Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:58])[C:29](=[N:55][O:56][CH3:57])[C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].[I-].[Na+:61].[SH:62][C:63]1[O:64][C:65]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)=[CH:66][N:67]=1>>[NH2:35][C:32]1[S:33][CH:34]=[C:30]([C:29](=[N:55][O:56][CH3:57])[C:28]([NH:27][C@@H:26]2[C:25](=[O:59])[N:7]3[C:8]([C:9]([O-:11])=[O:10])=[C:3]([CH2:2][S:62][C:63]4[O:64][C:65]([C:68]5[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=5)=[CH:66][N:67]=4)[CH2:4][S:5][C@H:6]23)=[O:58])[N:31]=1.[Na+:61]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Sc1ncc(-c2ccccc2)o1
Agent: [I-]
Agent: [Na+]
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3ncc(-c4ccccc4)o3)CS[C@H]12)c1csc(N)n1
Yield: 7.1 %

Procedure:
The same operation as in EXAMPLE 65 was conducted by using 600 mg (0.71 mmol) of benzhydryl 3-chloromethyl-7β-[2-methoxyimino-2-( 2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn-isomer), 160 mg (1.07 mmol) of sodium iodide and 130 mg (0.72 mmol) of 2-mercapto-5-phenyloxazole, whereby 70 mg (yield: 7.1%) of the above identified compound was obtained.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][NH:5]1.Br[CH2:15][C:16]1[S:17][C:18]([C:21]2[CH:22]=[C:23]([NH:28][C:29]3[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=3)[CH:24]=[C:25]([CH3:27])[CH:26]=2)=[CH:19][N:20]=1>O1CCCC1.C(OCC)(=O)C>[CH3:27][C:25]1[CH:26]=[C:21]([C:18]2[S:17][C:16]([CH2:15][C:8]3([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][NH:5][C:4]3=[O:3])=[N:20][CH:19]=2)[CH:22]=[C:23]([NH:28][C:29]2[N:34]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:32]=[CH:31][N:30]=2)[CH:24]=1
Reactant: CCOC(=O)C1CCNC1=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CBr)s2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CCNC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
To sodium hydride in mineral oil (60%, 0.007 g, 0.33 mmol) was added tetrahydrofuran (1.8 mL) and the suspension was cooled to 0° C. Ethyl 2-oxopyrrolidine-3-carboxylate (0.044 g, 0.28 mmol) was added and the solution was stirred for 15 minutes. N-{3-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (0.100 g, 0.23 mmol) was dissolved in tetrahydrofuran (1.8 mL) and then added to the flask. The reaction was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate, washed carefully with water, dried over magnesium sulfate, filtered and concentrated. The solid was purified by silica gel chromatography to yield ethyl 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-oxopyrrolidine-3-carboxylate (0.03 g, 27% yield). MS ESI: [M+H]+ m/z 505.7. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=5.2, 1H), 8.11 (s, 1H), 8.02-7.84 (m, 2H), 7.47 (s, 1H), 7.28 (d, J=5.2, 1H), 7.14 (s, 1H), 4.11 (q, J=7.4, 2H), 3.58 (m 1H), 3.28-3.21 (m, 2H), 3.15-3.03 (m, 1H), 2.66-2.54 (m, 1H), 2.31 (s, 3H), 2.27-2.16 (m, 1H), 1.15 (t, J=7.3, 3H). rhSYK activity=+++
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C(#N)C.CC1(C)[O:29][C@@H:28]([CH2:30][O:31][NH2:32])[CH2:27][O:26]1.Cl>C1(C)C=CC=CC=1>[OH:29][C@H:28]([CH2:27][OH:26])[CH2:30][O:31][NH:32][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[F:20]
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: O=C(NOC[C@H](O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reaction time: 1.5 h

Procedure:
