Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[Br:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]([N:60]1[CH2:66][CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)=[O:59]>CN(C=O)C.O>[C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[CH2:18][C:19]([N:63]2[CH2:64][CH2:65][CH2:66][N:60]([C:58](=[O:59])[C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=3[Br:51])[CH2:61][CH2:62]2)=[O:21])=[CH:14][CH:15]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(c1ccccc1Br)N1CCCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)cc1
Reaction time: 0.03 h
Yield: 54.2 %

Procedure:
DIPEA (146 mg, 0.2 mL, 1.17 mmol) was added dropwise to N-biphenyl-4-yl-malonamic acid (100 mg, 0.39 mmol) in DMF (2 mL) followed by EDCI (90 mg, 0.47 mmol) and HOBT (63 mg, 0.47 mmol). After 2 minutes, (2-bromo-phenyl)-[1,4]diazepan-1-yl-methanone hydrochloride (150 mg, 0.47 mmol) was added and stirring was continued at room temperature overnight. Cold water was then added and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford 110 mg (54.18% yield) of N-biphenyl-4-yl-3-[4-(2-bromo-benzoyl)-[1,4]diazepan-1-yl]-3-oxo-propionamide. LC/MS [M+H]+: 520.12, 96.67%. 1H NMR (300 MHz, DMSO-d6): δ 10.3-10.2 (m, 1H), 7.8-6.7 (m, 13H), 4.1-3.4 (m, 9H), 3.3-3.0 (m, 2H), 2.0-1.8 (m, 1H), 1.7-1.5 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:6]=1)[CH3:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[CH3:28][OH:29]>OS(O)(=O)=O.O.CC(=O)OCC>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:8]=[C:9]([CH2:28][OH:29])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccnc(CC(C)C)c1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(CO)nc(CC(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 2-isobutyl-isonicotinic acid ethyl ester (1.00 g, 4.83 mmol) in methanol (50 mL) and H2SO4 (0.3 mL) is heated to 80° C. before a solution of ammonium peroxydisulfate (2.20 g, 9.65 mmol) in water (1.5 mL) is added carefully. Stirring is continued for 1 h at 80° C. before another portion of ammonium peroxydisulfate (2.20 g, 9.65 mmol) in water (1.5 mL) is added. The mixture is refluxed over night, cooled to rt, diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with DCM containing 10% of methanol to give 2-hydroxymethyl-6-isobutyl-isonicotinic acid ethyl ester (560 mg) as an oil; LC-MS: tR=0.81 min, [M+1]+=238.40.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[CH2:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:21][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH3:4]
Reactant: OCc1ccccc1
Reactant: FC(F)(F)c1cncc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cncc(OCc2ccccc2)c1
Product: N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 3.63 g (20 mmol) sample of 3-chloro-5-trifluoromethylpyridine dissolved in 15 mL of DMF and cooled to 0° C. was added 960 mg of NaH (60%), 2.07 mL of benzyl alcohol was added slowly. The reaction mixture was stirred for 2 hours at 40° C. The solvent was then evaporated in vacuo and the mixture diluted with chloroform, washed with saturated NaHCO3 and a brine solution. The organic layer was then dried over MgSO4. The resulting crude material was purified by flash chromatography on silica gel to give the title product MS (DCI/NH3) m/e 154(M+H)+. 1HNMR (CDCl3, 300 MHz) δ: 8.56 (d, J=1.8 Hz, 1H), 8.47 (d, J=0.9 Hz, 1H), 7.51 (dd, J=1, 0.9 Hz, 1H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:69])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:46]([O:67][CH3:68])[CH2:45]2)[CH:7]([CH3:70])[CH:6]([O:71][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:79])[CH3:2].C1C=CN=CC=1.F>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:69])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:46]([O:67][CH3:68])[CH2:45]2)[CH:7]([CH3:70])[CH:6]([OH:71])[CH2:5][C:4]1=[O:79])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(OCc4ccccc4)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(OCc4ccccc4)c4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
To a solution of the product from Step A (22 mg) in THF (100 μl) was added hydrogen fluoride/pyridine and the reaction stirred at room temperature for 6 hours. The reaction was then quenched by the addition of saturated aqueous sodium bicarbonate and extracted into ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The crude material was purified by column chromatography on silica gel eluting with 50% hexane:50% ethyl acetate to give the title compound (15 mg).
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](Cl)=[O:17].[NH2:19][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][N:35]=1)[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH2:26]([NH:25][C:23](=[O:24])[C:22]1[CH:33]=[CH:34][N:35]=[C:20]([NH:19][C:16]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)=[O:17])[CH:21]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: O=C(Cl)c1cccs1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2cccs2)c1
Yield: 73 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with thiophene-2-carbonyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(thiophene-2-carboxamido)isonicotinamide was obtained as a colorless solid in 73% yield: mp 160-162° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 11.07 (s, 1H), 9.32 (t, J=5.7 Hz, 1H), 8.53-8.47 (m, 2H), 8.23-8.22 (m, 1H), 7.87 (d, J=5.0 Hz, 1H), 7.58-7.48 (m, 1H), 7.31-7.37 (m, 6H), 4.46 (d, J=5.9 Hz, 2H); MS (ES+) m/z 338.5 (M+1).
Reaction SMILES: CC1SC(C23CCC(CC[CH2:23][CH2:24][C:25]([OH:27])=[O:26])(CC2)CO3)=C(C2C=CC=CC=2)N=1.ICC12CCC(C3SC(C)=NC=3C3C=CC=CC=3)(CC1)OC2.I[CH2:51][C:52]12[CH2:59][CH2:58][C:55]([C:60]3[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH:67]4[CH2:72][CH2:71][CH2:70][CH2:69][O:68]4)[CH:61]=3)([CH2:56][CH2:57]1)[O:54][CH2:53]2>>[O:68]1[CH2:69][CH2:70][CH2:71][CH2:72][CH:67]1[O:66][C:62]1[CH:61]=[C:60]([C:55]23[CH2:58][CH2:59][C:52]([CH2:51][CH2:23][CH2:24][C:25]([OH:27])=[O:26])([CH2:57][CH2:56]2)[CH2:53][O:54]3)[CH:65]=[CH:64][CH:63]=1
Reactant: Cc1nc(-c2ccccc2)c(C23CCC(CCCCC(=O)O)(CC2)CO3)s1
Reactant: ICC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: Cc1nc(-c2ccccc2)c(C23CCC(CI)(CC2)CO3)s1
Product: O=C(O)CCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2

