Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16])=O.[BH4-].[Na+].Cl>C(O)C.O1CCCC1.O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:15]([N:6]2[CH2:7][C@H:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH2:9][C@H:5]2[CH2:3][OH:2])=[O:16])=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Yield: 70372.7 %

Procedure:
To a solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-carboxylic acid methyl ester (79.4 g: 0.197 mmole) in a mixture of ethanol (300 ml) and tetrahydrofuran (150 ml), sodium borohydride (10.44 g: 1.4 eq.) is added in small portions with stirring at 0° C. The mixture is stirred at 0° C. for 1.5 hours and at room temperature for 5 hours. To the reaction mixture under ice cooling, 5N-hydrochloric acid (100 ml) is added. The mixture is diluted with water, and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is recrystallized from a mixture of dichloromethane and ether to give (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (51.9 g). Yield: 70%. NMR δ(CDCl3) ppm: 1.93 to 2.14(m, 1H), 2.32 to 2.48(m, 1H), 3.06(s, 3H), 3.53 to 4.28(m, 6H), 5.26(s, 2H), 7.53(d, J=9 Hz, 2H), 8.24(d, J=9 Hz, 2H). IR ν (CHCl3) cm-1 : 3404, 1698, 1607.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH2:25]O)[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.CCOC(/N=N/C(OCC)=O)=O>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH2:25][O:12][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=3[O:10][CH3:11])[C:3]([OH:2])=[O:13])[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: OCC1(c2ccc(Cl)cc2)CCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Product: COc1ccc(C(=O)O)cc1OCC1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C

Procedure:
To a solution of 300 mg 3-Hydroxy-4-methoxy-benzoic acid methyl ester, 388 mg [1-(4-Chloro-phenyl)-cyclobutyl]-methanol 1645 mg polymerbound triphenyl phosphine (Fluka, 3 mmol triphenyl phosphine/g resin) and 762 μl DEAD were introduced and the mixture was shaken over night at RT. After filtration, evaporation of the solvent the residue was taken up in 5 ml MeOH/H2O 3:1 and 20 mg LiOH monohydrate was added. After heating the mixture at 60° C. for 2 h the mixture was acidified with half concentrated HCl and filtered through a chem elut® cartridge by elution with ethyl acetate. After concentration under reduced pressure the crude product was subjected to the following amide coupling without further purification.
Reaction SMILES: C(O[C:6]([N:8]([C:41](OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH:37]3[CH2:39][CH2:38]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.O1CCCC1.CNC>>[CH:37]1([C:33]2[CH:34]=[C:35]([CH3:36])[C:30]([N:27]3[CH2:28][CH2:29][N:24]([C:22]([C:11]4[CH:12]=[CH:13][C:14]([N:16]5[CH2:20][CH2:19][CH2:18][C:17]5=[O:21])=[CH:15][C:10]=4[C:9]([N:8]([CH3:41])[CH3:6])=[O:40])=[O:23])[CH2:25][CH2:26]3)=[N:31][CH:32]=2)[CH2:38][CH2:39]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Agent: CNC
Solvent: C1CCOC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2C(=O)N(C)C)CC1
Yield: 52.5 %

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 814 and 2 mol/L dimethylamine tetrahydrofuran solution (216 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (27 mg) was obtained.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]1([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[CH:13]1>C(Cl)(Cl)Cl>[O-:6][N+:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:24]2[N:12]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH:13]=[N:14][C:15]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)NCCCn1cnc2cnc3ccccc3c21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCCn1cnc2c[n+]([O-])c3ccccc3c21

