Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]C)=[O:31])=[O:26])=[CH:23][CH:22]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[N:13]2)=[CH:8][CH:7]=1.O1CCCC1.[OH-].[Na+]>CO>[CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:21]1[CH:35]=[CH:34][C:24]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:22]=1)[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[N:13]2)=[CH:10][CH:11]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2)CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(Cc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.6 %

Procedure:
Methyl 3-(4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pentan-2-yl)benzamido)propanoate (4.2 mg, 0.0080 mmol) was dissolved in 1:1 methanol: tetrahydrofuran (0.50 mL). 1N NaOH (0.024 mL) was added and the reaction was stirred at room temperature for 18 hours. The reaction was concentrated to dryness. The crude residue was taken up in water and acidified to pH=2 with 1N HCl. This solution was extracted three times with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated to give (+/−)-3-(4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pentan-2-yl)benzamido)propanoic acid (4.0 mg, 100%), as a white solid. 1H NMR (400 MHz, CD3OD, δ): 8.62 (s, 1H), 7.91 (s, 1H), 7.69-7.64 (m, 2H), 7.58-7.53 (m, 2H), 7.22-7.17 (m, 2H), 7.14-7.09 (m, 2H), 3.62-3.55 (m, 2H), 3.09-2.96 (m, 2H), 2.90-2.81 (m, 1H), 2.60 (t, J=6.9 Hz, 2H), 1.78-1.68 (m, 1H), 1.52 (ddd, J=13.7, 9.2, 4.9 Hz, 1H), 1.39-1.25 (m, 1H), 0.83 (dd, J=6.4, 4.7 Hz, 6H). MS (M+1): 488.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C(N(CC)CC)C.[Cl:22][C:23]1[C:28]([C:29](Cl)=[O:30])=[C:27]([Cl:32])[N:26]=[CH:25][N:24]=1>ClCCl>[Cl:22][C:23]1[C:28]([C:29]([NH:1][C:2]2[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)=[O:30])=[C:27]([Cl:32])[N:26]=[CH:25][N:24]=1
Reactant: COc1cc(N)cc(NS(C)(=O)=O)c1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2c(Cl)ncnc2Cl)cc(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
N-(3-Amino-5-methoxyphenyl)methanesulfonamide (1 g, 87% purity, 4.02 mmol) was dissolved in dichloromethane (36 ml) and triethylamine (1.35 ml, 9.65 mmol) was added. Then a solution of 4,6-dichloropyrimidine-5-carbonyl chloride (1.52 g, 67% purity, 4.82 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was added dropwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude was purified by flash chromatography (0% to 40%, hexane-ethyl acetate) using an Isolera® Purification System to give 617 mg (28% yield) of the title compound as a reddish oil. Purity 73%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:13]O.C([O-])=O.[Na+].O>C(O)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1c[nH]c2cc(F)ccc12
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1c[nH]c2cc(F)ccc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 59.9 %

Procedure:
To a solution of 6-fluoro-1H-indole-3-carbaldehyde (0.97 g) in 90% formic acid (25 mL) were added hydroxylamine (0.65 g) and sodium formate (0.81 g), and this mixture was stirred at 100° C. for 3 hours. After cooling to ambient temperature, water was added to this reaction mixture and the precipitated solid was collected by filtration, and washed with water, dried to give the title compound (0.57 g).
