Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14](F)[CH:13]=1.[C:20](#[N:24])[CH:21]([CH3:23])[CH3:22]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([C:21]([CH3:23])([CH3:22])[C:20]#[N:24])[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: CC(C)C#N
Reactant: Fc1cc(F)cc(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cc(F)cc(Br)c1
Reaction time: 20 h
Yield: 100 %

Procedure:
At 2-5° C. a solution of lithium bis(trimethylsilyl)amide in THF (326 ml of 1 M, 326 mmol, 1.05 equiv.) was added dropwise into a solution of 1-bromo-3,5-difluorobenzene (60 g, 311 mmol, 1.0 equiv.) and isobutyronitrile (25.8 g, 373 mmol, 1.2 equiv.) in 360 mL of THF. After stirring for 20 h, 13% starting reagent remained so an additional 0.1 eq of lithium bis(trimethylsilyl)amide was added. After an additional 6 hr, 10% starting reagent remained so another 0.1 eq. of lithium bis(trimethylsilyl)amide and 0.1 eq. of isobutyronitrile were added. The reaction mixture was stirred overnight. The reaction mixture was quenched with a 1 N HCl solution, then concentrated down to remove some of the THF. The reaction mixture was extracted with methyl-tert-butyl ether (2 times) and concentrated under reduced pressure to get the crude product (75.3 g) which was used as is.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([S:9][CH3:10])[S:8][C:4]=2[CH:3]=1.[Cl:13][C:14]1[C:19]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:18][C:17](B2CC(C)(C)C(C)(C)C2)=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:14]1[C:19]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:18][C:17]([C:2]2[CH:12]=[CH:11][C:5]3[N:6]=[C:7]([S:9][CH3:10])[S:8][C:4]=3[CH:3]=2)=[CH:16][N:15]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3CC(C)(C)C(C)(C)C3)cnc2Cl)cc1
Reactant: CSc1nc2ccc(Br)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(SC)sc4c3)cnc2Cl)cc1
Temperature: 90 °C
Yield: 10.9 %

Procedure:
In a 15 mL sealed-pressure tube was added 6-bromo-2-(methylthio)benzo[d]thiazole (60 mg, 0.231 mmol), N-(2-chloro-5-(3,3,4,4-tetramethylborolan-1-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (137 mg, 0.323 mmol), sodium carbonate (2M) (73 mg, 0.692 mmol) and 8 mol % Pd(PPh3)4 in 2.0 ml of EtOH. The tube was purged with argon for 10 minutes, back-filled with argon, sealed and placed in a pre heated oil bath at 90° C. for 2 hours. Analysis of an aliquot by LCMS shows a small amount of desired product (RT=2.66 min.), exhaustion of boronic ester starting material, remaining aryl bromide starting material, and an unidentified byproduct with mw 315. Added an additional 20 mg of Pd(PPh3)4 and 60 mg of boronic ester starting material. Continued to heat at 90° C. for two more hours. No additional conversion by LCMS. Stopped reaction and cooled to ambient temperature. Concentrated down in vacuo. Crude taken up in equal parts MeOH and DMSO, filtered and purified by Gilson RPHPLC with a 20-95% gradient of ACN in water with 0.1% TFA as a modifier. Following basification with saturated sodium bicarb and extraction with 10 ml DCM (2×), organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford N-(2-chloro-5-(2-(methylthio)benzo[d]thiazol-6-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (12 mg, 11% yield). MS (ESI pos. ion) m/z: 478 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=O.O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1ccc(F)c(-c2ccc(C(=O)O)cc2N2CCCCC2=O)c1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(C(=O)O)cc2N2CCCCC2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a cooled solution of 67.20B (0.4401 g, 1.282 mmol) in dry THF (8 mL) at 0° C. was added borane THF complex, 1.0 M in THF (2.5 mL, 2.5 mmol) dropwise. Upon complete addition, the reaction was maintained at 0° C. and monitored by TLC and LCMS. After 3 hours, water was added to quench the reaction, and the resulting solution was extracted three times with EtOAc. The organic extractions were combined and washed successively with saturated aqueous sodium bicarbonate, water, and then brine. After drying over anhydrous magnesium sulfate, filtration, and concentration, the residue was purified with silica gel flash chromatography (0-25% MeOH in DCM) to afford 67.20C as an oil (292.9 mg, 69% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (2H, m), 7.36 (1H, d, J=7.8 Hz), 7.11 (2H, m), 6.86 (1H, dt, J=8.9, 3.6 Hz), 3.83 (3H, s), 2.85 (4H, m), 1.46 (6H, m).
Reaction SMILES: NC1C2N=C(C[O:19]CC)N(CCC)C=2C2C=CC(O)=CC=2N=1.[CH2:23]([O:25][CH2:26][C:27]1[N:28]([CH2:50][CH2:51][CH3:52])[C:29]2[C:38]3[CH:37]=[CH:36][C:35]([O:39][CH2:40][CH2:41][N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:34][C:33]=3[N:32]=[C:31]([NH2:48])[C:30]=2[N:49]=1)[CH3:24]>O>[CH2:23]([O:25][CH2:26][C:27]1[N:28]([CH2:50][CH2:51][CH3:52])[C:29]2[C:38]3[CH:37]=[CH:36][C:35]([O:39][CH2:40][C:41]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[O:19])=[CH:34][C:33]=3[N:32]=[C:31]([NH2:48])[C:30]=2[N:49]=1)[CH3:24]
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(OCCN4CCOCC4)ccc3c21
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(O)ccc3c21
Solvent: O
Product: CCCn1c(COCC)nc2c(N)nc3cc(OCC(=O)N4CCOCC4)ccc3c21
Reaction time: 1 h

