Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])=[O:8])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCOS(C)(=O)=O
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a solution of (E)-tert-butyl 2-(6-hydroxyhex-3-enamido)phenylcarbamate (10) (398 mg, 1 mmol) and triethylamine (151.5 mg, 1.5 mmol) in DCM (10 mL) was added methanesulfonyl chloride (127.6 mg, 1.1 mmol) at 0° C. and stirred for 0.5 hour, then the reaction was stirred at room temperature for 1 hr, then water (10 mL) was added, the mixture was extracted with DCM (3×20 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the desired compound of (E)-6-(2-(tert-butoxycarbonylamino)phenylamino)-6-oxohex-3-enyl methanesulfonate (358 mg, yield 90%) as oil after purification by column chromatography (eluent: PE:EA=10:1). LC-MS found 399 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:23]([O:25]C)=[O:24])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO.O>[C:1]1([C:7]2[C:16]([N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:23]([OH:25])=[O:24])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCNCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCNCC3)nc2c1
Temperature: 30 °C
Reaction time: 3 h
Yield: 29.9 %

Procedure:
Solutions of methyl 2-phenyl-3-(piperazin-1-yl)quinoxaline-6-carboxylate (160 mg, 0.42 mmol, 1.00 equiv.) in THF/MeOH (1:1) (20 mL) and sodium hydroxide (91.9 mg, 2.30 mmol, 5.00 equiv) in water (1.5 mL) were placed in a 50-mL round bottom flask, stirred for 3 hrs at 30° C. in an oil bath, and then concentrated under vacuum. The residue was dissolved in 4 mL of DMSO and purified via silica gel column (DCM/MeOH (5:1)) yielding 42 mg (29%) of 2-phenyl-3-(piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[OH:27][C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31]([C:28]3([OH:27])[CH2:30][CH2:29]3)=[O:32])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)C1(O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1(O)CC1

Procedure:
The title compound, white solid (67 mg, 65%), MS (ISP) m/z=411.3 [(M+H)+], mp 200° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 1-hydroxy-cyclopropanecarboxylic acid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:6]([Cl:21])=[CH:7][C:8]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].O1CCOCC1.C(=O)([O-])[O-].[Cs+:32].[Cs+]>O>[NH2:1][S:2]([C:5]1[C:6]([Cl:21])=[CH:7][C:8]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11])(=[O:3])=[O:4].[Cs+:32]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)[O-])c(NCc2ccco2)cc1Cl
Yield: 191.3 %

Procedure:
Furosemide (10) (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid, Aldrich) (4.0 g, 12.1 mmol) was added to dioxane (100 mL), and water (50 mL) was added with stirring to give a solution. Cesium carbonate (1.97 g, 6.0 mmol) was added, and the clear solution was stirred for 1 hour. The solvent was removed by spin evaporation, and the solid was dried overnight on a vacuum pump to afford 5.31 g of cesium 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate as a white solid.
Reaction SMILES: [CH:1]1([N:4]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[C:45]=2[Cl:51])[C:5]([C:7]2[C@@H:8]([CH2:38][O:39][CH2:40][O:41][CH3:42])[N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=2)=[O:6])[CH2:3][CH2:2]1>FC(F)(F)C(O)=O.ClCCl>[CH:1]1([N:4]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[C:45]=2[Cl:51])[C:5]([C:7]2[C@@H:8]([CH2:38][O:39][CH2:40][O:41][CH3:42])[NH:9][CH2:10][CH2:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCOC[C@@H]1C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)=C(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCOC[C@H]1NCCC(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)=C1C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
9A (50 mg, 64 μmol) was dissolved in 10% trifluoroacetic acid in dichloromethane. The mixture was stirred at room temperature for 2 hours. Solvent was removed under vacuum. The residue was purified by preparatory LCMS (water:acetonitrile, 40-65%) to give Compound 5 (15 mg, 33%). ESI-MS:m/z 679.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.ClCCl.C(O)C.N>ClCCl.CO>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:1][CH2:2][CH:3]2[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)=[O:25])=[CH:19][CH:18]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOC(CNC(=O)Nc2ccc(Cl)cc2)C1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a stirred solution of tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (Prepared as described in EP 0 468231, 2.4 g) in dichloromethane (100 ml) was added 4-chlorophenylisocyanate (1.87 g). The mixture was stirred at 22° C. for 16 h before 10% 0.880 ammonia solution in methanol was added. Stirring was continued for a further 30 min before the solvent was removed in vacuo to give the title compound as a white foam (3.98 g).
Reaction SMILES: [CH3:1][Li].[C:3]([B:7](OC(C)C)[O:8][CH:9]([CH3:11])[CH3:10])([CH3:6])([CH3:5])[CH3:4].[B]>>[C:3]([B:7]([CH3:1])[O:8][CH:9]([CH3:11])[CH3:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)OB(OC(C)C)C(C)(C)C
Reactant: [Li]C
Agent: [B]
Product: CB(OC(C)C)C(C)(C)C