Procedure:
4-(1-(3-(Tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)butanoic acid was prepared using a procedure analogous to 5-(1-(2-methyl-4-phenylthiazol-5-yl)-2-oxabicyclo[2.2.2]octan-4-yl)pentanoic acid except that 5-(4-(iodomethyl)-2-oxabicyclo[2.2.2]octan-1-yl)-2-methyl-4-phenylthiazole was replaced with 4-(iodomethyl)-1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octane. The title compound was obtained (0.88 g, 2.2 mmol, 95% yield) as a clear oil. LCMS, [M−H]+=373.1. 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J=8.0 Hz, 1H), 7.17-7.10 (m, 1H), 7.05-6.99 (m, 1H), 6.95 (ddd, J=8.2, 2.5, 0.9 Hz, 1H), 5.45 (t, J=3.2 Hz, 1H), 3.94 (ddd, J=11.3, 9.9, 3.0 Hz, 1H), 3.84 (s, 2H), 3.67-3.58 (m, 1H), 2.36 (t, J=7.4 Hz, 2H), 2.11-1.99 (m, 5H), 1.91-1.82 (m, 2H), 1.77-1.54 (m, 9H), 1.26-1.16 (m, 2H).
Reaction SMILES: Cl[C:2](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[C:3](=[O:5])[CH3:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2](=[N:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3](=[O:5])[CH3:4])=[CH:18][CH:17]=1
Reactant: CC(=O)C(Cl)=NNc1cccc(Cl)c1
Reactant: Sc1ccc(Cl)cc1
Product: CC(=O)C(=NNc1cccc(Cl)c1)Sc1ccc(Cl)cc1
Yield: 95.9 %

Procedure:
The reaction of 2.23 g of 1-chloro-1-[(3-chlorophenyl) hydrazono]-2-propanone with 1.72 g of 4-chlorothiophenol as Example 11 yielded 3.14 g of 1-[(4-chlorophenyl)thio]-1-[(3-chlorophenyl)hydrazono]-2-propanone, mp 128°-131° C.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>C(#N)C.O>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(C)(Oc1ccc(Cl)cn1)C(=O)O
Temperature: 50 °C

