Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:38](OC)[O:39]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=2[N:28]([CH3:37])[S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CC(C)=O>[CH2:1]([S:8][CH:9]([CH:38]=[O:39])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:18][C:17]=2[N:28]([CH3:37])[S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(CNC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.5 %

Procedure:
A mixture of N-[2-(benzylthio)-3,3-dimethoxypropyl]-7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxamide (600 mg), Amberlyst (registered trade ark) 15 ion exchange resin (120 mg), water (0.05 mL) and acetone (15 mL) was stirred at room temperature for 15 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-3:1, volume ratio) to give the title compound (560 mg, yield 100%) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:50]=[CH:49][C:6]2[CH:7]([C:17]3[C:18]([S:47]C)=[N:19][C:20](=[O:46])[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:29]([CH3:45])[CH2:30][C:31]([NH:33][C:34]5[S:35][CH:36]=[C:37]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[N:38]=5)=[O:32])[N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]>N1C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([C:3]1[CH:50]=[CH:49][C:6]2[CH:7]([C:17]3[C:18](=[S:47])[NH:19][C:20](=[O:46])[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:29]([CH3:45])[CH2:30][C:31]([NH:33][C:34]5[S:35][CH:36]=[C:37]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[N:38]=5)=[O:32])[N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc(NC(=O)CN(C)c2nccc(-n3cc(C4c5ccc(C)cc5C=Cc5cc(CC)ccc54)c(SC)nc3=O)n2)n1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1csc(NC(=O)CN(C)c2nccc(-n3cc(C4c5ccc(C)cc5C=Cc5cc(CC)ccc54)c(=S)[nH]c3=O)n2)n1

Procedure:
The product from step (v) (0.61 g) was dissolved in dry pyridine (20 ml) and triethylamine (1.0 ml). Hydrogen sulphide gas was slowly bubbled through the solution for 15 minutes. The solvents were evaporated under reduced pressure and the residue azeotroped twice with toluene. The residue was purified by chromatography eluting with ethyl acetate in toluene. Yield 0.41 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:45][CH2:46][CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH2:49]([O:48][CH2:47][CH2:46][CH2:45][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: BrCCCOCc1ccccc1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(CCCOCc2ccccc2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and benzyl 3-bromopropyl ether to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[3-(benzyloxy)propyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (89%) as a colorless solid: mp 112-113° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.35-7.27 (m, 6H), 7.14 (d, J=6.0 Hz, 1H), 7.06-6.95 (m, 2H), 6.41-6.39 (m, 2H), 4.63 (AB, 2H), 4.54-4.48 (m, 4H), 3.94-3.80 (m, 2H), 3.54 (t, J=6.0 Hz, 2H), 2.95 (t, J=9.0 Hz, 2H), 2.07-1.99 (m, 2H); MS (ES+) m/z 428.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]2)[N:3]=1.C([Li])CCC.[Br:19]N1C(=O)CCC1=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:19][C:12]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=2)[N:9]=[CH:10][C:11]=1[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnn(-c2cccc(C)n2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(-n2ncc(C)c2Br)n1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a cold (−60° C.) solution of 2-methyl-6-(4-methyl-pyrazol-1-yl)-pyridine (0.52 g,) (prepared by Reaction Condition 1 in Step i) in 14 mL of anhydrous THF was added 1.33 mL of a 2.5M solution of n-butyllithium (0.21 g) in hexanes. The reaction mixture was stirred at −60° C. for one hour. A 10 mL solution of N-bromosuccinimide (0.59 g) in THF was added and then the final solution was stirred at −60° C. for 2 hours. Saturated ammonium chloride (20 mL) was added and then the reaction mixture was allowed to warm to 24° C. The reaction mixture was diluted with 300 mL of ethyl acetate and then the aqueous phase was separated. The organic phase was washed with additional saturated ammonium chloride (50 mL) and then with brine (50 mL). The organic layer was separated, dried (sodium sulfate), filtered, and then the filtrate was evaporated to give a crude red oil. Purification by flash chromatography (silica gel, 20% ethyl acetate in heptane) provided, after drying, 0.377 g of the title compound as a yellow oil; 1H-NMR (400 MHz; DMSO-d6) δ 7.88 (t, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 2.50 (s, 3H), 2.02 (s, 3H); MS (APCl+) m/z 254 (MH+).