Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][C:7](=[O:9])[O:6][C:5](=[O:10])[CH2:4]2)[CH2:2]1.Cl.[CH3:12][NH:13][O:14][CH3:15].N1C=CC=CC=1>ClCCl>[CH3:15][O:14][N:13]([CH3:12])[C:7]([CH2:8][C:3]1([CH2:4][C:5]([OH:6])=[O:10])[CH2:2][CH2:1]1)=[O:9]
Reactant: CNOC
Reactant: O=C1CC2(CC2)CC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)CC1(CC(=O)O)CC1
Temperature: 25 °C

Procedure:
To a mixture of 5 g 6-oxa-spiro[2.5]octane-5,7-dione (36 mmole), 3.8 g of N,O-dimethylhydroxylamine hydrochloride (39 mmole, 1.1 eq) and 75 ml of dichloromethane are added 7 ml of pyridine (78 mmole, 2.2 eq) at 0-5° C. The solution is warmed to room temperature, stirred over night and washed with 50 ml of brine. The aqueous phase is extracted with 3×30 ml of dichloromethane and the combined organic phases are dried over magnesium sulfate and evaporated to dryness. The resulting crude product is directly used in the next step ([1-(2-oxo-propyl)-cyclopropyl]-acetic acid).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][CH3:22])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:25]=1.C(N(C(C)C)CC)(C)C>C(O)C>[CH2:21]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[CH:11]=2)[C:16]([C:17]#[N:18])=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[C:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:25]=2)=[CH:7][CH:6]=1)[CH3:22]
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(-c2ccc(Nc3nc(-c4ccccc4)nc4ccccc34)cc2)c(C#N)c2ccc(OC)cc21
Yield: 82.4 %

Procedure:
A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.343 mmol), 4-chloro-2-phenyl-quinazoline (83 mg, 0.34 mmol) and diisopropylethylamine (0.10 mL, 0.57 mmol) in absolute ethanol (3 mL) is heated to reflux overnight. The solution is cooled and evaporated, and the residue taken up in ethyl acetate (50 mL). This is washed with water and saturated brine (50 mL each), then dried over anhydrous sodium sulfate, filtered and evaporated. The resulting solid is triturated with ether, collected by filtration and dried under vacuum to afford 1-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)-phenyl]-1H-indole-3-carbonitrile (139 mg, 0.280 mmol, 82%).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH2:18][CH3:19])[C:4]#[C:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=[O:16]>[C].[Pd].C1COCC1>[CH3:1][O:2][CH:3]([CH2:17][CH2:18][CH3:19])[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][C:11]2=[O:16]
Reactant: CCCC(C#Cc1cccc2c1CCCC2=O)OC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC(CCc1cccc2c1CCCC2=O)OC
Reaction time: 5 h
Yield: 80.6 %

Procedure:
To a THF (60 mL) solution of 5-(3-methyloxyhexyn-1-yl)tetralone (5) (11 g) was added 10% palladium-carbon (0.9 g), and the reaction mixture was stirred under a hydrogen gas atmosphere for 5 h. The reaction mixture filtered off, and the filtrate was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate=9:1) to obtain the compoumd (6) 9.0 g.
Reaction SMILES: C[CH2:2][C:3]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C>C(Cl)Cl>[CH3:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1
Reactant: CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: ClCCl
Product: CC(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
A methylene chloride solution of a bisphenol B oligomer having a chloroformate group at its molecular terminal was obtained in the same manner as that in Manufacturing Example 1 except that the bisphenol E was replaced by 65.8 g (0.272 mol) of 2,2-bis(4-hydroxyphenyl)butane (BisB), the amount of triethylamine was changed to 53.8 g (0.533 mol), and the methylene chloride solution of phosgene was replaced by a solution in which 52.7 g (0.533 mol) of phosgene was dissolved in 225 mL of methylene chloride in Manufacturing Example 1. The obtained solution had a chloroformate concentration of 0.99 mol/L, a solid concentration of 0.21 kg/L and an average number of repeating units (n′) of 1.21. A content of an amide compound in the obtained BisB oligomer was found to be 90 mass ppm. A mass of nitrogen derived from triethylamine was 0.3 mass ppm. This obtained ingredient will be referred to as “BisB-CF” hereinafter.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.C(O[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1)=[O:14])C.[Cl-].[NH4+]>O1CCCC1>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:13]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)([CH:15]2[CH2:16][CH2:17][N:18]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:22])=[O:23])[CH2:19][CH2:20]2)[OH:14])=[CH:4][CH:5]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 2 h

