Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][C:23]3[C:32]4[C:27](=[CH:28][C:29]([O:34][CH3:35])=[C:30]([OH:33])[CH:31]=4)[N:26]=[CH:25][N:24]=3)=[CH:19][N:20]=2)[CH:15]=[CH:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:55][S:56]([N:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][CH2:67]O)[CH2:61][CH2:60]1)(=[O:58])=[O:57]>CN(C=O)C>[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][C:23]3[C:32]4[C:27](=[CH:28][C:29]([O:34][CH3:35])=[C:30]([O:33][CH2:67][CH2:66][CH2:65][N:62]5[CH2:63][CH2:64][N:59]([S:56]([CH3:55])(=[O:58])=[O:57])[CH2:60][CH2:61]5)[CH:31]=4)[N:26]=[CH:25][N:24]=3)=[CH:19][N:20]=2)[CH:15]=[CH:14]1
Reactant: CS(=O)(=O)N1CCN(CCCO)CC1
Reactant: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Diethyl azodicarboxylate (0.09 g, 0.518 mmol) was added dropwise to a solution of 4-(7-azaindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.133 g, 0.432 mmol), triphenylphosphine (0.17 g, 0.647 mmol) and 3-(4-methylsulphonylpiperazin-1-yl)propan-1-ol (0.115 g, 0.519 mmol) in DMF (4 ml) and the mixture was stirred at ambient temperature for 1 hour. The volatiles were removed under vacuum and the residue was purified by column chromatography using increasingly polar mixtures of ethyl acetate and methylene chloride followed by methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The solid was then repurified by preparative LC/MS eluting with acetonitrile/water (containing 1% acetic acid). The fractions containing the expected product were combined and evaporated. The residue was dissolved in aqueous sodium hydrogen carbonate and methylene chloride. The organic phase was separated and dried over magnesium sulphate and evaporated. The residue was triturated under diethyl ether, filtered, washed with ether and dried under vacuum over P2O5 to give 4-(7-azaindol-5-yloxy)-7-methoxy-6-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazoline (0.09, 40%).
Reaction SMILES: [C:1]1([C:15]([OH:17])=O)[C:10]2[C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][CH2:5][C:4]=2[NH:3][N:2]=1.[N:18]1([CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]2)[CH2:21][CH2:20][CH2:19]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCCl.C(Cl)Cl>[N:18]1([CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][C:27]([NH:30][C:15]([C:1]3[C:10]4[C:9]5[N:11]=[CH:12][CH:13]=[CH:14][C:8]=5[CH2:7][CH2:6][CH2:5][C:4]=4[NH:3][N:2]=3)=[O:17])=[N:26]2)[CH2:19][CH2:20][CH2:21]1
Reactant: O=C(O)c1n[nH]c2c1-c1ncccc1CCC2
Reactant: Nc1ccn(CCCN2CCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Nc1ccn(CCCN2CCC2)n1)c1n[nH]c2c1-c1ncccc1CCC2
Yield: 8.8 %

Procedure:
7.8 mL of 1.7 M of t-BuLi in pentane is added dropwise under argon to a stirred solution of 1-bromo-3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene (1.4 g) in 75 mL of anhydrous THF at −78° C. After addition, dry carbon dioxide is bubbled into the mixture at the same temperature for 2 hours. The reaction mixture is allowed to warm to room temperature, quenched with 1N HCl solution, and diluted with water. The mixture is basified with 1N NaOH to pH 8-9, and then extracted with EtOAc. The aqueous layer is then acidified with HOAc to pH 4-5 and extracted with CH2Cl2 eight times. The combined extracts are washed with water, dried, and concentrated to give 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid as a tan solid. 