Procedure:
A mixture of ethyl 2-methyl-2-(5-chloro-2-pyridyloxy)propionate and sodium hydroxide (0.85 g, 21 mmol) in 15 mL acetonitrile and 15 mL water was heated at 50° C. overnight. The volatile materials were removed by concentrating on a rotary evaporator, and the residue was partitioned between 2 M hydrochloric acid (100 mL) and ether (100 mL). The organic layer was separated and washed with water (2×50 mL), dried over anhydrous MgSO4, filtered and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.02 (d, 1H), 7.65 (dd, 1H), 6.77 (d, 1H), 1.62 (s, 6H). LC-MS: m/e 216 (M+H)+ (2.33 min).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.[NH2:24][CH:25]1[C:46](=[O:47])[N:27]2[C:28]([C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])=[C:29]([Cl:32])[CH2:30][S:31][C@H:26]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([NH:24][CH:25]2[C:46](=[O:47])[N:27]3[C:28]([C:33]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][C:40]([N+:43]([O-:45])=[O:44])=[CH:41][CH:42]=4)=[O:34])=[C:29]([Cl:32])[CH2:30][S:31][C@H:26]23)=[O:12])[N:8]=1)=[O:2]
Reactant: CCCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 81.9 %

Procedure:
A solution of 2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetic acid (syn isomer, 1.5 g.), N,N-dimethylformamide (440 mg.) and phosphoryl chloride (920 mg.) in ethyl acetate (12 ml.) and a solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (2.03 g.), trimethylsilylacetamide (7 g.) and bis(trimethylsilyl)acetamide (2 ml.) in ethyl acetate (25 ml.) were treated in a similar manner to that of Example 21-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 2.8 g.), yellow powder.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CC(O)C>[CH2:12]([NH:19][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ncnc2cccnc12
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: c1ccc(CNc2ncnc3cccnc23)cc1
Temperature: 50 °C

Procedure:
A solution of freshly prepared 4-chloropyrido[3,2-d]pyrimidine (0.10 g, 0.60 mmol) (prepared as described in the previous experimental) and benzylamine (0.13 mL, 1.20 mmol) in propan-2-ol (15 mL) containing a trace of conc. HCl is warmed at 50° C. for 30 min, and then concentrated to dryness. The residue is partitioned between water and EtOAc, and the organic layer worked up and chromatographed on silica gel. EtOAc elutes foreruns, while MeOH/EtOAc (1:9) elutes 4-(benzylamino)pyrido[3,2-d]pyrimidine (0.11 g, 77%). 1H NMR (CDCl3) δ 8.67 (1H, s), 6.50 (1H, dd, J=4,3, 1.5 Hz), 8.10 (1H, dd, J=8.5, 1.5 Hz), 7.63 (1H, dd, J=8.8, 4,3 Hz), 7.55 (1H, brs), 7.41-7.29 (5H, m), 4.86 (2H, d, J=5.9 Hz).
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.[C:40]([OH:48])(=[O:47])[C@H:41]([CH2:43][C:44]([OH:46])=[O:45])[OH:42]>>[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.[C:40]([O-:48])(=[O:47])[C@H:41]([CH2:43][C:44]([O-:46])=[O:45])[OH:42]
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: O=C([O-])C[C@H](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-malic acid (0.066 g, 0.57 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 amorphous Nilotinib L-malate as characterized by the powder X-ray diffractogram depicted in FIG. 45.
Reaction SMILES: [Br:1][C:2](Br)(Br)[F:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C@H:33]2[CH2:38][CH2:37][C@H:36]([CH:39]=O)[CH2:35][CH2:34]2)[CH2:29][CH2:28]1)[CH3:26]>COCCOC.O1CCCC1>[CH2:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C@H:33]2[CH2:38][CH2:37][C@H:36]([CH:39]=[C:2]([F:3])[Br:1])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1)[CH3:26]
Reactant: FC(Br)(Br)Br
Reactant: CC[C@H]1CC[C@H]([C@H]2CC[C@H](C=O)CC2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: COCCOC
Product: CC[C@H]1CC[C@H]([C@H]2CC[C@H](C=C(F)Br)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tribromofluoromethane and triphenyl phosphine in ethylene glycol dimethyl ether was stirred at 70° C. for 1 hour. The reaction solution was cooled with ice, and a solution of trans-4-(trans-4-ethylcyclohexyl)cyclohexane carboaldehyde in tetrahydrofuran was added thereto. After the reaction solution was further stirred for 1 hour, the temperature of the solution was gradually raised up to room temperature, and insoluble substances were removed by filtration. Dilute hydrochloric acid was added to the filtrate, and it was extracted with toluene. After the organic layer was washed with water, it was dried by using anhydrous magnesium sulfate, and concentrated under a reduced pressure to obtain a brown oily product. After this product was purified by using a silica gel column chromatography, it was recrystallized from heptane to obtain trans-4-(trans-4-ethylcyclohexyl)cyclohexyl-2-fluoro-2-bromoethene.
Reaction SMILES: [CH2:1]1[C@:6]2([OH:10])[C:7]([O:9][C@@H:4]([CH2:5]2)[C@@H:3]([OH:11])[C@H:2]1[OH:12])=[O:8].Cl.C(=O)(O)[O-:15].[Na+].[Na+].[Cl-]>C1COCC1>[CH2:5]1[C@@H:4]([OH:9])[C@@H:3]([OH:11])[C@H:2]([OH:12])[CH2:1][C@@:6]1([C:7]([OH:15])=[O:8])[OH:10]
Reactant: O=C([O-])O
Reactant: O=C1O[C@H]2C[C@]1(O)C[C@H](O)[C@@H]2O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Temperature: 0 °C

