Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[N:13]1[CH:18]=CC=[CH:15][CH:14]=1.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([C:31]1[N:35]=[CH:34][NH:33][N:32]=1)(=[O:30])=[O:29].CNCC>ClCCl.C(OCC)(=O)C.CCCCCC>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[S:28]([C:31]1[N:35]=[CH:34][N:33]([C:5](=[O:11])[N:13]([CH3:18])[CH2:14][CH3:15])[N:32]=1)(=[O:29])=[O:30]
Reactant: Cc1cc(C)c(S(=O)(=O)c2nc[nH]n2)c(C)c1
Reactant: c1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CCNC
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(C)C(=O)n1cnc(S(=O)(=O)c2c(C)cc(C)cc2C)n1
Reaction time: 0.08 h

Procedure:
Triphosgene (20 mg) was dissolved in dichloromethane (1 ml). To this solution was added pyridine (0.017 ml) with cooling it on an ice-water bath, and the reaction mixture was stirred for 5 minutes. Then, 3-(2,4,6-trimethylphenyl)sulfonyl-1H-1,2,4-triazole (Example 35-a) (51 mg) was added, and stirred for additional 10 minutes. Then, N-methylethylamine (0.034 ml) was added, and the reaction mixture was stirred at room temperature for 6 hours. The reaction solution was subjected to a silica-gel column chromatography with 50% ethyl acetate/hexane to yield the title compound (52 mg).
Reaction SMILES: CS(Cl)(=O)=[O:3].[N:6]1C=CC=[CH:8][CH:7]=1.C(=NO)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C.N1C=CC=CC=1>>[C:7]([NH:6][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:3])[CH3:8]
Reactant: c1ccncc1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=NO)c1ccccc1
Product: CC(=O)Nc1ccccc1

Procedure:
A 0.15 mol/L methanesulfonyl chloride/pyridine solution was sent as a first fluid from the center at a ratio of supply pressure/back pressure of 0.15 MPa/0.07 MPa, a rotation speed of 500 rpm, and a sending temperature of 25° C., and a 0.1 mol/L acetophenone oxime/pyridine solution was introduced as a second fluid into a space between the processing surfaces at 30 mL/min. The first fluid and the second fluid were mixed in a thin film fluid, and then a solution obtained after processing was discharged from the space between the processing surfaces at 58 mL/min. As a result of HPLC analysis, substantially complete conversion to acetanilide was observed.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)=[O:34]>CO>[CH3:41][C:38]1[CH:39]=[CH:40][C:35]([C:33](=[O:34])[CH2:32][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])=[CH:36][CH:37]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(C)cc1
Yield: 77.8 %