Procedure:
3-Chloroperoxybenzoic acid (3.71 g of ˜60%, 13.48 mmol) was added in small portions over a period of 20 minutes to a solution of tert-butyl 3-(1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (4.0 g, 12.25 mmol) in chloroform (175 mL). After 1 hour the reaction was quenched with aqueous 1% sodium carbonate solution. The layers were separated. The organic layer was washed with aqueous 1% sodium carbonate solution (3×100 mL). The aqueous layer was extracted with chloroform (2×100 mL). The organic layers were combined and concentrated under reduced pressure to provide crude tert-butyl 3-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate.
Reaction SMILES: [N+:1]([O:4][CH:5]([CH2:33][O:34][N+:35]([O-:37])=[O:36])[CH2:6][O:7][C:8]([O:10][CH2:11]/[C:12](/[C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[C:13](/[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)\[C:14]([OH:16])=[O:15])=[O:9])([O-:3])=[O:2].[N+](=[CH:40][CH3:41])=[N-]>C1COCC1.C(OCC)C>[N+:1]([O:4][CH:5]([CH2:33][O:34][N+:35]([O-:37])=[O:36])[CH2:6][O:7][C:8]([O:10][CH2:11]/[C:12](/[C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=1)=[C:13](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)\[C:14]([O:16][CH2:40][CH3:41])=[O:15])=[O:9])([O-:3])=[O:2]
Reactant: CC=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(/C(COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])=C(/C(=O)O)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C(\COC(=O)OCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccc(S(C)(=O)=O)cc1)c1ccccc1

Procedure:
To a 0° C. solution of 454 mg of (2Z)-4-({[2,3-bis(nitrooxy)propoxy]carbonyl}oxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid in 20 mL of THF was added excess diazoethane in diethylether until crude NMR revealed complete conversion to ethyl ester. Evaporation of the solvent followed by flash chromatography of the crude residue over silica gel (30-90% EtOAc/hexane) afforded 420 mg of the title compound as a clear colourless oil. 1H NMR (500 MHz, acetone-d6): δ 7.80 (d, 2H), 7.49 (d, 2H), 7.23-7.18 (m, 3H), 7.14-7.08 (m, 2H), 5.79-5.73 (m, 1H), 5.35 (s, 2H), 5.05 (dd, 1H), 4.85 (dd, 1H), 4.64 (dd, 1H), 4.47 (dd, 1H), 4.31 (q, 2H), 3.08 (s, 3H), 1.29 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([C:19]1[C:27]2[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[CH2:13][C:14](OCC)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]([C:19]1[C:27]2[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[CH2:13][CH2:14][OH:15]
Reactant: CCOC(=O)CC(c1ccc(C(F)(F)F)cc1Cl)c1c[nH]c2c(CSC)cccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSCc1cccc2c(C(CCO)c3ccc(C(F)(F)F)cc3Cl)c[nH]c12

Procedure:
A solution of 1.30 g (2.85 mmol) of the compound from Example 99A in 20 ml of THF was added dropwise to 10 ml (9.98 mmol) of a 1N lithium aluminum hydride solution in THF under argon in 80 ml of THF at RT. 1N hydrochloric acid was then added, the mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 0.73 g (61% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][C:9]=2[CH3:17])=[CH:4][CH:3]=1.[CH3:20][C:21]([S@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[N:13]=[CH:12][C:11]([CH:14]([NH:26][S@@:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])[CH3:15])=[CH:10][C:9]=2[CH3:17])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCc2ccc(F)cc2)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCc1ccc(F)cc1
Yield: 79 %

Procedure:
The title compound is prepared in 79% yield (2.15 g, white solid) from 1-(6-((4-fluorobenzyl)oxy)-5-methylpyridin-3-yl)ethanone (1.94 g, 7.48 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide (1.36 g, 11.2 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [NH2:1]/[C:2](/OCC)=[CH:3]\[C:4](=O)[C:5]([F:8])([F:7])[F:6].[NH2:13][NH2:14]>CCO>[F:6][C:5]([F:8])([F:7])[C:4]1[NH:14][N:13]=[C:2]([NH2:1])[CH:3]=1
Reactant: NN
Reactant: CCO/C(N)=C/C(=O)C(F)(F)F
Solvent: CCO
Product: Nc1cc(C(F)(F)F)[nH]n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (5.00 g, 27 mmol) and hydrazine (1.05 g) in anhydrous EtOH (20 mL) was stirred at 80° C. in a sealed vial overnight. The reaction was quenched with water (50 mL), and extracted with EtOAc (100 ml, then 2×50 mL). The EtOAc layers were combined and sequentially washed with water (25 mL), brine (25 mL), dried over Na2SO4 and evaporated to give a light brown oily residue. The crude product was purified by silica chromatography (30-100% EtOAc in hexanes gradient) to give 5-(trifluoromethyl)-1H-pyrazol-3-amine as an off white solid; ESMS m/z 152.0 (M+H+).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[Cl:17])[CH2:15][CH:16]=1
Reactant: C1=C(c2nc3ccccc3s2)CCNC1
Reactant: Clc1ccccc1CBr
Agent: Cl
Product: Clc1ccccc1CN1CC=C(c2nc3ccccc3s2)CC1
Yield: 44 %