Procedure:
A solution of 12.7 g (12.2 mmol) 1,3-O-dicarbotrichloroethoxy-4-O-dicarbotrichloroethoxycaffeoyl quinide in 870 ml THF is treated for 3 days with 9 ml concentrated HCl. After cooling to 0° C., the reaction mixture is adjusted to pH 2 by addition of solid sodium bicarbonate and is then saturated with NaCl. The organic phase is then separated and the aqueous phase is extracted with 2×20 ml ethyl acetate. After the combined organic phases have been dried over sodium sulfate, the solvents are evaporated. Treatment of the residue with a solvent mixture of THF and hexane in a ratio by volume of 1:20 gives 12.7 g 1,3-O-dicarbotrichloroethoxy- 4-O-dicarbotrichloroethoxycaffeoyl quinic acid in the form of an amorphous white powder (yield 99%) .
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].C[Si](Cl)(C)C.CC1(C)[O:21][C:20](=O)[CH2:19][C:18](=[O:23])[O:17]1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:20](=[O:21])[CH2:19][C:18]([OH:23])=[O:17]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccccc1N
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1NC(=O)CC(=O)O
Yield: 30 %

Procedure:
To a solution of 2-methoxybenzeneamine (1.1 g, 8.93 mmol) in DCM (90 mL) was added TMSCl (1.1 mL, 8.93 mmol) at room temperature [Rigo, B.; Fasseur, D.; Cauliez, P. and Couturier, D. Tetrahedron Lett.; 30; 23; 1989; 3073-3076.]. The reaction mixture was stirred for 30 mins before the addition of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.29 g, 8.93 mmol) and then stirring was continued mixture for additional 2 hours. Water (1 mL) was added, and the reaction mixture was concentrated under reduced pressure. The residue was poured into saturated NaHCO3 solution, and extracted with EtOAc. The aqueous phase was collected, acidified with conc. HCl to pH˜4, extracted with EtOAc, the extract was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (eluent CHCl3/MeOH/AcOH 9:1:0.1) to afford the compound 27 (0.56 g, 30% yield) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 12.62 (bs, 1H), 9.52 (s, 1H), 8.02 (dd, 1H), 7.03 (m, 2H), 6.88 (m, 1H), 3.82 (s, 3H), 3.46 (s, 2H). MS (m/z): 210.1 (M+H).
Reaction SMILES: N1C2C(CCCC2)C[CH2:3][CH2:2]1.[CH3:11][C:12]1([CH3:23])[CH2:21][CH:20]([CH3:22])[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[NH:13]1.ICC>>[CH2:2]([N:13]1[CH:14]2[CH:19]([CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:20]([CH3:22])[CH2:21][C:12]1([CH3:23])[CH3:11])[CH3:3]
Reactant: CC1CC(C)(C)NC2CCCCC12
Reactant: C1CCC2NCCCC2C1
Solvent: CCI
Product: CCN1C2CCCCC2C(C)CC1(C)C
Temperature: 105 °C
Reaction time: 3 h