Procedure:
To a suspension of 33.78 g (1.39 mole) of magnesium trimmings in 1 liter of tetrahydrofuran (dried over molecular sieves 5A) under an atmosphere of N2 and cooled in an ice bath was added dropwise a solution of 243.25 g (1.39 mole) of p-bromofluorobenzene in 150 ml of tetrahydrofuran. The mixture was stirred for 2 hr after the addition was completed. To this mixture was added 103 g (0.346 mole) of 1-(phenylsulfonyl)-4-piperidinecarboxylic acid ethyl ester as a solid, and the solution was stirred at ambient temperature for 5 hr. The reaction was poured into an icy aqueous solution of ammonium chloride. The phases were separated, and the solvent was removed in vacuo from the organic phase. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and was reduced in vacuo to ≅1 liter volume. The title compound was obtained by adding hexane and cooling, recrystallizing the precipitate from ethyl acetate and hexane and drying the solid under high vacuum at 130° C. for 45 min. at which time the product had partially melted, m.p. 142.5°-144° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:17][CH2:16][C:11]2[N:12]=[C:13]([NH2:15])[S:14][C:10]=2[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].ClC([O-])=O>C(Cl)Cl>[CH2:32]([O:31][C:29](=[O:30])[NH:15][C:13]1[S:14][C:10]2[CH2:9][C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:18])[CH2:17][CH2:16][C:11]=2[N:12]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2nc(N)sc2C1
Agent: O=C([O-])Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCc2nc(NC(=O)OCc3ccccc3)sc2C1
Temperature: 4 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Dissolved ((S)-2-Amino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (32.6 g, 121.02 mmol) in 300 mL of CH2Cl2. To this was added DIPEA (41.8 mL, 240 mmol). The mixture was cooled to 4° C. To this was added the benzyl chloroformate (17.8 mL, 125 mmol). The mixture stirred overnight. TLC analysis indicated some starting material remaining. Added 0.3 eq more of chloroformate and 0.3 eq. more of DIPEA. Stirred for 4 h. TLC indicated remaining starting material Quenched with 200 mL of saturated NH4Cl. Washed with 2×200 mL of H2O, 200 mL of Na2CO3 and 1×200 mL of brine. Dried organic phase with MgSO4, filtered and concentrated. Applied to a SiO2 column and purified (5:5 CH2Cl2/hexanes to 9:1 CH2Cl2/MeOH) to give two main fractions. 1H NMR analysis indicated that both fractions were acceptable and they were combined to give 44.5 g of ((S)-6-tert-butoxycarbonylamino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid benzyl ester. 3.06 g of S.M recovered 9%.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4](=O)[CH2:5][C:6]([O:8]CC)=[O:7].[N:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].[O-]CC.[Na+].O>C(O)C>[CH2:23]([NH:22][C:20]([C:19]1[CH:25]=[CH:26][C:16]([N:13]2[C:4]([CH2:3][CH:2]([CH3:1])[CH3:12])=[C:5]([C:6]([OH:8])=[O:7])[N:15]=[N:14]2)=[CH:17][CH:18]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)CC(=O)CC(C)C
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CC(C)C)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 91.8 %

Procedure:
Ethyl 5-methyl-3-oxohexanoate (1.20 g, 6.99 mmol, 1.4 eq.) obtained in Example 93a) and 4-azido-N-ethylbenzamide (1.00 g, 4.99 mmol) were dissolved in ethanol (20 ml), sodium ethoxide (491 mg, 6.49 mmol, 1.3 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 18 hr. Water (20 ml) was added to the reaction mixture, and ethanol was evaporated. The residue was diluted with 2% aqueous sodium carbonate solution (25 ml), and the mixture was washed with ethyl acetate-hexane (2:1, 45 ml). The organic layer was extracted with 1% aqueous sodium carbonate solution (15 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified (pH<3) with 6N hydrochloric acid and extracted with ethyl acetate (40 ml and 30 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate was added. The precipitate was collected by filtration, washed with ethyl acetate and diethyl ether and dried to give the title compound as a white powder (1.45 g, 4.58 mmol, 91.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH3:23])[CH:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=[CH:27][N:26]=1.[CH2:37]=O>>[CH3:23][N:17]([CH:18]1[CH2:22][CH2:21][N:20]([CH3:37])[CH2:19]1)[C:14]1[CH:13]=[CH:12][C:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:24][C:25]3[N:30]=[C:29]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:28]=[CH:27][N:26]=3)[CH:4]=2)=[O:10])=[CH:16][CH:15]=1
Reactant: Cc1ccc(NC(=O)c2ccc(N(C)C3CCNC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: C=O
Product: Cc1ccc(NC(=O)c2ccc(N(C)C3CCN(C)C3)cc2)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
The product from Example 7 was methylated via reductive amination with HCHO/NaBHCN (1.5 eq) to give the title compound. Mass: (M+1), 494.
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:33][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([NH:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N)CC2)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(NS(C)(=O)=O)CC2)n1
Yield: 97 %

