Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[C:15]=2[O:14]1)=[N+:30]=[N-:31]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4C)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1ccccc1-c1cccc2c1OC(CN=[N+]=[N-])C2

Procedure:
Treatment of (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (7.79 g, 19.74 mmol) with sodium azide (5.13 g, 78.99 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.5 g, 10 wt. %) generally according to the procedure described for Example 1 provided 3.63 g (67%) of (±)-1-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >200° C.; Anal. calcd. for C16H17NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 69.83; H, 6.64; N, 5.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:26]=[CH:25][C:6](/[CH:7]=[C:8]2/[C:9]([CH3:24])=[C:10]([CH2:20][C:21](O)=[O:22])[C:11]3[C:16]/2=[CH:15][CH:14]=[C:13]([N:17]([CH3:19])[CH3:18])[CH:12]=3)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:30])=O>C1COCC1>[CH3:1][S:2][C:3]1[CH:26]=[CH:25][C:6](/[CH:7]=[C:8]2/[C:9]([CH3:24])=[C:10]([CH2:20][C:21]([Cl:30])=[O:22])[C:11]3[C:16]/2=[CH:15][CH:14]=[C:13]([N:17]([CH3:19])[CH3:18])[CH:12]=3)=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSc1ccc(/C=C2/C(C)=C(CC(=O)O)c3cc(N(C)C)ccc32)cc1
Solvent: C1CCOC1
Product: CSc1ccc(/C=C2/C(C)=C(CC(=O)Cl)c3cc(N(C)C)ccc32)cc1

Procedure:
(Z)-1-(p-methylthiobenzylidene)-5-dimethylamino-2-methyl-3-indenylacetic acid (70 mmol) in THF (500 ml) is allowed to react with oxalylchloride (2 M in CH2Cl2 ; 70 mmol) under reflux conditions (24 hours). The solvent is evaporated to yield the title compound, which is used as such in the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:26]([CH3:28])[CH3:27])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][C:10]=2[CH3:25])=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:24][C:12]1[CH:13]=[C:14]2[C:9](=[C:10]([CH3:25])[CH:11]=1)[N:8]=[C:7]([CH:26]([CH3:28])[CH3:27])[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: CCOC(=O)c1c(C(C)C)nc2c(C)cc(Cl)cc2c1Cc1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)cc2c(Cc3ccccc3Cl)c(C(=O)O)c(C(C)C)nc12

Procedure:
The title compound was prepared in analogy to example 6 step B from a mixture of 6-chloro-4-(2-chloro-benzyl)-2-isopropyl-8-methyl-quinoline-3-carboxylic acid ethyl ester (50 mg, 0.12 mmol) and 1N NaOH in ethanol. Off white solid (18 mg, 39%). LC-MS (ESI): 388 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.C[O:18][C:19](=[O:32])[C:20]1[CH:25]=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[C:22]([NH2:31])[CH:21]=1>>[CH:14]([N:5]1[C:4]2[N:3]=[C:2]([NH:31][C:22]3[CH:21]=[C:20]([CH:25]=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=3)[C:19]([OH:32])=[O:18])[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Reactant: COC(=O)c1cc(N)cc(NS(C)(=O)=O)c1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NS(C)(=O)=O)cc(C(=O)O)c3)nc21
Yield: 35 %

Procedure:
Starting from 2-chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (1.5 g; 6.25 mmol) and 3-amino-5-(methylsulfonyl)aminobenzoic acid methyl ester (3.49 g; 14.502 mmol), 950 mg (2.18 mmol; 35% yield) of the desired product were obtained as a powder.
Reaction SMILES: [C:1]([N:8]([CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[CH3:9])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[N:8]([CH:10]1[CH2:14][CH2:13][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:11]1)[CH3:9])([CH3:6])([CH3:7])[CH3:5]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCN1CCC(N(C)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 97.6 %