Reaction SMILES: [Na].[C:2]([CH2:4]P(=O)(OCC)OCC)#[N:3].[CH3:13][O:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH2:17]1.C(O)(=O)C>C(O)C>[CH3:13][O:14][CH2:15][C@@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]3[CH2:29][CH2:30][C:31](=[CH:4][C:2]#[N:3])[CH2:32][CH2:33]3)=[CH:24][CH:23]=2)[CH2:17]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COC[C@H]1CN(c2ccc(C3CCC(=O)CC3)cc2)C(=O)O1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: COC[C@H]1CN(c2ccc(C3CCC(=CC#N)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
0.66 g of sodium were dissolved in 70 ml of ethanol under argon. Thereafter, 5.08 g (=4.51 ml) of diethyl cyanomethylphosphonate dissolved in 20 ml of ethanol were added at 20°. The mixture was stirred at room temperature for 30 minutes and then 2.9 g of (R)-5-methoxymethyl-3-[4-(4-oxo-cyclohexyl)-phenyl]-oxazolidin-2-one were added. Thereafter, the reaction mixture was stirred at reflux for a further 1 hour, cooled to room temperature, adjusted to pH 6 with about 1 ml of glacial acetic acid and evaporated in a vacuum. The residue was dissolved in dichloromethane and washed three times with water, subsequently dried and evaporated. The excess phosphoric ester, which was still present in the residue, was distilled off at a bath temperature of ~100° and 0.03 mm vacuum (bP0.03 34°). The residue remaining (3.2 g) was chromatographed over 250 g of silica gel using medium pressure. Elution was carried out with dichloromethane, dichloromethane/ethyl acetate 20:1. The fractions which were pure according to thin-layer chromatography were combined and concentrated in a vacuum. 2.6 g of mixture of (R)- and (S)-[4-[4-[(R)-5-methoxymethyl-2-oxo-oxazolidin-3-yl]-phenyl]-cyclohexylidene]-acetonitrile (~1:2 E/Z or Z/E) were obtained as a slightly turbid oil. This was used directly for the reduction.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].C(=O)([O-])[O-].[K+].[K+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[C:13]1([CH2:12][O:4][C:1](=[O:5])[C:2]#[CH:3])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: C#CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
To a stirring mixture of propiolic acid (1.79 mL (2.04 g), 28.65 mmol) and potassium carbonate (4.87 g, 35.2 mmol) in anhydrous DMF (40 mL) was added benzyl bromide (3.78 mL (5.43 g of 99% pure), 31.4 mmol). The reaction mixture was stirred at room temperature for 16 h. The resulting heterogeneous mixture was poured into 40 mL of H2O and was extracted with ethyl ether (3×40 mL). The combined ether extracts were dried (Na2SO4). Filtration and concentration provided 12.16 g of crude product, which upon high vacuum distillation yielded 2-propynoic acid phenylmethyl ester (bp 60° C. 0.5 mm) as a clear oil (3.57 g, 22.3 mmol) in 78% yield.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([CH2:17][O:18][CH2:19][O:20][CH3:21])([CH2:12][O:13][CH2:14][O:15][CH3:16])C(O)=O)[CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C([N:31](CC)CC)C.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH2:31])([CH2:17][O:18][CH2:19][O:20][CH3:21])[CH2:12][O:13][CH2:14][O:15][CH3:16])[CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: COCOCC(COCOC)(C(=O)O)c1cccc(Br)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COCOCC(N)(COCOC)c1cccc(Br)n1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a suspension of 2-(6-bromo-pyridin-2-yl)-3-methoxymethoxy-2-methoxymethoxymethyl-propionic acid (18.0 g) in toluene (150 ml)diphenyl phosphoryl azide (4.08 g, 148.27 mmol) and triethylamine (14.97 g [20.6 ml], 148.27 mmol) were added at rt and stirred at 100° C. for 15 h. Reaction mixture was cooled to rt and concentrated under reduced pressure. The residue obtained was dissolved in THF (600 ml) and 20% NaOH solution was added at rt and stirred for 1 h. Solvent was removed under reduced pressure and the product formed was extracted with ethyl acetate. Organic layer was washed with brine, followed by dried over MgSO4. The organic portion was concentrated under reduced pressure and column chromatographic purification of the crude product using 35% ethyl acetate in hexane furnished title compound as a brown liquid. Yield=15.0 g (88% [2 steps]). TLC (70% ethyl acetate in hexane) Rf=0.51; LCMS: RtH7=0.28, [M+1]=335.0 and 337.