, m, H-3), 2.55 (1H, dd, J=11, J=3, H-1'), 2.2 (1H, m, O--H), 0.9 (9H, s, t-Bu and 0.22 ppm (6H, s, CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14].[Cl:16][S:17](O)(=[O:19])=[O:18]>>[C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[C:10]([S:17]([Cl:16])(=[O:19])=[O:18])[CH:9]=2)[C:5]([CH3:15])([CH3:14])[CH2:6]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1CC(C)(C)c2cc(F)ccc21
Reactant: O=S(=O)(O)Cl
Product: CC(=O)N1CC(C)(C)c2cc(F)c(S(=O)(=O)Cl)cc21

Procedure:
1-(5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (1.1 g, 6.0 mmol) was treated with chlorosulfonic acid (10 mL) following similar methods to those described in Preparation 63) to give the desired compound (900 mg) as a grey solid. 1H NMR (Acetone-d6): 8.76 (1H, d), 7.54 (1H, d), 4.10 (2H, s), 2.32-2.23 (3H, m), 1.48 (6H, s).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13]O)=[CH:12][C:7]=2[N:6]=[C:5]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:2][CH3:3].[Cl:21]CCl.CS(Cl)(=O)=O>C(N(CC)CC)C>[Cl:21][CH2:13][C:11]1[CH:10]=[CH:9][C:8]2[N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:6][C:7]=2[CH:12]=1
Reactant: CCCn1c(-c2cccnc2)nc2cc(CO)ccc21
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCCn1c(-c2cccnc2)nc2cc(CCl)ccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 66 %

Procedure:
(b-1) To a stirred solution of 4.01 parts of 1-propyl-2-(3-pyridinyl)-1H-benzimidazole-5-methanol in 65 parts of dichloromethane and 3 parts of N,N-diethylethanamine were added 2.23 parts of methanesulfonyl chloride. The whole was stirred for 45 minutes at room temperature. The mixture was poured into crushed ice and the dichloromethane layer was separated, dried, filtered and evaporated. The residue was dissolved in methylbenzene. The precipitate was filtered off and the filtrate was evaporated, yielding 2.3 parts (66%) of 5-(chloromethyl)-1-propyl-2-(3-pyridinyl)-1H-benzimidazole as a residue (int. 16).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([C:18](O)=[O:19])=[CH:15][CH:16]=3)[O:11][C:10](=[O:21])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[BH4-].[Na+].O.[Cl-].[NH4+]>C1COCC1>[OH:19][CH2:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:9][C:10](=[O:21])[O:11]2)=[CH:16][CH:15]=1
Reactant: Cc1cccc(-c2cc(=O)oc3cc(C(=O)O)ccc23)c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2cc(=O)oc3cc(CO)ccc23)c1

