Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[C:12](Cl)([Cl:14])=[O:13]>C(Cl)(Cl)Cl>[Cl:14][C:12]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)OCc1ccccc1[N+](=O)[O-]
Temperature: 65 °C

Procedure:
15.3 g. (0.1 mole) of o-nitrobenzyl alcohol is dissolved in 200 ml. of chloroform in a glass bomb tube. The tube is cooled in an ice bath and phosgene is introduced until 20 g. has been condensed. The tube is sealed and heated at 65° C. for 4 hours. The solvent and excess reagent are then removed by distillation and the product, o-nitrobenzyl chloroformate, is obtained as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][NH:18][C:17](=[O:21])[CH:16]1[CH2:22][CH2:23][S:24][CH3:25])=O)(C)(C)C>C(SCC)C>[CH3:25][S:24][CH2:23][CH2:22][CH:16]1[NH:15][CH2:20][CH2:19][NH:18][C:17]1=[O:21]
Reactant: CSCCC1C(=O)NCCN1C(=O)OC(C)(C)C
Solvent: CCSCC
Solvent: O=C(O)C(F)(F)F
Product: CSCCC1NCCNC1=O

Procedure:
Trifluoroacetic acid (30 ml.) is added at 0° to a stirred solution of 4-t-butoxycarbonyl-3-[2-(methylthio)ethyl]piperazinone (XVII, Example 43, 2.6 g., 0.0095 mole) in diethyl sulfide (20 ml.). After 1 hour the solvents are removed and the residual oil is partitioned between chloroform (300 ml.) and 5 N sodium hydrochloride solution (10 ml.). The chloroform is washed with water (2×10 ml.) and the chloroform is removed under reduced pressure. The residual oil is chromatographed on silica gel eluted with methanol:chloroform (1:9), the appropriate fractions are pooled and concentrated to give a solid which upon recrystallization from ethyl acetate:SSB gives the title compound, m.p. 68°-70°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:26]#[N:27])=[C:11]([C:19]2[CH:24]=[CH:23][N:22]=[C:21](F)[CH:20]=2)[S:12][C:13]=1[C:14]1[NH:18][N:17]=[CH:16][CH:15]=1.COC1C=C(OC)C=CC=1C[NH2:33].CCN(C(C)C)C(C)C.C(O)CCC.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:33][C:21]1[CH:20]=[C:19]([C:11]2[S:12][C:13]([C:14]3[NH:18][N:17]=[CH:16][CH:15]=3)=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:10]=2[C:26]#[N:27])[CH:24]=[CH:23][N:22]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: N#Cc1c(-c2ccnc(F)c2)sc(-c2ccn[nH]2)c1-c1ccc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: N#Cc1c(-c2ccnc(N)c2)sc(-c2ccn[nH]2)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
4-(2,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)-5-(1H-pyrazol-5-yl)thiophene-3-carbonitrile (0.372 g, 0.903 mmol), 2,4-dimethoxybenzylamine (821 mg, 4.91 mmol) and DIPEA (317 mg, 2.46 mmol) in 1-Butanol (3.74 mL, 40.9 mmol) was irradiated in microwave at 160° C. for 2 hr under nitrogen. The solvent was evaporated and the residue was purified by column chromatography to afford an intermediate which was in the next step. LC/MS (FA) ES+ 562, 564. The above intermediate was dissolved in DCM (26 mL, 4.0E2 mmol) and TFA (8.5 mL, 110 mmol). The mixture was stirred at rt for 30 min. The mixture was concentrated and the residue was basified by ammonium hydroxide. The solvent was evaporated and the mixture was purified by column chromatography to afford the title compound (0.375 g, 100%). LC/MS (FA) ES+ 412, 414. 1H NMR (400 MHz, d4-methanol) δ: 8.00 (1H, d, J=6.62 Hz), 7.77 (1H, d, J=2.01 Hz), 7.59 (1H, d, J=2.45 Hz), 7.56 (1H, dd, J=8.26, 2.02 Hz), 7.49 (1H, d, J=8.27 Hz), 7.38 (1H, d, J=1.59 Hz), 7.24 (1H, dd, J=6.64, 1.77 Hz), 5.58 (1H, d, J=2.38 Hz)
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][C:8]3=[O:13])=[CH:4][C:3]=2[O:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]1[O:12][C:11]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][CH:8]3[OH:13])=[CH:4][C:3]=2[O:2]1
Reactant: O=C1CCc2cc3c(cc21)OCO3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC1CCc2cc3c(cc21)OCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