Procedure:
To a solution of 3-(N-BOC-N-methylamino)pyrrolidine (150 mg, 0.75 mmol) in DMF (1.5 mL) was added potassium iodide (25 mg, 0.15 mmol) and potassium carbonate (207 mg, 1.50 mmol) followed by 1-bromopentane (0.097 mL, 0.78 mmol). The mixture was stirred 7 h at room temperature. Most of the DMF was then removed under low pressure and the residue partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate and concentrated to give the title compound (198 mg, 98% yield) as an oil. MS m/e 271.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:21])([F:33])[F:34])[CH:25]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(OC(F)(F)F)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-(trifluoromethoxy)-phenylboronic acid (67 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[CH:7]3)[CH2:25][CH2:26]2)=[CH:17][CH:16]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: ClCCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2c(c1)ncn2CCCCN1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.6 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(4-pyridyl) piperazine (4.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.3 g compound (I-13) with a yield of 62.1%. ESI-MS [M+H]+: m/z 336.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[C:14]([C:15]([O:17]CC)=O)=[CH:13][C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:11]2)=[CH:4][CH:3]=1.[CH2:27]([NH2:30])[CH2:28][NH2:29]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[NH:30][CH2:27][CH2:28][N:29]2[C:15](=[O:17])[C:14]2[N:10]([N:11]=[C:12]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:13]=2)[CH2:9]3)=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: CCOC(=O)c1cc(-c2ccccn2)nn1CC(=O)c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: O=C1c2cc(-c3ccccn3)nn2CC2(c3ccc(Cl)cc3)NCCN12

Procedure:
Ethyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-3-(pyridin-2-yl)-1H-pyrazole-5-carboxylate (630 mg, 1.77 mmol) and ethane-1,2-diamine (1.77 mL, 26.6 mmol) was combined and stirred at reflux in 1,4-dioxane. After 48 hours (monitored by LCMS) the reaction mixture was concentrated in vacuo and the residue partitioned between CH2Cl2 (20 mL) and brine (10 mL). The organic layer was separated and the aqueous layer extracted with further CH2Cl2 (2×10 mL). The combined organic layers were dried (MgSO4), filtered and evaporated in vacuo to give a yellow residue that was purified by flash column chromatography (Biotage SP4, 40 g cartridge, gradient 2 to 15% methanol in CH2Cl2). To give 10a-(4-chlorophenyl)-7-(pyridin-2-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrazolo[1,5-d]pyrazin-5-one as an off white solid (150 mg, yield: 23%). ESI-MI m/z [M+H]+ 366.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=1[O:21]C(C)=C)[C:12]([O:14]C(C)=C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCN(CC1)CC2.Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=1[OH:21])[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)OC(=O)c1ccc(OC(=C)C)c(OCc2ccccc2)c1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(O)c(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A mixture of propen-2-yl 3-benzyloxy-4-(propen-2-yloxy)benzoate (1.0356 g, 3.19 mmol), tris(triphenyl-phosphine)rhodium chloride1 (204 mg, 0.22 mmol) and 1,4-diazabicyclo[2.2.2]octane (74 mg, 0.66 mmol) in ethanol (18 cm3) and water (2 cm3) was heated under reflux under an atmosphere of nitrogen for 16 h. The cooled mixture was poured into 1 M hydrochloric acid (100 cm3), stirred for 60 min, then extracted with dichloromethane (3×100 cm3). The combined extracts were dried over MgSO4 and evaporated to an orange solid which was purified by flash column chromatography (eluent: 1:1 EtOAc:light petroleum) to give 3-benzyloxy-4-hydroxybenzoic acid as an orange solid (650 mg, 83%), m.p. 167.2-171.3° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[CH:2][C:1]([C:4]1[CH:5]=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(Cl)nc1
Product: CN(C)C=CC(=O)c1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
A homogeneous mixture of 3-acetyl-6-chloropyridine (5 mL) (which can be prepared in a similar manner by the methods disclosed in Lee, C-H. et al., J. Med. Chem. (2001), Vol. 44, pp. 2133-2138) in N,N-dimethylformamide dimethylacetal (15 mL) was refluxed for 4 h. After cooling the reaction mixture to ambient temperature, it was diluted with hexanes (100 mL), sonicated for 30 seconds and the solid formed was isolated by filtration. The resulting solid was then washed with hexanes (3×25 mL), dried and analyzed to afford 3-(3-(dimethylamino)prop-2-en-1-onyl)-6-chloropyridine; LCMS: purity: 92%; MS (m/e): 212 (MH+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][CH2:40][S:41][C:42]5[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][CH2:40][S:41][C:42]5[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCSc4nccn4C)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCSc4nccn4C)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-[(1-methylimidazol-2-yl)sulfanyl]ethyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.20 g) was dissolved in methylene chloride (24.0 ml), and a solution of metachloroperbenzoic acid (0.52 g) in methylene chloride (24.0 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and to the mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was allowed to be warmed to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-[(1-methylimidazol-2-yl)sulfanyl]ethyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 310) (0.68 g).
Reaction SMILES: C(O[C:4]1[CH2:8][CH:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]=1)C.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[S:23]>C(O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][S:9][CH:7]2[CH2:6][NH:5][C:4](=[N:20][NH:21][C:22]([NH2:24])=[S:23])[CH2:8]2)=[CH:12][CH:13]=1
Reactant: CCOC1=NCC(SCc2ccc(OC)cc2)C1
Reactant: NNC(N)=S
Agent: Cl
Solvent: CCO
Product: COc1ccc(CSC2CNC(=NNC(N)=S)C2)cc1
Yield: 21.8 %