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:15]=[C:14]([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([OH:28])=O)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[C:13]2[CH2:12][CH:11]=[CH:10][CH2:9][C:8]=2[N:7]=1>C(Cl)Cl>[CH3:5][C:6]1[CH:15]=[C:14]([CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([C:26]([Cl:3])=[O:28])=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[C:13]2[CH2:12][CH:11]=[CH:10][CH2:9][C:8]=2[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(Cn2ccc3cc(C(=O)O)ccc32)c2c(n1)CC=CC2
Solvent: ClCCl
Product: Cc1cc(Cn2ccc3cc(C(=O)Cl)ccc32)c2c(n1)CC=CC2
Temperature: 25 °C
Yield: 80 %

Procedure:
Thionyl chloride (5 mL) was added to a suspension of the 1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-iindole5-carboxylic acid from step (501a) (0.67 g, 2.1 mmol) in methylene chloride (15 mL) and was heated to reflux for 2 h. The reaction was cooled to room temperature, concentrated in vacuo to give the 1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indole-5-carbonyl chloride (0.68 g, 80%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10]>CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd]>[CH:2]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(Br)c(C)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Product: COc1ccc(C2CCCCC2)c(C)c1
Temperature: 100 °C

Procedure:
1-Bromo-4-methoxy-2-methyl-benzene (520 mg, 2.6 mmol) is dissolved in cyclohexylzinc bromide THF solution (0.5 M, 15 mL) in a microwave tube. Pd(t-Bu3P)2 (66 mg, 0.13 mmol, 0.05 eq.) is added to this solution. The mixture is purged with N2 (g) for 5 minutes and heated at 100° C. for 30 minutes using microwave irradiation. Upon completion, the reaction mixture is diluted with EtOAc, washed with 1 N HCl (aq), brine, filtered through celite, and dried over Na2SO4. After concentration, the residue is partially purified by silica gel chromatography (5% EtOAc in hexanes) to give crude 1-cyclohexyl-4-methoxy-2-methyl-benzene.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[CH3:16][C:17](C)([O-:19])C.[Na+].C(OCCBr)(=O)C>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:16][CH2:17][OH:19])[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: CC(C)(C)[O-]
Agent: CC(=O)OCCBr
Agent: [Na+]
Solvent: CS(C)=O
Product: OCCN1C[C@@H]2COCCN2c2nc(Cl)ncc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 100 mg, 0.441 mmol) in DMSO (7 mL), sodium tert-butoxide (51 mg, 0.529 mmol) and bromoethyl acetate (81 mg, 0.485 mmol) (79 mg, 66%). ESI-MS m/z [M+H]+ calc'd for C11H15ClN4O2, 271.09; found 271.1.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][NH:60][CH2:61][C:62]1[CH:74]=[CH:73][C:65]([CH2:66][N:67]2[CH2:71][CH2:70][CH:69]([OH:72])[CH2:68]2)=[CH:64][CH:63]=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:60]([CH2:61][C:62]3[CH:74]=[CH:73][C:65]([CH2:66][N:67]4[CH2:71][CH2:70][CH:69]([OH:72])[CH2:68]4)=[CH:64][CH:63]=3)[CH3:59])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CNCc1ccc(CN2CCC(O)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.036 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}pyrrolidin-3-ol dihydrochloride (34 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=1)[C:6]([O:8]C)=[O:7])[CH3:3].[OH-].[K+:24]>C1COCC1.CO>[C:17]([O:16][C:14]([C:13]1[CH:21]=[CH:22][C:10]([CH:5]([CH2:4][N:2]([CH3:3])[CH3:1])[C:6]([O-:8])=[O:7])=[CH:11][CH:12]=1)=[O:15])([CH3:19])([CH3:18])[CH3:20].[K+:24]
Reactant: COC(=O)C(CN(C)C)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CC(C(=O)[O-])c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-{1-[(dimethylamino)methyl]-2-methoxy-2-oxoethyl}benzoate (859 mg, 2.79 mmol) in THF (9 mL) and MeOH (3 mL) was added KOH (1N, 2.93 mL, 2.93 mmol). The reaction was stirred at room temperature for 30 minutes. An additional 100 μL of 1N KOH was added, and the solution was stirred for another 30 minutes. Concentration of the reaction mixture to dryness yielded potassium 2-[4-(tert-butoxycarbonyl)phenyl]-3-(dimethylamino)propanoate as a white solid that was carried on without purification. MS (EST) calcd [M+H]+ 294.1, found 294.1.