A solution of 30 g of 5,6-methylenedioxyindan-1-one in 120 ml of tetrahydrofuran was added dropwise to a suspension of 2.4 g of lithium aluminum hydride in 160 ml of anhydrous tetrahydrofuran under cooling with ice. The mixture was stirred at room temperature overnight. 2.4 ml of water, then 2.4 ml of 15% aqueous sodium hydroxide solution and finally 7.2 ml of water were added thereto and insoluble substances were filtered off. The filtrate was distilled and the residue was washed with diisopropyl ether to obtain 24.3 g of the intended compound in the form of faint brown crystals.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:25])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc([N+](=O)[O-])ccc3nc21
Temperature: 0 °C
Yield: 65 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-nitroanthranilic acid (3.8 g, 13.77 mmol) and POCl3 (20 ml) was refluxed for 8 hours. The reaction mixture was poured into ice-water, neutralized with concentrated NH4OH and the resulting solid was collected by filtration, washed with water and dried to afford 2.5 g (65%) of 1-ethyl-4-chloro-6-nitro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[BrH:12].OO.N>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([Br:12])[N:6]=1)=[O:4]
Reactant: Br
Reactant: COC(=O)c1ccc(N)cn1
Agent: N
Agent: OO
Product: COC(=O)c1ccc(N)c(Br)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5.00 g 5-amino-pyridine-2-carboxylic acid methyl ester in 75 mL of a 48% aqueous solution of hydrobromic acid, 3.39 mL of a 32% aqeous solution of hydrogen peroxide were added. The mixture was stirred at room temperature for 2 hours, then additional 0.80 mL hydrogen peroxide solution were added. After stirring for 1 hour the reaction mixture was cooled down and brought to pH 8 by addition of concentrated aqueous ammonia. The mixture was extracted with 300 mL ethyl acetate. The aqueous layer was washed with additional ethyl acetate and then the combined organic phases were dried over sodium sulfate. After filtration the solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel eluting with a n-heptane/ethyl acetate gradient. Yield: 2.83 g MS(ES+): m/e=231.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16])=[O:14]
Reactant: COc1ccc(Br)cc1NC(=O)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Product: COc1ccc(C#C[Si](C)(C)C)cc1NC(=O)C(F)(F)F
Yield: 37.9 %

Procedure:
N-[5-Bromo-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (5.79 g, 19.4 mmol) and (trimethylsilyl)acetylene (4.1 mL, 29.1 mmol) were coupled according to the procedure of Example 56, Step B to give the desired product (2.32 g, 38%). ES-LC/MS m/z=314 [M−H]−.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]3[O:20][CH2:19][O:18][C:15]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1.C([O:24][C:25](=[O:27])[CH3:26])(=O)C.[N+:28]([O-:31])([OH:30])=[O:29].[C:32]([OH:35])(=[O:34])[CH3:33]>>[C:25]([OH:24])(=[O:27])/[CH:26]=[CH:33]\[C:32]([OH:35])=[O:34].[N+:28]([O-:31])([OH:30])=[O:29].[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]3[O:20][CH2:19][O:18][C:15]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: OCCCCCNc1nccc2cc3c(cc12)OCO3
Solvent: O=[N+]([O-])O
Product: O=C(O)/C=C\C(=O)O
Temperature: 3 °C
Reaction time: 0.33 h

Procedure:
A solution of 0.835 g. of 1-(5-hydroxypentyl)amino-6,7-methylenedioxyisoquinoline and 1 ml. of acetic acid is added dropwise to a stirred mixture of 1.32 ml. of acetic anhydride and 0.44 ml. of nitric acid at a temperature of minus 3°C. The reaction mixture is stirred for about 20 minutes at about minus 3°C., and then added to an excess of ice-cold aqueous ammonia solution and twice extracted with ethyl acetate. The combined organic extracts are dried, filtered and evaporated in vacuo to an oil which is redissolved in chloroform. The resulting solution is passed through silica gel to obtain 0.965 g. of an oil of the free base of the above title compound. This oil is dissolved in methylene chloride and 0.5 g. of maleic acid is added. The resulting solution is filtered, evaporated to a small volume and diethyl ether added to crystallize a material which is then recrystallized from methanol/diethyl ether to obtain 1-(5-hydroxypentyl)amino-6,7-methylenedioxyisoquinoline nitrate maleate, m.p. 138°-139.5°C.