1H NMR(DMSO): 1.95(m, 2H), 2.96(m, 2H), 3.07(t, 2H), 7.45(m,1H), 7.97(d,1H), 8.52(d, 2H). LR-MS: MW 229.23, Found: 230.2(M+1). Step 6: A mixture of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid (80 mg), 1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-ylamine (68 mg), EDCI(85 mg) and DMAP(55 mg) in 10 mL of 1,2-dichloroethane is refluxed overnight, cooled and diluted with CH2Cl2. The mixture is washed with aqueous NaHCO3 solution, water, dried over Na2SO4 and concentrated under vacuum. Purification on a silica gel plate, eluting with 10% MeOH in CH2Cl2 yields 12 mg of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid [1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-yl]-amide as a colorless foam. 1H NMR (CDCl3): 2.01-2.31(m, 6H), 2.67-2.92(m, 8H), 3.63(m, 2H), 4.17(t, 2H), 6.65(d, 1H), 7.23(m, 1H), 7.33(d, 1H), 7.65(d, 1H), 8.62(d, 1H), 14.13(bs, 1H). LR-MS: MW 391.48, Found: 392.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[CH2:12][CH2:11][N:10]=[C:9]1[NH:13][C:14]1[CH:15]=[C:16]([C:20]([NH:22][CH2:23][C:24]([NH:26][CH:27]([C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=2)[CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[O:21])[CH:17]=[CH:18][CH:19]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:10]1[CH2:11][CH2:12][N:8]=[C:9]1[NH:13][C:14]1[CH:15]=[C:16]([C:20]([NH:22][CH2:23][C:24]([NH:26][CH:27]([C:34]2[CH:35]=[C:36]([C:44]([F:46])([F:47])[F:45])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=2)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCN2)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(NC(=O)CNC(=O)c1cccc(NC2=NCCN2)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To the product from Example 178 (360 mg, 0.0005 mole) in H2O (8 mL) and CH3CN (8 mL) was added LiOH (88 mg, 0.0021 mole). The reaction was stirred at room temperature for 3 hours. The pH was lowered to ~3 with TFA and the product was isolated by RPHPLC to yield the title compound (300 mg after lyophilization) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC(C)=O>[Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH2:20][CH:19]=[CH2:18])=[O:7]
Reactant: C=CCBr
Reactant: O=C(O)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOC(=O)c1cccc(CCl)c1

Procedure:
A solution of 3-(chloromethyl)-benzoic acid (50.0 g, 0.293 mol), potassium carbonate (48.61 g, 0.352 mol) and allyl bromide (50.7 mL, 0.586 mol) in acetone (500 mL) is refluxed for 2 hours, after which time the solution was cooled to room temp. and filtered through celite. The filtrate is evaporated and the residue chromatographed (silica, 5% EtOAc/hexane) to yield allyl 3-(chloromethyl)-benzoate as a clear oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.C([Li])CCC.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(OC)cc(OC)c1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 71.4 %

Procedure:
To a solution of 1-bromo-3,5-dimethoxybenzene (2.17 g, 10 mmol) in THF (15 mL) was dropwise added n-butyl lithium (8 mL, 2.5 mol/L in hexane, 20 mmol) at −78′C. After stirring for 50 mins at −78° C., a solution of diethyl oxalate (4 g, 27 mmol) in THF (10 mL) was added. The mixture was stirred at −78° C. for another 4 h, then quenched with saturated ammonium chloride and extracted with ethyl acetate (50 mL*3). The organic layers were combined, washed by brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel to give the title compound (1.7 g, 71%). MS (ES+) C12H14O5 requires: 238. found: 239 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8](O)=O)([O-:3])=[O:2].[NH2:16][NH:17][C:18]([NH2:20])=[S:19].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O.O1CCOCC1>[N+:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][CH:7]([C:8]1[S:19][C:18]([NH2:20])=[N:17][N:16]=1)[CH3:11])([O-:3])=[O:2]
Reactant: NNC(N)=S
Reactant: CC(Oc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(Oc1ccccc1[N+](=O)[O-])c1nnc(N)s1
Reaction time: 0.33 h

Procedure:
