Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]2[S:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.C(N(C(C)C)CC)(C)C.[CH3:31][C:32]1([CH3:40])[O:36][C@@H:35]([CH2:37][O:38][NH2:39])[CH2:34][O:33]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[CH3:31][C:32]1([CH3:40])[O:36][C@@H:35]([CH2:37][O:38][NH:39][C:19]([C:11]2[CH:12]=[CH:13][C:14]3[CH:15]=[N:16][S:17][C:18]=3[C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:21])[CH2:34][O:33]1
Reactant: O=C(O)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Reactant: CC1(C)OC[C@H](CON)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CONC(=O)c2ccc3cnsc3c2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-6-carboxylic acid (377 mg, 0.91 mmol) and diisopropylethylamine (0.47 mL, 2.73 mmol) in DMF (4 mL) were added O—((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (268 mg, 1.82 mmol), EDCI (349 mg, 1.82 mmol) and HOBt (246 mg, 1.82 mmol). The reaction mixture was stirred for 18 hours at room temperature, diluted with ethyl acetate, and washed with water, a saturated aqueous solution of sodium hydrogen carbonate, then brine before being dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0% to 100%, TBME in cyclohexane) to afford the title compound as a yellow solid (266 mg, 54%). LCMS (method B): RT=4.04 min, [M+H]+=544.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=1)[CH2:16][OH:17].C(N(CC)C(C)C)(C)C>C(O)CCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:14]([C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][Si:27]([CH3:29])([CH3:28])[CH3:30])[CH:20]=1)[CH2:16][OH:17])[CH2:12]2
Reactant: C[Si](C)(C)C#Cc1cccc(C[C@H](N)CO)c1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[Si](C)(C)C#Cc1cccc(C[C@@H](CO)N2Cc3cc(Br)ccc3C2=O)c1

Procedure:
A solution of methyl 4-bromo-2-(bromomethyl)benzoate (0.75 g, 2.4 mmol), (2S)-2-amino-3-{3-[(trimethylsilyl)ethynyl]phenyl}propan-1-ol (0.60 g, 2.4 mmol) and N,N-diisopropylethylamine (2.1 mL, 12 mmol) in 1-butanol (2 mL) in a sealed tube was stirred at 140° C. for 2 h. The solvent was removed under vacuum and the residue was eluted with 0-100% EtOAc in hexanes giving 0.78 g (73% yield) of the pure desired product as off white solid. LC/MS found: 442.0 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH:14]1[CH2:19][CH2:20][OH:21])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]([O:4][CH3:5])=[O:3])[CH2:15][CH:14]1[CH2:19][CH2:20][OH:21])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1CCO
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Yield: 77.4 %

Procedure:
A solution of methyl chloroformate (0.52 ml, 6.73 mmol) in dichloromethane (5 ml) was added dropwise over 0.1 h to a stirred solution of (RS)-1-(tert-butyloxycarbonyl)-2-(2-hydroxyethyl)piperazine (D6) (1.4 g, 6.09 mmol) and triethylamine (1.7 ml, 12.2 mmol) in dichloromethane (45 ml) at 0° C. under argon. The resultant mixture was stirred at room temperature for 18 h, washed with saturated sodium hydrogen carbonate and the organic layer dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 10-100% ethyl acetate in hexane to give the title compound as a colourless gum (1.36 g, 78%). 1H NMR (CDC13)δ: 1.48 (9H, s), 1.60-1.95 (2H, m), 2.80-3.00 (2H, m), 3.05-3.45 (2H, m), 3.50-3.70 (2H, m), 3.70 (3H, s), 3.75-4.45 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:10]=[CH:11][N:12](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=2)=[CH:4][CH:3]=1.[Cl:33][C:34]1[N:39]=[C:38]([N:40]2[CH:45]=[CH:44][C:43]([CH2:46]N3C(CC4C=CC(C#N)=CC=4)=CN=C3)=[CH:42][C:41]2=[O:61])[CH:37]=[N:36][CH:35]=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[N:10]([CH2:46][C:43]3[CH:44]=[CH:45][N:40]([C:38]4[CH:37]=[N:36][CH:35]=[C:34]([Cl:33])[N:39]=4)[C:41](=[O:61])[CH:42]=3)[CH:11]=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3cncc(Cl)n3)c(=O)c2)cc1
Reactant: Brc1ccc(Oc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Solvent: CC#N
Product: O=c1cc(Cn2cncc2Oc2ccc(Br)cc2)ccn1-c1cncc(Cl)n1
Temperature: 60 °C