Reaction SMILES: C12CC3CC(CC(C3)C1CC(O)=O)C2.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH:33]1[CH2:42][N:43]=[C:44]=[O:45])[CH2:39]2.[F:46][C:47]1[C:48](=[O:54])[NH:49][C:50](=[O:53])[NH:51][CH:52]=1>N1C=CC=CC=1>[CH:34]12[CH2:40][CH:38]3[CH2:37][CH:36]([CH2:41][CH:32]([CH2:39]3)[CH:33]1[CH2:42][NH:43][C:44]([N:51]1[CH:52]=[C:47]([F:46])[C:48](=[O:54])[NH:49][C:50]1=[O:53])=[O:45])[CH2:35]2
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C=NCC1C2CC3CC(C2)CC1C3
Agent: O=C(O)CC1C2CC3CC(C2)CC1C3
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: O=C(NCC1C2CC3CC(C2)CC1C3)n1cc(F)c(=O)[nH]c1=O

Procedure:
The reaction of 2-adamantylacetic acid and diphenyl phosphoryl azide in dry pyridine provided a solution comprising 2-adamantylmethyl isocyanate [I.R.: 2260 cm-1 ], which was reacted with 5-fluorouracil to provide 1-[N-(2-adamantylmethyl)carbamoyl]-5-floururacil substantially in the similar method to that of Example 45.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[C:21]([CH3:29])=[N:22][C:23]([O:27][CH3:28])=[N:24][C:25]=1[CH3:26].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[C:21]([CH3:29])=[N:22][C:23]([O:27][CH3:28])=[N:24][C:25]=3[CH3:26])[N:12]([CH2:13][CH2:14][CH2:15][OH:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(C)nc(OC)nc2C)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)nc(OC)nc3C)n(CCCO)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A mixture of methyl 4-chloro-2-[(3-hydroxypropyl)amino]-3-{[(2-methoxy-4,6-dimethylpyrimidin-5-yl)carbamothioyl]amino}benzoate (13.1 g, 28.9 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.10 g, 31.8 mmol), and triethylamine (4.4 mL) in tetrahydrofuran (96 mL) was stirred at 60° C. for 2 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with tetrahydrofuran/ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with ethyl acetate/diisopropyl ether to give the title compound as a pale yellow powder (11.9 g, 28.3 mmol, 98%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:7](=[O:25])[C@@:6]2([NH:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1)=[O:37])[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2].[O:50]1[CH2:53][C:52](=O)[CH2:51]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[Na].[OH-].[Na+]>ClCCl.O.C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:7](=[O:25])[C@@:6]2([NH:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([CH:44]2[CH2:45][CH2:46][N:47]([CH:52]3[CH2:53][O:50][CH2:51]3)[CH2:48][CH2:49]2)[CH2:40][CH2:39]1)=[O:37])[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2]
Reactant: O=C1COC1
Reactant: CCOc1ncccc1[C@]1(NC(=O)N2CCN(C3CCNCC3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1ncccc1[C@]1(NC(=O)N2CCN(C3CCN(C4COC4)CC3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Reaction time: 0.08 h
Yield: 24.4 %

Procedure:
In a 100 ml 3-necked flask, 100 mg (0.145 mmol) of (S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-4-(piperidin-4-yl)-piperazine-1-carboxamide were stirred in 4 ml of dichloromethane. 10.45 mg (0.145 mmol) of oxetan-3-one dissolved in 2 ml of dichloromethane were added and the mixture was stirred for 5 min. 30.7 mg of Na2SO4 were added and the mixture was stirred for another 5 min. 17.41 mg of acetic acid were added and the reaction was stirred for another 30 min. 46.1 mg (0.217 mmol) of sodium triacetoxyhydroborate were added and the reaction was stirred overnight. 1 ml of 2N NaOH and then 7 ml of water were added and the mixture was extracted thrice with ethylacetate and water. The organic phase was died over MgSO4 and the solvent was removed. The resulting crude product was subjected to flash chromatography (silica gel/gradient from 0 to 5% methanol in dichloromethane) to yield 26.4 mg (24.4%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18]Br)=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].CO.[C:22]([O-])(O)=[O:23].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18][O:23][CH3:22])=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CBr
