Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[O:12][C:13]([CH3:44])=[C:14]([CH2:16][O:17][C:18]2[CH:41]=[CH:40][C:21]([CH2:22][O:23][C:24]3[C:28](/[CH:29]=[CH:30]/[C:31](O)=[O:32])=[CH:27][N:26]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:25]=3)=[CH:20][C:19]=2[O:42][CH3:43])[N:15]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.C(N(CC)CC)C.CN(C)C=O>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[O:12][C:13]([CH3:44])=[C:14]([CH2:16][O:17][C:18]2[CH:41]=[CH:40][C:21]([CH2:22][O:23][C:24]3[C:28](/[CH:29]=[CH:30]/[C:31]([N:3]([O:4][CH3:5])[CH3:2])=[O:32])=[CH:27][N:26]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:25]=3)=[CH:20][C:19]=2[O:42][CH3:43])[N:15]=1
Reactant: CNOC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)N(C)OC)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (0.56 g) and N,N-dimethylformamide (30 mL) was added triethylamine (0.69 g) at room temperature, and the mixture was stirred for 15 min. To the reaction mixture were added (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (2.0 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.09 g) and 1-hydroxybenzotriazole monohydrate (0.87 g), and the mixture was further stirred at room temperature for 20 hr. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-N-methoxy-N-methyl-2-propenamide as colorless crystals (1.92 g, yield 88%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 173-174° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[C:4]([C:11]([OH:13])=O)[CH:3]=1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C(C)=O.C(N(CC)CC)C>C(OC(=O)C)(=O)C>[CH2:21]([O:20][C:14]([CH:15]1[C:8](=[O:10])[C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][C:4]=2[C:11]1=[O:13])=[O:19])[CH3:22]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cc(C(=O)O)c(C(=O)O)cn1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1C(=O)c2cnc(C)cc2C1=O
Reaction time: 8 h

Procedure:
6-Methyl-pyridine-3,4-dicarboxylic acid (440 mg) (see, Emil J. Moriconi and Francis A. Spano, J. Am. Chem. Soc., Vol. 86, pp. 38-46, 1964) was suspended in acetic anhydride (10 ml) and the mixture was refluxed for 10 minutes. Ethyl acetoacetate (0.325 ml) and triethylamine (0.745 ml) were dropwise added to the mixture at room temperature and the mixture was stirred overnight. The mixture was concentrated to dryness and purified by silica gel column chromatography developed by dichloromethane and by dichloro-methane-methanol (15:1). The desired compound was obtained as a dark red oil which contained 1 equivalent of triethylamine.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:21]Br>ClCCl>[Br:21][C:18]1[CH:19]=[C:14]([CH2:13][CH2:12][C@H:9]2[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)[CH:15]=[CH:16][C:17]=1[OH:20]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(O)cc2)CC1
Reactant: BrBr
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(O)c(Br)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of 2.7 g of 4-[2-(trans-4-pentylcyclohexyl)ethyl]phenol in absolute dichloromethane was treated dropwise at 0° C. with a solution of 1.6 g of bromine in 20 ml of absolute dichloromethane. The mixture was stirred for 1 hour and then poured into ice-water. The organic phase was separated and the aqueous phase was back-extracted three times with 50 ml of dichloromethane each time. The combined organic phases were washed with 50 ml of 2N sodium carbonate solution and several times with water, dried over magnesium sulphate and concentrated. Recrystallization of the resulting crude product from hexane at 0° C. gave 3.4 g of 2-bromo-4-[2-(trans-4-pentylcyclohexyl)ethyl]phenol.
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:13])=[CH:3][C:2]2=1.Br[CH2:15][CH2:16][O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:17][CH2:16][CH2:15][N:12]1[CH:9]2[CH2:10][CH2:11][CH:1]1[C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[CH2:8]2
Reactant: Nc1ccc2c(c1)C1CCC(C2)N1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCN1C2CCC1c1cc(N)ccc1C2
Yield: 12.5 %