Procedure:
A mixture of 4-(4-bromophenyloxy)-1-trityl-1H-imidazole (0.164 g, 0.34 mmol) and 4-bromomethyl-1-(6-chloro-pyrazin-2-yl)-1H-pyridin-2-one from example 7 (98.5 mg, 0.34 mmol) in anhydrous acetonitrile (10 mL) was heated under reflux at 60° C. for 24 h. The resultant solution was concentrated, and the residue dissolved in a mixture of methanol (10 mL) and 1,2-dichloroethane (1 mL). The solution was heated under reflux for 2 h, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1:1 v/v 6% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provided the titled compound.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([C:26]1[O:27][CH:28]=[CH:29][C:30]=1B(O)O)(=[O:25])[CH3:24].O.[F-].[K+].[Br-].[Na+]>FC(F)(F)C1C=CC=CC=1.O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:23]([C:26]1[O:27][CH:28]=[CH:29][C:30]=1[C:14]1[C:15]([OH:21])=[C:16]([C:11]([CH2:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:12][CH:13]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:25])[CH3:24]
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Reactant: CC(=O)c1occc1B(O)O
Agent: [Pd]
Agent: [Br-]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Solvent: FC(F)(F)c1ccccc1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C(C)=O)c1O
Temperature: 175 °C
Yield: 48.8 %

Procedure:
A mixture of methyl 6-(benzenesulfonylmethyl)-3-bromo-2-hydroxybenzoate (Intermediate 40, 0.4 g), 2-acetylfuran-3-boronic acid (0.24 g), tetrakis-(triphenylphosphine) palladium (0.12 g), potassium fluoride monohydrate (0.302 g) and sodium bromide (0.192 g) in α,α,α-trifluorotoluene (8 mL) and dioxane (4 mL) was degassed and then heated in the microwave at 175° C. for 30 minutes. The mixture was cooled and ethyl acetate and water were added. The organic layer was separated, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-25% to give methyl 3-(2-acetylfuran-3-yl)-6-(benzenesulfonylmethyl)-2-hydroxybenzoate (0.21 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7]([NH2:10])(=[O:9])=[O:8])[N:4]=[CH:3]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:52]1[CH:57]=[C:56]([O:58][CH:59]([F:61])[F:60])[N:55]=[C:54]([S:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[C:65]=2[F:71])[N:53]=1.FC(F)OC1N=C(SCC2C=CC=C(F)C=2F)N=C(NS(N2CCC2)(=O)=O)C=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:61][CH:59]([F:60])[O:58][C:56]1[N:55]=[C:54]([S:62][CH2:63][C:64]2[CH:69]=[CH:68][CH:67]=[C:66]([F:70])[C:65]=2[F:71])[N:53]=[C:52]([NH:10][S:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)(=[O:9])=[O:8])[CH:57]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(OC(F)F)n2)c1F
Reactant: Cn1cnc(S(N)(=O)=O)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cnc(S(=O)(=O)Nc2cc(OC(F)F)nc(SCc3cccc(F)c3F)n2)c1

Procedure:
The title compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 1-methyl-1H-imidazole-4-sulfonamide (0.25 g), tris(dibenzylideneacetone)dipalladium (0) (0.10 g), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (60 mg), cesium carbonate (0.26 g), 4-chloro-6-(difluoromethoxy)-2-[[(2,3-difluorophenyl)methyl]thio]-pyrimidine (product of example 12, step (0.18 g) and anhydrous dioxane (5 ml). Purification was by tituration with methanol/DCM. The resulting white solid was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O (×2) then brine and dried (MgSO4), filtered and evaporated. The resulting oil was triturated with methanol/DCM to give the title compound as a white solid. Yield: 15 mg
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C1CCCCC1)C.Cl.[CH2:25]([NH2:27])[CH3:26].[Cl:28][C:29]1[S:37][C:36]2[S:35](=[O:39])(=[O:38])[NH:34][C:33](=O)[NH:32][C:31]=2[CH:30]=1>O>[Cl:28][C:29]1[S:37][C:36]2[S:35](=[O:39])(=[O:38])[N:34]=[C:33]([NH:32][CH2:31][CH3:30])[NH:27][C:25]=2[CH:26]=1
Reactant: CCN
Reactant: O=C1Nc2cc(Cl)sc2S(=O)(=O)N1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CN(C)C1CCCCC1
Product: CCNC1=NS(=O)(=O)c2sc(Cl)cc2N1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 21.2 %