A 100 milliliter, 3-neck flask adapted with a Claisen adaptor, paddle stirrer, thermometer, an addition funnel and condenser, was charged with 8.4 grams (0.040 moles) of 2-(2-nitrophenoxy)propanoic acid, (3.6 grams, 0.040 mole) of thiosemicarbazide and 30 ml. of dioxane. The slurry was heated to 90° centigrade and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (6.7 grams, 0.044 mole) was slowly added (for 26 minutes) while maintaining the temperature within 90°-95° C., and then stirred for an additional 20 minutes. It was refluxed for 60 minutes and cooled. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), leaving a viscous gummy residue to which 50 ml. of water was added and the slurry was made basic by adding 50 percent solution of NaOH until the pH of the solution was 10, and a solid precipate formed. The solid precipate was filtered off, washed with water, dried in a vacuum oven at 80 degrees Centigrade to tan crystals, 5-(1-(2-nitrophenoxy) ethyl)-2-amino-1,3,4-thiadiazole. (Melting point 137-142 degrees Centigrade).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH:7]=1)[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1>O1CCCC1>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:9]2[C:8](=[O:11])[CH:7]=[C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:10]2)=[CH:23][CH:22]=1
Reactant: CC(C)COC1=CC(=O)CC1
Reactant: BrCc1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)COC1=CC(=O)C(Cc2ccc(Br)cc2)C1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
3-Isobutoxycyclopent-2-enone (3, 0.130 g, 0.84 mmol) in anhydrous tetrahydrofuran (2.0 mL) was cooled to −78° C. and a freshly prepared 1M solution of lithium diisopropylamide (1.0 mL, 1.0 mmol) was added dropwise. The mixture was stirred at −78° C. for 45 min and a solution of 1-bromo-4-(bromomethyl)benzene (0.210 g, 0.84 mmol) in anhydrous tetrahydrofuran (3.0 mL) was added dropwise. The resulting mixture was stirred for 1 h allowing the temperature to rise to rt. The reaction was quenched with a saturated aqueous solution of ammonium chloride (3.0 mL). The aqueous phase was extracted with ethyl acetate (2×10 mL) and combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel column chromatography using a gradient of ethyl acetate in hexanes as eluant provided 5 as a white solid (40% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)c(Cl)n2)CC1
Yield: 65.2 %

Procedure:
tert-Butyl 4-[6-chloro-5-(trifluoromethyl)pyridin-2-yl]piperazine-1-carboxylate (1.67 g, yield 65%, off-white solid) was synthesized from 2,6-dichloro-3-(trifluoromethyl)pyridine (1.51 g, 7.0 mmol) and tert-butyl piperazine-1-carboxylate (1.56 g, 8.38 mmol) by a method similar to Production Example 96, step 2.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N:34]1[CH:39]=[CH:38][N:37]=[CH:36][C:35]=1[C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1>C1COCC1>[CH3:12][O:13]/[CH:14]=[CH:44]/[C:43]1[CH:46]=[CH:47][C:40]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][N:34]=2)=[CH:41][CH:42]=1
Reactant: O=Cc1ccc(-c2cnccn2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO/C=C/c1ccc(-c2cnccn2)cc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
Sodium hexamethyldisilazide (10.80 mL, 10.80 mmol, 1.0M in THF) was added to a suspension of methoxymethyltriphenylphosphonium chloride (3.72 g, 10.80 mmol) in THF (20 mL) at −10° C., and the red-orange mixture was stirred for 15 min at −10° C. A solution of 4-pyrazinylbenzaldehyde (1.00 g, 5.43 mmol) prepared as described in reference example 17) in THF (3 mL) was added dropwise, and stirring was continued at −10° C. for 1 h. The reaction mixture was quenched with sat. aq. NH4Cl, extracted with ethyl acetate, the organic layer dried with Na2SO4, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 3:1 hexane/ethyl acetate) yielded 820 mg (71%) of the title compound (E:Z=1:1). MS 213 (M+H)+.