Procedure:
4-(Benzothiazol-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (200 mg, 0.8 mmol) was reacted with 2-chlorobenzyl bromide (0.13 ml, 0.8 mmol) as exemplified in Example 1. The crude product was purified by flash chromatography eluting with 15% ethyl acetate in petroleum ether to give the title compound as a yellow solid (120 mg, 44%). (Found: C, 65.13; H, 4.72; N, 7.33. C19H17ClN2S. 0.5H2O requires C, 65.22; H, 5.19; N, 8.01%). δH (CDCl3), 2.84 (4H, m, CH2), 3.33 (2H, m, NCH2CH2), 3.80 (2H, s, NCH2Ar), 6.70 (1H, m, NCH2CH), 7.41 (6H, m, ArH), 7.82 (1H, d, J 7.8Hz, ArH), 7.98 (1H, d, J 8.1Hz, ArH). m/z (ES+) 341 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[C:5]2[N:6]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:8][C:4]=2[CH:3]=1.[C:27]1(C)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(B(O)O)C=CC=CC=1.C>CO.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[NH4+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH2:9]([C:7]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:5]2[C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH:22][C:2]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:3][C:4]=2[N:8]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1nc2cc(Br)cc(C(=O)OC)c2n1Cc1ccccc1Cl
Reactant: Cc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nc2cc(-c3ccccc3)cc(C(=O)OC)c2n1Cc1ccccc1Cl
Temperature: 80 °C
Yield: 68 %

Procedure:
A mixture of methyl 5-bromo-2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxylate (600 mg, 1.38 mmol), tetrakis(triphenylphosphine)palladium(O) (50 mg), toluene (3 mL) and 2M sodium carbonate solution (1.5 mL) was treated with a solution of phenylboronic acid (200 mg, 1.64 mmol) in methanol (0.3 mL). The resulting mixture was vigorously stirred under an argon atmosphere and heated at 80° C. for 18 hours. The cooled reaction was diluted with methylene chloride, 2M sodium carbonate solution and a few drops of ammonium hydroxide solution. Some insolubles were filtered, the organic phase was separated, dried (magnesium sulfate) and concentrated to 0.55 g of crude product. TLC on silica with 4:1 hexane/ethyl acetate gave an Rf of 0.33 for the product; the starting material had an Rf of 0.43. The crude product was dissolved in methylene chloride, treated with activated charcoal and the filtrate was concentrated to a small volume and chilled. The separated off-white crystals were filtered to afford 0.41 g (68%) of methyl 2-n-butyl-1-(2-chlorophenyl)methyl-5-phenyl-1H-benzimidazole-7-carboxylate; mp 103°-105° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH:7]=[CH:6][C:5]=1[OH:31])[CH2:2][CH3:3].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:31][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)[O:16][C:17]=2[CH3:18])=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3])[CH3:38]
Reactant: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1OCC(=O)OCC
Temperature: 55 °C