To a flask containing 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (2.6 kg, 6.6 mol) and N,N′-carbonyldiimidazole (1.1 kg, 6.8 mol) under nitrogen atmosphere, was added 12 L of dry acetonitrile. After stirring at 22°±5° C. for about 90 minutes, a solution of (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine in toluene was added (8.5 L total volume, about 8 moles of amine). The solution was stirred for at least 6 hours at 22°±5 C. Aqueous hydrochloric acid (9 L, 1.5 molar) was added, and after stirring for about 5 minutes, the layers were separated. Aqueous hydrochloric acid (9 L, 1.5 molar) was added to the remaining top layer, and after stirring for about 20 hours, the layers were separated. The remaining top layer was concentrated by vacuum distillation, and then diluted with 15 L toluene and 2 L ethanol. The mixture was warmed to 35–45° C. and diluted with 20 L warm water, then cooled to 0–5° C. The product was collected by filtration and washed with 2 L toluene. The product was recrystallized by dissolving in 12 L toluene and 2 L ethanol (50°±5 C), adding 10 L water and cooling to 0–5° C. After collecting the product by filtration and washing with toluene, the product was dried in a vacuum oven resulting in 2.6 kg of N-[(R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:6][C:5]2([CH2:24][C:25]([O:27][CH3:28])=[O:26])[NH:17]S(C(C)(C)C)=O.Cl.O1CCOCC1>CO>[NH2:17][C:5]1([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:4]2[C:14](=[CH:15][CH:16]=[C:2]([Br:1])[CH:3]=2)[O:13][C:7]2([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:6]1
Reactant: COC(=O)CC1(NS(=O)C(C)(C)C)CC2(CCCCC2)Oc2ccc(Br)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CC1(N)CC2(CCCCC2)Oc2ccc(Br)cc21
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a solution of methyl 2-(6-bromo-4-(1,1-dimethylethylsulfinamido)spiro[chroman-2,1′-cyclohexane]-4-yl)acetate (200 mg, 0.42 mmol) in MeOH (2 mL) was added 4 N HCl/1,4-dioxane (2 mL). After stirring for 30 minutes, the mixture was concentrated. The residue was dissolved in MeOH (1 mL) stirring for 5 minutes and evaporated again to afford methyl 2-(4-amino-6-bromospiro[chroman-2,1′-cyclohexane]-4-yl)acetate (140 mg, 90%). 1H NMR (CDCl3): 1.22-1.38 (m, 1H), 1.39-1.52 (m, 6H), 1.72-1.88 (m, 3H), 1.93-2.02 (d, 2H), 2.13-2.24 (t, 1H), 2.59 (d, 1H), 2.86 (d, 1H), 3.65 (s, 3H), 6.74 (d, 1H), 7.24 (s, 1H), 7.52 (s. 1H).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2.N1C=CC=CC=1>O>[N:21]1[C:22]2[C:17](=[CH:16][C:15]([NH:14][C:11]([C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[O:12])=[CH:24][CH:23]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc2ncccc2c1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc2ncccc2c1)C12CC3CC(CC(C3)C1)C2
Yield: 99.5 %

Procedure:
Prepared from 1-adamantanecarbonyl chloride (1.37 g, 6.90 mmol), 6-aminoquinoline (0.59 g, 4.1 mmol), pyridine (20 mL), and water (200 mL) yielding 1.25 g (100%) of (18):
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:4]2([CH2:9][C:10](=[O:12])[CH:11]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2>CCCCCC.[Pd]>[CH3:1][C@H:2]1[CH2:11][C:10](=[O:12])[CH2:9][C:4]2([CH2:5][CH2:6][CH2:7][CH2:8]2)[C@H:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C1C(C)=CC(=O)CC12CCCC2
Agent: [Pd]
Solvent: CCCCCC
Product: CCOC(=O)[C@H]1[C@@H](C)CC(=O)CC12CCCC2
Yield: 91 %

Procedure:
A solution of ethyl 7-methyl-9-oxospiro[4.5]dec-7-ene-6-carboxylate (2.5 g, 10.6 mmol, prepared as described in Example 16) in hexane (40 ml) was treated with 10% Pd/C (0.5 g) and hydrogenated (10 bar) for 1.5 h. The resulting mixture was filtered and concentrated to give cis-ethyl 7-methyl-9-oxospiro[4.5]decane-6-carboxylate (2.29, 91%).
