Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([Cl:13])[CH:7]=[C:6]2[CH3:14].[OH-:15].[Na+]>CSC.C(OCC)(=O)C>[Cl:13][C:8]1[CH:7]=[C:6]([CH3:14])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][OH:15])[CH:4]=2)[N:9]=1
Reactant: Cc1cc(Cl)nc2ccc(CBr)cc12
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CSC
Product: Cc1cc(Cl)nc2ccc(CO)cc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-methylquinoline (0.39 g) in dimethyl sulfide (5 mL) was added 1 M aqueous sodium hydroxide (5 mL) at room temperature, and the mixture was stirred at 70° C. for 1 h. After cooled to room temperature, the reaction solution was diluted with ethyl acetate. The organic layer was washed with saturated brine, the organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=3:1−ethyl acetate/hexane/chloroform=1:3:1−ethyl acetate) to obtain (2-chloro-4-methylquinolin-6-yl)methanol (0.14 g).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Br[CH2:17][CH2:18]Br>CS(C)=O.O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:18][CH2:17]1)#[N:2]
Reactant: BrCCBr
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a solution of methyl 3-(cyanomethyl)benzoate (1.5 g, 8.6 mmol) in dimethyl sulfoxide (30 mL) was added sodium hydride (60% in oil, 1.0 g, 26 mmol) while cooling to not more than 25° C. without causing solidification. The reaction mixture was stirred at room temperature for 30 min, 1,2-dibromoethane (2.4 g, 12.8 mmol) was added, and the mixture was further stirred at room temperature for 10 hr. The reaction mixture was diluted with water (100 mL), and extracted with ethyl acetate (300 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, and the insoluble material was filtered off. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→50/50), and the fraction containing the object product was concentrated under reduced pressure to give the title compound (1.3 g, 76%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([F:38])[CH:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39]OC(OC)N(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:18]([CH3:39])[C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([F:38])[CH:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c(-c3ccnc(F)c3)[nH]2)CC1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: Cn1c(C2CCN(C(=O)OCc3ccccc3)CC2)nc(-c2cccc(C(F)(F)F)c2)c1-c1ccnc(F)c1
Temperature: 120 °C

Procedure:
To a stirring solution of 4-[5-(2-fluoropyridin-4-yl)-4-(3-trifluoromethylphenyl)1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (13.1 g, 0.025 mmole) in toluene (130 mL) was added N,N-dimethylformamide dimethyl acetal (13.1 mL). This mixture was heated to 120° C. under argon for 28 hours. The reaction was cooled, concentrated in vacuo, poured into a saturated aqueous solution of sodium bicarbonate (300 mL) which was extracted with ethyl acetate (1×1 L, 2×300 mL). The organic extracts were combined, washed with water (300 mL), brine (300 mL), dried over anhydrous sodium sulfate and concentrated to an oil. The oil was dissolved in methylene chloride (5 mL) and chromatographed on silica using 2% acetone/methylene chloride to give upon concentration of the product containing fractions the title compound 2.00 g.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][CH2:14][C:4]=2[N:5]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][OH:24])=[CH:20][CH:19]=1>O1CCOCC1>[CH:9]1([O:8][C:6]2[N:7]=[C:2]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([CH2:22][CH2:23][OH:24])=[CH:20][CH:19]=3)[C:3]3[CH2:16][CH2:15][CH2:14][C:4]=3[N:5]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(CCO)cc1
Reactant: Clc1nc(OC2CCCC2)nc2c1CCC2
Solvent: C1COCCO1
Product: OCCc1ccc(Nc2nc(OC3CCCC3)nc3c2CCC3)cc1
Yield: 15.4 %