Procedure:
A mixture of 2-propyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol) (see Ex. 60, part B), ethyl 2-bromoethanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL,), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{ 4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-2-propylphenoxy}ethanoic acid ethyl ester, 1H NMR (400 MHz, CDCl3) δ8.05 (d, J=8.3 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 21H), 7.44 (t, J=7.5 Hz, 2H), 7.36 (t, J=7.3 Hz, 1H), 6.72 (brs, 1H), 6.64 (brs, 2H), 4.59 (s, 2H), 4.54 (q, J=7.3 Hz, 2H), 4.20 (t, J=6.6 Hz, 2H), 2.97 (t, J=6.8 Hz, 2H), 2.58-2.61 (m, 2H), 2.38 (s, 3H), 1.61 (sextet, J=7.3 Hz, 2H), 1.27 (t, J=7.3 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:11]([OH:13])[CH3:12]>Cl[Cu].COCCOC>[CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:1]([O:3][Si:4]([O:13][CH2:11][CH3:12])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCO
Agent: Cl[Cu]
Agent: CCO[SiH](OCC)OCC
Solvent: COCCOC
Product: CCO[Si](OCC)(OCC)OCC
Reaction time: 0.17 h

Procedure:
The preparation of triethoxysilane was carried out in a reactor having working capacity of 9 L, which was equipped with an electric heating control device of reaction capacity, and an impeller stirrer having 4 wings to control rotational speed to 300-1500 rpm. 3.3 kg of metal silicon was ground in a solvent environment of 6.6 kg of THERMINOL® 66 using Planetary Mill until the particle size is 30-100 μm. In the pulverizing process, 0.2 kg of CuCl catalyst was put into the suspension. In the state of continuous operation of the stirrer at 850 rpm, contact mass was heated to temperature of 242+2° C., the feed of ethanol as anhydrous alcohol to the reactor was started at 600 ml/hr using dosing pump (Digital dosing pump), GRUNDFOS® DME 60-10 AR. Samples were taken when liquid product was generated in the reactor, then every 30 minutes. As a result of analysis of the samples in Gas chromathograph, Agilent® GC7890A, synthesis reaction was started 10 minutes after alcohol was poured, and reaction rate increased for initial 60 minutes. The synthesis reaction rate of triethoxysilane decreased after 180 minutes, and completely slowed down 260 minutes after alcohol was fed. Herein, 1635 g of triethoxysilane and 105 g of tetraethoxysilane were obtained. The selectivity of triethoxysilane was 94%.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([S:26]C#N)=[CH:18][C:17]=1[CH3:29])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])[CH3:3].SC[C@H]([C@@H](CS)O)O.OP([O-])(O)=O.[K+]>CCO>[CH3:15][C:12]([O:11][C:9]([N:8]([C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([SH:26])=[CH:18][C:17]=1[CH3:29])[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[O:10])([CH3:13])[CH3:14]
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=P([O-])(O)O
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CCO
Product: Cc1cc(S)c(C(C)(C)C)cc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of [4-(cyanothio)-5-(1,1-dimethylethyl)-2-methylphenyl]-imidodicarbonic acid bis(1,1-dimethylethyl) ester obtained in Example EEEE (11.65 g, 27.7 mmol) in denatured EtOH (160 mL) was added dithiothreitol (16.8 g, 109.1 mmol), and 0.2 M KH2PO4 solution (40 mL). The mixture was stirred overnight at 50° C. The solvent was evaporated, and H2O and CHCl3 were added; the organic layer was washed with brine, dried (Na2SO4) filtered and concentrated. The resulting residue was flash chromatographed on silica gel, eluting with 1:1 CHCl3 :hexanes switching to 19:1 CHCl3 :EtOAc, to afford the title compound. 1H NMR (CDCl3) δ 1.40-1.46 (m, 27 H), 2.07 (s, 3 H), 7.00 (s, 1 H), 7.05 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18](=[O:23])[CH2:19]2>O1CCCC1>[CH3:14][N:15]1[CH:20]2[CH2:21][CH2:22][CH:16]1[CH2:17][C:18]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)([OH:23])[CH2:19]2
Reactant: CN1C2CCC1CC(=O)C2
Reactant: Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CC3CCC(C2)N3C)cc1