Procedure:
Reaction of 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinamine (460 mg, 1.0 mmol) with methanesulfonyl chloride (1 mL, 12.7 mmol) and K2CO3 (2.0 g, 14.5 mmol) in CH2Cl2 (10 mL) gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide in 97% yield: mp (CH2Cl2/MeOH) 225-228° C.; 1H NMR (DMSO-d6) δ 7.88 (d, J=8.0 Hz, 1H), 7.68 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 7.15 (d, J=5.7 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.52-4.45 (m, 2H), 3.97 (s, 3H), 3.81-3.79 (m, 4H), 3.70-3.69 (m, 4H), 3.50 (br m, 1H), 3.29-3.21 (m, 2H), 2.96 (s, 3H), 1.96 (br, 2H), 1.44-1.42 (m, 2H); Anal. Calcd. for C22H28F2N8O5S: C, 49.1; H, 5.2; N, 20.8. Found: C, 49.2; H, 5.2; N, 20.9%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([F:26])([F:25])[F:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1.S1C=CC(B(O)O)=C1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([C:29]4[CH:30]=[CH:31][O:27][CH:28]=4)=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([F:26])([F:25])[F:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: OB(O)c1ccoc1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1
Agent: OB(O)c1ccsc1
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccoc3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 17 using 1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole and furan-3-boronic acid, instead of thiophen-3-boronic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7].FC(F)(F)C(O)=O>C(OCC)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccs2)CC1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccs1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mix 4-[(thiophene-2-yl)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (12.9 g, 43.67 mmol) and trifluoroacetic acid (80 mL) and stir at room temperature for 2 hours. Cool in an ice/water bath and dilute with ethyl ether. Collect the resulting solid by filtration, wash with ethyl acetate and recrystallize (methanol/ethyl ether) to give the title compound as an off-white solid; mp 186°-187° C.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([N:13]1C(=O)C2C(=CC=CC=2)C1=O)[C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:26]N>C(O)C>[C:6]1([C:5]2[NH:26][N:2]=[CH:3][C:4]=2[NH2:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NN
Reactant: CN(C)C=C(C(=O)c1ccccc1)N1C(=O)c2ccccc2C1=O
Solvent: O
Solvent: CCO
Product: Nc1cn[nH]c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 250 ml round-bottomed flask is charged at RT with 20.5 g of a mixture of the E and Z isomers of 2-[1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl]-1H-isoindole-1,3(2H)dione in 75 ml of ethanol. 7.8 ml of hydrazine hydrate are added. The suspension is stirred at RT for 1 h 30 min and then heated to reflux. After 1 h 30 min of heating, a thickening of the mixture may be observed, and it takes on a yellow colour. The suspension is filtered off hot with suction on a frit and the precipitate is washed with ethanol. The filtrate is concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with DCM and with a DCM/methanol mixture (95/5 by vol.), to give 9.45 g of 5-phenyl-1H-pyrazol-4-amine (brown solid). LC-MS-DAD-ELSD: 163 (+)=(M+H)(+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:44][CH2:45][O:46][Si:47]([C:60]([CH3:63])([CH3:62])[CH3:61])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C)C=O.C(OCC)(=O)C>[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH2:44][CH2:45][O:46][Si:47]([C:60]([CH3:61])([CH3:63])[CH3:62])([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:14])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCCOc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
Potassium carbonate (722 mg, 5.23 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (prepared as in Example 13, 900 mg, 1.72 mmol) in N,N-dimethylformamide (2 mL) at room temperature. The mixture was stirred for 30 min and then treated with (2-bromo-ethoxy)-tert-butyl-diphenyl-silane (658 mg, 1.81 mmol) at room temperature. The mixture was heated at 80° C. and stirred for 3 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 33% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethoxy]-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (870 mg, 62.8%) as a white solid.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([C:11]([NH2:13])=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15]>N1C=CC=CC=1>[N:1]1[C:10]2[CH:9]([C:11](=[S:15])[NH2:13])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: NC(=O)C1CCCc2cccnc21
Solvent: c1ccncc1
Product: NC(=S)C1CCCc2cccnc21
Reaction time: 8 h

