Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([OH:16])[CH:15]=1.[H-].[Na+].Br[CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCOC(C)=O>CN(C=O)C>[Si:24]([O:23][CH2:22][CH2:21][O:16][C:14]1[CH:15]=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:11]=[CH:12][C:13]=1[CH3:17])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3ccccc3o2)cc1OCCO[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of 5-(1,3-benzoxazol-2-yl)-2-methylphenol (355 mg, 1.6 mmol) in DMF (10 mL) was cooled to 0° C. and NaH (70 mg, 1.7 mmol) was added slowly. After 15 min, (2-bromoethoxy)(tert-butyl)dimethylsilane (370 μL, 1.7 mmol) was added. The reaction was then elevated to 90° C. for 1 h and EtOAc (100 mL) was added. The EtOAc solution was washed with brine (3×20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash column (silica gel, hexanes:EtOAc 1:5) to afford 2-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}-ethoxy)-4-methylphenyl]-1,3-benzoxazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1.[CH3:32][CH:33]([CH3:38])[CH:34]([OH:37])[C:35]#[CH:36]>>[CH3:32][CH:33]([CH3:38])[CH:34]([OH:37])[C:35]#[C:36][C:2]1[CH:3]=[C:4]([C:22]([OH:31])([C:27]([F:29])([F:30])[F:28])[C:23]([F:26])([F:25])[F:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1
Reactant: C#CC(O)C(C)C
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Product: CC(C)C(O)C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(S(=O)(=O)c2cccs2)CC1

Procedure:
Following the procedure outlined for Example 152, 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (Example 69) was coupled to 4-methyl-1-pentyn-3-ol (Aldrich, St. Louis, Mo.) to afford 4-methyl-1-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-pentyn-3-ol as a mixture of enantiomers.
Reaction SMILES: ClC1C=CC=CC=1CN1C(CCN[C@H](C(O)=O)CC2C=CC=CC=2)=CN=C1CCCC.[CH2:32]([C:36]1[N:37]([CH2:43][C:44]2[C:49]([F:50])=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:51])[C:38](CO)=[CH:39][N:40]=1)[CH2:33][CH2:34][CH3:35]>>[CH2:32]([C:36]1[N:37]([CH2:43][C:44]2[C:49]([F:50])=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:51])[CH:38]=[CH:39][N:40]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCc1ncc(CO)n1Cc1c(F)cccc1Cl
Agent: CCCCc1ncc(CCN[C@@H](Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Product: CCCCc1nccn1Cc1c(F)cccc1Cl

Procedure:
The procedures of Example 1(ii iii) were used. From 7.63 g of crude 2-n-butyl-1-(2-chloro-6-fluorophenyl)methyl-1H-imidazole was obtained 2.8 q of 2-n-butyl-1-(2-chloro-6-fluorophenyl)methyl-5-hydroxymethyl-1H-imidazo le; mp 106°-108° C. (from ethyl acetate). This material was oxidized with manganese dioxide and worked up as described to give 0.88 g (63%) of 2-n butyl-2-(2-chloro-6-fluorophenyl)methyl-1H-imidazol-5-carboxaldehyde; mp 88°-90° C. (from ethyl acetate).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][C@H:13]2[CH2:22][OH:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([O:23][CH2:22][C@@H:13]2[CH2:14][C@@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:16][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:24]=[CH:25][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
To a solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (28.8 g: 77 mmole) in dichloromethane (150 ml) under ice cooling, p-toluenesulfonyl chloride (19.11 g: 1.3 eq.), triethylamine (10.4 ml: 1.3 eq.) and dimethylaminopyridine (0.94 g: 0.1 eq.) are added. The mixture is stirred at 25° C. for 7 hours. The reaction mixture is diluted with ice water. The resultant organic layer is taken, successively washed with aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate, and concentrated in vacuo. The residue is recrystallized from n-hexane to give (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (37.7 g). Yield: 93%.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20](Cl)(=[O:22])=[O:21]>>[CH2:1]([N:4]1[CH2:5][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:12][S:20]([C:16]3[S:15][CH:19]=[CH:18][CH:17]=3)(=[O:22])=[O:21])=[CH:13][CH:14]=2)[CH2:7]1)[CH2:2][CH3:3]
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Reactant: O=S(=O)(Cl)c1cccs1
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3cccs3)cc2)C1