Procedure:
Using the procedure described in example 5, treatment of L-proline-L-isoleucine benzylamide (191 mg, 0.60 mmol), with sodium carbonate (70 mg, 0.66 mmol), and 2-bromo-4'-methylacetophenone (141 mg, 0.66 mmol, 1.1 eq), in methanol (5 mL), provided 210 mg (78%) of L-isoleucine, N-[1-(2-(4-methylphenyl)-2-oxoethyl)-L-prolyl] benzylamide as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([NH:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1)(=[O:19])[CH3:18]
Reactant: Cc1cc(N)ncc1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc(N)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-diamino-4-picoline, prepared as shown in Example 30, (50 mg, 0.41 mmol) in methylene chloride (1.0 mL) were added triethylamine (70 uL, 0.49 mmol) and acetic anhydride (43 uL, 0.45 mmol). After stirring 0.5 h at room temperature, the reaction mixture 25 was evaporated to dryness and purified by silica gel chromatography using 40:10:1 chloroform-methanol-water as eluant to give the title compound.
Reaction SMILES: [OH-].[Na+].OO.[OH:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]1[C:15]([NH2:16])=[C:14]([C:17]#[N:18])[C:13]([CH3:19])=[N:12]1.C(O)(=[O:22])C>O>[OH:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]1[C:15]([NH2:16])=[C:14]([C:17]([NH2:18])=[O:22])[C:13]([CH3:19])=[N:12]1
Reactant: CC(=O)O
Reactant: Cc1nn(C2CCCC2O)c(N)c1C#N
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(C2CCCC2O)c(N)c1C(N)=O
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of sodium hydroxide (1.2 g, 30 mmol) in water (50 ml) in an ice-bath was added 30% hydrogen peroxide (3.3 ml, 29 mmol). The reaction mixture was stirred for 5 minutes then 1-(2-hydroxycyclopentyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile (2.5 g, 12 mmol) was added. The reaction mixture was stirred in an ice-bath for 5 hours, additional 30% hydrogen peroxide (1.5 ml) was added and stirring was continued for 2 hours. Acetic acid (2 ml) was added to the reaction mixture, all but approximately 25 ml of the solvent was removed in vacuo and the resulting solid was collected by filtration and washed with water. The solid was air dried to afford 2.4 g (90%) of 1-(2-hydroxycyclopentyl)-3-methyl-5-amino-1H-pyrazole-4-carboxamide as a white solid, m.p. 120°-124° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:4][CH:3]=1.[CH2:18](Cl)Cl.C=O.C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[N:10]=[C:6]2[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:4][CH:3]=1
Reactant: ClCCl
Reactant: Cc1nc2c(N3CCNCC3)ncc(Br)n2n1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c(N3CCN(C)CC3)ncc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A 100 mL round bottom flask was charged with 5-bromo-2-methyl-8-(piperazin-1-yl)-[1,2,4]-triazolo[1,5-a]pyrazine (0.5 g, 1.7 mmol), CH2Cl2 (20 mL), MeOH (10 mL), 40% aqueous formaldehyde (2 mL) and NaBH3(CN) (0.5 g, 8.0 mmol). The resulting solution was stirred at room temperature for 0.5 h. Work-up: the reaction mixture was poured into saturated aqueous NaHCO3 and extracted with CH2Cl2 (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 1-10% MeOH in CH2Cl2, to afford 0.4 g (76%) of the product as a yellow solid. MS m/z: 311 (M+H+).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].ClC1N2C=CC=CC2=NC=1COC1C=CC([C:24]2[C:25](=[O:39])[C:26]([CH3:38])([CH3:37])[O:27][C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=CC=1>C(Cl)Cl.C(OCC)C>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([C:28]2[O:27][C:26]([CH3:37])([CH3:38])[C:25](=[O:39])[CH:24]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(C2=C(c3ccc(OCc4nc5ccccn5c4Cl)cc3)C(=O)C(C)(C)O2)cc1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 159.1 %

Procedure:
Methanesulfonic acid (50.5 mg, 0.52 mmol) was added to a solution of 4-(4-((3-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (250 mg, 0.52 mmol) in DCM (2.5 ml) and diethyl ether (25 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h upon which the compound was filtered, washed with 20% DCM in diethyl ether and dried in vacuo to afford 4-(4-(3-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one methanesulfonate (260 mg, 86%) as white solid. 1H NMR: 500 MHz, DMSO-d6: δ 8.55 (d, 1H), 8.0 (s, 1H), 7.65 (Ar, 3H), 7.3-6.85 (Ar, 7H), 5.2 (s, 2H), 3.85 (s, 3H), 2.15 (s, 3H) 1.25 (s, 6H), HPLC: (98.8%, Condition-A).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[C:23]1([CH3:35])[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=1[S:31]([Cl:34])(=[O:33])=[O:32]>>[ClH:34].[C:23]1([CH3:35])[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=1[S:31]([N:18]1[C:19]2[C:15](=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)(=[O:32])=[O:33]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Product: Cc1cc(C)c(S(=O)(=O)n2ccc3c(N4CCNCC4)cccc32)c(C)c1
Product: Cl

Procedure:
The title compound was prepared from 4-(4-boc-piperazinyl)-indole and mesitylsulfonylchloride according to Method 3: 1H NMR (270 MHz, DMSO-d6) δ 9.10 (br, 1H), 7.71 (d, J=5 Hz, 1H), 7.40-7.20 (m, 3H), 7.00-6.80 (m, 2H), 6.51 (d, J=8 Hz, 1H), 3.30-3.20 (m, 8H), 2.41 (s, 6. H), 2.27 (s, 3H); MS (ESI+) for m/z 384 (M+H)+.
Reaction SMILES: C1(=O)NCCCCC1.[CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:10]>O>[CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:10]
Reactant: COC(=O)CCCCC=O
Agent: O=C1CCCCCN1
Solvent: O
Product: O=CCCCCC(=O)O