Procedure:
A modification on the procedure described in Example 646 was used to convert 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol (prepared as described in Parts A and B of Example 51) into 2-(ethoxymethyl)-7-(2-morpholin-4-ylethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine. The reaction mixture was heated overnight then was poured slowly into water. After the mixture was stirred for 1 hour, a tan solid was isolated by filtration and recrystallized from acetonitrile to afford 2-(ethoxymethyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as off-white crystals, mp 213° C.
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[O:16][C:15]2[CH:14]=[C:13]([CH3:17])[N+:12]([O-])=[CH:11][C:10]=2[CH:9]=1)(=[O:7])=[O:6].Cl.C(=O)([O-])[O-:22].[Na+].[Na+].C(OCC)C>C(OC(=O)C)(=O)C>[S:5]([C:8]1[O:16][C:15]2[CH:14]=[C:13]([CH2:17][OH:22])[N:12]=[CH:11][C:10]=2[CH:9]=1)(=[O:7])(=[O:6])[NH2:4]
Reactant: Cc1cc2oc(S(=O)(=O)N=CN(C)C)cc2c[n+]1[O-]
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: NS(=O)(=O)c1cc2cnc(CO)cc2o1
Temperature: 140 °C
Yield: 43 %

Procedure:
A mixture of N,N-dimethyl-N'-(5-oxido-6-methylfuro[3,2-c]pyridine-2-sulfonyl)formamidine (3.96 g, 14 mmol) in acetic anhydride (12 ml), under a nitrogen atmosphere was heated at 140° C. for 15 minutes to give a dark brown solution. The reaction was cooled to 100° C. and 20% aqueous hydrochloric acid (40 ml) was added and heat was maintained at this temperature for 4 hours. The cooled reaction was carefully made basic with sodium carbonate solution and then exhaustively extracted with ethyl acetate/methanol to isolate product. This extract was dried over sodium sulfate, filtered through a charcoal pad and solvent evaporated to give, after trituration of the residue with diethyl ether, nearly pure product (1.39 g, 43% yield). Recrystallization from hot ethanol afforded pure product (1.14 g), mp 222°-223° C.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:26][N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:10]=[CH:11][C:12]5[N:13]([C:15]([C:18]([F:20])([F:21])[F:19])=[N:16][N:17]=5)[N:14]=4)[CH2:3]3)[CH2:6]2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CC4CN(Cc5cccc(Cl)c5)CC4C3)nn12