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1COC
Temperature: 70 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of compound 16A (31 mg, 0.09 mmol) in 1:1 MeOH:CH2Cl2 (2 mL) was added NaHCO3 (30 mg, 0.36 mmol). The reaction was kept at room temperature for 3 h, heated to 70° C. for 1 h, cooled to room temperature, concentrated to dryness, redissolved in CH2Cl2 and filtered. The filtrate was concentrated to give compound 17A as a yellow solid (26 mg, 98%).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:12]3[NH:13][CH:14]=[CH:15][N:16]=3)[CH:8]=2)[N:3]=1.N([O-])=[O:18].[Na+].[OH-].[NH4+]>S(=O)(=O)(O)O.O>[NH:16]1[CH:15]=[CH:14][N:13]=[C:12]1[C:7]1[CH:8]=[C:9]2[C:4](=[N:5][CH:6]=1)[NH:3][C:2](=[O:18])[CH:11]=[CH:10]2
Reactant: Nc1ccc2cc(-c3ncc[nH]3)cnc2n1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=c1ccc2cc(-c3ncc[nH]3)cnc2[nH]1
Temperature: 25 °C

Procedure:
To a mixture of 2-amino-6-(2-imidazolyl)-1,8-naphthyridine (211 mg., 1 mmole) in 40% sulphuric acid (2.5 ml.) at 5° C. is added with stirring sodium nitrite (69 mg., 1 mmole). The solution is allowed to warm to room temperature and then heated at 50° C. for 4 hours. The reaction mixture then is cooled to 5° C. and more sodium nitrite (40 mg., 0.57 mmole) added to ensure reaction goes to completion. The mixture then is heated at 50° C. for two hours, cooled to room temperature, diluted with water and neutralized with ammonium hydroxide affording 140 mg. of solid. The product is purified by dissolving in dilute acetic acid (5 ml.), treating the solution with charcoal, and neutralizing the filtered solution with a few drops of ammonium hydroxide. The product (100 mg., 47%) did not melt below 350° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([S:9][C:10]#N)[CH:6]=[CH:5][C:3]=1[NH2:4].CN(C)C=O.[S-2].[Na+].[Na+].I[C:21]1[CH:26]=[CH:25]C=[CH:23][CH:22]=1>O>[Br:1][C:2]1[CH:8]=[C:7]([S:9][C:10]2[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Ic1ccccc1
Reactant: N#CSc1ccc(N)c(Br)c1
Agent: [Na+]
Agent: [S-2]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Sc2ccccc2)cc1Br
Temperature: 50 °C

Procedure:
A solution of 2-bromo-4-thiocyanoaniline (91.6 g., 0.4 mole) and dimethylformamide is added dropwise to a solution of sodium sulfide (0.48 mole) and water, under nitrogen, and the resulting solution is heated at 50° C. for one hour. Cuprous oxide (34.33 g., 0.24 mole) and iodobenzene (97.9 g., 0.48 mole) are added and the mixture is heated at a heating bath temperature of 150° C. for 4.5 hours. The reaction is quenched with water, methylene chloride is added and the resulting mixture is filtered through filter aid to remove suspended solids. The aqueous and organic layers are separated, and the aqueous layer is extracted three times with methylene chloride. The methylene chloride extracts are combined, washed with water and dried. Removal of the drying agent and methylene chloride gives the desired product in 95% of the theoretical yield. A purified sample melts at 61°-63° C.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:10]([C:18]([C:20]2[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])=[N:22][O:23][C:24]=2[CH2:25]Cl)=[O:19])[N:9]=[N:8]1.C(N(CC)CC)C.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>ClCCl>[F:38][C:37]([F:39])([F:40])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:41])([F:1])[F:42])[CH:36]=1)[CH2:6][N:7]1[C:11]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[C:10]([C:18]([C:20]2[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])=[N:22][O:23][C:24]=2[CH2:25][N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:19])[N:9]=[N:8]1