Procedure:
1-ethyl-2,2,4-trimethyl decahydroquinoline was prepared by the reaction of the intermediate saturated decahydroquinoline with the alkyl halide. 36.3 grams (0.2 mole) of 2,2,4-trimethyl decahydroquinoline of about 76% cis structure was placed into a reactor vessel equipped for heating and agitation. 15.6 grams (0.1 mole) of iodoethane was added dropwise to the reactor vessel. The mix was heated to 105° C. while stirring for 3 hours. A thick slurry formed which was filtered out and washed with acetone. The acetone wash liquid was then concentrated and distilled using a 3" Vigreaux column to yield 7.1 grams of a product boiling at 58°-60° C. at 0.25 mm Hg. The NMR spectra of the product was consistent with the desired product, 1-ethyl-2,2,4-trimethyl decahydroquinoline. Calculated carbon, hydrogen, nitrogen content for the formula C14H27N is 80.31% carbon, 13.00% hydrogen, and 6.69% nitrogen while the measured contents were 79.93% carbon, 13.54% hydrogen, and 6.35 % nitrogen respectively.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[CH:5][C:4]=2[NH:3]1.[Br:17]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:17][C:13]1[S:14][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH:12]=1
Reactant: N#Cc1ccc2c(c1)[nH]c(=O)c1ccsc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc2c(c1)[nH]c(=O)c1cc(Br)sc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carbonitrile (1.0 eq, 350 mg, 1.55 mmol) was mixed with N-bromosuccinimide (1.1 eq, 303 mg, 1.70 mmol) in acetic acid (4 ml). The mixture was stirred at 100° C. for 4 hours. The mixture was cooled down to 80° C., more NBS (303 mg) was added and the mixture stirred overnight. Water was added and the material filtered and dried. Trituration in methanol and filtration afforded 2-bromo-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carbonitrile as a grey solid (396 mg, 84% yield). LCMS (ES)>80% pure, m/z 305 [M]+, 307 [M+2]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]#[N:25].[NH2:26][C:27]1[C:28]([CH3:34])=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1.Cl.N1C=CC=CC=1.C(OCCO)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[OH:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:24]#[N:25])=[C:28]([CH3:34])[CH:29]=1
Reactant: Cc1cc(O)ccc1N
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(O)cc3C)c(C#N)cnc2cc1OCCCN1CCOCC1
Yield: 61.8 %

Procedure:
A mixture of 0.3 g of 4chloro-6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoline-3-carbonitrile derivative, 0.12 g of 4amino-m-cresol, 0.1 g of pyridine hydrochloride and 4 ml of 2-ethoxy ethanol was stirred under nitrogen at reflux temperature for 1.5 hr. The mixture was cooled and added to the mixture of ethyl acetate and saturated solution of sodium bicarbonate, stirred for 15 minutes. Following separation of layers, the organic layer was dried over anhydrous sodium sulfate, filtered and filtrate was evaporated to yield dark oil. The oil was purified by silica gel flash chromatography utilizing a gradient of methylene chloride/methanol (95:5 to 90:10 ) to give 0.23 g of the title compound as a tan solid, mp120-126 C; mass spectrum (electrospray, m/e):M+H 449.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C=O.C(O)(=O)[C:26](O)=[O:27]>O.C1(C)C(C)=CC=CC=1.C1(C)C(C)=CC=CC=1>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3].[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH:15][C:12]1[CH:11]=[CH:10][C:9]([C:1]([C:4]2[CH:5]=[CH:8][C:16]([OH:22])=[CH:17][CH:18]=2)([CH3:2])[CH3:3])=[CH:14][CH:13]=1.[CH2:26]=[O:27]
Reactant: O=C(O)C(=O)O
Agent: C=O
Agent: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Solvent: Oc1ccccc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 170 °C

Procedure:
375 g. (1.8 moles) of p-tert-octylphenol, 75 g (0.8 mole) of phenol, 50 g (0.22 mole) of 4,4'-isopropylidene-biphenol (bisphenol A), 215 g (2.65 moles) of 37% formalin, 10 g of oxalic acid and 100 g of xylene were put into a reactor, and they were refluxed for 7 hours at the boiling point of the water-xylene azeotrope. The reaction mixture was then heated to 170° C. while removing water and the solvent, thereby giving a p-tert-octylphenol/phenol/bisphenol A/formaldehyde co-condensate having a softening point of 85° C.