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-chlorobenzaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[2-[(3-chlorophenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C@:8]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])([CH3:19])[CH2:9][S:10][C:11]([CH3:18])([CH3:17])[C:12]([O:14]CC)=[O:13])[CH:7]=1.[OH-].[Na+].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C@:8]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=2[O:30][CH3:31])([CH3:19])[CH2:9][S:10][C:11]([CH3:18])([CH3:17])[C:12]([OH:14])=[O:13])[CH:7]=1
Reactant: CCOC(=O)C(C)(C)SC[C@](C)(NCc1ccc(OC)cc1OC)c1cc(Br)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CN[C@@](C)(CSC(C)(C)C(=O)O)c2cc(Br)ccc2F)c(OC)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of (R)-ethyl 2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino) propylthio)-2-methylpropanoate (3 g, 5.68 mmol, Eq: 1.00) in ethanol (35.7 ml) was added 3 N NaOH (3.78 ml, 11.4 mmol, Eq: 2.0). The reaction mixture was stirred at 70° C. for 2 hours. 1 N HCl (11.4 ml, 11.4 mmol, Eq: 2.0) was added to the reaction mixture at 23° C. (pH=5-6) and evaporated. The residue was triturated with dichloromethane/methanol 9:1, solid Na2SO4 was added. The mixture was filtered off. The filtrate was evaporated to dryness to give the crude (R)-2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)-2-methylpropanoic acid (2.6 g, 5.2 mmol, 91.5% yield) as an off-white foam which was used without further purification. MS (ISP): m/z=500.0 [M+H]+ and 502.3 [M+2+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.CC(CC)=O.[CH2:17]([NH2:19])[CH3:18].[OH-].[Na+]>O>[CH2:17]([NH:19][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([S:9][CH3:10])=[C:4]([Cl:11])[N:3]=1)[CH3:18]
Reactant: CCN
Reactant: CSc1c(Cl)nc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: O
Product: CCNc1nc(Cl)c(SC)c(Cl)n1
Temperature: 5 °C

Procedure:
45.9 Grams of 2,4,6-trichloro-5-methylthio-pyrimidine, 150 g of methylethylketone and 130 g of water are introduced into a 250 ml reactor provided with a stirrer. To this mixture maintained at 5° C. are added in a period of 30 minutes 9.44 g of ethylamine in 32.5% aqueous solution. The temperature of 5° C. is maintained for one and one half hours. Then 8.08 g of caustic soda in 30% aqueous solution are added. The mixture is maintained at 20° C. for 4 hours and over night in a refrigerator at about 0° C. A precipitate appears which is isolated by filtration, washed with 16 ml of methylethylketone and recrystallized twice from 180 ml of ethanol. 10.5 G of 2-ethylamino-4,6-dichloro-5-methylthio-pyrimidine are thus obtained, which melts at 147° C. and which is identified by its infra-red spectrum (IR) and it nuclear magnetic resonance spectrum (NMR).
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]([CH3:20])[C:18](=[O:21])[CH:17]=[C:16]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[N:15]=2)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+].CO>[Pd].O>[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]([CH3:20])[C:18](=[O:21])[CH:17]=[C:16]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[N:15]=2)[CH2:10]1
Reactant: Cn1c(N2CC[C@@H](NCc3ccccc3)C2)nc(-c2ccncc2)cc1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cn1c(N2CC[C@@H](N)C2)nc(-c2ccncc2)cc1=O
Temperature: 95 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
To a solution of 2-((R)-3-benzylaminopyrrolidin-1-yl)-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (1.6 g, 4.4 mmol) and ammonium formate (0.55 g, 8.9 mmol) in tatrahydrofuran (15 ml), methanol (30 ml) and water (5 ml) was added 10% palladium on charcoal (wet, 160 mg). After stirring for 4 hours at 95° C., palladium on charcoal was removed by filtration. The solvent was evaporated off under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure to afford 2-((R)-3-aminopyrrolidin-1-yl)-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (1.0 g, 84%) as colorless crystals.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([C:11](=[O:15])[CH:12]=[N+]=[N-])[CH:8]=[CH:9][CH:10]=1)(=[O:4])(=[O:3])[NH2:2].[ClH:16].C(O)C>COCCOCCOC>[Cl:16][CH2:12][C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:1](=[O:4])(=[O:3])[NH2:2])[CH:6]=1)=[O:15]
Reactant: [N-]=[N+]=CC(=O)c1cccc(S(N)(=O)=O)c1
Reactant: Cl
Solvent: COCCOCCOC
Solvent: CCO
Product: NS(=O)(=O)c1cccc(C(=O)CCl)c1