Procedure:
The reaction was run following the procedure described in Example 1 using methyllithium (38.4 mmol, 24.6 mL) and tert-butyldiisopropoxyborane (7.15 g, 38.3 mmol). Volatiles were removed at atmospheric pressure and the product distilled to yield 3.9 g (27.5 mmol, 73%), bp 90°-92° C. (741 mm Hg); proton NMR (CDCl3) δ4.30 (septet, J=18 Hz, 1H), 1.15 (d, J=18 Hz, 6H), 0.83 (s, 9H), 0.30 (brs, 3H); boron NMR (neat) δ+52.9 ppm (s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][C:10]#[CH:11].C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH2:11]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:10][C:9]#[CH:8]
Reactant: C#CCCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCCN1CCCCC1
Temperature: 25 °C
Yield: 43.1 %

Procedure:
A solution of piperidine (2.9 g, 33.8 mmol), 4-bromobut-1-yne (5 g, 37.6 mmol) and K2CO3 (3 g, 2.2 mmol) in CH3CN was stirred at 80° C. for 2 h. After it was cooled to room temperature, the solution was diluted with H2O and extracted with ethyl acetate (3×200 mL). Then the combined organic layers were dried over Na2SO4 and concentrated to give 2 g of the crude product, which was directly used for the next step without further purification. MS (ESI): 138 (MH+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=[O:8].[Br:10][CH:11]([CH:14]=O)[CH:12]=O>Cl>[Br:10][C:11]1[CH:12]=[N:1][C:2]2[N:6]([N:5]=[CH:4][C:3]=2[C:7]([OH:9])=[O:8])[CH:14]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1[nH]ncc1C(=O)O
Agent: Cl
Product: O=C(O)c1cnn2cc(Br)cnc12
Temperature: 95 °C

Procedure:
A suspension of 5-amino-1H-pyrazole-4-carboxylic acid (1 g, 7.8 mmol) and 2-bromomalonaldehyde (1.2 g, 7.8 mmol) in an aqueous solution of hydrochloric acid (6 M, 20 mL) was heated at 95° C. for 15 minutes. The resulting mixture was cooled to room temperature and the solid formed was collected by filtration, rinsed with water and dried in vacuum oven to give 6-bromo-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].CN(C)C=O.[BH4-].[Na+].[CH2:21](Br)[C:22]#C>O.C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:21]#[CH:22])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: C#CCBr
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: C#CCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
5.85 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 20 ml. dimethylformamide is treated, under nitrogen, with 1.14 g. sodium borohydride at 20°-30° C. After 1 1/2 hours 5 ml. of propargyl bromide is added. The mixture is stirred for three hours at 20°-30° C, then diluted with water. The product, a red solid, is isolated by extraction into chloroform yielding 1-amino-2-nitro-4-propargylthiobenzene.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].CO[C:17]1[C:21](OC)=[N:20][S:19](=[O:25])(=[O:24])[N:18]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28]>CO>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]2[C:21]([NH:29][CH2:26][CH2:27][CH3:28])=[N:20][S:19](=[O:25])(=[O:24])[N:18]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CCCN
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CO
Product: CCCNC1=NS(=O)(=O)N=C1NCCSCc1ccc(CN(C)C)o1
Reaction time: 0.25 h