Reaction SMILES: [CH:1]([N:3]([CH3:5])[NH2:4])=[O:2].[F:6][C:7]1[C:24]([F:25])=[CH:23][C:22]([I:26])=[CH:21][C:8]=1[C:9]([C:11](=[CH:17]OCC)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[F:6][C:7]1[C:24]([F:25])=[CH:23][C:22]([I:26])=[CH:21][C:8]=1[C:9]([C:11](=[CH:17][NH:4][N:3]([CH:1]=[O:2])[CH3:5])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(I)cc(F)c1F
Reactant: CN(N)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNN(C)C=O)C(=O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 1-formyl-1-methylhydrazine (0.217 g) in toluene (0.5 mL) is added to a solution of ethyl 2-(2,3-difluoro-5-iodobenzoyl)-3-ethoxy-2-propenoate (Preparation 21, 1.00 g) in toluene (2.5 mL) at 33° C. After stirring at ambient temperature for 20 minutes, a precipitate formed and an additional 1.5 mL of toluene is added. After an additional 1.75 h, solid anhydrous Na2CO3 (0.285 g) is added and the reaction mixture is heated to reflux. After 1 h, the reaction mixture is concentrated at reduced pressure and the residue suspended in 8 mL of water which is used as is in the following step. Physical characteristics: MS (ESI+) m/z 419 (M+H)+.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:6][N:7]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>ClCCl.CCOC(C)=O>[C:25]1([O:24][C:22](=[O:23])[NH:2][C:3]2[S:4][C:5]([CH2:8][CH2:9][N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])=[CH:6][N:7]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ncc(CCN2C(=O)c3ccccc3C2=O)s1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1ncc(CCN2C(=O)c3ccccc3C2=O)s1)Oc1ccccc1
Reaction time: 2 h

Procedure:
To a suspension of a HBr salt of 2-[2-(2-amino-thiazol-5-yl)-ethyl]-isoindole-1,3-dione (compound 58.1; 1.42 mmol) in dichloromethane was added TEA (4.30 mmol) followed by the addition of phenyl chloroformate (1.43 mmol) at room temperature. After 2 hours, the reaction was concentrated to dryness to give a solid that was suspended in EtOAc, filtered, washed with additional EtOAc and dried under vacuum to provide {5-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-thiazol-2-yl}-carbamic acid phenyl ester (compound 58.2, which is contaminated with triethyl amine salts) which was used in the next reaction without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:21]=2[N:20]=1)[C@H:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:12]([O:11][C@H:9]([CH3:10])[C@H:8]([NH2:7])[C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:21]=2[N:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OCc1ccccc1)[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
To a solution of [(1R,2R)-2-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propyl]carbamic acid tert-butyl ester (0.971 g, 2.0 mmol) in DCM (15 mL) was added TFA (8 mL) and the mixture stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The two phase system was stirred for 10 min, then the organic fraction was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound (100 mg, 13%). LCMS (Method C): RT 2.59 min [M+H]+ 376.4.