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:10].[NH2:21][C:22]1[C:23]2[C:30]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][CH:32]=3)=[CH:29][N:28]([CH:44]3[CH2:48][CH2:47][CH:46]([OH:49])[CH2:45]3)[C:24]=2[N:25]=[CH:26][N:27]=1>ClCCl>[C:9](=[O:10])([O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)[O:49][CH:46]1[CH2:47][CH2:48][CH:44]([N:28]2[C:24]3[N:25]=[CH:26][N:27]=[C:22]([NH2:21])[C:23]=3[C:30]([C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:35][CH:36]=3)=[CH:29]2)[CH2:45]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(O)C1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
N-Methylmorpholine (0.007 ml, 0.062 mmol) was added dropwise to solution of 4-nitrophenyl chloroformate (12.5 mg, 0.062 mmol) in dichloromethane (1 ml) with stirring under nitrogen at 0° C. After 20 minutes, the ice-water bath was removed and the mixture was allowed to warm up to ambient temperature. 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentanol (20 mg, 0.052 mmol) was added to the mixture and the resulting solution was stirred for 24 hours. The reaction mixture was diluted with dichloromethane and washed with water, saturated sodium bicarbonate, and brine. The organic layer was dried (MgSO4), filtered and evaporated to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclopentyl (4-nitrophenyl) carbonate. The structure was confirmed by 1H NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([F:32])=[CH:16][C:17]3[N:21]=[C:20]([CH2:22][C:23](OCC)=[O:24])[N:19]([CH:28]4[CH2:30][CH2:29]4)[C:18]=3[CH:31]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:36])[NH:34][NH2:35]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]([F:32])=[CH:16][C:17]3[N:21]=[C:20]([CH2:22][C:23]([NH:35][NH:34][C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:24])[N:19]([CH:28]4[CH2:29][CH2:30]4)[C:18]=3[CH:31]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)Cc1nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2n1C1CC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NNC(=O)Cc1nc2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)cc2n1C1CC1
Reaction time: 65 h

Procedure:
Ethyl 6-[4-(tert-butoxycarbonyl)-1-piperazinyl]1-cyclopropyl-5-fluoro-2-benzimidazoleacetate (1.8 g, 4 mmol; from Example 2d) and tert.butyl carbazate (21 g, 16 mmol) are dissolved in pyridine (40 ml) and stirred at 115° under argon for 65 hours. The reaction solution is concentrated and triturated with 50 ml of ether. The separated product is filtered off under suction and dried. There is obtained tert-butyl 3-[[6-[4-(tert-butoxycarbonyl)-1-piperazinyl]-1-cyclopropyl-5-fluoro-2-benzimidazolyl]acetyl]carbazate. Yield: 0.49 g (23%); m.p. 202°-203°.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:25][CH2:24][C:6]2([CH2:14][C:13]3[C:8](=[CH:9][C:10]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#[N:19])=[CH:11][CH:12]=3)[C:7]2=O)[CH2:5][CH2:4]1.C[Si]([N:30]=[C:31]=[N:32][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:18]([C:17]1[CH:16]=[C:15]([C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[CH2:14][C:6]2([CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:25][CH2:24]2)/[C:7]/3=[N:32]\[C:31]#[N:30])[CH:22]=[CH:21][CH:20]=1)#[N:19]
Reactant: COC1CCC2(CC1)Cc1ccc(-c3cccc(C#N)c3)cc1C2=O
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC1CCC2(CC1)Cc1ccc(-c3cccc(C#N)c3)cc1/C2=N/C#N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 93.8 %

Procedure:
To a solution of 3-(4-methoxy-1′-oxo-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-6′-yl)benzonitrile (30 mg, 0.09 mmol) in CH2Cl2 (3 mL) was added TiCl4 (0.2 mL). It was stirred in microwave at 50° C. for 5 minutes. Then bis-trimethylsilylcarbodiimide (0.2 mL, 0.146 mmol) was added. The resulting mixture was stirred in microwave at 60° C. for 10 minutes. The reaction mixture was poured into ice-water, extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to give (E)-N-(5′-(3-cyanophenyl)-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)cyanamide (30 mg, crude).