Procedure:
A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (2.41 g; 11.2 mmoles) in 25 ml of dry methanol was added dropwise over a period of 30 minutes to a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) in 200 ml of dry methanol that had been cooled to 2° in an ice-water bath. After 15 minutes, 4.0 ml of n-propylamine was added all at once and the mixture stirred at ambient temperature for 30 minutes. The reaction mixture was evaporated under reduced pressure and the residue placed on 55 g of silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined, evaporated under reduced pressure and the syrup crystallized with ether to give 3.7 g of the title compound, mp 164°-166°; the NMR spectrum (100 MHz) in d6 dimethyl sulfoxide showed the presence of approximately 0.9 moles of methanol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH2:8]([Br:12])[CH2:9][CH2:10][CH3:11]>C(C(C)=O)C>[Br-:12].[CH2:8]([N+:2]1([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)[CH2:9][CH2:10][CH3:11]
Reactant: CN1CCOCC1
Reactant: CCCCBr
Solvent: CCC(C)=O
Product: CCCC[N+]1(C)CCOCC1
Product: [Br-]
Yield: 23 %

Procedure:
A sulfonating flask (250 ml) fitted with stirrer, drip funnel and reflux condenser is charged with 22.3 ml (0.2 mol) of N-methylmorpholine and 80 ml of methyl ethyl ketone (MEK), and then 21.4 ml (0.2 mol) of n-butyl bromide are added dropwise over 20 minutes. After initial turbidity under reflux conditions (ca. 80° C.), the reaction mixture becomes more dense and turns an orange-brown colour. After a reaction time of 7 hours, the crystalline slurry is filtered with suction and the filter residue is washed with a small amount of MEK and dried under vacuum. Yield: 23%; m.p. 205° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CN(CCN(C)C)C.[Li]C(CC)C.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:24][C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1cccc(F)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=C(O)c1cccc(F)c1Cl
Temperature: -90 °C
Reaction time: 0.58 h
Yield: 74.4 %

Procedure:
A solution of 3-fluorobenzoic acid (4.02 g, 28.71 mmol) in 20 mL of THF was added dropwise to a suspension of TMEDA (10.00 mL, 66.3 mmol) and 1.3M sec-BuLi (48 mL, 62.4 mmol) in 50 mL of THF at −90° C. The mixture was stirred at −90° C. for 35 min. The mixture was warmed to −78° C. when a solution of hexachloroethane (27.0 g, 113.9 mmol) in 50 mL of THF was added. After 20 h, the reaction was quenched with water and diluted with diethyl ether. The bilayer was adjusted to pH ˜1-2 with conc. HCl. The organic layer was washed with water, brine, dried and concentrated to give 30.4 g crude as a tan solid, which was washed with hexane to give 3.728 g (74%) of the desired product 1a (light tan solid). MS (m/z) 175.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[Se:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([O-:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[CH3:1][C:2]1[Se:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N+:6]=1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: Cc1nc2ccccc2[se]1
Reactant: CCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(Cl)cc1
Product: CCCCCCCCCCCCCCCCCC[n+]1c(C)[se]c2ccccc21
Product: O=S(=O)([O-])c1ccc(Cl)cc1
Temperature: 130 °C
Yield: 50.6 %