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[O:18]=[C:19]1[NH:23][C@H:22]([C:24]([OH:26])=O)[CH2:21][S:20]1.[N+]([O-])(O)=O.[N+:31]([O:34][CH2:35][CH2:36][NH2:37])([O-:33])=[O:32]>O1CCCC1>[N+:31]([O:34][CH2:35][CH2:36][NH:37][C:24]([C@@H:22]1[CH2:21][S:20][C:19](=[O:18])[NH:23]1)=[O:26])([O-:33])=[O:32]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1N[C@H](C(=O)O)CS1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Solvent: C1CCOC1
Product: O=C1N[C@H](C(=O)NCCO[N+](=O)[O-])CS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
11.4 ml of triethylamine and 5.3 ml of diethyl cyanophosphonate were added, whilst ice-cooling, to a suspension of 4.0 g of (4R)-2-oxothiazolidine-4-carboxylic acid and 4.6 g of N-(2-nitrooxyethyl)amine nitrate in 80 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with ethyl acetate. The resulting mixture was then washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residual brown oil thus obtained was purified by column chromatography through silica gel, using ethyl acetate as the eluent. The brown crystals thus obtained were recrystallized from ethyl acetate, to give 1.68 g of the title compound as colorless needles, melting at 130°-131° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([CH3:17])[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1.[CH:19]([N-]C(C)C)(C)C.[Li+].C1CCCCC1.CI.C(O)(=O)C>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][O:2][C:3](=[O:18])[C:4]([CH3:19])([CH3:17])[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCCCC1
Product: COC(=O)C(C)(C)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66 %

Procedure:
To a solution of α-methyl-6-methoxy-2-naphthaleneacetic acid methyl ester (12.2 g, 50 mmol) in tetrahydrofuran (100 ml) at -70 ° c. is added a solution of lithium diisopropylamide in cyclohexane (50 ml, 1.5 equiv). After 20 min, methyl iodide (4.0 ml, 1.3 equiv) is added followed by hexamethylphosphoramide (20 ml). After allowing the reaction mixture to warm to room temperature and stir 16 hours, the reaction is quenched by addition of acetic acid (4.3 ml, 75 mmol). The solvent is then removed and the residue is partitioned between ethyl acetate and water. The organic layer is washed with water 3 times and finally with brine. After drying over magnesium sulfate, the organic extract is evaporated to afford a crude solid. Recrystallization of this solid from hexane affords 8.56 g (66%) of α,α-dimethyl-6-methoxy-2-naphthaleneacetic acid methyl ester as white crystals, m.p. 97°-98° C. A solution of this ester (7.4 g, 28.6 mmol) in 48% HBr(50 ml) and acetic acid (50 ml) is refluxed for 3 hours. After the reaction mixture is cooled to room temperature, 0.8 L of water is added and the reaction mixture is extracted with ethyl acetate 5 times. The combined organic extract is washed sequentially with saturated sodium bicarbonate solution and water. After drying over magnesium sulfate, the organic extract is evaporated to afford 6.1 g (93%) of α,α-dimethyl-6-hydroxy-2-naphthaleneacetic acid as white crystals, m.p. 208°-210° C. The title compound is prepared according to the method of Example 7 using α,α-dimethyl-6-hydroxy-2-naphthaleneacetic acid. A white solid is obtained having a melting point of 207°-209° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[NH:7][CH:8]=1)(=O)[NH2:2].C([O-])([O-])=O.[Na+].[Na+]>O=P(Cl)(Cl)Cl>[C:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[NH:7][CH:8]=1)#[N:2]
Reactant: COc1ccc(-c2nc(C(N)=O)c[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc(C#N)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of 64 (7.6 g, 0.035 mol) and POCl3 (100 ml) was heated at reflux for 5.5 hours. After stirring at room temperature overnight, the suspension was poured into saturated Na2CO3 and the mixture extracted with 20% CH3OH--CHCl3 (3×). The organic extracts were washed with saturated NaCl, dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product eluted with 5% CH3OH--CHCl3 to yield 5.0 g (71%) of 65; m.p. 219°-20° C. (CH3CN).