Procedure:
Following the same procedure as described in Example 1.7, 4-(1-propylazetidin-3-yl)aniline was coupled with thiophene-2-sulfonyl chloride to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.[Mg].ClC(C)C.CN(C)CCOCCN(C)C.C[O:33][B:34](OC)[O:35]C>O1CCCC1>[F:1][C:2]1[CH:9]=[C:8]([B:34]([OH:35])[OH:33])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COB(OC)OC
Reactant: N#Cc1ccc(Br)cc1F
Agent: CC(C)Cl
Agent: CC(C)[Mg]Cl
Agent: CN(C)CCOCCN(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(B(O)O)cc1F
Temperature: 16 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
A solution of 2-fluoro-4-bromobenzonitrile (18, 12.5 Kg, 62.5 mol) in anhydrous tetrahydrofuran (THF, 30 L) was treated with a solution of isopropylmagnesium chloride generated from magnesium (Mg, 1.8 Kg, 150 mol, 1.2 equiv) an 2-chloropropane (7.2 Kg, 92 mol, 1.47 equiv) in THF (20 L) and 2-(2-(dimethylamino)ethoxy)-N,N-dimethylethanamine (11 Kg, 69 mol, 1.1 equiv) at room temperature. The resulting mixture was then stirred at 12-20° C. for an additional 2 h before being treated with trimethylborate (9 Kg, 86.7 mol, 1.4 equiv) at 10-15° C. The reaction mixture was stirred at 7-16° C. for 40 min. When TLC and LC/MS showed that the reaction was deemed complete, the reaction mixture was quenched with 1 N aqueous hydrochloric acid (HCl, 35 Kg) at room temperature. The quenched aqueous reaction mixture was then extracted with ethyl acetate (EtOAc, 4×35 L). The combined organic extracts were washed with water (50 L), dried over magnesium sulfate (MgSO4), and concentrated under the reduced pressure. The residual solids were then recrystallized from acetonitrile (20 L) and hexanes (45 L) to afford the corresponding crude 3-fluoro-4-cyanophenyl boronic acid (5.0 Kg, 48% yield).
Reaction SMILES: [N:1]1([CH:7]2[CH2:30][N:29](C(OC(C)(C)C)=O)[C:10]3=[N:11][C:12]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[N:14]=[C:9]3[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH:7]2[CH2:30][NH:29][C:10]3=[N:11][C:12]([C:22]4[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=4)=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[N:14]=[C:9]3[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(C(=O)OC(C)(C)C)CC(N2CCCCC2)C3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCC(N2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl 7-(piperidin-1-yl)-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (step 6) (90 mg, 0.180 mmol) in DCM (1 ml) was treated with TFA (0.501 mL, 6.50 mmol) and stirred at room temperature for 3 hours. The resulting mixture was diluted with DCM (3 ml) and washed with a saturated solution of sodium hydrogen carbonate. The organic portion was passed through a phase separating column and the solvent removed under reduced pressure to afford the titled compound;
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]2[N:12]=[C:11]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])[N:10]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH:8]=2)[CH2:4]1.[C:30](OC(=O)C)(=[O:32])[CH3:31].N1C=CC=CC=1>ClCCCl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C@@H:14]([NH:13][C:11]2[N:12]=[C:7]([N:5]3[CH2:4][CH:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])[CH2:6]3)[CH:8]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:10]=2)[CH3:15])=[CH:21][CH:20]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(CN)C2)n1)c1ccc(F)cc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)NCC1CN(c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
23 mg of (S)-6-[3-(aminomethyl) azetidin-1-yl]-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine was dissolved in 2 ml of 1,2-dichloroethane, and 7 μl of acetic anhydride and 11 μl of pyridine were added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 20 mg of the objective compound as a brown amorphous solid.
Reaction SMILES: [CH:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CO>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][NH:10][CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: NC1CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)CNC1CCc2ccccc21
Temperature: 0 °C
Yield: 41.1 %

Procedure:
To a solution of 13.3 g of 1-indanamine in 100 ml of methanol are added 6.9 g of potassium carbonate and 16.9 g of ethyl bromoacetate, and the mixture is refluxed for 30 minutes. The reaction mixture is poured into 300 ml of ice-water, and subjected to extraction with 500 ml of ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography and eluted with acetone-benzene (1:20) to give 9.0 g of N-(1-indanyl) glycine ethyl ester as a colorless oil. To this oil are added 5 ml of 20% alcoholic hydrochloric acid and 200 ml of ethyl ether, and the mixture is allowed to stand at room temperature to give 9.0 g of N-(1-indanyl)glycine ethyl ester hydrochloride as colorless needles. Melting point: 130°-132° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11](=O)[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[O:19][CH3:20])#[N:2].[OH-:22].[Na+].OO>CCO>[CH3:20][O:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH3:18])[C:12]=1[C:11]1[NH:2][C:1](=[O:22])[C:3]2[C:4](=[CH:5][C:6]([CH3:9])=[CH:7][CH:8]=2)[N:10]=1
Reactant: COc1cccc(C)c1C(=O)Nc1cc(C)ccc1C#N
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(C)c1-c1nc2cc(C)ccc2c(=O)[nH]1
Yield: 6.4 %