Procedure:
Into a sealed tube in which air was replaced by nitrogen were placed 1.50 g (7.4 mmoles) of 2-methylbenzoselenazole and 3.34 g (7.5 mmoles) of octadecyl parachlorobenzenesulfonate. The resulting mixture was heated at 130° C. for 5 hours. The reddish purple solid obtained was washed with ether and recrystallized from n-propanol, giving 2.40 g (yield: 50.5%) of 2-methyl-3-octadecylbenzoselenazolium parachlorobenzenesulfonate as a reddish purple powder.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]1=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=3.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>N1C=CC=CC=1>[CH:31]1([C:34]([O:1][C@@H:2]2[C@H:8]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[S:7][C:6]3[C:17]4[C:22]([CH:23]=[CH:24][C:5]=3[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]2=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:35])[CH2:33][CH2:32]1
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2OC(=O)C2CC2)cc1
Reaction time: 17 h
Yield: 99 %

Procedure:
To a solution of 2.0 g of (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b]-1,4-thiazepin-4(5H)-one in 25 mL pyridine was added dropwise at ice-bath temperature 0.9 g of cyclopropanecarboxylic acid chloride and the solution was kept at this temperature for 17 hours. The mixture was concentrated and the residue, in water, was made basic with concentrated ammonium hydroxide. The aqueous suspension was extracted with ethyl acetate (3×60 mL). The combined ethyl acetate solutions were washed with brine and dried (magnesium sulfate). Removal of the solvent gave 2.3 g (100%) of (±)-cis-3-[(cyclopropylcarbonyl)oxy]-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)naphtho[1,2-b]-1,4-thiazepin-4(5H)-one as an amorphous compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[CH:11]=[C:10]3[NH:19][CH2:20][CH2:21][S:22][C:9]3=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2].C=O.[BH3-][C:26]#N.[Na+]>C(O)(=O)C>[CH3:26][N:19]1[C:10]2=[CH:11][C:12]3[C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[N:6][C:7]=3[CH:8]=[C:9]2[S:22][CH2:21][CH2:20]1
Reactant: [BH3-]C#N
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)SCCN3
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)SCCN3C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
To a solution of 2,3-dihydro-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline (11 mg, 0.033 mmol) and paraformaldehyde (9.9 mg, 0.33 mmol) in 0.5 mL acetic acid was added NaBH3CN (12 mg, 0.19 mmol). After 16 h, the solution was quenched with sat'd NaHCO3 (20 mL), and was extracted with EtOAc (20 mL). The organic layer was washed sequentially with sat'd NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated to afford 11 mg (97%) of 2,3-dihydro-1-methyl-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline, a yellow solid. Data for 2,3-dihydro-1-methyl-7-isopropoxy-9-(trifluoromethyl)-1H-[1,4]thiazino[3,2-g]quinoline: 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.01 (s, 1H), 6.98 (broad s, 1H), 5.45 (hept, 1H, J=6.2), 3.58-3.64 (m, 2H), 3.14-3.20 (m, 2H), 3.05 (s, 3H), 1.37 (d, 6H, j=6.2).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19]Br)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])=[CH:14][CH:13]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCc1ccc(Cl)cc1)OCC

Procedure:
Combine 24.9 g (0.15 mole) of triethyl phosphite and 32.9 g of 2-(4-chlorophenyl)ethyl bromide. Heat the mixture at reflux under a nitrogen atmosphere for 5-6 hours. Distill the reaction mixture at reduced pressure (0.2 mm Hg) and collect the fraction distilling at 110°-148° C. to obtain the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.N1CCCC1>C(OC)(C)(C)C>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: COC(C)(C)C
Solvent: C1CCNC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (5.0 g 0.018 moles) and 5-Fluoro-1,3-dihydro-indol-2-one (2.705 g; 0.018 moles) in methyl tertiary butyl ether were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at reflux temperature for 2-8 hours. The resultant Sunitinib base was triturated in methyl tertiary butyl ether at reflux temperature for 1-2 hours and isolated at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N+:13]([O-])=[C:12]([CH3:18])[C:11]=2[CH3:19])[CH2:4][O:3]1.C([O-])(=[O:23])C.[Na+].C(OC(=O)C)(=O)C.C(OC(C)C)(C)C>O>[OH2:3].[CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:18][OH:23])[C:11]=2[CH3:19])[CH2:4][O:3]1
Reactant: Cc1c[n+]([O-])c(C)c(C)c1OCC1COC(C)(C)OC1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)OC(C)C
Solvent: O
Product: Cc1cnc(CO)c(C)c1OCC1COC(C)(C)OC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 108.1 %