Reaction SMILES: [OH:1][CH:2]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:39])([CH3:38])[C:33]([O:35]CC)=[O:34])=[CH:28][CH:27]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[OH-].[Na+].C(O)(=O)C>CO>[OH:25][C:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:9]1[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH:2]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:39])([CH3:38])[C:33]([OH:35])=[O:34])=[CH:28][CH:27]=2)[OH:1])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C(=O)O)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
Ethyl 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethylbenzeneacetate (0.5 g) was dissolved in MeOH (10 mL), and sodium hydroxide solution (0.35 g, water 3 mL) was added. The reaction mixture was heated at reflux for 5 h, and cooled to 22° C., followed by the addition of acetic acid to reach a pH 4-5. MeOH (5 mL) was added to the solution and stirred for 1 h. The precipitate was collected by filtration to give 0.42 g of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid. 1H NMR (DMSO-d6) d 1.45-1.49(m, 2H), 1.67 (s, 6H), 1.67-1.78 (m, 6H), 2.12-2.20 (m, 2H), 2.45-2.50 (m, 2H), 2.68-2.78 (m 3H), 3.10 (broad s, 2H), 4.71 (m, 1H), 5.50 (broad s, 1H), 7.35 -7.40 (m, 2H), 7.45-7.55 (m, 8H), 7.76-7.78 (m, 4H). MH+ 502.3.
Reaction SMILES: C(OC([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH3:17])[C:7]1=[O:18])=O)C.C([O:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)C.C(OC(C1CCC2C(=CC=C(Cl)C=2)C1=O)=O)C.C(ON)C1C=CC=CC=1.COC1C=C2C(=CC=1)C(=O)C(CCCCC(O)=O)CC2.C(ONC(=O)CCCCC1CCC2C(=CC=C(OC)C=2)C1=O)C1C=CC=CC=1.C(ONC(=O)CCCCCC1CCC2C(=CC=CC=2OC)C1=O)C1C=CC=CC=1>COC1C=CC=C2C=1CCC(CCCCCC(O)=O)C2=O.C(OC(C1(CCCCCC(O)=O)CCC2C(=CC=CC=2OC)C1=O)=O)C.CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:17][O:16][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH2:14][CH2:15][CH:6]([CH:26]([CH3:27])[CH2:25][CH2:24][CH2:23][C:22]([OH:21])=[O:29])[C:7]2=[O:18]
Reactant: CCOC(=O)CCCCCBr
Reactant: CCOC(=O)C1CCc2c(OC)cccc2C1=O
Agent: [Pd]
Agent: CCOC(=O)C1(CCCCCC(=O)O)CCc2c(OC)cccc2C1=O
Agent: CCOC(=O)C1CCc2cc(Cl)ccc2C1=O
Solvent: CO
Product: COc1cccc2c1CCC(C(C)CCCC(=O)O)C2=O

Procedure:
5-methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester (2,34 g; 8a) (Genet, J. P., et al., Tetrahedron Lett. 35 (1994) 4559-4562) is treated with ethyl-6-bromo-hexanoate in a analogues way to that described for the conversion of 3a in example 3. This resulted in a mixture of 6-(5-methoxy-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-hexanoic acid (8b) and 2-(5-Carboxy-pentyl)-5-methoxy-1-oxo-1,2,3,4-tetrahydro-naphtalene-2-carboxylic acid ethyl ester (8c) in a ratio of approximately 1:1. This mixture of acids is treated with O-benzylhydroxylamine in a similar way as described for the conversion of 2b into 2c in example 2. The crude product is subjected to column chromatography yielding an inseparable mixture of 2-(5-benzyloxycarbamoyl-pentyl)-5-methoxy-1-oxo-1,2,3,4-tetrahydro-naphtalene-2-carboxyclic acid ethyl ester (8d) and 6-(5-methoxy-1-oxo-1,2,3,4-tetrahydro-naphtalen-2-yl)-hexanoic acid benzyloxy-amide (8e). This mixture is hydrogenated in methanol with Pd/C/BaSO4 as a catalyst.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Cl:10][SiH:11]([Cl:13])[Cl:12]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:2]1([CH3:1])[CH:9]=[CH:8][C:5]([CH2:6][CH2:7][Si:11]([Cl:13])([Cl:12])[Cl:10])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(C)cc1