Procedure:
To a solution of 4-(3-methylphenyl)-2-oxo-2H-chromene-7-carboxylic acid (520 mg, 1.86 mmol) and triethylamine (1.0 mL, 7.4 mmol) in THF (15 mL), cooled at 0° C., isobutylchloroformate (726 uL, 5.6 mmol) was added dropwise. After 1 hour stirring at 0° C. a solution of sodium borohydride in water (353 mg, 9.3 mmol in 6 mL) was added slowly and the mixture was stirred for another hour. The reaction mixture was poured into a saturated ammonium chloride solution and the product was extracted (3×) with ethyl acetate, the combined organic extracts were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was purified by column chromatography (ethyl acetate/hexanes, 50:50) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.51-7.39 (m, 5H), 7.37 (d, 1H), 7.32 (d, 1H), 6.29 (s, 1H), 4.79 (d, 2H), 4.57 (t, 1H), 2.46 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[S:14][CH2:13][CH:12]([OH:15])[CH2:11][C@@H:10]1[N+:16]([O-])=O.Cl.[OH-].[Na+].[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>CCO.CCOCC.[Zn]>[C:26]([O:25][C:23](=[O:22])[NH:16][C@H:10]1[CH2:11][CH:12]([OH:15])[CH2:13][S:14][C@@H:9]1[C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=[N+]([O-])[C@H]1CC(O)CS[C@@H]1c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC(O)CS[C@@H]1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5S,6R)-6-(2,5-Difluorophenyl)-5-nitrotetrahydro-2H-thiopyran-3-ol 5 (1.75 g, 6.36 mmol) and Zn dust (3.5 g, 53.5 mmol) were suspended in EtOH (50 mL) and cooled in an ice bath. 6N HCl (19.4 mL, 116.4 mmol) was added dropwise over 13 min to give a suspension. After 120 min, 5N NaOH (22.6 mL, 113 mmol) was added to give a heavy suspension. A solution of BOC2O (2.03 mL, 8.84 mmol) in Et2O (42 mL) was then added and the suspension was stirred rapidly in the ice bath. After 120 min, additional BOC2O (200 μL, 0.87 mmol) was added and the solution was slowly warmed to room temperature and stirred for an additional 18 h. The organic phase was decanted and the precipitated solids were extracted with 20% EtOH/EtOAc (4×50 mL), the organic phase was combined and evaporated to give an orange oil. The oil was suspended in 1:1 EtOAc/hexanes and loaded onto a 2.75×30 cm silica gel column eluting with 1:1 EtOAc/hexanes and collecting 8 mL fractions. Fractions containing the product were combined and evaporated to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.CC(C)(OC([N:14]([CH:22]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([CH:38]2[O:42][N:41]=[C:40]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)[CH2:39]2)=[O:37])=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C(=O)OC(C)(C)C)=O)C>C(Cl)Cl>[NH2:14][CH:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:36]([CH:38]2[O:42][N:41]=[C:40]([C:43]3[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=3)[CH2:39]2)=[O:37])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
) Trifluoroacetic acid (50 ml) was added dropwise to a solution of compound (125) (0.037 mol) in CH2Cl2 (500 ml), stirred at RT. The reaction mixture was stirred overnight at RT. The solvent was evaporated under reduced pressure. Toluene was added and azeotroped on the rotary evaporator (2×). The residue (crude oil) was dissolved in CH2Cl2. The organic solution was washed with 1 N NaOH (2×), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was crystallized from EtOAc, filtered off, washed with EtOAc, then dried, yielding 7.4 g (54%) of (±)-N-[4-(aminophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide. (compound 126)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22]O)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCOC.[CH2:30]([Al](CC(C)C)CC(C)C)[CH:31](C)[CH3:32].[OH-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH:31]([CH3:32])[CH3:30])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)nc3N21
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(C)Cc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
To a solution of 2.0 g (5.43 mmol) (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) in 50 ml 1,2-dimethoxyethane 0.75 g (0.65 mmol) tetrakis(triphenylphosphine)palladium was added. After 20 min, 16.3 ml (16.3 mmol) triisobutylaluminium (1M solution in n-hexane) was added and the reaction mixture was heated under reflux for 66 h. After cooling to room temperature another 8.1 ml (8.1 mmol) triisobutylaluminium (1M solution in n-hexane) was added and the reaction again heated under reflux. After 5 h the reaction was poured onto 1M aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:3) as eluant to afford the desired compound as a light brown oil (76.2%).
Reaction SMILES: [F-].[K+].FC([P:10](=[O:25])([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(F)C(F)(F)F.[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[P:10]([O:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:18]([C:19]([F:22])([F:21])[F:20])([F:23])[F:24])([C:11]([C:12]([F:13])([F:15])[F:14])([F:17])[F:16])=[O:25]
Reactant: O=P(C(F)(F)C(F)(F)F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: Oc1ccccc1
Agent: [F-]
Agent: [K+]
Product: O=P(Oc1ccccc1)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
Potassium fluoride (0.122 g; 2.1 mmol) is suspended in cooled (0° C.) tris(pentafluoroethyl)phosphine oxide (7.378 g; 18.3 mmol) in a 100 ml glass flask, and phenol (1.797 g; 19.1 mmol) is added. The reaction suspension is warmed and stirred at 80° C. for 4.5 h. A pale-brown reaction suspension is then observed. After recondensation in vacuo (10−3 mbar) at 40° C., phenyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OC6H5, is isolated as clear and colourless liquid (3.127 g; 8.3 mmol) in a yield of 45% and a purity of 90%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.ClC1C=CC=C(C(OO)=[O:24])C=1>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][N+:10]1([O-:24])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: COCCOCOCCN1CCOCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCCOCOCC[N+]1([O-])CCOCC1
Reaction time: 1 h