Procedure:
To a mixture of 4-(2,2-dimethyl-1,3-dioxan-5-yl)methoxy-2,3,5-trimethylpyridine N-oxide (1.20 kg) and sodium acetate (0.18 kg) heated at 50° C. to 60° C., acetic anhydride (1.10 kg) was added dropwise over 1.5 hours. After 0.5 hours, the mixture was heated at 80° C. for 4.5 hours and cooled to an inner temperature below 30° C. or less, allowed to stand, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (1.0 L) and the solution was added to a mixture of a 48% aqueous sodium hydroxide solution (0.71 kg) and cold water (2.85 L) for one hour. After stirred at room temperature for 5 hours and 45 minutes, the mixture was concentrated under reduced pressure. To the residue thus concentrated, water (3.0 L) was added and the mixture was extracted with toluene (2.3 L×4). The toluene layers were combined and washed with water (1.2 L). The obtained organic layer was filtrated through celite and concentrated. To the residue obtained, diisopropyl ether (1.15 L) was added at a room temperature and further warm water (45° C., 74 mL) was added. After crystal precipitation was confirmed, the mixture was stirred at 25° C. for one hour. After heptane (3.6 L) was poured, the mixture was stirred overnight. The mixture was further stirred under ice-cool for 5 hours and then filtrated to obtain yellow crystal. To the yellow crystal obtained, diisopropylether (3.5 L) was added and the mixture was dissolved at 50° C. After insoluble substance was removed by filtration, the mixture was gradually cooled and allowed to stand at 5° C. overnight. The obtained crystal was filtrated and washed with heptane (0.5 L) and dried by air to obtain a desired product (0.69 kg).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9]([CH:12]1[CH2:15][NH:14][CH2:13]1)(=[O:11])=[O:10].CS(O[CH:21]([C:23]1[CH:24]=[N:25][C:26]([NH:55][C:56]2[CH:57]=[N:58][C:59]([O:62][CH3:63])=[CH:60][CH:61]=2)=[C:27]([C:29]2[N:34]=[C:33]([N:35]([CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:32]=[C:31]([CH3:54])[N:30]=2)[CH:28]=1)[CH3:22])(=O)=O>C(Cl)Cl>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][N:35]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[C:33]2[N:34]=[C:29]([C:27]3[C:26]([NH:55][C:56]4[CH:57]=[N:58][C:59]([O:62][CH3:63])=[CH:60][CH:61]=4)=[N:25][CH:24]=[C:23]([CH:21]([N:14]4[CH2:15][CH:12]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:13]4)[CH3:22])[CH:28]=3)[N:30]=[C:31]([CH3:54])[N:32]=2)=[CH:51][CH:50]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)OS(C)(=O)=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CS(=O)(=O)C1CNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)N4CC(S(C)(=O)=O)C4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 35.5 %

Procedure:
Triethylamine (0.327 mL, 2.345 mmol) and 3-(methylsulfonyl)azetidine (PharmaBlock, Carrboro, N.C.; 241 mg, 1.786 mmol) were sequentially added to a solution of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl methanesulfonate (375 mg, 0.558 mmol) in CH2Cl2 (5.5 mL) and the resulting mixture was stirred at 25° C. for 21 h. The reaction mixture was then concentrated in vacuo and chromatographically purified (silica gel, 0 to 100% (10% MeOH-EtOAc)/hexanes) to furnish N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(1-(3-(methylsulfonyl)azetidin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (141.0 mg, 0.198 mmol, 35.5% yield) as a yellow oil. m/z (ESI, +ve) 711.3 (M+H)+.