Procedure:
An ε-caprolactam preparation process starting from methyl 5-formylvalerate is described in U.S. Pat. No. 4,730,040. In this process, methyl 5-formylvalerate is first hydrolyzed (step x) in the presence of water and an acidic agent to yield 5-formylvaleric acid. The acid is then further reacted (step y) in aqueous solvent with ammonia and hydrogen in the presence of a Raney nickel catalyst in one reaction step to yield 6-aminocaproic acid. After separation of ammonia, the aqueous mixture is heated to 300° C. (step z) to form ε-caprolactam by cyclization of the 6-aminocaproic acid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.Cl.C([NH:23][CH2:24][CH2:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])C1C=CC=CC=1.C(=O)([O-])O.[Na+].O>C(O)(C)C>[O:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:23][CH2:24][CH2:25][C:26](=[O:27])[NH:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1cc(OCC2CO2)c2ccoc2c1
Reactant: O=C(CCNCc1ccccc1)NCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=C(CCNCC(O)COc1cccc2occc12)NCc1ccccc1

Procedure:
In a similar manner to that described above but using a mixture of 1-(benzo[b]furan-4-yloxy)-2,3-epoxypropane (1.9 g.), β-benzylamino-N-benzylpropionamide hydrochloride (3.05 g.), sodium hydrogen carbonate (0.84 g.), water (5 ml.) and isopropanol (40 ml.) there is obtained 1-(benzo[b]furan-4-yloxy)-3-β-(N-benzylcarbamoyl)ethylamino-2-propanol, m.p. 109°-110° C. The β-benzylamino-N-benzylpropionamide hydrochloride used as starting material may also be prepared in the manner described above, m.p. 237°-239° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[O:5]1[CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][NH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([N:8]1[CH2:9][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:5][C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]1=2)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1CNc2ccccc2O1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(C(C)=O)c2ccccc2O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.7 %

Procedure:
Acetyl chloride (23 L, 0.33 mmol) was added to a solution of (±)-ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (Example 3a, 55 mg, 0.27 mmol), DMAP (1.6 mg, 0.013 mmol), and Hunig's base (63 L, 0.36 mmol) in dichloromethane (2 mL). The solution was stirred at 25° C. for 24 h, then the reaction mixture was diluted with dichloromethane (60 mL) and the mixture was extracted with 0.1 M sodium carbonate (7 mL) and half-saturated brine (7 mL). The organic layer was dried over sodium sulfate and concentrated. Purification of the product by flash column chromatography (40% EtOAc/hexane) afforded the title compound (46 mg, 0.18 mmol). MS m/z: 250 (M+1).
Reaction SMILES: C([Li])CCC.[O:6]1[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)OCC1.[C:16]1([C:22]2[N:31]=[C:30]([C:32](OCC)=[O:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CCCCCC.O1CCCC1>[C:16]1([C:22]2[N:31]=[C:30]([C:32]([N:13]3[CH2:12][CH2:11][C:10](=[O:6])[CH2:15][CH2:14]3)=[O:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: C1CC2(CCN1)OCCO2
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)c2nc(-c3ccccc3)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1.6M solution of butyllithium in hexane (37 ml) is added, under a nitrogen atmosphere and at 0° C., to 1,4-dioxa-8-azaspiro[4,5]decane (7.5 ml) in anhydrous tetrahydrofuran (30 ml). After 30 minutes, a solution of ethyl 2-phenylquinazoline-4-carboxylate (8 g) in anhydrous tetrahydrofuran (30 ml) is added. After 2 hours at ambient temperature, water is added and the mixture is extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is taken up in acetone (100 ml) and concentrated hydrochloric acid (20 ml) and the mixture is stirred for 5 hours at ambient temperature.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[N:12]=[C:11]([NH:15][CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[N:10]=[CH:9][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([C:22]([NH2:24])=[O:23])=[N:3]1.[Si](Cl)(C(C)(C)C)(C)C.C(N(CC)CC)C.CN(C)[CH:42]=[O:43]>CN(C)C1C=CN=CC=1>[CH:42]([N:19]1[CH2:18][CH2:17][CH:16]([NH:15][C:11]2[N:10]=[CH:9][C:8]3[CH2:7][CH2:6][C:5]4[C:4]([C:22]([NH2:24])=[O:23])=[N:3][N:2]([CH3:1])[C:14]=4[C:13]=3[N:12]=2)[CH2:21][CH2:20]1)=[O:43]
Reactant: Cn1nc(C(N)=O)c2c1-c1nc(NC3CCNCC3)ncc1CC2
Reactant: CN(C)C=O
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: Cn1nc(C(N)=O)c2c1-c1nc(NC3CCN(C=O)CC3)ncc1CC2
Temperature: 37.5 °C
Reaction time: 25 h
Yield: 80 %