Procedure:
Phosphorus pentoxide (2.84 g, 20 mmol), N,N-dimethylcyclohexylamine (3 ml, 20 mmol) and ethylamine hydrochloride (1.63 g, 20 mmol) were carefully mixed and heated with stirring on an oil bath at 180° C. for 20 min. To the homogeneous mass was added 6-chloro-2,3-dihydro-3-oxo-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.2 g, 5 mmol) and the mixture was stirred at 180° C. for 5 h. After cooling to ca. 100° C., water (150 ml) was added and the mixture was stirred for 1 h at room temperature. Then the mixture was extracted with ethyl acetate (3×100 ml). The organic phase was washed with saturated aqueous sodium hydrogen carbonate, dried and evaporated to dryness. The residue was recrystallised from ethyl acetate/methanol to give 282 mg (21%) of the pure title compound; m.p. 271°-274° C.; 1H-NMR (DMSO-d6): δ 1.11 (t, 3H, CH3), 3.22 (m, 2H, CH2), 7.04 (s,1H, 5-H), 7.3 (br. s, 1H, NH), 11.1 (br. s, 1H, NH); MS m/e: 265/267 (M+); (C7H8N3Cl1O2S2) calc. C 31.64 H 3.03 N 15.81, found C 31.57 H 3.12 N 15.63.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[CH2:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)[CH2:32][CH3:33]>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([CH2:31][CH2:32][CH3:33])=[CH:35][CH:36]=4)[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: CCCc1ccc(C(=O)Cl)cc1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1ccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 500 mg (1.1 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoroacetate with 210 μl (1.2 mmol) of 4-propylbenzoyl chloride and after purification, 300 mg (55%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-ylmethyl]-N-methyl-4-propylbenzamide, with a melting point of 280° C., are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[F:15].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[F:15][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[N:8]([CH3:11])[C:7](=[O:12])[C:6]2([CH3:13])[CH3:14]
Reactant: CN1C(=O)C(C)(C)c2cc(F)c(N)cc21
Reactant: O=C(O)c1ccncc1
Product: CN1C(=O)C(C)(C)c2cc(F)c(NC(=O)c3ccncc3)cc21

Procedure:
Prepared in analogy to example 17 from 6-amino-5-fluoro-1,3,3-trimethylindolin-2-one and isonicotinic acid. The title compound was obtained as white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:28]([NH:32][CH2:33][CH3:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O1CCOCC1>[C:28]([N:32]([CH2:33][CH3:34])[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:15][N:14]=1)=[O:18])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C(O)c1ccc(C#Cc2cccc(F)c2)cn1
Reactant: CCNC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCN(C(=O)c1ccc(C#Cc2cccc(F)c2)cn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.7 %

Procedure:
(100 mg, 0.41 mmol) 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid (Example 1, step 2) was dissolved in dioxane (1 ml) and Hunig's Base (217 μl, 1.24 mmol, 3 equiv.), tert.-butylethylamine (63 mg, 0.62 mmol, 1.5 equiv.) and TBTU (146 mg, 0.45 mmol, 1.1 equiv.) were added at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and extracted saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 0:100. The desired 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-ethyl-amide (102 mg, 76% yield) was obtained as a light yellow oil, MS: m/e=325.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:29]([O:31][CH:32]([CH3:35])[CH2:33][NH2:34])[CH3:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:29]([O:31][CH:32]([CH3:35])[CH2:33][NH:34][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH3:30]
Reactant: CCOC(C)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(C)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 34.2 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-propyl)-amide (31 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 2-ethoxy-propylamine (21 mg), HBTU (84 mg), and DIEA (48 uL). LC/MS: m/z 494.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (s, 1H), 8.43 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.83-7.66 (m, 2H), 7.48 (d, 1H), 7.36 (d, 1H), 3.79-3.43 (m, 5H), 3.41-3.30 (m, 2H), 3.29-3.18 (m, 1H), 1.14-1.08 (m, 6H).
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]>CC(OC)(C)C>[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
Solvent: COC(C)(C)C
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 (0.076 g, 0.57 mmol) in TFE (1 mL) at 40° C. The resulting clear solution was stirred for about 4 h at 40° C. and subsequently cooled to 5° C. The mixture was kept at 5° C. overnight and then MTBE (1.5 v/v) was added to the mixture at room temperature leading to precipitation. The precipitate was filtered and the filter cake was dried at 40° C. in a vacuum oven overnight to give Nilotinib L-aspartate form III.
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29]Cl.Cl.Cl.C(OC1CC2C3C(=CC=CC=3)NC=2CC1)(=O)C1C=CC=CC=1>CN(C)C=O>[C:1]([O:9][CH:10]1[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])[C:13]=2[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1CCc2[nH]c3ccccc3c2C1)c1ccccc1
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCn1c2c(c3ccccc31)CC(OC(=O)c1ccccc1)CC2