Procedure:
9.5 g of 3'-sulfamoyl-diazoacetophenone were reacted as prescribed in Example 66b) with 37% HCl in diethylene glycol dimethyl ether and worked up. Colorless crystals, melting point: 118° C (from a small amount of ethanol).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.C=O.[BH3-][C:32]#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:32])[CH2:24][C:23]4=[O:28])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(N3CCNCC3=O)cc2)nn1)c1ccc(Cl)s1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)C(=O)C1
Reaction time: 0.17 h

Procedure:
5-Chloro-N-((1-(4-(2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (24 mg, 0.06 mmol, prepared as shown in Example 60) was stirred in 2 mL acetic acid at RT. To it was added formaldehyde (37% in water, 22 μL, 0.3 mmol). The mixture was stirred for 10 min. NaBH3CN (30 mg, 0.48 mmol) was added. The reaction was allowed for 10 min, and directly subjected to reverse phase prep HPLC to isolate the title compound. MS found for C19H19ClN6O2S (M+H)+ 431.1, 433.1 (Cl pattern).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:26][C:27]([NH2:29])=[O:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:52]([NH:59][CH2:60][CH:61]=O)([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]>C(Cl)(Cl)Cl>[C:55]([O:54][C:52]([NH:59][CH2:60][CH2:61][N:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:11]3[N:10]=[CH:9][C:8]([CH2:26][C:27]([NH2:29])=[O:28])=[C:7]([NH:6][CH2:5][C:4]4[CH:3]=[C:2]([F:1])[CH:32]=[C:31]([F:33])[CH:30]=4)[CH:12]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22]1)=[O:53])([CH3:58])([CH3:57])[CH3:56]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
20 mg of 4-[(3,5-difluorobenzyl)amino]-6-{[4-(piperazin-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 221) was dissolved in 0.5 mL of chloroform, to which 1.4 mg of acetic acid, 15 mg of sodium triacetoxyborohydride and 8.7 mg of N-Boc-2-aminoacetaldehyde were added, and stirred overnight at room temperature. The reaction mixture was washed with water and saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1) to obtain 19 mg (71%) of the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][C:12](Cl)=[O:13].[OH-].[Na+]>ClCCl>[Cl:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9])=[O:13]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a solution of 2-amino-5-fluorophenol (1.0 g, 7.87 mmol) in dichloromethane (50 mL) at 0° C. was added 2-Chloroacetyl chloride (978 mg, 8.66 mmol). The reaction mixture was stirred at rt for 2 h, followed by addition of aqueous saturated NaOH solution. The organic layer was washed with brine, dried over Na2SO4 and solvent was removed under reduced pressure to afford 550 mg (35%) of 2-chloro-N-(4-fluoro-2-hydroxyphenyl)acetamide (I-21) as a brown solid. ESI-LC/MS (m/z): (M−H)− 201.6, RT 2.65 min.
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:15]=[CH:14][C:13]=2[F:27])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O[C:34]1[C:35]([CH3:45])=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][N:40]=[C:39]([Cl:44])[CH:38]=2)(=O)=O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:44][C:39]1[CH:38]=[C:37]2[C:42]([CH:43]=[C:34]([C:16]3[CH:15]=[CH:14][C:13]([F:27])=[C:12]([NH:11][C:9]([NH:8][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)=[O:10])[CH:17]=3)[C:35]([CH3:45])=[N:36]2)=[CH:41][N:40]=1
Reactant: CC1(C)OB(c2ccc(F)c(NC(=O)NC3CCCCCC3)c2)OC1(C)C
Reactant: Cc1nc2cc(Cl)ncc2cc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2cc(Cl)ncc2cc1-c1ccc(F)c(NC(=O)NC2CCCCCC2)c1
Temperature: 60 °C
Yield: 142.5 %