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][C:6]1[CH:7]=[C:8](Br)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH3:3])[CH3:2].[CH2:23]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[CH:35])=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH2:26][CH3:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCN(CC)CC.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:23]([C:28]1[CH:29]=[CH:30][C:31]([C:34]#[C:35][C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:6]([O:5][Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:1]([CH3:3])[CH3:2])[CH:7]=2)=[CH:32][CH:33]=1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC(C)[Si](Oc1cc(Br)c2ccccc2c1)(C(C)C)C(C)C
Reactant: C#Cc1ccc(CCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(C#Cc2cc(O[Si](C(C)C)(C(C)C)C(C)C)cc3ccccc23)cc1
Yield: 33.1 %

Procedure:
A solution of 3-triisopropylsilyoxy-1-bromonaphthalene (2.32 g, 6.1 mmol), (4-pentylphenyl)acetylene (1.58 g, 9.2 mmol), Pd(PPh3)2Cl2 (129 mg, 3 mol %), PPh3 (240 mg, 15 mol %) and CuI (88 mg, 7.5 mol %) in Et3N (20 mL) under N2 was heated at reflux for 4 h. The resulting mixture was cooled, diluted with Et2O, filtered and the solvent removed under reduced pressure. The residue was chromatographed on silica using hexanes as eluent. The solvent was removed under reduced pressure to give the title compound (0.95 g, 33%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1nccc(CO)n1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
2-Amino-4-hydroxymethylpyrimidine (750 mg, 6.0 mmol, Reference Compound No. 4-1) and tert-butyldimethylsilyl chloride (990 mg, 6.6 mmol) were suspended in anhydrous N,N-dimethylformamide (8.0 mL), then imidazole (0.90 g, 13 mmol) was added thereto and the mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL), washed twice with saturated aqueous sodium hydrogencarbonate solution (50 mL), and then washed with brine (50 mL), and dried over anhydrous magnesium sulfate. Then the solvent was evaporated under reduced pressure, the precipitated solid was filtered off with 50% ethyl acetate-n-hexane solution, and dried under reduced pressure to give 1.2 g of the title Reference Compound as a white solid (Yield: 84%).
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:47]([OH:49])=[O:48])[CH2:42][CH2:43][C:44]([OH:46])=[O:45]>>[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:47]([O-:49])=[O:48])[CH2:42][CH2:43][C:44]([O-:46])=[O:45]
Reactant: N[C@@H](CCC(=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](CCC(=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-glutamic acid (0.042 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. No precipitation was observed upon cooling. 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 glutamate form I.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:7]2[N:8]=[CH:9][C:10]([S:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:13])=[O:12])=[C:6]2[NH:5][CH:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3]1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-].[Na+]>C1COCC1.O>[CH2:29]([N:5]1[CH:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3][C:2]([CH3:28])([CH3:1])[N:7]2[N:8]=[CH:9][C:10]([S:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:12])=[O:13])=[C:6]12)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(CS(=O)(=O)c2cnn3c2NC(c2ccccc2)CC3(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CS(=O)(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a solution of 0.34 g (0.86 mmol) of 5 in 10 mL of THF at 0° C. was added 0.128 mL (1.07 mmol) of benzyl bromide followed by 0.034 g (0.86 mmol) of sodium hydride (60% dispersion in mineral oil). The reaction was allowed to warm to room temperature after 30 min and stirred for an additional 30 min before being quenched with water. The quenched reaction was diluted with five volumes of water and extracted with AcOEt. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography eluting with 70% hexanes/AcOEt to give 0.39 g (93%) of the title compound as a white solid. 1H NMR (CDCl3) δ 1.27 (s, 3H), 1.52 (s, 3H), 1.93-2.05 (m, 2H), 2.27 (s, 3H), 3.83 (d, J=15.8 Hz, 1H), 4.18-4.30 (m, 3H), 5.51 (d, J=15.8 Hz, 1H), 6.98-7.00 (m, 2H), 7.09 (dd, J=8.2, 12.1 Hz, 4H), 7.17 (d, J=6.8 Hz, 2H), 7.26-7.30 (m, 3H), 7.32-7.40 (m, 3H), 7.47 (s, 1H)