Procedure:
16.1 g of N-2-((2-methoxyethoxy)methoxy)ethylmorpholine was dissolved in 85 g of dichloromethane, which was ice cooled. To the solution, 24.9 g of 65% pure m-chloroperbenzoic acid in 250 g of dichloromethane was added dropwise at such a rate that the mixture might not exceed 5° C. The mixture was allowed to mature for one hour at room temperature. The reaction solution was concentrated below 30° C., and the residue was purified by column chromatography (basic alumina, elute: dichloromethane/methanol). The eluate was concentrated whereupon the desired compound solidified. The amount was 15.5 g.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20]Cl)[CH:14]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH:14]=1
Reactant: c1nc[nH]n1
Reactant: ClC[C@@H]1CCCN1c1cncc(Br)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Brc1cncc(N2CCC[C@H]2Cn2cncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of NaH (0.011 g, 0.272 mmol) in DMF (1 mL) was added 1H-1,2,4-triazole (0.016 g, 0.236 mmol) and the reaction mixture was stirred at room temperature for 30 min. Then, 3-bromo-5-((S)-2-chloromethyl-pyrrolidin-1-yl)-pyridine (0.05 g, 0.181 mmol) in DMF (0.5 mL) was added to the reaction mixture which was heated to 80° C. over night. The mixture was diluted with DCM, poured into aq. NaHCO3 (5 mL) and the aqueous layer was extracted with DCM (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness to give the title compound (0.04 g, 72%) as a yellow oil. MS: 308.0, 310.0 (M+H+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]([N:19]1[C:27]2[CH2:26][CH2:25][CH2:24][C:23](=[O:28])[C:22]=2[CH:21]=[N:20]1)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][CH:24]1[CH2:25][CH2:26][C:27]2[N:19]([S:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=3)(=[O:11])=[O:10])[N:20]=[CH:21][C:22]=2[C:23]1=[O:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c2CCCC3=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ncc3c2CCC(Br)C3=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
According to Scheme 3 Step 3: N-Bromosuccinimide (3.44 mmol, 613 mg) was added to a solution of 1-tosyl-6,7-dihydro-1H-indazol-4(5H)-one (3.44 mmol, 1.00 g) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 12 hours. A solution of NaHCO3 was added to the reaction mixture and the aqueous phase was extracted with DCM. The organic phase was dried over Na2SO4 and concentrated to yield 5-bromo-1-tosyl-6,7-dihydro-1H-indazol-4(5H)-one (2.44 mmol, 900 mg, 42%) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([CH2:17][C:18](=O)[CH3:19])[C:14]([CH3:16])=O.O>C1(C)C=CC=CC=1>[CH3:9][N:8]([CH3:10])[C:6]([C:5]1[CH:11]=[CH:12][C:2]([N:1]2[C:18]([CH3:19])=[CH:17][CH:13]=[C:14]2[CH3:16])=[CH:3][CH:4]=1)=[O:7]
Reactant: CC(=O)CCC(C)=O
Reactant: CN(C)C(=O)c1ccc(N)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(C(=O)N(C)C)cc1

Procedure:
A solution of 26.4 g of 4-amino-N,N-dimethylbenzamide in 500 ml toluene and 60 g acetonylacetone is refluxed for 16 hours under a Dean-Stark water separator. The solution is washed with water and brine, dried over MgSO4, filtered and the solvent evaporated at 60° and reduced pressure. The residue is crystallized from ether-hexane 1:1 to yield 1-(4-dimethylcarbamoylphenyl)-2,5-dimethyl-1H-pyrrole, m.p. 102°-104°.
Reaction SMILES: [CH2:1]([P:5](Cl)([CH:7]([CH2:9][CH3:10])[CH3:8])=[O:6])[CH:2]([CH3:4])[CH3:3].[CH2:12]([Mg]Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:1]([P:5](=[O:6])([CH:7]([CH2:9][CH3:10])[CH3:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:2]([CH3:4])[CH3:3]
Reactant: CCC(C)P(=O)(Cl)CC(C)C
Reactant: CCCCCCC[Mg]Br
Product: CCCCCCCP(=O)(CC(C)C)C(C)CC

Procedure:
Iso-butyl sec-butyl phosphinyl chloride prepared as in Part A and n-heptyl magnesium bromide were allowed to react together as in Preparative Example A to give iso-butyl sec-butyl n-heptyl phosphine oxide bp. 123°-5°/0.004 mm.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:57][CH3:58])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]([CH2:54][CH3:55])([O:49][Si](C)(C)C)[CH2:47][CH3:48])=[C:40]([CH3:56])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:59])[CH:28]=1>O1CCCC1.C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:60])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]([CH2:54][CH3:55])([OH:49])[CH2:47][CH3:48])=[C:40]([CH3:56])[CH:39]=3)[CH2:57][CH3:58])=[CH:31][C:30]=2[CH3:59])[CH:28]=1
Reactant: CCC(C#Cc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)c(C)c2)cc1C)(CC)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.316 mL, 0.316 mmol) was added to a solution of [5-(4-{1-ethyl-1-[4-(3-ethyl-3-trimethylsilanyloxy-1-pentynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 151-(1); 36.9 mg, 0.063 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 30 minutes. Then, the reaction mixture was diluted with ethyl acetate and was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (16.7 mg, 52%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1.C(C1C=C2C(=CC=1)NC=C2)#N.ClCCCC(Cl)=[O:33].[Cl-].[Al+3].[Cl-].[Cl-]>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1)=[O:33]
Reactant: N#Cc1ccc2[nH]cc(CCCCO)c2c1
Reactant: O=C(Cl)CCCCl
Agent: N#Cc1ccc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Product: N#Cc1ccc2[nH]cc(C(=O)CCCO)c2c1

Procedure:
The present inventors have further surprisingly and unexpectedly found that 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile intermediate can be prepared, in high purity and with high yield, by reacting 5-cyanoindole with 4-chlorobutyryl chloride in the presence of aluminium chloride to produce an intermediate compound, followed by reacting the compound with an aqueous alcohol to produce 3-(4-hydroxybutyryl)-1H-indole-5-carbonitrile, which is then reduced with sodium cyanoborohydride in the presence of hydrochloric acid and water in acetonitrile solvent to produce 3-(4-hydroxybutyl)-1H-indole-5-carbonitrile.