Procedure:
500 mg (1.53 mmol) of 1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide were dissolved in 10 mL of dimethylformamide, containing 253 mg (1.68 mmol) of tert-butyldimethylsilyl chloride, 0.26 mL of triethylamine and 7 mg of 4-dimethylaminopyridine (0.06 mmol), and the mixture stirred at 35-40° C. for 25 hours under nitrogen. The mixture was then partitioned between dichloromethane and water, the organic layer was separated, washed with brine and dried over sodium sulfate. Evaporation of the volatiles in vacuo afforded 435 mg (80% yield) of the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Cl:19])=[CH:12][C:13]([C:17]#[N:18])=[N:14]2)=[CH:9][CH:8]=1.O>CCO>[N:1]([CH2:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([Cl:19])=[CH:12][C:13]([C:17]#[N:18])=[N:14]2)=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cc(Cl)c2ccc(CBr)cc2n1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc(Cl)c2ccc(CN=[N+]=[N-])cc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
Sodium azide (1.690 g, 26.0 mmol, 1.3 equiv.) was added to a stirred solution of 7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4, 5.63 g, 20.00 mmol) in 100 ml of EtOH, and the resulting slurry mixture was refluxed for 1 h. The mixture was cooled to rt, water (100 ml) was added, and the slurry was stirred at rt for 30 min. The resulting solid was collected by filtration and air dried to afford 7-(azidomethyl)-4-chloroquinoline-2-carbonitrile (3-12, 4.75 g, 97%) as a white solid. LRMS m/z (M+H)+ 244.1 found, 244.65 required.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][O:20][CH2:21][CH2:22][N:23](C)[CH3:24]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH3:24])=[O:14]
Reactant: COCCN(C)C
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: COCCN(C)C(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(2-methoxyethyl) -N-methylisonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.42 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.57 mmol of (2-methoxy-ethyl)-dimethyl-amine LC/MS [7.84 min; 430 (M+1)]
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][CH3:14])=[O:12])[CH:6]=1)([CH3:4])[CH3:3].[CH:15]([CH:17]=[O:18])=[O:16].[OH-].[Na+]>C(O)C>[CH3:4][C:2]([C:5]1[O:9][N:8]=[C:7]([N:10]2[CH:15]([OH:16])[CH:17]([OH:18])[N:13]([CH3:14])[C:11]2=[O:12])[CH:6]=1)([CH3:1])[CH3:3]
Reactant: CNC(=O)Nc1cc(C(C)(C)C)on1
Reactant: O=CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(c2cc(C(C)(C)C)on2)C(O)C1O
Reaction time: 8 h

Procedure:
To a solution of 2.0 grams (0.010 mole) of 1-[5-(1,1-dimethylethyl)-3-isoxazolyl]-3-methylurea in 50 milliliters of 95 percent ethanol was added 7.3 grams of a 40 percent aqueous glyoxal solution which had been previously adjusted to pH 7 with dilute sodium hydroxide solution. After standing at room temperature overnight, the solution was topped on a rotary evaporator to give an oily residue which was extracted with two 20 milliliter portions of chloroform. The extract was washed with saturated sodium chloride solution, filtered through silicone-treated paper, and concentrated on a rotary evaporator to give 2.0 grams of oily residue. Crystallization from ether gave 0.4 grams of white crystals of 3-[5-(1,1-dimethylethyl)-3-isoxazolyl]-4,5-dihydroxy-1-methyl-2-imidazolidinone, M.P. 153°-157° C., which had consistent mass, infrared and NMR spectra.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:17][S:18][CH2:19][C:3]1=2.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:17][S:18][CH:19]=[C:3]12
Reactant: CCOC(=O)c1ccc2nc3c(c(=O)n2c1)CSC3
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2nc3cscc3c(=O)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno-[3,4-d]pyrimidine-7-carboxylate (2.0 g., 0.0072 mol) and m-chloroperbenzoic acid (1.47 g., 0.0072 mol) in chloroform (75 ml) is stirred at room temperature overnight. The solvent is evaporated at reduced pressure to give a syrup, which crystallizes from ethanol. Recrystallization from ethanol, silica gel chromatography and a further recrystallization from ethanol gives the product as yellow crystals (mp 175° C.).
Reaction SMILES: NC(C(O)=O)CS.[Cl:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:21]3[N:20]4[CH2:24][CH2:25][CH:26]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:19]4=[CH:18][C:17]=3[CH:16]=2)=[CH:11][C:10]=1[C:37]([F:40])([F:39])[F:38]>C(O)(C(F)(F)F)=O>[Cl:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:21]3[N:20]4[CH2:24][CH2:25][CH:26]([CH2:27][C:28]([OH:30])=[O:29])[C:19]4=[CH:18][C:17]=3[CH:16]=2)=[CH:11][C:10]=1[C:37]([F:40])([F:38])[F:39]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(Cl)c(C(F)(F)F)c3)ccc12
Agent: NC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CCn2c1cc1cc(OCc3ccc(Cl)c(C(F)(F)F)c3)ccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of D,L-cysteine (0.056 g, 0.460 mmol) in TFA (0.9 mL) was added tert-butyl 2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.079 g, 0.153 mmol). The reaction was stirred for 2 h and poured into ice water. The resulting precipitate was collected by vacuum filtration to give the title compound as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[OH:15][CH:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][OH:27])[CH:20]=1)[CH2:17][NH2:18]>C(O)C.[Pd].C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:18][CH2:17][CH:16]([OH:15])[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][OH:27])[CH:20]=2)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1ccc(O)c(CO)c1
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(O)c(CO)c2)cc1
Reaction time: 18 h
Yield: 43 %