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[C:12](=O)([O:18]C(C)(C)C)[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][CH:3]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-aminobenzotrifluoride (100 g, 0.62 mol) and di-tert-butyl carbonate (150 g, 0.69 mol) in anhydrous THF (400 mL) is heated at reflux temperature for 6 hours and then cooled to room temperature. Most of the solvent is removed using a rotary evaporator and the non-volatile material that remains is triturated with water (1000 mL) to form a solid. The solid is isolated by filtration and washed with additional water (500 mL), then washed with hexanes (500 mL) to give 4-(BOC-amino)benzotrifluoride (m.p. 123–124° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=2)[CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)#[CH:18]>>[N:11]1([C:9]2[N:10]=[C:5]3[N:4]=[CH:3][C:2]([C:18]#[C:17][C:19]4[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=4)=[CH:7][N:6]3[N:8]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C#Cc1cccc(C)c1
Reactant: Brc1cnc2nc(N3CCOCC3)nn2c1
Product: Cc1cccc(C#Cc2cnc3nc(N4CCOCC4)nn3c2)c1

Procedure:
The title compound, a brown solid, MS: m/e=320.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47, step 1) and ethynyl-3-methylbenzene.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([N:22]3[C:21]([CH3:20])=[CH:25][C:24]([CH3:26])=[N:23]3)[N:10]=[C:9]3[C:5]=2[N:6]([CH3:11])[CH:7]=[N:8]3)=[CH:14][CH:15]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Cn1cnc2nc(Cl)nc(Nc3ccc(Cl)cc3)c21
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3c(ncn3C)n2)n1

Procedure:
Was prepared according to Example 6 from (2-chloro-7-methyl-7H-purin-6-yl)-(4-chloro-phenyl)-amine and 3,5-dimethylpyrazole.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:28]([O:29]C(=O)C)[C@H:27]([O:33]C(=O)C)[C@@H:26]([CH2:37][O:38]C(=O)C)[O:25][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1)[C@@H:6]1[O:25][C@H:26]([CH2:37][OH:38])[C@@H:27]([OH:33])[C@H:28]([OH:29])[C@H:5]1[OH:4]
Reactant: COC(=O)c1ccc(Cc2ccccc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of 2-(4-methoxycarbonylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside (0.066 g) in methanol (5 mL) was added sodium methoxide (0.006 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to give 2-(4-methoxycarbonylbenzyl)phenyl β-D-glucopyranoside (0.040 g).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].O.C([O:11][C:12]1[C:17]([CH3:18])=[C:16]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:15][C:14](=[O:28])[C:13]=1[CH3:29])(=O)C>CO>[CH2:21]([O:20][CH2:19][C:16]1[O:15][C:14](=[O:28])[C:13]([CH3:29])=[C:12]([OH:11])[C:17]=1[CH3:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)Oc1c(C)c(COCc2ccccc2)oc(=O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(COCc2ccccc2)oc(=O)c(C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
K2CO3 (3.0 g) and water (10 ml) were added to a solution of 4-acetyloxy-6-(benzyloxy)methyl-3,5-dimethyl-2H-pyran-2-one (6.08 g) in MeOH (100 ml), and after stirring at room temperature overnight, the reaction solution was celite filtered and the mother liquor was concentrated under reduced pressure. Water was added to the residue, extraction was performed with AcOEt, and the organic layer was dried with Na2SO4 and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=5/1→1/1) to obtain 6-(benzyloxy)methyl-3,5-dimethyl-4-hydroxy-2H-pyran-2-one.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)[CH2:11]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=[O:37].ClC1C=CC=C(C(OO)=O)C=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2]([CH3:1])=[O:37])=[CH:8][CH:7]=2)[N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)[CH2:11]2)=[CH:31][CH:30]=1)#[N:33]