Procedure:
The 3-benzoyloxy-9-[3-(dimethylamino)propyl]-1,2,3,4-tetrahydrocarbazole was prepared by following an alkylation procedure similar to that described in Example 11 and using 29.1 g. of 3-benzoyloxy-1,2,3,4-tetrahydrocarbazole and 4.3 g. of sodium hydride (50% in mineral oil) in 200 ml. of dimethylformamide, and 13 g. of 3-(dimethylamino)propyl chloride. The crude free base was extracted from the water diluted reaction mixture into ether and the ethereal solution was treated with ethereal hydrogen chloride. The resulting precipitate was recrystallized from isopropyl alcohol and ethyl acetate to give 6.2 g. of 3-benzoyloxy-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. 162°-180° C.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CC(C)=O>[CH2:23]([O:22][C:20]([CH2:19][C:18]([C:17]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH:1]=1)=[O:25])=[O:21])[CH3:24]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC(=O)c1cc2ccccc2o1
Temperature: 25 °C

Procedure:
122 g of salicylaldehyde 1 and 350 g of potassium carbonate are dissolved in 2L of acetone. While stirring at room temperature, add slowly 165 g of ethyl 4-chloroacetoacetate 2 over a period of 2 hours. When addition is over, stir at reflux for another 4 hours. Cool to room temperature and filter. Wash the filtration cake with 0.5L of acetone. Evaporate the solvent.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[C:19](Cl)(=[O:21])[CH3:20].O>N1C=CC=CC=1>[C:19]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1nc(N)sc1-c1ccc(SC)cc1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1nc(NC(C)=O)sc1-c1ccc(SC)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Methyl 2-amino-5-[4-(methylthio)phenyl]-1,3-thiazole-4-carboxylate (8.8 g) was dissolved in pyridine (88 ml), and then acetyl chloride (6.7 ml) was added dropwise to the solution at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes and at 50° C. for 2 hours. After cooled to 0° C., water was added to the solution. The precipitate was filtered in vacuo, and the solid was washed with ethyl ether to give methyl 2-(acetylamino)-5-[4-(methylthio)phenyl]-1,3-thiazole-4-carboxylate (9.3 g) as an off-white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]2[C@@H:11]3[C@@H:16]([CH2:17][CH2:18][O:19][C:7]=2[CH:6]=1)[NH:15][CH2:14][CH2:13][O:12]3)[CH3:3].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:27][CH2:28][C:29]([N:15]1[CH2:14][CH2:13][O:12][C@@H:11]2[C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:2][CH3:3])=[CH:6][C:7]=3[O:19][CH2:18][CH2:17][C@@H:16]12)=[O:30]
Reactant: CCOc1ccc2c(c1)OCC[C@H]1NCCO[C@H]21
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc2c(c1)OCC[C@@H]1[C@@H]2OCCN1C(=O)CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.21 g of trans-3,4,4a,5,6,11b-hexahydro-9-ethoxy-2H-[1]benzoxepino[5,4-b]-1,4-oxazine hydrochloride, prepared via an analogous procedure to the preceding Example, and 1.65 ml of triethylamine in 25 ml of methylene chloride is treated dropwise with a solution of 0.70 ml of chloroacetyl chloride dissolved in 10 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, washed with a dilute solution of hydrochloric acid, followed by a water wash, a wash of dilute sodium hydroxide solution and finally by a wash of a saturated solution of sodium chloride. The reaction mixture is dried over anhydrous magnesium sulfate and evaporated to dryness to obtain 1.44 g of trans-N-chloroacetyl-3,4,4a,5,6,11b-hexahydro-9-ethoxy-2H-[1]benzoxepino[5,4-b]-1,4-oxazine.
Reaction SMILES: ClC1C=C(C=CC=1Cl)CN1CCOC(CN)C1.FC(F)(F)C([NH:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][NH:26][CH2:25]1)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36]Br>>[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][N:26]1[CH2:27][CH2:28][O:29][CH:24]([CH2:23][NH2:22])[CH2:25]1
Reactant: Fc1ccc(CBr)cc1F
Reactant: O=C(NCC1CNCCO1)C(F)(F)F
Agent: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: NCC1CN(Cc2ccc(F)c(F)c2)CCO1

Procedure:
Intermediate 20 was prepared in an analogous manner to Intermediate 1 (Alternative Procedure) from Intermediate 19 and 3,4-difluorobenzyl bromide, followed by deprotection to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:29][C:25]=1[C:26](O)=[O:27].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:29][C:25]=1[C:26]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[N:10]=[CH:9][N:8]=[C:7]2[O:6][C:5]1[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)=[O:27]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ncnc23)c1
Yield: 32.8 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-8, 50 mg, 0.164 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 88 mg, 0.326 mmol), oxalyl chloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (63 mg, 0.49 mmol) in CH2Cl2 (2 mL) to afford 30 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.35 (s, 1H), 8.92 (d, 1H), 8.77 (s, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.85 (m, 2H), 7.73 (s, 3H), 7.59-7.53 (m, 2H), 7.39 (d, J=7.2 Hz, 1H), 4.29 (d, J=5.4 Hz, 2H), 1.11 (s, 9H); MS [M+H]+: 557.14.