Procedure:
A solution of 1-(4-carbomethoxyphenyl)propan-2-one (70 g) and 2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethanamine (66.7 g) in ethanol (1750 cm3) was stirred under reflux for 4 hours. The solution was cooled and added to a suspension of 10% palladium on charcoal, (Johnson Matthey type 87L), (20 g) in ethanol (50 cm3) and the resulting mixture hydrogenated at 90 psi and 50°-55° for 18 hours. The mixture was filtered through a Claraid bed, the residue washed with ethanol (about 500 cm3) and the filtrate evaporated under reduced pressure to yield a viscous gum. The gum was dissolved in hot ethyl acetate (100 cm3) and decanted from a small amount of residual brown oil. On standing a white solid crystallised which was filtered off, washed with diethyl ether (about 100 cm3) and dried to give the title compound 56.3 g (43%), mp 139°-141°. (13C NMR: indicated this to be a 7:3 mixture of diastereoisomers). On standing two further crops of the title compound crystallised from the filtrate giving a total yield of 84.7 g (64.7%).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[CH2:30]([OH:32])[CH3:31].C([O:37]C)(C)(C)C>C(O)(=O)C>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([O-:37])(=[O:32])[CH3:31]
Reactant: CCO
Reactant: COC(C)(C)C
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CC(=O)O
Product: CC(=O)[O-]
Temperature: 50 °C

Procedure:
Sunitinib base (3 g) was dissolved in acetic acid (6 ml) and absolute ethanol (6 ml) by stirring for 10 min at 20° C. and the solution was heated to 50° C. Then methyl tert-butyl ether (60 ml) was added within 300 min with stirring, the mixture was cooled to −10° C. After 16 h at −10° C. the solid was filtered, washed with 2×20 ml of MTBE, dried on filter for one hour obtaining a red solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.O>C(Cl)Cl>[OH:4][C@@H:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][NH:1][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)[CH2:16][CH2:17]1
Reactant: NC[C@@H](O)c1cccnc1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Solvent: O
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@@H](O)c4cccnc4)CC3)cc2)S1

Procedure:
The title compound was prepared from (1S)-2-amino-1-(3-pyridinyl)-1-ethanol (which was obtained in Example 130) and 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (which was obtained in Example 38) in substantially the same manner, as described in Example 125. The product was obtained as a yellow solid; mp:>88° C. decomposed; 1H NMR (400 MHz, DMSO-d6) δ 1.38–1.50 (m, 2 H), 1.90–1.98 (m, 2 H), 2.63–2.71 (t, 2 H), 2.78–2.96 (m, 4 H), 3.23–3.27 (m, 1 H), 3.62–3.65 (m, 2 H), 4.62–4.67 (m, 1 H), 4.76–4.79 (m, 1 H), 6.83–6.86 (d, 2 H), 7.03–7.05 (d, 2 H), 7.36–7.38 (m, 1 H), 7.76–7.79 (m, 1 H), 8.46–8.48 (m, 1 H), 8.57–8.58 (m, 1 H); MS (ES) m/z: 427 (MH+); Anal. Calcd. for C22H36N4O2×0.3 H2O×0.3 CH2Cl2: C, 55.87; H, 5.51; N, 11.69. Found: C, 55.92; H, 5.80; N, 11.45.