Procedure:
12-Aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (J. Med. Chem. 1988, 31, 433-444) (150 mg, 0.86 mmol), 1-bromo-2-methoxy-ethane (120 mg, 0.86 mmol) and potassium carbonate (119 mg, 0.86 mmol) were stirred together in acetone (5 mL) at 50° C. for 6 h. The mixture was filtered and concentrated before purifying on silica gel chromatography (0-50% MeOH in CH2Cl2) to obtain 12-(2-Methoxy-ethyl)-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine as a clear oil (25 mg, 13%). MS (m/e) 233 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([O:23][CH3:24])=[O:22]>C(OCC)(=O)C>[CH3:24][O:23][C:21]([C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1)=[O:22]
Reactant: COC(=O)[C@@H]1CCCCN1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(N2CCCC[C@H]2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 97.6 %

Procedure:
Methyl 6-chloro-5-nitronicotinate (2.333 g, 10.77 mmol) was added to (S)-methyl piperidine-2-carboxylate (2.93 g, 20.46 mmol) neat while stirring. The reaction was stirred 1 h at 90° C., cooled to room temperature and taken up in ethyl acetate (10 mL). The mixture was purified by SiO2 (330 g, 20-30% EA in Hexanes) to yield 3.4 g (98%) of the title compound as a yellow oil. [M+H] calc'd for C14H17N3O6, 324; found, 324.
Reaction SMILES: C([Mg]Br)C.Br[C:6]1[N:10]([CH3:11])[CH:9]=[N:8][CH:7]=1.CON(C)[C:15]([C:17]1[CH:22]=[CH:21][N:20]=[N:19][CH:18]=1)=[O:16]>C(Cl)Cl>[CH3:11][N:10]1[C:6]([C:15]([C:17]2[CH:22]=[CH:21][N:20]=[N:19][CH:18]=2)=[O:16])=[CH:7][N:8]=[CH:9]1.[CH3:11][N:10]1[CH:6]=[CH:7][N:8]=[CH:9]1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1ccnnc1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cn1ccnc1
Product: Cn1cncc1C(=O)c1ccnnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethylmagnesium bromide (3 M in Et2O, 1.04 mL, 3.11 mmol) was added dropwise to a solution of 5-bromo-1-methyl-1H-imidazole (500 mg, 3.11 mmol) in DCM (6 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature 15 min, then was cooled in an ice bath prior to addition of N-methoxy-N-methylpyridazine-4-carboxamide (419 mg, 2.51 mmol, Intermediate 29, step a). The resulting suspension was stirred at room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous NH4Cl, diluted with water, and extracted three times with EtOAc. The aqueous phase was saturated with NaCl and back-extracted with DCM (three times). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, gradient 30-100% CH3CN-DCM, followed by isocratic 5% MeOH-acetone), affording title compound contaminated with 1-methyl-1H-imidazole, the mixture of which was used in the next reaction without further purification.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.O[C:24]1C2N=[N:30][NH:29]C=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:48]([N:52]1[CH2:59][CH2:58][CH2:57][C@H:53]1[C:54]([NH2:56])=[O:55])([CH3:51])([CH3:50])[CH3:49]>>[N:29]#[N:30].[NH2:11][C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:20]([OH:22])[CH2:24][C@@:53]1([C:54]([NH2:56])=[O:55])[CH2:57][CH2:58][CH2:59][N:52]1[C:48]([CH3:51])([CH3:49])[CH3:50]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)N1CCC[C@H]1C(N)=O
Reactant: Oc1cccc2[nH]nnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@@H](N)Cc1ccccc1)C(N)=O
Product: N#N