Procedure:
Sparge a suspension of 1-cycloheptyl-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.420 g, 1.116 mmol), 7-chloro-2-methyl-1,6-naphthyridin-3-yl trifluoromethanesulfonate (0.438 g, 1.339 mmol) and K2CO3 (0.463 g, 3.35 mmol) in dioxane (4 mL) and H2O (1 mL) with Ar, add Pd(PPh3)4 (0.064 g, 0.056 mmol) and heat at 60° C. for 3 h. Concentrate the mixture to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (679 mg, 61%) as a white solid. MS(ESI) m/z: 427.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]([OH:18])[CH2:16]Cl)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:1]([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)[CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: COc1ccccc1N1CCNCC1
Reactant: NC(=O)c1cc2ccc(OCC(O)CCl)cc2o1
Product: COc1ccccc1N1CCN(CC(O)COc2ccc3cc(C(N)=O)oc3c2)CC1

Procedure:
The procedures of Example 9b were repeated except that 1.3 g (0.005 mole) of 2-carbamoyl-6-(3-chloro-2-hydroxypropoxy)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine were employed to give the desired compound.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:6]([C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])#[CH:5]
Reactant: CC(C)(C)OC(=O)c1cccc(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl 3-((trimethylsilyl)ethynyl)benzoate (I16) (4.40 g, 16.0 mmol) in THF (100 mL) at 0° C. under nitrogen was added 1.0 M TBAF in THF (20.0 mL, 20.0 mmol). The mixture was then stirred at 0° C. for 1 hour then 16 hours at room temperature. The mixture was then concentrated under reduced pressure, diluted with ethyl acetate (100 mL) and washed with water (3×100 mL). The organic extract was then purified using silica gel column chromatogaphy (0-5% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I17) (2.72 g, 84%) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J=1.5, 1.5 Hz, 1H), 7.97 (ddd, J=7.9, 1.5, 1.5 Hz, 1H), 7.63 (ddd, J=7.7, 1.4, 1.4 Hz, 1H), 7.38 (ddd, J=7.8, 7.8, 0.5 Hz, 1H), 3.11 (s, 1H), 1.59 (s, 9H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:4].C([O-])(=O)C.[NH4+:26]>CS(C)=O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[NH:5][C:3](=[O:4])[N:26]=1
Reactant: [NH4+]
Reactant: O=C(c1ccccc1F)c1ccsc1NC(=O)C(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: O=c1nc(-c2ccccc2F)c2ccsc2[nH]1
Temperature: 95 °C

Procedure:
To a solution of 2.11 g of 2-trichloroacetamido-3-(o-fluorobenzoyl)thiophene in 18 ml of dimethylsulfoxide was added 0.89 g of ammonium acetate. The mixture was heated at 95° C for 2 hours and poured into ice water, and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was chromatographed on 60 g of Silica gel, using ethyl acetate as an eluent to obtain 4-(o-fluorophenyl)-1,2-dihydrothieno(2,3-d)-pyrimidin-2-one as crystals having a melting point of 272°-275° C. Recrystallization from acetone gave crystals melting at 247.5°- 249° C. The following compounds were prepared similarly:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:7][CH2:6]2)[O:4]CC1.O>C(O)(=O)C>[C:5]1(=[O:4])[CH2:6][CH2:7][CH:8]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:9][CH2:10]1
Reactant: FC(F)(F)c1cccc(COCc2ccccc2)c1C1CCC2(CC1)OCCO2
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(c2c(COCc3ccccc3)cccc2C(F)(F)F)CC1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 2, using 20.3 grams (0.050 mole) of phenylmethyl [(1,4-dioxaspiro-[4.5]decan-8-yl)(3-trifluoromethylphenyl)]methyl ether and 35 mL of water in 125 mL of acetic acid, yielding phenylmethyl [(cyclohexanon-4-yl)(3-trifluoromethylphenyl)]methyl ether.