Reactant: Cl[SiH](Cl)Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: Cc1ccc(CC[Si](Cl)(Cl)Cl)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
Into a 3 liter round-bottom flask fitted with a reflux condenser, addition funnel and magnetic stir bar, was charged 4-methylstyrene (904.4 g, 7.65 mols), VCAT (2.25 g, 50 ppm) and phenothiazine (1.94 g, 1000 ppm). The reaction mixture was heated to 70° C. and then trichlorosilane (1036.6 g, 7.65 mols) was added dropwise to the reaction mixture. During the addition, the reaction mixture was maintained between 80 to 100° C. After the addition was finished, the reaction mixture was kept at 70° C. for additional two hours. After distillation, >98% pure (2-p-tolyl-ethyl)trichlorosilane (1565 g, 6.19 mols) was obtained (collected at 75° C./1 mmHg). The product structure was characterized by GC-MS.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([CH3:22])[C:13]([C:23](OC)=[O:24])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([CH3:22])[C:13]([CH:23]=[O:24])=[CH:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccc(F)cc2)c(-c2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1c(C=O)cn(S(=O)(=O)c2ccc(F)cc2)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Under a nitrogen atmosphere, a solution (40 mL) of methyl 1-[(4-fluorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carboxylate (1.48 g) in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/L solution (7.9 mL) of diisobutylaluminum hydride in toluene was added dropwise over 15 min, and the mixture was further stirred at −78° C. for 30 min. 1 mol/L Hydrochloric acid (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile solution (60 mL), added tetra-n-propylammonium perruthenate (0.14 g), N-methylmorpholine N-oxide hydrate (0.80 g) and molecular sieves 4A powder (4.0 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate (200 mL) was added to the residue, the suspension was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→3:1) to give the title compound as a colorless oil (yield 721 mg, 53%).
Reaction SMILES: [N:1]1[N:2]=[C:3]([NH:6][CH:7]2[CH2:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8]2)[NH:4][CH:5]=1.[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([C:37](=O)[CH2:38][CH2:39][CH3:40])[C:32](OCC)=[O:33])=[C:26]([F:42])[CH:25]=1)#[N:17].C(N(CC)C1C=CC=CC=1)C.Cl>>[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[C:32](=[O:33])[N:6]([CH:7]3[CH2:8][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10]3)[C:3]3[N:2]([N:1]=[CH:5][N:4]=3)[C:37]=2[CH2:38][CH2:39][CH3:40])=[C:26]([F:42])[CH:25]=1)#[N:17]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Reactant: CCOC(=O)C1CC(Nc2nnc[nH]2)C1
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CC(C(=O)OCC)C2)c2ncnn12
Temperature: 180 °C
Reaction time: 48 h
Yield: 40.9 %

Procedure:
A mixture of ethyl 3-(4H-1,2,4-triazol-3-ylamino)cyclobutanecarboxylate (4.0 g), ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (12 g) and N,N-diethylaniline (15 mL) was stirred at 180° C. for 48 hr and then at room temperature for 38 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid and then 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 to give the title compound as a colorless solid (4.0 g, 41%).