Reactant: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1)c1c(-c2ccccc2Cl)noc1CCl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1)c1c(-c2ccccc2Cl)noc1CN1CCOCC1
Temperature: 25 °C
Yield: 93 %

Procedure:
Heat a mixture of [1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-[5-chloromethyl-3-(2-chloro-phenyl)-isoxazol-4-yl]-methanone (100 mg, 0.158 mmol), triethylamine (80 mg, 0.790 mL) and morpholine (0.79 mL) at 50° C. for 18 h. Cool to RT, dilute the mixture with dichloromethane (50 mL) and wash with water (4×40 mL). Dry the organic layer with anhydrous MgSO4, filter, and concentrate in vacuo. Purify the residue by flash chromatography on silica gel to give the title compound (93% yield) as a brown oil. MS (ES) 685.2 (M++1); TLC Rf=0.1 (75% EtOAc in hexanes).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2([C:32]([O:34]C(C)(C)C)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:21][CH2:20]1)=[O:16]>C(Cl)Cl.FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:10]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][C:26]2([C:32]([OH:34])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23][CH2:24]1)=[O:16]
Reactant: CC(C)(C)OC(=O)C1(CN2CCC(CNC(=O)N3C(=O)C4(CCCC4)c4ccccc43)CC2)CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CCN(CC2(C(=O)O)CCOCC2)CC1)N1C(=O)C2(CCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-{[4-({[(2′-oxospiro[cyclopentane-1,3′-indol]-1′(2′H)-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylate (2.3 g, 4.38 mmol, step 6 of Example 1) in CH2Cl2 (14 mL), trifluoroacetic acid (18 mL) was added at room temperature, and the mixture was stirred overnight at room temperature. The mixture was concentrated to give yellow oil, CH2Cl2 (200 mL) was added and washed with sat. NaHCO3 aq. (80 mL), dried over MgSO4, filtered and concentrated gave a syrup, which was chromatographed on a column of silica gel eluting with CH2Cl2/methanol (15:1) to give 2.1 g (quant.) of the title compound as white solid. Recrystallization from ethyl acetate/n-heptane gave white powder.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](OCC)=[O:24])=[C:17]([CH3:28])[C:16]=2[CH3:29])=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][CH:31]=2)[S:10][N:9]=1>>[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[C:17]([CH3:28])[C:16]=2[CH3:29])=[C:11]([C:30]2[CH:31]=[CH:32][C:33]([CH2:36][CH3:37])=[CH:34][CH:35]=2)[S:10][N:9]=1
Reactant: CCOC(=O)CCc1ccc(OCc2c(Cl)nsc2-c2ccc(CC)cc2)c(C)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2snc(Cl)c2COc2ccc(CCCO)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 156 following Step 2 by LAH reduction of ethyl 3-(4-((3-chloro-5-(4-ethylphenyl)isothiazol-4-yl)methoxy)-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=7.5 Hz, 2H), 7.32 (d, J=7.5 Hz, 2H), 6.98 (d, J=6.5 Hz, 1H), 6.75 (d, J=6.5 Hz, 1H), 4.90 (s, 2H), 2.92 (t, J=7.0 Hz, 2H), 2.65 (q, J=6.8 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H), 2.25 (s, 3H), 2.15 (s, 3H), 1.78 (t, J=7.6 Hz, 2H). LCMS (ESI, M/Z) for C23H26ClNO2S: 415.1, 417.1.
