Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([CH3:27])[CH2:15][CH2:14][C:13]3[C:16]([CH3:26])=[C:17]([O:22]C(=O)C)[C:18]([CH3:21])=[C:19]([CH3:20])[C:12]=3[O:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)(=O)C>C(O)C.O>[C:1]1([NH:7][C:8]([C:10]2([CH3:27])[CH2:15][CH2:14][C:13]3[C:16]([CH3:26])=[C:17]([OH:22])[C:18]([CH3:21])=[C:19]([CH3:20])[C:12]=3[O:11]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Nc1ccccc1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)Nc1ccccc1)O2
Reaction time: 2 h
Yield: 86 %

Procedure:
In a two-necked, round-bottomed flask, 2.75 g (7.48 mmol) of the compound obtained in Stage B of Example 1 are dissolved in 60 cm3 of 80% ethanol. Under a nitrogen stream, 18 cm3 of 2.5N sodium hydroxide are added. The mixture is left to stir at ordinary temperature for 2 h. The mixture is diluted with water, acidified with acetic acid and then the product is extracted with dichloromethane. The organic phase is washed with water and then dried. The mixture is purified by passing through a column of silica gel, eluting with isopropyl ether to obtain N-phenyl-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxamide (yield: 86%; melting point: 107°-109° C.) and then the reaction is carried out as in Stage C of Example 1, replacing N-phenyl-6-acetoxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxamide with N-phenyl-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxamide.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].N1C=CC=CC=1.[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:3]([O:4][CH3:5])[CH3:2])=[O:18])=[CH:15][CH:14]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To N,O-dimethylhydroxylamine hydrochloride (27.7 g, 284 mmol) in DCM (660 mL) was added pyridine (45.8 mL, 569 mmol) followed by 4-fluorobenzoyl chloride (31.0 mL, 258 mmol). The resulting suspension was stirred at room temperature for 20 hours, then was filtered to remove a white solid precipitate. The solid was washed with DCM and the filtrate was washed with 1 N aqueous HCl (2×), then water. The organic phase was dried (Na2SO4), filtered, and concentrated, yielding the crude title compound which was used without further purification.
Reaction SMILES: C(O)(C)(C)C.C1(P([N:20]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([CH3:42])(C)[C:38](O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([NH2:20])([CH3:42])[CH3:38]
Reactant: CC(C)(C(=O)O)c1ccccc1F
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CC(C)(N)c1ccccc1F

Procedure:
t-Butyl alcohol (30 mL), diphenylphosphoryl azide (1.63 mL) and triethylamine (1.05 mL) were added to a solution of 2-(2-fluorophenyl)-2-methylpropionic acid (1.15 g) in toluene (60 mL), and the reaction solution was heated to reflux overnight. The reaction solution was returned to room temperature, and water and ethyl acetate were added thereto and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. 10 mL of 5 N hydrochloric acid was added to a solution of the residue in THF (5 mL), and the reaction solution was heated to reflux for 3 hours. The reaction solution was returned to room temperature, made basic with 5 N sodium hydroxide, and then extracted with ethyl acetate. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 735 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.O.[O:17]1[CH2:19][CH:18]1[CH2:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>CC(O)C>[C:26]([C:25]1[CH:28]=[CH:29][C:22]([O:21][CH2:20][CH:18]([OH:17])[CH2:19][N:3]2[CH2:4][CH:5]3[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[CH:23][CH:24]=1)#[N:27]
Reactant: N#Cc1ccc(OCC2CO2)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1C2CCC1CN(CC(O)COc1ccc(C#N)cc1)C2
Temperature: 75 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.08 g, 14.5 mmol; from Preparation B above) in 2-propanol (200 mL) was added H2O (20 mL) and 4-(2-oxiranylmethoxy)benzonitrile (2.54 g, 14.5 mmol; prepared as described in international patent application WO 99/31100). The resulting solution was warmed to 75° C., stirred for 18 h, cooled and concentrated in vacuo. Flash chromatography of the residue on silica gel eluting with CH2Cl2:EtOAc (3:1 to 2:1 gradient) gave 3.86 g (69%) of the sub-title compound.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[N+:17]([O-])=O)[C:8]1=[O:20])(=[O:4])=[O:3].CO>>[NH2:17][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[CH:16][N:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:8]2=[O:20]
Reactant: CS(=O)(=O)CCn1ccc2c([N+](=O)[O-])cccc2c1=O
Solvent: CO
Product: CS(=O)(=O)CCn1ccc2c(N)cccc2c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 250 ml round bottom flask was combined 2-(2-(methylsulfonyl)ethyl)-5-nitroisoquinolin-1(2H)-one (1.20 g, 0.00405 mol) Palladium/C (0.04 g, 0.0004 mol) and methanol (40 mL, 1 mol). The flask was evacuated and purged with hydrogen 3 times. The mixture was stirred at room temperature under hydrogen (1 atm) for three hours. The mixture was filtered over celite and the filtrate was reduced in vacuo. The mixture was purified by column chromatography using a Methanol:methylene chloride (0-10%) gradient. The combined pure fractions were reduced in vacuo to yield the title compound as an off white solid.