Procedure:
In a manner analogous to that described in Example 92, from 0.15 g of N-(benzyloxycarbonyl)-L-phenylalanine, 0.066 g of hydroxybenzotriazole, 0.1 g of dicyclohexylcarbodiimide and 0.166 g of N2 -[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide there was obtained 0.1 g of N2 -[3(S)-[N-(benzyloxycarbonyl)-L-phenylalanyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as a white solid of melting point 78°-80° C.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14]C)=[O:13])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].O.[OH-].[Li+].CO.O>O1CCCC1>[C:1]([C:3]1([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([OH:14])=[O:13])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)c1cccc(C2(C#N)CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#CC1(c2cccc(C(=O)O)c2)CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a solution of methyl 3-(4-cyanotetrahydro-2H-pyran-4-yl)benzoate (0.62 g, 2.5 mmol) in tetrahydrofuran (6.0 mL) were added lithium hydroxide-monohydrate (0.18 g, 4.3 mmol), methanol (2.0 mL) and water (2.0 mL), and the mixture was stirred at room temperature for 12 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with water (5.0 mL). The mixture was adjusted to pH 3 by slowly adding 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure to give the title compound (0.48 g, 83%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:6]([CH3:14])[C:7]=2[C:11]([NH2:13])=[O:12])[CH:3]=1.[CH2:21]([N:23]([CH2:26][CH2:27]Cl)[CH2:24][CH3:25])[CH3:22]>>[ClH:1].[CH2:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH2:25][NH:13][C:11]([C:7]1[N:6]([CH3:14])[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]2[C:8]=1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3]2)=[O:12])[CH3:22]
Reactant: CCN(CC)CCCl
Reactant: Cn1c(C(N)=O)c2ccc(Cl)cc2c1-c1ccccc1
Product: CCN(CC)CCNC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1C
Product: Cl

Procedure:
In accordance with the procedure described in Example 2, 2.85 g. of 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid amide are reacted with 0.02 mol. of diethylaminoethyl chloride. The methylene chloride extract containing the free base is concentrated to dryness and the pasty residue chromatographed on 300 g. of aluminum oxide (neutral, Brockmann, activity I) using methylene chloride/ethyl acetate (4:1) for the elution. The homogeneous fractions are combined and evaporated. The residual solid residue is dissolved in 10 ml. of acetone and treated with excess ethereal hydrochloric acid. The hydrochloride which crystallizes out is removed by filtration and washed with diethyl ether, whereby there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid[ 2-(diethylamino)ethyl]amide hydrochloride having a melting point of 211°-214° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([OH:6])=O.[CH2:14]([C:17]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19])[CH2:15][CH3:16]>OS(C(F)(F)F)(=O)=O>[OH:19][C:18]1[CH:20]=[CH:21][C:22]([C:4](=[O:6])[CH2:3][C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:7])=[C:23]([OH:24])[C:17]=1[CH2:14][CH2:15][CH3:16]
Reactant: CCCc1c(O)cccc1O
Reactant: CC(C)(CC(=O)O)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Product: CCCc1c(O)ccc(C(=O)CC(C)(C)c2ccccc2)c1O

Procedure:
Using the procedure in Example 51, step 1; 3-methyl-3-phenylbutyric acid and 2-(n-propyl)resorcinol were condensed in triflic acid to form 1,3-dihydroxy-4-(3-methyl-3-phenylbutyryl)-2-(n-propyl)benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH2:21])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].CCCCCC.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH3:21])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: [H][H]
Reactant: C=Cc1cc(Cl)c2c(c1)CN(Cc1ccc(Cl)cc1)C2=O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cc(Cl)c2c(c1)CN(Cc1ccc(Cl)cc1)C2=O
Yield: 62.5 %

Procedure:
A mixture of 7-chloro-5-ethenyl-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.032 g, 0.1 mmol) and 10% palladium on carbon (20 mg) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using combinations 3:1 hexane-ethyl acetate afforded 7-chloro-5-ethyl-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.020 g, 63%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.23 (t, 3H), 2.68 (q, 2H), 4.18 (s, 2H), 4.72 (s, 2H), 7.09 (s, 1H), 7.22-7.32 (m, 5H). GC-MS: m/z 319 (M−1)+, 284 (M−35)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)[CH3:10])=[O:7]
Reactant: Fc1cccc(CBr)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2cccc(F)c2)cc1
Yield: 79.5 %

Procedure:
The title compound (D31) (55 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (D14) (50 mg, 0.18 mmol) and 3-fluoro benzyl bromide (0.044 ml, 0.36 mmol). (Na2CO3: 2.5 eq; reaction time: 5 hrs; 70° C.)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:26])=[C:10]([N:14]3[CH2:17][C:16]([CH3:25])([NH:18]C(=O)C(F)(F)F)[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:27])[C:5]([C:28]([OH:30])=[O:29])=[CH:4]1)[CH3:2].[OH-].[Na+].C(O)C>O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:26])=[C:10]([N:14]3[CH2:15][C:16]([NH2:18])([CH3:25])[CH2:17]3)[C:11]=2[F:13])[C:6](=[O:27])[C:5]([C:28]([OH:30])=[O:29])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)(NC(=O)C(F)(F)F)C3)c(F)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC(C)(N)C3)c(F)c21