Procedure:
Following General Procedure B1, 4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.200 g, 0.84 mmol), dioxane (3 mL) was reacted with 4-aminophenethyl alcohol (0.172 g, 1.26 mmol) to afford the title compound (0.044 g, 22%) as a white solid. MW=339.43. 1H NMR (DMSO-d6, 300 MHz) δ 9.23 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 5.49-5.40 (m, 1H), 3.65-3.50 (m, 2H), 2.73 (t, J=7.6 Hz, 2H) 2.69-5.59 (m, 5H), 2.09-1.90 (m, 4H), 1.80-1.53 (m, 6H); APCI MS m/z 340 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC(N)=[S:21]>C(O)C>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:2](=[S:21])[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:13][CH:14]=1
Reactant: NC(N)=S
Reactant: Fc1ccc(-c2cc3ccccc3nc2Cl)cc1
Solvent: CCO
Product: Fc1ccc(-c2cc3ccccc3[nH]c2=S)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-chloro-3-(p-fluorophenyl)quinoline (6.03 g., see Example 3) and thiourea (1.8 g.) in ethanol (30 ml.) was heated under reflux for 2 hr. The solution was allowed to cool to ambient temperature, the solid which precipitated was filtered off, dispersed in 1 M-sodium hydroxide solution (100 ml.), and the dispersion heated on a steam bath for 20 min. The mixture was acidified with 2 M-hydrochloric acid solution. The resulting mixture was filtered, the solid residue was stirred with hot ethanol (75 ml.) for 5 min., and then filtered. There was thus obtained as the solid residue 3-(p-fluorophenyl)quinolin-2-thione, m.p. 259°-262°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br:9]Br>Br.C(O)(=O)C>[Br:9][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: BrBr
Reactant: Cc1ccc(O)cn1
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccc(O)c(Br)n1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
16.0 g (0.14 mol) of 3-hydroxy-6-methylpyridine are dissolved in 122 ml of 30% strength HBr in glacial acetic acid, and the solution is heated to 70° C. 70.4 [lacuna] (24.3 ml, 0.47 mol) of bromine are added dropwise at this temperature over a period of 1 hour. The reaction solution is stirred at this temperature for another 5 hours. After the reaction is complete, nitrogen is passed through the reaction solution for 2 hours (to drive off bromine). The reaction solution is then concentrated to 50 ml in vacuo. In this manner, an orange-red paste of the hydrobromide of the desired compound is obtained. The hydrobromide is boiled in 400 ml of water and then brought to a PH of 8 with a 1N bicarbonate solution. The dirty brown crude product obtained is recrystallized from water/methanol (2:3), giving colorless crystals of the pure product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]1[C:28]2([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:27][C:26](=[O:34])[NH:25]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[C:26](=[O:34])[CH2:27][C:28]4([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24]3)=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1CC2(CCCCC2)CN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC5(CCCCC5)CC4=O)cc3)CC2)c(C)c1
Yield: 14.7 %

Procedure:
Using (4-bromophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (747 mg) described in Preparation Example 170 and 2-azaspiro[4.5]decan-3-one (306 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (131 mg) was obtained.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[CH2:5]([Li])[CH2:6][CH2:7][CH3:8].CN(CCN(C)C)C>CCCCCC>[CH2:1]=[CH:2][CH:3]=[CH2:4].[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [Li]CCCC
Agent: C=CC=C
Agent: CN(C)CCN(C)C
Solvent: CCCCCC
Product: C=Cc1ccccc1
Temperature: 88 °C
Reaction time: 0.51 h

Procedure:
In this experiment, a styrene-butadiene polymer was synthesized utilizing the continuous polymerization procedure of this invention. A two-reactor system which consisted of a 1-gallon first reactor and a 2-gallon second reactor was utilized with the polymerization temperature being maintained at about 190° F. (88° C.). In the procedure used, 1,3-butadiene was charged into the first reactor at a rate of 115.2 grams per minute, n-butyl lithium was charged into the first reactor as a 0.25 M solution at a rate of 1.6 grams per minute and TMEDA was charged into the first reactor as a 0.25 M solution at a rate of 1.04 grams per minute. The 1,3-butadiene monomer was charged into the reactor as a 16 weight percent premix solution in hexane. The residence time in the first reactor was 0.51 hours.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: Cn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(N2CCNCC2)nc2cccnc21