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>C1(C)C=CC=CC=1>[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: Cc1ccccc1
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 toluene were reacted in presence of catalytic amount of pyrrolidine (0.08 mL) as base at 80-85° for 2-8 hours. The resultant Sunitinib base was triturated in toluene at 80-85° 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: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[C:13]([O:17][C:18](=[O:33])[N:19]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH:20]([CH3:22])[CH3:21])([CH3:16])([CH3:15])[CH3:14]>CN(C)C=O>[C:13]([O:17][C:18](=[O:33])[N:19]([CH:20]([CH3:21])[CH3:22])[CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]=[C:1]=[S:2])=[CH:30][CH:31]=1)([CH3:15])([CH3:16])[CH3:14]
Reactant: CC(C)N(CCOc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)N(CCOc1ccc(N=C=S)cc1)C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
Thiocarbonyldiimidazole (3.64 g, 20.44 mmol) (Aldrich) was dissolved in N,N-dimethylformamide (3 mL) and the solution was cooled to −15° C. A solution [2-(4-amino-phenoxy)-ethyl]-isopropyl-carbamic acid tert-butyl ester (from step C above) in N,N-dimethylformamide (7 mL) was added dropwise and stirred at room temperature for 90 minutes. The mixture was poured into ice/water (1500 mL) and extracted with ether (4×250 mL). The ether was dried (Na2SO4) and concentrated in vacuo to give 6.5 g, (95%) isopropyl-[2-(4-isothiocyanato-phenoxy)-ethyl]-carbamic acid tert-butyl ester. Mass spectrum (ES) MH+=367.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a solution of 4-fluorophenylmagnesium bromide (110.0 mmol, 55.0 mL of 2.0 M solution) in 150.0 mL THF at 0° C. was added 1-benzyl-4-piperidone (55.0 mmol, 10.2 mL) dropwise. The resulting solution was stirred under argon atmosphere for 1.5 hours and then quenched with 100.0 mL of saturated NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with 100.0 mL of Et2O. The combined organic extracts were washed with brine, separated, and dried over Na2SO4. The solution was filtered and the solvent was removed in vacuo to obtain a yellow oil which was purified by passing through a silica gel column with 4:1 hexane/EtOAc followed by 1:1 hexane/EtOAc as the eluting system. 1-Benzyl-4-(4-fluoro-phenyl)-piperidin-4-ol was obtained as a pale yellow oil in 89% yield (13.9 g). It was dissolved in 150.0 mL of toluene and p-toluenesulfonic acid monohydrate (50.0 mmol, 9.5 g) was added. The resulting suspension was heated to reflux for 8 hours. After the suspension was cooled, it was basified with 3 N NaOH solution and was extracted with Et2O (2×50 mL). The organic extracts were combined, washed with brine, and the organic layer was dried over Na2SO4. The solvent was removed in vacuo to obtain 1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridine as a yellow viscous oil (12.0 g, 92% yield) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:13])=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>>[CH2:1]([O:3][C:4]1[C:5]([F:13])=[C:6]2[C:12]([N+:14]([O-:16])=[O:15])=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cnc2[nH]ccc2c1F
Product: CCOc1cnc2[nH]cc([N+](=O)[O-])c2c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
Cold (about 0 to about 5° C.) fuming nitric acid (10 mL) was added to 5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridine (340 mg, 0.944 mmol). The reaction was stirred at 0° C. for 15 minutes and then ice was added. The resulting solid was filtered and dried to yield 5-ethoxy-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (165 mg, 78% yield) as a solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C1(C)C=CC(S([N:28]=[N+:29]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N+:28]=[N-:29])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)C2CC2)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=[N+]=[N-])c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
Ethyl 2-(4-cyclopropylsulfonylphenyl)acetate [obtained as described in WO2004/072031 (40 g, 149.07 mmol)] was dissolved in dry acetonitrile (745 mL) under argon atmosphere. To the above solution para toluene sulfonyl azide (32.33 g, 163.97 mmol) was added, followed by DBU (33.40 mL, 223.6 mmol) in dropwise manner, and stirred for 30 min. Reaction mixture was poured in ice cold water (500 mL), solid obtained was filtered through buchner funnel and dried under vaccum which yielded ethyl 2-(4-cyclopropylsulfonylphenyl)-2-diazo-acetate (40 g).
Reaction SMILES: O[C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:22])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[Cl:22][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: COCc1ncnc(O)c1OC
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COCc1ncnc(Cl)c1OC
Temperature: 80 °C
Reaction time: 3 h

Procedure:
85.0 g (0.5 mol) of 4-hydroxy-5-methoxy-6-methoxymethylpyrimidine were suspended in 600 ml of dichloroethane, 50.5 g of triethylamine were added, and 260 g (1.7 mol) of phosphorus oxychloride were then added without cooling. The mixture was stirred for 3 hours at 80° C., poured into ice-water and neutralized by adding solid sodium carbonate, the organic phase was separated, and the water phase was extracted several times by stirring with methylene chloride. The combined organic phases were dried and concentrated. The residue was distilled under a water pump vacuum. 66.1 g (70% of theory) of a yellow oil were obtained. B.p. 93°-96° C./0.1mm.