Procedure:
A mixture of 0.65 g (1.5 mmoles) of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-methyl-3-trifluoroacetamido-1-azetidinyl)-quinoline-3-carboxylic acid (example 21) 2 ml of 10% sodium hydroxide and 3 ml of ethanol is refluxed in 10 ml of water for 3 hours. It is filtered while hot, cooled, acidified with acetic acid, and filtered. After washing with water, 0.48 g (95%) of 1-ethyl-6,8-difluoro-7-(3-amino-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 293°-6° C.
Reaction SMILES: [NH:1]([CH2:8][C:9]([NH2:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](=[O:15])(O)[O-].[K+].[N:17]#CBr.N1CCN=C1>C(O)C.C(O)C.CO>[C:2]1([N:1]2[CH2:8][C:9]([NH2:11])=[N:17][C:12]2=[O:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)CNc1ccccc1
Reactant: N#CBr
Reactant: O=C([O-])O
Agent: C1=NCCN1
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: NC1=NC(=O)N(c2ccccc2)C1

Procedure:
To a mixture of 3.75 g. of anilinoacetamide, 2.5 g. of potassium bicarbonate and 40 ml. of ethanol was added dropwise 2.7 g. of cyanogen bromide in 20 ml. of ethanol. This mixture was heated to reflux overnight. On cooling, a light tan precipitate formed in the flask. The precipitate was filtered, washed with ethanol, water, and dried overnight. The yield of product, m.p. 277°-9° C. was 3.3 g. (75%). The mass spectrum of the compound gave a parent ion at m/e 175. An analytical sample was prepared by recrystallization from ethanol-methanol, m.p. 280°-2° C. In this case the ethanol filtrate was basic at the conclusion of the reaction leading to formation of the imidazoline in situ. This product is used in Examples 10 and 11.
Reaction SMILES: [ClH:1].CCOCC.C(OC([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[C:30]3[O:29][CH:28]=[CH:27][C:26]=3[CH:25]=[C:24]([NH:31][S:32]([C:35]3[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:36]=3[O:42][CH3:43])(=[O:34])=[O:33])[CH:23]=2)=[O:21])[CH2:16][CH2:15]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[CH3:43][O:42][C:36]1[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:35]=1[S:32]([NH:31][C:24]1[CH:23]=[C:22]([C:20]([N:17]2[CH2:16][CH2:15][NH:14][CH2:19][CH2:18]2)=[O:21])[C:30]2[O:29][CH:28]=[CH:27][C:26]=2[CH:25]=1)(=[O:33])=[O:34]
Reactant: COc1ccc(C)cc1S(=O)(=O)Nc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2occc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc(C)cc1S(=O)(=O)Nc1cc(C(=O)N2CCNCC2)c2occc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Deprotection of the N-t-BOC group in 4-[5-(2-methoxy-5-methyl-benzenesulfonylamino)-benzofuran-7-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (Step 3) was performed by adding HCl/ether to a solution of the said substrate in ethyl acetate and allowed to stir overnight at ambient temperature. Concentration of the solution gave the title product as a white solid. Yield: 31 mg. HPLC 96% RT=2.73 min (System A; 30-80% MeCN over 3 min), 1.05 min (System C; 2-95% MeCN over 2 min). 1H NMR (400 Mz, methanol-d4) δ ppm 2.17 (s, 3H), 3.19 (m, 2H), 3.34 (m, 2H), 3.49 (m, 2H), 3.91 (s, 3H), 4.01 (m, 2H), 6.80 (d, J=2.2 Hz, 1H), 6.99 (d, J=8.6 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.28 (dd, J=8.6, 2.0 Hz, 1H), 7.45 (d, J=2.2 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H). 13C NMR (400 Mz, MeOH-d4) δ ppm 19.15, 55.60, 94.55, 106.86, 112.31, 116.62, 118.32, 118.44, 125.90, 129.07, 129.89, 130.51, 133.47, 135.37, 140.33, 147.22, 147.92, 154.75, 166.24 (C═O). MS (ESI) for C21H23N3O5S m/z 430 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([C:26]#[N:27])=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][C:36]1([CH3:42])[CH3:41]>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:38]5[CH2:39][CH2:40][N:35]([CH3:34])[C:36]([CH3:42])([CH3:41])[CH2:37]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([C:26]#[N:27])=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1
Reactant: CN1CCNCC1(C)C
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C#N)nn3Cc2ccc(Cl)cc2C(F)(F)F)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(C#N)nn4Cc3ccc(Cl)cc3C(F)(F)F)S2)CC1(C)C