Procedure:
N-(2-Cyano-5-methyl-phenyl)-2-methoxy-6-methyl-benzamide (25 g, 0.09 mol) was suspended in 500 mL EtOH, and 121.3 g of 33% aq. NaOH (1 mol, 11 equiv) was added. To this was added a 35% H2O2 solution (50 mL, 0.58 mol), and the reaction was heated to reflux. Additional H2O2 was added dropwise until the reaction mixture became clear. EtOH was removed under reduced pressure, and the precipitate formed was removed by filtration. The solution was acidified with acetic acid to pH 5, and the precipitate formed was collected by filtration. The precipitate was washed twice with water and once with diethyl ether. The product was purified over alumina using EtOAc/heptane (1:1) as an eluent. Another purification was performed, over silica gel with the same eluent to yield 2-(2-methoxy-6-methyl-phenyl)-7-methyl-3H-quinazolin-4-one (1.61 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=O)=[CH:3][CH:2]=1.[NH2:24][NH2:25].Cl>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12](=[N:24][NH2:25])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccnc2ccccc12)c1cccc(C(F)(F)F)c1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: NN=C(Cc1ccnc2ccccc12)c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2-quinolin-4-yl-1-(3-trifluoromethyl-phenyl)-ethanone (1.0 g, 3.2 mmol) in ethanol (13 mL) is cooled to 0° C. and treated with hydrazine (0.6 g, 19 mmol) and concentrated hydrochloric acid (0.13 mL, 1.6 mmol). The mixture is refluxed for 2 h and concentrated in vacuo. The residue is taken up in dichloromethane and washed with saturated sodium bicarbonate (30 mL), water (2×30 mL), and brine (30 mL). The solution is dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated to yield the title compound, 1.0 g (97%), as a pale yellow foam.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:20]2[NH:29][C:23]3=[N:24][CH:25]=[C:26]([F:28])[CH:27]=[C:22]3[CH:21]=2)=[CH:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([NH:5][C:6](=[O:30])[C:7]1[CH:8]=[CH:9][C:10]([CH:13]([C:20]2[NH:29][C:23]3=[N:24][CH:25]=[C:26]([F:28])[CH:27]=[C:22]3[CH:21]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NC(=O)c1ccc(C(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 50 °C
Yield: 91.6 %

Procedure:
A mixture of N-tert-butyl-4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-benzamide (380 mg, 0.938 mmol) and 10% palladium on activated carbon (100 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 6 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford N-tert-butyl-4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-benzamide (350 mg, 91.9%) as a white solid: LC/MS m/e calcd for C25H30FN3O [M+H]+ 408.54, observed 408.1.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:2].[CH2:14]([C:16](=[CH2:20])[C:17](O)=[O:18])[CH3:15]>>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:17](=[O:18])[C:16]([CH2:14][CH3:15])=[CH2:20])=[CH:5][C:4]=1[C:10]([F:11])([F:12])[F:13])#[N:2]
Reactant: C=C(CC)C(=O)O
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Product: C=C(CC)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Following the procedure described in Example 1, starting from 4-cyano-3-trifluoromethyl-aniline and 2-ethyl-acrylic acid, the title compound was prepared as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:11][NH2:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C[O:14][C:15](=O)[N:16]=[C:17](SC)[C:18]([C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=1[F:42])=[N:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][NH:8][C:7]=1[N:11]1[C:15](=[O:14])[NH:16][C:17]([CH:18]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=2[F:42])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[N:30]=[C:29]([CH3:31])[O:28][N:27]=3)=[CH:22][CH:21]=2)=[N:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C)n3)cc2)c2cc(OC)c(OC)cc2F)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.9 %

Procedure:
A solution of 0.140 g of 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester, 0.236 g of [2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example 1d) and 0.209 ml of triethylamine in 6 ml of DMF was heated at 85° C. for 15 hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure, the residue was dissolved in 7 ml of methanol, and then 0.251 g of sodium cyanotrihydroborate, 0.086 ml of acetic acid and 0.5 g of MS3A were added and the mixture was stirred at room temperature for 20 hours. Next, 100 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (0.152 g) as a light green solid.
Reaction SMILES: [CH3:1][C:2]([CH3:51])([CH2:49][CH3:50])[CH2:3][C:4]1[N:5]=[C:6]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH2:43][C:44]3[NH:48][CH:47]=[N:46][N:45]=3)=[CH:32][CH:31]=2)[N:7](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=1.C(O)(C(F)(F)F)=O>>[CH3:1][C:2]([CH3:51])([CH2:49][CH3:50])[CH2:3][C:4]1[N:5]=[C:6]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[O:42][CH2:43][C:44]3[NH:48][CH:47]=[N:46][N:45]=3)=[CH:32][CH:31]=2)[NH:7][CH:8]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CCc2ccc(-c3ccccc3OCc3nnc[nH]3)cc2)n1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)Cc1c[nH]c(CCc2ccc(-c3ccccc3OCc3nnc[nH]3)cc2)n1