Reactant: CSc1ccc(C(c2ccc(C#N)cc2)N2CC[C@@H](NC(=O)c3ccc(C#N)cc3)C2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1ccc(C(c2ccc(C#N)cc2)N2CC[C@@H](NC(=O)c3ccc(C#N)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of (3R)-1-[(4-methylthiophenyl)(4-cyanophenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine (45.3 mg) in methylene chloride (2 mL) was added trifluoroacetic acid (31 μL) under ice-cooling and the mixture was stirred at room temperature or 30 minutes. Thereto was added m-chloroperbenzoic acid (23 mg) under ice-cooling and the mixture was stirred at the same temperature for 1 hour and then stirred at room temperature for 4 hours. To the reaction mixture was added an aqueous saturated sodium hydrogen carbonate solution and the organic layer was extracted by a diatomaceous earth column (Chem Elut; VARIAN Inc.). The extract was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; chloroform/methanol=98:2→90:10). The resultant product was dissolved in t-buthanol and lyophilized to give (3R)-1-[(4-cyanophenyl)-(4-methylsulfinylphenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine (42.5 mg, yield: 91%) as a powder. MS(APCI) m/z: 469 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:18]>C(Cl)Cl.CO>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([C:14]([O:16][CH3:18])=[O:15])[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(C(=O)O)c2ccc(F)cc2O1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CC(C)(C)Oc2cc(F)ccc21
Yield: 75.5 %

Procedure:
To 7-fluoro-2,2-dimethyl-3,4-dihydro-2H-chromene-4-carboxylic acid (0.280 g, 1.25 mmol) in CH2Cl2 (5 mL) and MeOH (1 mL) was added TMSCHN2 (0.937 mL, 1.87 mmol) dropwise. After the addition, the reaction was concentrated, loaded onto silica gel, and the product eluted using a gradient of 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes to provide the title compound (0.225 g, 75.6% yield).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C:18]4[S:19][C:20]5[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=5[N:22]=4)=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:29]I>CN(C=O)C>[CH3:29][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][C:18]3[S:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:12]=2)[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:9]1
Reactant: c1ccc2sc(Oc3ccc4c(CN5CCOCC5)c[nH]c4c3)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(CN2CCOCC2)c2ccc(Oc3nc4ccccc4s3)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
To a cooled (0° C.) solution of 2-(3-morpholin-4-ylmethyl-1H-indol-6-yloxy)-benzothiazole (280 mg, 0.77 mmol) in DMF (4 mL) was added NaH (95%, 29 mg, 1.15 mmol) and the resulting suspension was stirred (0° C., 15 min) then warmed (rt, 30 min). The reaction mixture was cooled (0° C.) and treated with methyliodide (72 μL, 163 mg, 1.15 mmol) and then warmed (rt, 30 min). The reaction mixture was partitioned with EtOAc and brine (20 mL each). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH:DCM (0-20%) to provide the title compound as a clear oil (126 mg, 43%). MS (ESI): mass calcd. for C21H21N3O2S, 379.4; m/z found, 380.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.79 (d, J=8.6, 1H), 7.76 (d, J=7.7, 1H), 7.66 (d, J=8.0, 1H), 7.41-7.38 (m, 1H), 7.29 (d, J=2.1, 1H), 7.29-7.25 (m, 1H), 7.12 (dd, J=8.6, 2.1, 1H), 3.77 (5, 3H), 3.74 (t, J=4.6, 4H), 3.71 (5, 2H), 2.53 (br s, 4H).