Procedure:
The title compound was prepared from 4-bromotoluene (13.9 g, 81.4 mmol), n-butyllithium in hexanes (31.2 mL, 2.5 M; 78 mmol) and 8-methyl-8-azabicyclo[3.2.1]-octan-3-one (5 g, 35.9 mmol) in anhydrous tetrahydrofuran (40 mL). Yield 3.5 g (42%) as a white solid, m.p. 247-249° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1)=[O:6].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([BH3-])#N.[Na+].C1COCC1>O.C(O)(=O)C>[CH2:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1)=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2ccc(C(=O)c3cccc(NCc4ccccc4)c3)cc2N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26 %

Procedure:
A dry round bottom flask was charged with 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.100 g, 0.397 mmol), benzaldehyde (0.042 g, 0.397 mmol) and acetic acid (0.1 mL). The mixture was allowed to stir for 5 hours at room temperature. A 1M solution of sodium cyanoborohydride in THF (1.19 mL, 1.19 mmol) was then added, and the mixture was allowed to stir for 45 minutes. Subsequently the reaction mixture was poured into H2O (˜30 mL) and allowed to stir for 15 minutes. The suspension was filtered and the filtrate was extracted with EtOAc (3×˜10 mL). The organics were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford a brown oil. The brown oil was then chromatographed over silica (97/3, chloroform/methanol w/0.5% NEt3) to afford 6-[3-(benzylamino)benzoyl]-1,3-dihydro-2H-indol-2-one in 26% yield (0.035 g, 0.103 mmol).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]1(=[O:13])[NH:11][C:10](=[O:12])[CH2:9][CH2:8]1.Br[CH2:15][C:16]1[C:25]([F:26])=[C:24]2[C:19]([C:20]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[N:23]2)=[CH:18][CH:17]=1>CN(C=O)C>[O:13]=[C:7]1[CH2:8][CH2:9][C:10](=[O:12])[N:11]1[CH2:15][C:16]1[C:25]([F:26])=[C:24]2[C:19]([C:20]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:21][C:22]([C:27]([O:29][CH3:30])=[O:28])=[N:23]2)=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)N1
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CBr)c(F)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CN3C(=O)CCC3=O)c(F)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cs2CO3 (1.745 g, 5.35 mmol) was added to a solution of Succinimide (0.292 g, 2.94 mmol) and methyl 7-(bromomethyl)-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylate 7-10 (1.05 g, 2.68 mmol) in DMF (13.39 ml) and the reactant stirred at rt for 30 min. The reaction was quenched with KH2PO4 (saturated) and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The solvent was removed in vacuo and the residue purified by column chromatography on a silica gel column, eluting with EtOAc/hexane (0-100%) to afford Methyl 7-[(2,5-dioxopyrrolidin-1-yl)methyl]-8-fluoro-4-(4-fluorophenyl)quinoline-2-carboxylate 7-11 as a white solid, LCMS shows the compound is 90% pure, LRMS m/z (M+H)+ 411.2 found, 411.1 required.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:22](#[N:25])[CH:23]=[CH2:24]>N1C=CC=CC=1.O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:24][CH2:23][C:22]#[N:25])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC#N
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1CCC#N
Temperature: 90 °C
Yield: 86 %

Procedure:
To a solution of Example 109A (65 mg, 0.200 mmol) in pyridine (1 mL) and water (1 mL) was added acrylonitrile (0.185 ml, 3.00 mmol) and the reaction heated at 90° C. for 7 hr. The reaction was concentrated and the residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexane) to afford the title compound (65 mg, 86%). 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.36 (s, 9H) 3.05 (t, J=6.44 Hz, 2H) 3.90 (s, 3H) 4.40 (t, J=6.44 Hz, 2H) 6.74 (s, 1H) 6.92 (d, J=8.81 Hz, 1H) 7.35 (dd, J=8.81, 3.05 Hz, 1H) 7.90 (d, J=3.05 Hz, 1H); MS (DCI/NH3) m/z 378 (M+H)+. Anal. calcd C18H20ClN3O2S: C, 57.21; H, 5.33; N, 11.12. Found: C, 56.93; H, 5.42; N, 10.92.