Procedure:
A solution of 5,6,7,8-tetrahydroquinoline-8 -carboxamide (1.2 g.) in pyridine (15 ml.) was treated with P2S5 (0.8 g.) and the mixture heated at reflux for 30 mins. The solvent was removed in vacuo and the residual oil treated with 2N NaOH (5 ml.) and saturated with solid K2CO3 and extracted into chloroform (3× 50 ml.). The combined extracts were dried and the solvent removed in vacuo. The residual oil was dissolved in pyridine (4 ml.) and triethylamine (1 ml.) and the solution saturated with H2S (6 hours) and allowed to stand overnight. Removal of the solvent gave a solid (850 mgs.) which was recrystallised from methanol giving the title compound as the quarter hydrate, colourless needles m.p. 160° C. Found: C, 59.8; H, 6.2; N, 14.0%. C10H12N2S.1/4 H2O requires: C, 59.6; H, 6.4; N, 13.9%.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:31][CH2:32][N:33]([C:2]3[C:3]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:4][C:5]4[C:10]([N:11]=3)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=4)[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: Clc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(Cl)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 4-(4-chlorophenyl)piperidine hydrochloride (204.2 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv), N,N-dimethylformamide (4 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 6×15 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 146.2 mg (71%) of methyl 3-(4-(4-chlorophenyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:12]3[O:11][C:10]=2[CH2:18][C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1.I>C(O)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:12]3[O:11][C:10]=2[CH2:18][C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3cccc-3oc2CC(=O)O)cc1
Agent: I
Solvent: CC(=O)O
Product: O=C(O)Cc1oc2cccc-2cc1-c1ccc(O)cc1

Procedure:
3-(4-methoxyphenyl)-7-benzofuranacetic acid is acetic acid is heated at reflux with 47% hydroiodic acid overnight to provide 3-(4-hydroxyphenyl)-7-benzofuranacetic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][CH:5]([C:7]([O:9]C)=[O:8])[CH:4]([C:11]([O:13][CH3:14])=[O:12])[O:3]1.[OH-].[Na+]>CO>[CH3:14][O:13][C:11]([CH:4]1[CH:5]([C:7]([OH:9])=[O:8])[O:6][C:2]([CH3:15])([CH3:1])[O:3]1)=[O:12]
Reactant: COC(=O)C1OC(C)(C)OC1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1OC(C)(C)OC1C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 1.23 mL of dimethyl 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate in 12 mL of methanol was added slowly 3.0 mL of 2 mol/L sodium hydroxide solution under ice-cooling. After being stirred at room temperature for 24 hours, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with 15 ml of water. After the mixture was washed with diethyl ether, acidified by addition of 4 mL of 2 mol/L hydrochloric acid. After the aqueous layer was extracted with dichloromethane, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 0.686 g of 2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylic acid monomethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:37]5[NH:38][C:39]([C@@H:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)[CH:33]=4)[CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].COC(N[C@H](C1C=CC=CC=1)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:61])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[C:32]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:60])[CH:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]6[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=6)=[N:40][CH:41]=5)[CH:33]=4)[CH:28]=3)=[CH:25][CH:26]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Agent: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Yield: 58 %

Procedure:
This compound was prepared following the procedure for [1-(2-{5-[4-(6-{2-[1-(2S)-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using (R)-methoxycarbonylamino-phenyl-acetic acid (0.02 g, 0.09 mmol, 1.5 equiv.) to provide [1-(2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 58%) as a white powder. LCMS-ESI+: calc'd for C47H50N8O6: 822.4 (M+). Found: 823.8 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: (Mixture of rotomers) 7.62-7.87 (m, 9H), 7.29-7.43 (m, 6H), 7.18 (s, 2H), 6.09 (m, 1H), 5.46 (m, 2H), 5.33 (s, 1H), 5.27 (s, 1H), 4.33 (t, 1H), 3.84 (m, 1H), 3.71 (m, 1H), 3.68 (s, 3H), 3.61 (s, 3H), 3.24 (m, 1H), 2.83-2.93 (m, 3H), 2.35 (m, 1H), 1.92-2.23 (m, 6H), 0.86-0.97 (m, 6H).