Reaction SMILES: [C:1]([C:4]1[O:9][Si:8]([CH3:11])([CH3:10])[CH:7]([CH3:12])[CH2:6][N:5]=1)([CH3:3])=[CH2:2].[CH3:13][OH:14]>>[CH3:10][Si:8]([CH3:11])([O:14][CH3:13])[CH:7]([CH3:12])[CH2:6][NH:5][C:4](=[O:9])[C:1]([CH3:3])=[CH2:2]
Reactant: CO
Reactant: C=C(C)C1=NCC(C)[Si](C)(C)O1
Product: C=C(C)C(=O)NCC(C)[Si](C)(C)OC

Procedure:
The addition of 2 parts methanol to 1 part 2-isopropenyl-4,4,5-trimethyl-1-aza-3-oxa-4-silacyclohex-1-ene resulted inthe instantaneous evolution of heat and completion of the reaction. Removalof methanol by stirring the reaction mixture in a vacuum for 1 hour at roomtemperature yielded the essentially pure methanol adduct, N-[2-(dimethylmethoxysilyl)propyl]methacrylamide.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[CH2:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:24][CH2:25][C:26]#[CH:27]>CCCCCCC>[C:28]1([CH2:23][CH2:24][CH2:25][C:26]#[C:27][C:6]2[CH:5]=[C:4]([O:3][C:2]([F:1])([F:21])[F:22])[CH:9]=[CH:8][CH:7]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OC(F)(F)F)cc2)cc1
Reactant: C#CCCCc1ccccc1
Solvent: CCCCCCC
Product: FC(F)(F)Oc1cccc(C#CCCCc2ccccc2)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-trifluoromethoxy-phenyl ester and pent-4-ynyl-benzene. Chromatography eluent: heptane; yield (140 mg, 93%); 1H NMR δ (CDCl3): 7.41 (d, J=8.32 Hz, 2H), 7.38-7.28 (m, 2H), 7.27-7.18 (m, 3H), 7.21 (d, J=8.34 Hz, 2H), 2.77 (t, J=7.12 Hz, 2H), 2.45 (t, J=7.13 Hz, 2H), 1.93 (p, J=7.21 Hz, 2H); LCMS m/z: 300.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.[ClH:31]>>[ClH:31].[CH3:18][O:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:28]3[CH2:29][CH2:30][N:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[CH2:26][CH2:27]3)=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Agent: Cl
Product: COc1nn(-c2ccccc2)c2cc(N3CCN(c4ccncc4)CC3)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 57 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 1-pyridin-4-yl-piperazine, followed by de-protection with HCl.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:11][C:10]1[C:5]2[C:6](=[N:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2nc(F)ccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nc(CBr)c2ccc(F)nc21
Temperature: 25 °C

Procedure:
A stirring solution of 8.88 g (35.2 mmol) of 37-4, 6.88 g (38.7 mmol) of NBS and 851 mg (3.52 mmol) of benzoyl peroxide in 250 mL of CCl4 was heated to reflux for 6 hours. The reaction was stopped after a 66% conversion of starting material as determined by LC/MS. The reaction mixture was cooled to room temperature, filtered through a pad of Celite to remove precipitated succinimide, and the filtrate concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-70% ethyl acetate/hexanes) to afford the title product as a solid. 1H NMR (CDCl3): 1.75 (s, 9H), 4.75 (s, 2H), 7.00 (d, 1H), 8.30 (t, 1H).
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=3)[C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=3)[C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3cc(C(F)(F)F)cnc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)sc2cc(C(F)(F)F)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a mixture of ethyl 3-[{[4-({cyclohexyl[3-methyl-6-(trifluoromethyl)thieno[3,2-b]pyridin-2-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (310 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (284 mg, 96%) as a white solid.
Reaction SMILES: [H-].[Na+].[O:3]([CH2:10][CH2:11][NH:12][C:13]([C:15]1[NH:16][C:17](=[O:33])[C:18]2[C:19]([N:32]=1)=[N:20][C:21]1[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH3:31])[CH:22]=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:35][C:36]([OH:38])=[O:37]>CN(C)C=O>[O:3]([CH2:10][CH2:11][NH:12][C:13]([C:15]1[N:16]([CH2:35][C:36]([OH:38])=[O:37])[C:17](=[O:33])[C:18]2[C:19]([N:32]=1)=[N:20][C:21]1[C:26]([CH:27]=2)=[CH:25][C:24]([O:28][CH3:29])=[C:23]([O:30][CH3:31])[CH:22]=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)CBr
Reactant: COc1cc2cc3c(=O)[nH]c(C(=O)NCCOc4ccccc4)nc3nc2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2cc3c(=O)n(CC(=O)O)c(C(=O)NCCOc4ccccc4)nc3nc2cc1OC
Temperature: 25 °C

Procedure:
A mixture of sodium hydride (0.22 g., 4.6 mM of 50%); N-(2-phenoxyethyl) 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxamide (1.0 g., 2.2 mM); bromoacetic acid (0.319 g., 2.3 mM) and N,N-dimethylformamide (50 ml.) is refluxed for 6 hours and then cooled to room temperature. The precipitate which forms is separated by filtration and dried under vacuum to give 0.476 g. (43%) of product; m.p. 310°-315° C.