Procedure:
A solution of 2.74 g (8.63 mmol) of tert.butyl 4-(3-methyl-3H-imidazo[4,5]pyridin-2-yl)-piperazin-1-carboxylate and 3.5 ml of trifluoroacetic acid in 50 ml of dichloromethane is stirred for 14 hours while refluxing. Dilute sodium carbonate is added cautiously, the organic phase is separated off and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulphate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[S:9](=O)(=[O:12])([OH:11])[OH:10]>>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([S:9]([OH:12])(=[O:11])=[O:10])=[C:2]([Cl:1])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1cccc(Cl)c1
Product: Nc1ccc(S(=O)(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloroaniline, 0.4 ml, was slowly added to 4 ml of fuming sulfuric acid and stirred at room temperature overnight. While cooling to 0°, the reaction solution was poured onto water and the solid precipitated was separated by filtration. The solid filtered was dissolved in 2N sodium hydroxide aqueous solution and conc. hydrochloric acid was then added to the solution to make the liquid acidic. The solid precipitated was taken by filtration to give the crude product of 4-amino-2-chlorobenzenesulfonic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.[C:12](OC(C)=C)(=[O:14])[CH3:13]>C(OCC)(=O)C>[C:12]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:9]1)(=[O:14])[CH3:13]
Reactant: Nc1ccc2c(c1)CNCC2
Reactant: C=C(C)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2ccc(N)cc2C1

Procedure:
A mixture of 2.5 g. (16.8 mmol) 7-amino-1,2,3,4-tetrahydroisoquinoline, 30 ml. ethyl acetate and 2 ml. isopropenyl acetate was refluxed for approximately 16 hours and was then concentrated to dryness at reduced pressure. The residue was then recrystallized from a mixture of ethyl acetate and petroleum ether to afford 2-acetyl-7-amino-1,2,3,4-tetrahydroisoquinoline with a melting point of 98°-100° C.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:3]1=[O:21].[C:22]([NH:29][C@H:30]([C:38](O)=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].N1(C2C=CN=CC=2)CCCC1.Cl>C(Cl)Cl>[O:9]=[C:8]1[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:3](=[O:21])[CH:2]1[NH:1][C:38](=[O:39])[C@@H:30]([NH:29][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CN1C(=O)C(N)C(=O)N(c2ccccc2)c2ccccc21
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CN1C(=O)C(NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N(c2ccccc2)c2ccccc21
Reaction time: 16 h
Yield: 111.3 %

Procedure:
A mixture of 2.4 g of the product of Step D, 40 ml of methylene chloride, 2.26 g (8.5 mmoles) of BOC-L-phenylalanine, 1.8 g (9.4 mmoles) of dicyclohexycarbodiimide and 1.26 g (8.5 mmoles) of 4-pyrrolidinopyridine was stirred for 16 hours. The mixture was poured into 100 ml of hydrochloric acid and the decanted organic phase was washed three times with water. After drying, the solvent was eliminated to obtain 5 g of a yellowish foam.
Reaction SMILES: [CH:1]1([Li])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH2:7]([N:9]1[CH:13]=[CH:12][C:11]([SiH:15]([CH3:17])[CH3:16])(Cl)[B:10]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:8]>C1COCC1>[CH2:7]([N:9]1[CH:13]=[CH:12][CH:11]([Si:15]([CH:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)([CH3:17])[CH3:16])[B:10]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:8]
Reactant: CCN1C=CC(Cl)([SiH](C)C)B1c1ccccc1
Reactant: [Li]C1C=CC=C1
Solvent: C1CCOC1
Product: CCN1C=CC([Si](C)(C)C2C=CC=C2)B1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.1 %