Procedure:
A solution of 2-ethoxy-4-p-methoxybenzylthio-1-pyrroline (900 mg) and thiosemicarbazide hydrochloride (433 mg) in ethanol (30 ml) was refluxed under heating for 1.5 hours. The reaction solution was evaporated to dryness under reduced pressure, then the residue was distributed between ethyl acetate and 5% aqueous solution of sodium hydroxide and the organic phase was dried over Na2SO4 before the solvent was distilled off under reduced pressure. The resultant residue was passed through a column packed with 25 g of silica gel and eluted with ethyl acetate and thus 230 mg of the objective compound was obtained as colorless foam.
Reaction SMILES: [C:1]([N:5]([CH2:10][C@H:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)[CH2:6][CH2:7][C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].CCOP(Cl)(OCC)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C1COCC1>[C:1]([N:5]1[CH2:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@@H:7]([C:8]#[N:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N(CCC#N)C[C@@H](O)c1ccc(Cl)cc1
Agent: CCOP(=O)(Cl)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)N1C[C@H](C#N)[C@H](c2ccc(Cl)cc2)C1
Reaction time: 0.5 h
Yield: 10.7 %

Procedure:
3-{t-Butyl[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-amino}propanenitrile (5 g, 17.80 mmol) prepared according to the process described in WO 2004/09126 was dissolved in THF (27 mL). The reaction mixture was cooled to −20° C. or less, to which was added chlorodiethylphosphate (2.69 ml, 18.70 mmol). The reaction temperature was maintained at 12˜18° C., during which 1M LHMDS (37.4 ml, 37.38 mmol) was added dropwise over 2 hours. After the reaction was completed, water (45 mL) was added while the temperature was maintained at 15° C. or less. The resulting mixture was stirred for 30 minutes and extracted with EtOAc. Thus extracted organic solution was concentrated in vacuo and purified by column chromatography (eluent: EtOAc/Hex=1/3) to give the title compound (0.5 g, 10.69%).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])=[C:19]([CH3:29])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].CO.[BH4-].[Na+]>C1COCC1>[CH2:13]([C:12]([C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:25])=[O:26])=[C:19]([CH3:29])[CH:18]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:31])[C:2]([CH3:32])([CH3:33])[CH3:1])=[C:7]([CH3:30])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(N(C)S(C)(=O)=O)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(N(C)S(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.1 %

Procedure:
To a 0° C. mixture of N-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-N-methyl-methanesulfonamide (100 mg, 0.21 mmol), MeOH (5 mL), and THF (10 mL) is added NaBH4 (12 mg, 0.32 mmol). The reaction is warmed to RT and stirred for 5 h and concentrated. The residue is partitioned between EtOAc and 0.2 N HCl. The organic phase is Na2SO4 dried, concentrated, and chromatographed (0% to 25% EtOAc/Hex) to give the title compound (60 mg, 60%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([O:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH:7]=[CH:6][CH:5]=1)(=[O:11])[CH2:9][CH3:10]
Reactant: CCC(=O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCC(=O)c1cccc(OS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 32.5 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 1-(3-hydroxy-phenyl)-propan-1-one (2 kg, 13.32 mol) and potassium carbonate (3.681 kg, 26.64 mol) in dichloromethane (20 L), p-toluenesulfonyl chloride (2.8 kg, 14.65 mol) was added at 30-35° C. The reaction mixture was stirred at 30-35° C. for 1 hour. Reaction mixture was diluted with dichloromethane (10 L) and washed with water (2×10 L). Dichloromethane layer separated, dried and solvent distilled off to give title compound. Cyclohexane (10 L) was added to the resulting product at 65-70° C. and stirred for 2 hours. Mixture was cooled to ambient temperature, filtered and dried to give 3.87 kg the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23])([O-:19])=[O:18].[OH-].[Na+].Cl>C(OCC)(=O)C.C(N(CC)CC)C>[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:23])([O-:19])=[O:18]
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)CCCNC(=O)c1ccccc1NC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 3.90 g (17.50 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 40 ml of dry ethyl acetate, add 3.26 g (17.56 mmol) of 2-nitrobenzoyl chloride dissolved in 5 ml of dry ethyl acetate and 1.76 g of triethylamine. Allow the reaction mixture to stir for 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the solid has completely disappeared. Immediately acidify with concentrated HCl and extract the product with ethyl acetate. Eliminate the solvent at low pressure and recombine the crude product with dry ether, obtaining a white solid. Purify the reaction product by recrystallization (EtOH/H2O). This yields 3.34 g (51%) of 4-[2-(2-nitrobenzoylamino)benzoylamino]butanoic acid as a white solid.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[C:12]1(/[C:18](/[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-:32]#[N:33].[Na+].O>CS(C)=O>[C:32]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]/[CH:19]=[C:18](\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:33]
Reactant: [C-]#N
Reactant: OCCCCC/C=C(\c1ccccc1)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCC/C=C(\c1ccccc1)c1cccnc1
Reaction time: 18 h
Yield: 75.4 %