Reaction SMILES: CS([C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[N:7][N:6]=1)(=O)=O.O.[N:28]#[C:29][NH2:30].C(N(CC)CC)C>CN(C)C=O.CCOCC>[F:24][C:23]([F:26])([F:25])[C:19]1[CH:18]=[C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:8]2[O:9][C:5]([NH:30][C:29]#[N:28])=[N:6][N:7]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: N#CN
Reactant: CS(=O)(=O)c1nnc(-c2ccccc2Nc2cccc(C(F)(F)F)c2)o1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: N#CNc1nnc(-c2ccccc2Nc2cccc(C(F)(F)F)c2)o1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To an ambient solution of N-[2-[5-(methylsulfonyl)-1,3,4-oxadiazol-2-yl]phenyl]-3-trifluoromethyl benzenamine (210.4 mg, 0.549 mmoles) in 5 ml of dimethylformamide is added 1 ml of water followed by cyanamide (196.0 mg, 4.66 mmoles) and triethylamine (100 μl, 0.717 mmoles). The reaction mixture is stirred at 80° C. overnight. An additional amount of cyanamide (96 mg) is added, and heating is continued for six hours. The mixture is poured into ether and extracted into 0.3N sodium hydroxide. The aqueous layer is acidified with 1N hydrochloric acid, and the resulting white solid is collected by filtration, washing with water. Recrystallization from acetonitrile provides 95.8 mg (51%) of 5-[2-[[3-(trifluoromethyl)phenyl]amino]phenyl]-1,3,4-oxadiazol-2-yl-cyanamide, mp above 230° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:30]6[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH:38]=C)[CH:31]=6)[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:40])[C:16]=3[C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([O:44]C)=[O:43])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=C.[OH-].[Na+]>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl.CO>[C:47]([O:46][C@@H:41]([C:16]1[C:17]([CH3:40])=[N:18][C:19]2=[CH:23][C:22]3=[N:21][N:20]2[C:15]=1[C:12]1[C:13]([Cl:14])=[C:5]2[C:6]([O:7][CH2:8][CH2:9][N:4]2[CH2:1][CH:2]=[CH:38][CH2:37][O:36][C:32]2[CH:31]=[C:30]([C:26]4[CH:25]=[C:24]3[CH:29]=[CH:28][CH:27]=4)[CH:35]=[CH:34][CH:33]=2)=[CH:10][CH:11]=1)[C:42]([OH:44])=[O:43])([CH3:50])([CH3:48])[CH3:49]
Reactant: C=CCOc1cccc(-c2cccc(-c3cc4nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c5ccc6c(c5Cl)N(CC=C)CCO6)n4n3)c2)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCCl
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)-c1ccc2c(c1Cl)N(CC=CCOc1cccc(c1)-c1cccc-3c1)CCO2
Temperature: 50 °C
Yield: 25.9 %

Procedure:
A mixture of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(3′-(allyloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (40 mg, 0.058 mmol) and Hoveyda-Grubbs 2nd generation catalyst (4.90 mg, 5.77 μmol) catalyst in DCE (2 mL) was heated at 50° C. for 5 h. Mixture was then cooled to room temp and concentrated under reduced pressure. Mixture was then treated with 1N NaOH (0.173 mL, 0.173 mmol) in MeOH (2.0 mL) at 50° C. for 3 h. Mixture was then cooled to room temp and purified by prep-HPLC to afford desired product (10 mg, 0.015 mmol, 26.6% yield) as inseparable mixture of cis and trans isomers. Used as is in the next step without further purification. LCMS (M+H)=651.3.