Procedure:
A solution of cyclopentadienyl lithium (0.16 g, 2.27 mmol) in 10 mL of THF was added slowly to a solution of 1-ethyl-3-chlorodimethylsilyl-2,3-dihydro-2-phenyl-1H-1,2-azaborole (0.60 g, 2.27 mmol) in 10 mL of THF at −50° C. The reaction mixture wag slowly warmed to 25° C. and stirred for 12 h. The solvent was removed in vacuo and the residue was extracted with pentane. Solvent was removed from the extracts leaving the desired product as a brown oil (0.58 g, 87 percent).
Reaction SMILES: Cl.Cl.[CH:3]1([NH:8][C:9]2[N:14]3[N:15]=[C:16]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:17]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[N:19]=4)=[C:13]3[CH:12]=[CH:11][C:10]=2[C:37]([OH:39])=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.S(Cl)(Cl)=O.[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>ClCCl>[CH:3]1([NH:8][C:9]2[N:14]3[N:15]=[C:16]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[C:17]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)[N:19]=4)=[C:13]3[CH:12]=[CH:11][C:10]=2[C:37]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1NC1CCCC1
Reactant: C1CCNC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn2c1NC1CCCC1)N1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylic acid dihydrochloride (19 mg, 0.033 mmol) was added to a dry flask and cooled to −78° C. Thionyl chloride (14 μL, 0.19 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under a stream of nitrogen then placed under high vacuum. To a solution of the crude residue in dichloromethane (600 μL) was added pyrrolidine (150 μL, 1.80 mmol). The reaction mixture was stirred at room temperature for 10 minutes then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The combined extracts were washed with water and brine, then dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:1 hexanes:ethyl acetate to 100% ethyl acetate) provided N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-6-(1-pyrrolidinylcarbonyl)pyrazolo[1,5-a]pyridin-7-amine (9 mg, 49%) as a clear oil. Rf 0.13 (1:1 hexanes:ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.04 (d, 1H), 7.72 (d, 1H), 7.62 (m, 2H), 7.26 (d, 1H), 7.14 (t, 2H), 6.54 (d, 1H), 6.30 (d, 1H), 5.11 (d, 1H), 4.31 (m, 1H), 4.19 (m, 1H), 3.66 (broad, 2H), 3.38 (broad, 2H), 2.11-1.88 (m, 8H), 1.80-1.50 (m, 12H); MS m/z 554 (M+1). To a solution of the product in ether was added 1 M HCl in ether. The precipitated solid was isolated to give the corresponding HCl salt.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH3:11])[C:8](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:26]=[CH:25][C:21]2[N:22]=[CH:23][S:24][C:20]=2[CH:19]=1>>[S:24]1[C:20]2[CH:19]=[C:18]([NH:17][C:14](=[O:16])/[CH:13]=[CH:12]/[C:8]3[C:9]([CH3:11])=[N:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)[CH:26]=[CH:25][C:21]=2[N:22]=[CH:23]1
Reactant: Nc1ccc2ncsc2c1
Reactant: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)O
Product: Cc1nc(C(C)(C)C)ccc1/C=C/C(=O)Nc1ccc2ncsc2c1

Procedure:
Analogous to the procedure used to prepare Example 1, (2E)-3-[6-(tert-butyl)-2-methyl(3-pyridyl)]prop-2-enoic acid, Example 75(c), (220 mg, 1.0 mmol) and 6-aminobenzothiazole (150 mg, 1.0 mmol, Lancaster) provided, after purification by silica gel chromatography (55:45 hexane:EtOAc), the title compound as a pale yellow amorphous solid. MS (ESI, pos. ion) m/z: 352 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[NH2:40][C@H:41]([C:46]([OH:48])=[O:47])[CH2:42][C:43]([OH:45])=[O:44]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[NH2:40][C@H:41]([C:46]([O-:48])=[O:47])[CH2:42][C:43]([O-:45])=[O:44]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 5 °C
Reaction time: 8 h