Reaction SMILES: C(Br)C.Cl[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1.CN([CH:16]=[O:17])C>C1COCC1>[CH:9]([C:8]1[CH:11]=[CH:12][C:5]([CH:16]=[O:17])=[CH:6][CH:7]=1)=[CH2:10]
Reactant: CN(C)C=O
Reactant: C=Cc1ccc(Cl)cc1
Solvent: CCBr
Solvent: C1CCOC1
Product: C=Cc1ccc(C=O)cc1
Reaction time: 2 h
Yield: 95 %

Procedure:
7.6 gms (0.312 moles) of Mg tunings were transferred to an RB flask containing 50 ml of dry THF under nitrogen atmosphere. 2 ml of ethyl bromide was then added to the Mg metal and the reaction mixture was warmed to 50°-55° C. The mixture reacted vigorously and activated Mg metal was formed. A solution of 20 ml (0.156 moles) of 4-chlorostyrene in 50 ml of THF was added dropwise at room temperature to the activated Mg. The reaction mixture was stirred for an additional two hours. A dark gray solution appeared and was allowed to settle down. In a separate IL RB flask, a solution of 12 ml (0.15 moles) of anhydrous DMF was prepared in 300 ml of THF. The DMF solution was cooled in an icebath under dry nitrogen atmosphere for 15 mins. Grignard reagent was added dropwise to the DMF solution over a period of 1 hr with vigorous stirring. The reaction flask was then allowed to stir for three hrs. at 5° C. and RT overnight. The reaction was quenched by pouring the entire reaction mixture into 300 ml of dilute HCl in an icebath. The product was separated by solvent extraction with ether. The ether layer was dried over anhyd. MgSO4 and filtered. Finally, ether was evaporated under reduced pressure. A viscous yellow liquid was obtained and was dried under vacuum for 2 hrs and stored in a freezer at -10° C. containing a small amount of hydroquinone as an inhibitor. A yield of 65% high purity (above 95%) 4-vinyl benzaldehyde was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[NH:14][C:13]=2[CH:12]=[C:11]([Br:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][C:9]1[C:17]2[N:16]=[C:15]([C:18]([F:21])([F:19])[F:20])[N:14]([CH3:23])[C:13]=2[CH:12]=[C:11]([Br:22])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1nc2c(OCc3ccccc3)cc(Br)cc2[nH]1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1c(C(F)(F)F)nc2c(OCc3ccccc3)cc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
A solution of 40 g (107.8 mmol) 4-benzyloxy-6-bromo-2-trifluoromethyl-1H-benzimidazole in acetone (600 ml) was treated with 44.7 g (323.4 mmol) potassium carbonate and the reaction was refluxed for 1 h. 13.4 ml Methyl iodide were added and the mixture was stirred for 2 h. After cooling to room temperature, the precipitate was filtered off and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography on silica gel (petroleum ether/ethyl acetate=15:1) afforded 13.2 g (32%) of the title compound as a white solid. m.p. 141°-142° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.CC1C=CC(S(OC[CH2:24][CH2:25][CH2:26][O:27][CH3:28])(=O)=O)=CC=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:28][O:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCCOc1ccc2c(c1)C(=O)CC2
Temperature: 80 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
To a solution of 6-hydroxyindan-1-one (1.48 g) in acetonitrile (30 mL) were added 4-methoxybutyl 4-methylbenzenesulfonate (2.93 g), potassium iodide (166 mg) and potassium carbonate (2.07 g), and the mixture was heated to stir at 80° C. for 5 hours. To the reaction mixture was added water under ice-cooling, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=7/3), and then triturated with n-hexane/isopropyl ether (2:1) to give 6-(3-methoxypropoxy)indan-1-one [REx(11-1)] (1.1 g) as a colorless powder.