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]([C:6]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([C:31]([N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)=[O:32])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:40]([NH2:42])=[O:41])=[CH:20][CH:19]=2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.Cl>[F:1][C:2]1[CH:44]=[CH:43][C:5]([CH:6]([OH:7])[C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([C:31]([N:33]5[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]5)=[O:32])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:40]([NH2:42])=[O:41])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc5c(C(=O)c6ccc(F)cc6)cccc45)c23)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4cccc5c(C(O)c6ccc(F)cc6)cccc45)c23)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(5-(4-fluorobenzoyl)naphthalen-1-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 3-96, 30 mg, 0.051 mmol) in ethanol (0.5 mL) was treated with a couple granules of sodium borohydride and stirred at rt. After 90 min, the mixture was treated with 2 drops of 1 M hydrochloric acid and purified by preparative HPLC to provide two diastereomers of 4-(5-((4-fluorophenyl)(hydroxy)methyl)naphthalen-1-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide. Diastereomer 1 (Example 13-1) was isolated as a white powder (10.4 mg, 31%). 1H NMR (400 MHz, methanol-d4) δ 8.23 (1H, d, J=8.6 Hz), 7.99 (1H, d, J=7.7 Hz), 7.48-7.61 (3H, m), 7.36-7.46 (3H, m), 7.31 (1H, d, J=8.4 Hz), 7.19 (1H, dd, J=8.4, 7.0 Hz), 7.12 (1H, d, J=7.7 Hz), 7.02 (2H, t, J=8.8 Hz), 6.59 (1H, dd, J=8.1, 1.5 Hz), 6.51 (1H, s), 6.31 (1H, d, J=8.1 Hz), 3.68 (2H, br. s.), 3.35 (2H, br. s.), 2.43 (2H, br. s.), 2.28 (2H, br. s.), 2.23 (3H, s). Mass spectrum m/z 587.4 (M+H)+. Diastereomer 2 (Example 13-2) was isolated as a white powder (8 mg, 23%). 1H NMR (400 MHz, methanol-d4) δ 8.19 (1H, d, J=8.6 Hz), 7.99 (1H, d, J=7.9 Hz), 7.61 (1H, d, J=6.8 Hz), 7.59 (1H, s), 7.49-7.56 (1H, m), 7.43 (1H, dd, J=6.8, 0.7 Hz), 7.38 (2H, dd, J=8.5, 5.4 Hz), 7.26-7.32 (1H, m), 7.16-7.24 (1H, m), 7.11 (1H, d, J=7.7 Hz), 7.00 (2H, t, J=8.8 Hz), 6.61 (1H, dd, J=8.1, 1.3 Hz), 6.58 (1H, s), 6.36 (1H, d, J=8.1 Hz), 3.68 (2H, br. s.), 3.35 (2H, br. s.), 2.43 (2H, br. s.), 2.28 (2H, br. s.), 2.22 (3H, s). Mass spectrum m/z 587.4 (M+H)+.
Reaction SMILES: CC([O-])(C)C.[K+].[O:7]([CH2:14][C:15]([NH:17][CH3:18])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:19]([O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[CH:27][CH:26]=1)[CH2:20][CH2:21][CH3:22]>C1COCC1>[CH2:19]([O:23][C:24](=[O:34])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([N:17]([CH3:18])[C:15](=[O:16])[CH2:14][O:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[S:33])=[CH:29][CH:30]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CNC(=O)COc1ccccc1
Reactant: CCCCOC(=O)c1ccc(N=C=S)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCOC(=O)c1ccc(NC(=S)N(C)C(=O)COc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 10 %

Procedure:
t-BuOK (0.55 mL of 1.0 N solution) in THF is added to a solution of phenoxy-N-methylacetamide (83 mg, 0.5 mmol) in THF (5 mL). After 5 minutes, butyl-4-isothiocyanatobenzoate (118 mg, 0.5 mmol) is added in one portion and the resultant mixture is stirred overnight. The crude mixture is filtered through a silica pad. After purification on silica eluting with 25% EtOAc in llexaiie, the desired acyithiouraea is obtained as a yellow oil (20 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]2[S:11][C:10]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)=[CH:9][CH:8]=2)=[N:3]1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[Cl:18][CH2:19][C:20]([N:15]1[CH2:14][CH:13]=[C:12]([C:10]2[S:11][C:7]([C:4]3[N:5]=[CH:6][N:2]([CH3:1])[N:3]=3)=[CH:8][CH:9]=2)[CH2:17][CH2:16]1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Cn1cnc(-c2ccc(C3=CCNCC3)s2)n1
Solvent: ClCCl