Procedure:
3-(4′-{2-[4-(2,2-Dimethylbutyl)-1-trityl-1H-imidazol-2-yl]ethyl}biphenyl-2-yloxymethyl)-4H-[1,2,4]triazole was converted to the title compound by treatment with TFA at 60° C. for 30 minutes. The crude product was purified by flash column chromatography on silica gel eluting with 0-20% methanol/ammonium hydroxide (10:1) in methylene chloride to afford the title compound. 1H NMR (300 MHz, CD3OD) δ 8.30 (s, 1H), 7.38 (d, J=8.2 Hz, 2H), 7.28 (m, 2H), 7.12 (m, 4H), 6.57 (s, 1H), 5.11 (s, 2H), 2.96 (m, 4H), 2.38 (s, 2H), 1.22 (m, 2H), 0.84 (s, 9H); LC-MS: m/e (M+H).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([OH:42])(=[O:41])[CH2:31][C:32]([CH2:37][C:38]([OH:40])=[O:39])([C:34]([OH:36])=[O:35])[OH:33]>CO>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:29])=[C:13](/[CH:17]=[C:18]2/[C:19]3[CH:20]=[C:21]([F:28])[CH:22]=[CH:23][C:24]=3[NH:25][C:26]/2=[O:27])[NH:14][C:15]=1[CH3:16])=[O:10])[CH2:4][CH3:5].[C:30]([O-:42])(=[O:41])[CH2:31][C:32]([CH2:37][C:38]([O-:40])=[O:39])([C:34]([O-:36])=[O:35])[OH:33]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CO
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
Sunitinib (2.21 g, 5.55 mmol) suspended in methanol (75 ml), 1.07 g of citric acid was added. Mixture was stirred at room temperature for several hours, and then filtered to obtain crystalline sunitinib citrate, 3.2 g. Melting point: 166-174° C. (Form I).
Reaction SMILES: Br[C:2]1[C:3]([CH3:25])=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=4)=[CH:10]3)[C:6]=2[CH:24]=1.[CH:26]([N:29]1[CH2:34][CH2:33][CH:32]([SH:35])[CH2:31][CH2:30]1)([CH3:28])[CH3:27].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.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]>[CH:21]([N:16]1[C:15]([C:9]2[N:8]=[C:7]3[N:11]([CH2:12][CH2:13][O:14][C:5]4[CH:4]=[C:3]([CH3:25])[C:2]([S:35][CH:32]5[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[CH2:30][CH2:31]5)=[CH:24][C:6]=43)[CH:10]=2)=[N:19][C:18]([CH3:20])=[N:17]1)([CH3:23])[CH3:22]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(C)cc2OCC3)n(C(C)C)n1
Reactant: CC(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)C)CC4)c(C)cc2OCC3)n(C(C)C)n1
Temperature: 120 °C
Yield: 64.2 %

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (146 mg, 0.363 mmol), 1-isopropylpiperidine-4-thiol (87 mg, 0.545 mmol), Pd2(dba)3 (17 mg, 5 mol %), XantPhos (21 mg, 10 mol %) and DIPEA (254 μl, 1.45 mmol) in dioxane (4 mL) was purged with nitrogen and then heated at 120° C. for 2 h using microwave irradiation. The reaction mixture was then diluted with DCM (80 mL) and purified by column chromatography (Si-PCC, gradient 0-8% 2M NH3/MeOH in DCM) followed by (C18, gradient 20-55% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-(1-isopropylpiperidin-4-ylsulfanyl)-8-methyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a colorless solid (112 mg, 64%). LCMS: RT 2.23 and 2.28 min [M+H]+ 480.9
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][C:34]([CH3:38])=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:40].O1CCOCC1>O1CCOCC1>[ClH:40].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][C:34]([CH3:38])=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Cc1ccc2c(ccc(=O)n2CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(ccc(=O)n2CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 5 mL of a 1,4-dioxane solution containing 206 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 5 mL of 4 mol/L hydrogen chloride/1,4-dioxane was added, and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, 1,4-dioxane was added to the residue thus obtained, and the resulting solid was filtered to give 110 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-6-methylquinolin-2(1H)-one hydrochloride as a white solid.