Procedure:
1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[4-oxo-2-(3,3,4-trimethylpiperazin-1-yl)-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile was prepared from 1-(4-Chloro-2-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrile and 1,2,2-Trimethyl-piperazine following General Procedure C.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([N+:10]([O-])=O)[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[H][H]>C(O)(C)C.C(O)(=O)C.[Pd]>[NH2:10][CH:3]([CH:2]([CH3:13])[CH3:1])[CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8]
Reactant: [H][H]
Reactant: CC(C)C(C(O)C(F)(F)F)[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)C(N)C(O)C(F)(F)F
Temperature: 5 °C

Procedure:
A solution of 4-methyl-3-nitro-1,1,1-trifluoro-2-pentanol (17.1 g) in isopropanol (115 ml) and acetic acid (0.43 ml) was hydrogenated over 10% palladium on carbon (2.4 g) at 3.5 barg pressure until uptake of hydrogen was complete. The catalyst was removed by filtration through diatomaceous earth and the filter cake washed with isopropanol. The filtrate was evaporated under vacuum until no further isopropanol distilled and the residue dissolved in acetonitrile (40 ml). A solution of oxalic acid (3.94 g) in acetonitrile (80 ml) was added with stirring and the mixture cooled to 5° C. The product which crystallised was collected by filtration, washed with cold acetonitrile and dried at 50° C. to give 3-amino-4methyl-1,1,1-trifluoro-2-pentanol as its oxalate salt (9.08 g). ##STR4##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:20][C:19]2[C:18]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][CH:26]=[CH:25]4)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:20][C:19]3[C:18]([NH:21][C:22]4[CH:23]=[C:24]5[C:28](=[CH:29][CH:30]=4)[NH:27][CH:26]=[CH:25]5)=[N:17][CH:16]=[N:15][C:14]=3[CH:13]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Product: Fc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from p-fluorobenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.4 (s, 1H), 8.82 (s, 1H), 7.79 (m, 4H), 7.41 (m, 5H), 7.21 (d, 1H). 6.50 (s, 1H), M.P. 193-205° C.; LC-MS: 361 (MH+); HPLC RT: 4.88 minutes.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:22])([CH3:21])[CH3:20])[C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1)=O.[CH3:23][S:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)(=[O:26])=[O:25]>CN1C(=O)CCC1.O>[CH3:23][S:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:4]2[N:9]=[C:8]([C:10]3[N:14]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:22])([CH3:20])[CH3:21])[C:13]4=[N:12][CH:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:30][CH2:29]1)(=[O:25])=[O:26]
Reactant: CS(=O)(=O)CC1CCC(N)CC1
Reactant: CS(=O)c1nccc(-c2cnc3c(C(C)(C)O)cccn23)n1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(O)c1cccn2c(-c3ccnc(NC4CCC(CS(C)(=O)=O)CC4)n3)cnc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
A mixture of 2-[3-(2-methylsulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyridin-8-yl]-propan-2-ol (75 mg), 4-methanesulfonylmethyl-cyclohexylamine (162 mg), and TEA (0.165 mL) in NMP (2 mL) was stirred at 100° C. overnight. The reaction mixture was then cooled to RT, and diluted with water. The resulting precipitate was filtered and dried, then purified by ISCO using 100% DCM to 10% MeOH/DCM. The fractions were collected, concentrated, and titurated with EtOAc. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide 2-{3-[2-(4-methanesulfonylmethyl-cyclohexylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyridin-8-yl}-propan-2-ol (Compound 1, 55.5 mg). Mp=223-224° C.