Product: Cn1cnc(-c2ccc(C3=CCN(C(=O)CCl)CC3)s2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cold (0° C.) solution of 4-[5-(1-methyl-1H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-1,2,3,6-tetrahydro-pyridine (7BW) (1.5 g, 4.72 mmol) in dichloromethane (50 ml) was added TEA (4.5 ml, 28.32 mmol) dropwise. After stirred at 0° C. for 10 min, chloroacetyl chloride (1.12 ml, 14.2 mmol) was added to the reaction mixture. The resulting mixture was stirred at 0° C. for 1 hr., and quenched with water (15.6 ml). The reaction mixture was diluted with dichloromethane (200 ml). The organic layer was separated and washed with brine, dried over MgSO4. Reaction mixture was concentrated to ˜50 ml, ether was added and the solid was filtered out to get the desired product (8BW).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[C:9]([CH2:18][CH2:19][OH:20])=[C:10]([CH:14]=[CH:15][C:16]=1[F:17])[C:11](O)=[O:12]>C1COCC1>[F:7][C:8]1[C:16]([F:17])=[CH:15][CH:14]=[C:10]([CH2:11][OH:12])[C:9]=1[CH2:18][CH2:19][OH:20]
Reactant: O=C(O)c1ccc(F)c(F)c1CCO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1c(CO)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
To a solution of LiAlH4 (2.45 g, 0.065 mol) in THF (30 mL) was added 3,4-difluoro-2-(2-hydroxyethyl)benzoic acid (8.7 g, 0.043 mol) in THF (60 mL) at 0° C. The mixture was stirred at room temperature overnight. The reaction was quenched with 3 mL of H2O, followed by aqueous NaOH solution (3 mL, 10%). The solution was filtered and the filtrated was concentrated to give the residue, which was purified by chromatography to give 2-(2,3-difluoro-6-(hydroxymethyl)phenyl)ethanol (2.5 g, 31%). 1H NMR (CDCl3): 2.99 (m, 2H), 3.58 (s, 2H), 3.83 (t, 2H), 4.52 (s, 2H), 7.03 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>Cl>[C:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a mixture of 4-hydroxybenzoic acid (16) (20.0 g, 144.8 mmol) and pyridine (60 ml, 742 mmol) at 0° C. was added acetyl chloride (12 ml, 169 mol) over 5 minutes. The resulting mixture was stirred at ice bath temperature for 30 minutes and for 1 hour at room temperature. The mixture was poured into ice water (500 ml) and the pH of the medium was brought to 1-2 by adding conc. HCl (ca. 40 ml). The precipitate was filtered, washed with water (100 ml), and dried (Na2SO4). The obtained solid material was crystallized from methanol-water (1:1) (200 ml) affording the title compound (21.485 g, 82.3%) as white crystals, m.p. 181-183° C. 1H NMR (CDCl3, HMDSO) δ: 2.32 (3H, s); 7.22 (2H, d, J=8.2 Hz); 8.16 (2H, d, J=8.2 Hz); 10.50 (1H, brs).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20](Cl)=[CH:21][N:22]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([CH3:39])=[CH:33]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[NH:35][C:34]([CH3:39])=[CH:33]5)=[CH:21][N:22]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)cnnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(-c3ccc4[nH]c(C)cc4c3)cnnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 16.7 %

Procedure:
A mixture of 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)4chloro-6-methoxycinnoline (204 mg, 0.5 mmol), 5-hydroxy-2-methylindole (81 mg) and cesium carbonate (326 mg, 1 mmol) in DMF (2.5 ml) was stirred at 90° C. for 2 hours. After cooling, the mixture was filtered, wash ed with DMF and the volatiles were removed under vacuum. The crude product was dissolved in methylene chloride (4 ml) containing TEA (1.5 ml) and was stirred at ambient temperature for 1 hour. The volatiles were removed under vacuum. The residue was partitioned between methylene chloride and 1N aqueous sodium hydroxide. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography eluting with a gradient of methylene chloride/methanol saturated with ammonia (5/95 to 15/85). The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and the precipitate was filtered, washed with ether and dried under vacuum to give 7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-6-methoxy-4-(2-methylindol-5yl)cinnoline (42 mg, 20%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([NH:39][C:40]([C@@H:42]1[CH2:47][NH:46][CH2:45][CH2:44][NH:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:46]4[CH2:45][CH2:44][NH:43][C@H:42]([C:40]([NH:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:47]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC(C)(C)NC(=O)[C@@H]1CNCCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)NC(=O)[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-tert-butylpiperazine-2-(S)-carboxamide was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperazine-2-(S)-carboxylic acid tert-butylamide following General Procedure C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)O)=[CH:7][C:6]=2[CH:19]=1.S(Cl)([Cl:22])=O>C(Cl)Cl.C1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([Cl:22])[C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[CH:7][C:6]=2[CH:19]=1
Reactant: O=S(Cl)Cl
Reactant: OC(c1ccc(Cl)cc1)c1cc2cc(Br)ccc2o1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: Clc1ccc(C(Cl)c2cc3cc(Br)ccc3o2)cc1
Reaction time: 4 h

Procedure:
To 36.2 g of (5-bromobenzofuran-2-yl)(p-chlorophenyl)methanol dissolved in 50 ml of methylenchloride, 8.5 ml of thionylchloride in 25 ml of cyclohexane are added drop by drop, under agitation. After a 4 hour rest at 10° C., the solution is brought to dryness under vacuum condition. The residue is crystallized from petroleum ether: m.p. 83°-85° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:12]=2)[N:7]=[CH:6][N:5]=1.Br[CH2:23][C:24]1[S:28][C:27]2[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:26]=2[CH:25]=1.C([O-])([O-])=O.[K+].[K+].FC(F)(F)C(O)=O>CN(C=O)C.O>[NH2:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH2:23][C:24]4[S:28][C:27]5[CH:29]=[C:30]([Cl:33])[CH:31]=[CH:32][C:26]=5[CH:25]=4)[CH2:17][C:16]3=[O:21])=[CH:11][CH:12]=2)[N:7]=[CH:6][N:5]=1
Reactant: Clc1ccc2cc(CBr)sc2c1
Reactant: Nc1ncnc2cc(CN3CCNCC3=O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ncnc2cc(CN3CCN(Cc4cc5ccc(Cl)cc5s4)CC3=O)ccc12
Reaction time: 16 h

Procedure:
To a solution of 1-(4-aminoquinazoline-7-ylmethyl)piperazine-2-one bishydrochloride (1.84 g, 5.73 mmol), EXAMPLE 72, in DMF (20 mL) is added 2-bromomethyl-6-chloro-benzo[b]thiophene, EXAMPLE 5, (1.5 g, 5.73 mmol) and K2CO3 (4.0 g, 28.7 mmol). The solution is stirred for 16 hours. After this time, the solution is diluted with water. The solution is acidified with trifluoroacetic acid. The product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 50% CH3CN/H2O (0.1% TFA). The appropriate collected fractions are lyopholized to afford the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ9.78 (bs, 3H), 8.82 (s, 1H), 8.34 (d, 1H), 8.07 (s, 1H), 7.81 (d, 1H), 7.63 (d, 1H), 7.51 (s, 1H), 7.32 (m, 2H), 4.71 (s, 2H), 3.95 (s, 2H), 3.28 (m, 4H), 2.80 (m, 2H).
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]#[C:14][C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:27]=[N:28][N:29]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)[CH:30]=3)[N:16]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2]>CCOC(C)=O.CO.[Pd]>[C:1]([C:4]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][CH2:14][C:15]2[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:27]=[N:28][N:29]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:33][CH2:32]4)[CH:30]=3)[N:16]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(C#Cc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl 4-(4-((4-((2-(1-carbamoylcyclopropyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate A76 (0.405 g, 0.680 mmol) and 10% Pd/C (wetted with ca. 53% water, 0.200 g) in EtOAc (30 mL) and MeOH (15 mL) was stirred under an atmosphere of H2 at room temperature for 16 hours. The mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo. Purification by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-10% MeOH in DCM) gave a yellow oil which was further purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 10-90% EtOAc in petroleum benzine 40-60° C.) to give the title compound A77 as a yellow solid (0.213 g, 52%). LCMS-D: rt 3.62 min; m/z 600 [M+H]+.