Procedure:
p-Toluensulfonate of (E)-7-phenyl-7-(3-pyridyl)-6-hepten-1-ol (1.0 g, 2.4 mmoles) was dissolved in dimethyl sulfoxide (10 ml), and sodium cyanide (0.3 g, 6 mmoles) was added, followed by stirring for 18 hours. To the reaction mixture was added water (100 ml) and the product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography using ethyl acetate-isopropyl ether (1:1) as the developing solvent to give (E)-1-cyano-7-phenyl-7-(3-pyridyl)-6-heptene (0.5 g, 76%).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32]>>[CH3:26][O:25][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([O:27][CH3:28])[C:19]=1[CH:16]1[CH2:17][CH2:18][N:13]([C:11]([C:6]2[C:5]3[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=3)[N:8]([CH2:30][C:31]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:32])[CH:7]=2)=[O:12])[CH2:14][CH2:15]1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CN1CCN(C(=O)CCl)CC1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(CC(=O)N3CCN(C)CC3)c3ccccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: [Na+].[C:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O-:15])(=O)=[O:13])=[CH:8][CH:7]=1)(=[O:4])[CH3:3].CN(C)C=O.S(Cl)([Cl:23])=O>>[Cl:23][S:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][C:2](=[O:4])[CH3:3])=[CH:7][CH:8]=1)(=[O:15])=[O:13]
Reactant: CC(=O)Oc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C

Procedure:
42.9 g 4-Acetoxy-benzenesulfonic acid sodium salt were suspended in 135 ml thionyl chloride. Then 0.5 ml dimethylformamide were added. The reaction mixture was heated under reflux for one hour. The cooled reaction mixture was evaporated in vacuo. The residue was coevaporated with 600 ml toluene twice. The residue was suspended in 500 ml dichloromethane and stirred at room temperature for thirty minutes. The suspension was filtered and the filtrate reduced in vacuo to one fifth of its volume. To this stirred solution 400 ml n-heptane were added dropwise and acetic acid 4-chlorosulfonyl-phenyl ester precipitated as a white solid. The precipitate was filtered off and dried in vacuo to obtain 40.4 g acetic acid 4-chlorosulfonyl-phenyl ester.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[Li]CCCC.[CH3:35][CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:37]=O.O>C1COCC1>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]=[CH:35][CH:36]([CH3:37])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:28][CH:29]=1
Reactant: Cc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCCCC(C)C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCC(C)C=CCc1ccc(C)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
p-Methylphenethyltriphenylphosphonium bromide (2.90 g, 6.29 mmol, 1.0 equiv.) in THF (12 mL), was cooled to 0° C. After adding n-BuLi (1.6 M in hexanes, 3.9 mL, 6.29 mmol, 1.0 equiv.) at 0° C., the red solution was stirred at 65° C. for 1 h. The mixture was re-cooled to 0° C., 2-methylundecanal (1.74 g, 9.43 mmol, 1.5 equiv.) in THF (5 mL) was added, and the mixture was stirred at 65° C. for 16 h. After addition of H2O, the aqueous layer was extracted with cyclohexane (2×), the combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3) to yield 1.24 g (69%) of the title compound as a colorless oil.