Procedure:
Nilotinib base (0.300 g, 0.57 mmol) was dissolved in TFE (2 mL) at 40° C. to obtain a mixture. The mixture was stirred and added to a solution of L-aspartic acid (0.038 g, 0.28 mmol) in TFE (1 mL) at 40° C. The resulting solution was stirred for about 4 h and subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then a sample (1 mL) was taken from the mixture and evaporated to dryness under reduced pressure at 40° C. to give Nilotinib L-aspartate form I.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:18](O)(=[O:20])[CH3:19]>>[C:18]([C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:20])[CH3:19]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1c(O)c2ccccc2oc1=O
Temperature: 0 °C

Procedure:
120 g of 4-hydroxycoumarin in 600 ml of glacial acetic acid are heated to the boil and 380 ml of phosphorus oxychloride are added dropwise in the course of 60 minutes at the boil. The reaction mixture is heated to the boil under reflux for a further 30 minutes and is cooled and discharged into 4 l of ice-water. The crystalline residue is filtered off, washed with water and dried in vacuo at 50° C. 127 g of 3-acetyl-4-hydroxycoumarin are obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.Cl[C:24]1[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:16][C:14]1[CH:13]=[CH:12][C:11]([N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[NH:2][C:24]1[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1)=[O:22]
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)c1

Procedure:
A microwave vial was charged with N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 450 mg, 1.40 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 306 mg, 1.68 mmol) and DIPEA (733 μl, 4.20 mmol) in dry DMSO (4.7 ml). The reaction was subjected to microwave irradiation at 140° C. for 2 hours and then partitioned between ethyl acetate and water, washed with water, brine and concentrated in vacuo. The crude product was then purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to give a cream solid which was then recrystallised from a mixture of ethyl acetate and pentane to afford the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[NH:13][C:12]1([CH3:20])[CH3:19].C(O[Cl:26])(C)(C)C>CO>[Cl:26][N:13]1[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]1([CH3:20])[CH3:19]
Reactant: CC(C)(C)OCl
Reactant: COCCOCCOCCN1C(=O)C(C)(C)NC1(C)C
Solvent: CO
Product: COCCOCCOCCN1C(=O)C(C)(C)N(Cl)C1(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
To a 0° C. solution of 3-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-2,2,5,5-tetramethylimidazolidin-4-one (15.03 g, 52.1 mmol) in methanol (150 ml) was added tert-butylhypochlorite (8.50 g of 0.91 g/mL, 78.3 mmol), over a 10 minute period. The mixture was stirred for 1 hour at 0° C. The reaction mixture was checked for completion by high pressure liquid chromatography. The reaction mixture was concentrated in vacuo, and crude material was purified by silica gel flash chromatography (0 to 10% methanol in dichloromethane) to give 15.43 g (92%) of the title compound. 1H NMR (D2O, 400 MHz) δ 3.74-3.65 (m, 8H), 3.62-3.60 (m, 2H), 3.55 (t, J=6 Hz, 2H), 3.37 (s, 3H), 1.53 (s, 6H), 1.36 (s, 6H). 13C NMR (D2O, 100 MHz) δ 175.00, 83.68, 70.98, 69.59 (2 peaks), 69.39, 67.65, 66.02, 57.99, 40.16, 24.07, 22.52. LRMS (ESI/APCI) m/z 323 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([CH:9]=1)[CH2:7]O.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([CH:9]=1)[CH2:7][Br:18]
Reactant: OCc1cc(Br)ccc1OCc1cccs1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cc(Br)ccc1OCc1cccs1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A solution of 5-bromo-2-(2-thienylmethoxy)benzyl alcohol (0.53 g, 1.77 mmoles) in dichloromethane (12 ml) was cooled in an ice bath and treated with carbon tetrabromide (0.73 g, 2.2 mmol) polymer bound triphenylphosphine (0.65 g, 1.95 mmol) and stirred at ambient temperature for 42 hours. The reaction was filtered and evaporated. Chromatography (eluant: ethyl acetate/hexane) gave 5-bromo-2-(2-thienylmethoxy)benzyl bromide as a white solid (0.29, 45%).