Reaction SMILES: ClC1C=C(C=CC=1Cl)OC1C=CC(C2[NH:13][C:14]3[C:15]([N:23]=2)=[N:16][C:17]([C:20]([NH2:22])=O)=[CH:18][CH:19]=3)=CC=1.NC1N=C(C#N)C=CC=1[N+]([O-])=O>[Pd].C(O)C>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:22])=[N:16][C:15]=1[NH2:23]
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(Oc4ccc(Cl)c(Cl)c4)cc3)nc2n1
Agent: [Pd]
Agent: N#Cc1ccc([N+](=O)[O-])c(N)n1
Solvent: CCO
Product: N#Cc1ccc(N)c(N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-[4-(3,4-Dichloro-phenoxy)-phenyl]-1H-imidazo[4,5-b]pyridine-5-carboxylic acid amide. A flask containing 6-amino-5-nitro-pyridine-2-carbonitrile (67 mg, 0.40 mmol), 10% palladium on carbon (catalytic) and ethanol (2.0 mL) was put under an atmosphere of H2 using a balloon. The mixture was stirred at room temperature for 3 h, and filtered through a pad of celite. The filtrate was concentrated to provide crude 5,6-diamino-pyridine-2-carbonitrile. A portion of this 5,6-diamino-pyridine-2-carbonitrile (89 mg, 0.66 mmol) was treated with 4-(3,4-dichloro-phenoxy)-benzaldehyde (177 mg, 0.66 mmol), Na2S2O5 (188 mg, 0.99 mmol) and N,N-dimethylacetamide (3.0 mL). The mixture was stirred at 120° C. for 24 h. The reaction mixture was then diluted with water (8 mL), and the resulting precipitate was collected by filtration. The crude filtrate, 2-[4-(3,4-dichloro-phenoxy)-phenyl]-1H-imidazo[4,5-b]pyridine-5-carbonitrile (35 mg, 0.09 mmol), was treated with boron trifluoride/acetic acid complex (461 μL) and water (10 μL), and held at 115° C. for 30 min. The reaction mixture was cooled to room temperature and diluted with 4 N NaOH (10 mL). The resulting precipitate was collected by filtration, washed with water, and dried to provide 34 mg (94%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]1([CH3:26])[C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:25])[O:13]1>O>[CH3:11][C:12]1([CH3:26])[O:13][C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:2]3[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=3)=[CH:18][C:17]1=2
Reactant: N#CCc1cccc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(CC#N)c3)cc21

Procedure:
Prepared according to the procedure B from 3-bromophenylacetonitrile and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl) boronic acid. White solid: mp 188-190° C. 1H-NMR (DMSO-d6) δ 10.33(s, 1H), 7.62 (m, 2H), 7.55 (m, 2H), 7.48 (d, 1H J=8.00 Hz), 7.33 (d, 1H, J=7.57 Hz), 6.99 (d, 1H, J=8.81 Hz) 4.09 (s, 2H), 1.67 (s, 6H); MS m/z 291(M−H). Anal. Calc. for (C18H16N2O2)2.0.3 H2O: C,72.61; H, 5.62; N, 9.41. Found: C, 73.00; H, 5.43; N, 8.81.