Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.N1C=CC=CC=1.[CH3:31][N:32]1[CH:36]=[C:35]([C:37](Cl)=[O:38])[CH:34]=[N:33]1>ClCCl>[CH:21]1([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:37]([C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)=[O:38])[CH:3]=[CH:4][C:5]=2[CH3:24])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1
Reactant: Cn1cc(C(=O)Cl)cn1
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2cnn(C)c2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.6 %

Procedure:
To a solution of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (53.8 mg, 0.144 mmol) in methylene chloride (2.0 mL, 31 mmol) was added pyridine (0.10 mL, 1.2 mmol) and 1-methyl-1H-pyrazole-4-carbonyl chloride (27.7 mg, 0.192 mmol). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was then poured into 50 mL dichloromethane, washed with aqueous NaHCO3, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 37.1 mg (61%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-1-methyl-1H-pyrazole-4-carboxamide. LCMS (ESI): RT (Min)=4.307, M+H=426.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.80 (s, 1H), 9.19 (s, 1H), 8.50 (s, 1H), 8.28 (s, 1H), 8.01 (d, J=4.9 Hz, 2H), 7.93 (d, J=8.6 Hz, 1H), 7.70 (dd, J=10.3, 4.6 Hz, 3H), 7.30 (d, J=8.0 Hz, 1H), 3.89 (s, 3H), 2.25 (s, 3H), 2.19-1.98 (m, 1H), 0.85 (m, 4H).
Reaction SMILES: [CH3:1][C@:2]12[N:18]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:25]4[C:26]5[CH2:31][NH:30][C:28](=[O:29])[C:27]=5[C:15]5=[C:16]([C:17]=43)[N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=35)[C@H:6]([O:7]1)[CH2:5][C@@H:4]([NH:32][CH3:33])[C@H:3]2[O:34][CH3:35].C[C@H](N)CC1C=CC=CC=1.C[C@H](N)CC1C=CC=CC=1.[OH:56]S(O)(=O)=O>CS(C)=O.[OH-].[Na+].C(OCC)(=O)C>[CH3:1][C@:2]12[N:18]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:25]4[C:26]5[C@H:31]([OH:56])[NH:30][C:28](=[O:29])[C:27]=5[C:15]5=[C:16]([C:17]=43)[N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=35)[C@H:6]([O:7]1)[CH2:5][C@@H:4]([NH:32][CH3:33])[C@H:3]2[O:34][CH3:35]
Reactant: O=S(=O)(O)O
Reactant: CN[C@@H]1C[C@H]2O[C@@](C)([C@@H]1OC)n1c3ccccc3c3c4c(c5c6ccccc6n2c5c31)C(=O)NC4
Agent: C[C@H](N)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN[C@@H]1C[C@H]2O[C@@](C)([C@@H]1OC)n1c3ccccc3c3c4c(c5c6ccccc6n2c5c31)C(=O)N[C@H]4O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
100 mg (0.21 mmol) of staurosporine (commercially available from Kyowa Medex Co., Ltd., Japan) was dissolved in a mixture of 4 ml of DMSO and 1 ml of 2N sodium hydroxide. The solution was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with water and brine in order, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography using the elution with 0%, 4%, 6%, and 10% acetone-containing chloroform in order to obtain 60 mg (yield: 59%) of UCN-01.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][C:11](=[O:16])[CH:12](O)[CH:13]=[CH2:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:9][O:10][C:11](=[O:16])[CH:12]=[CH:13][CH2:14][C:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(O)C(=O)OC
Reactant: O=CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=CCC1(C=O)CCCCC1
Temperature: 25 °C

Procedure:
To a solution of cyclohexanecarbaldehyde (6.3 mL) and 2-hydroxy-3-butenoic acid methyl ester (5 mL) in toluene (40 mL) was added para-toluenesulfonic acid monohydrate (20 mg), and the reaction mixture was heated under reflux by using a Dean-Stark apparatus for 16.5 hours. After cooling down to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate (volume ratio)=50:1 to 10:1) to give 4-(1-formyl-cyclohexyl)-but-2-enoic acid methyl ester (3.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]2([OH:62])[CH2:61][CH2:60][NH:59][CH2:58]2)[CH:52]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:59]3[CH2:60][CH2:61][C:57]([C:53]4[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=4)([OH:62])[CH2:58]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Reactant: OC1(c2cccnc2)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(O)(c3cccnc3)C2)cc1Cl
Yield: 50 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)-isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-pyridin-3-ylpyrrolidin-3-ol dihydrochloride (9 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (8 mg). MS (ESI, pos. ion) m/z: calcd for C20H18ClN3O4: 399.0986, found 399.0986.
Reaction SMILES: C([O:8][C:9]1[CH:40]=[CH:39][C:12]([O:13][CH2:14][C:15]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:38])[C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:28](=[O:37])[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.O.C(O)(=O)C>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:38])[C@@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:28](=[O:37])[CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:16])=[CH:39][CH:40]=1
Reactant: O=C(COc1ccc(OCc2ccccc2)cc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(COc1ccc(O)cc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.2 %

Procedure:
To a solution of (2S)-2-[4-(benzyloxy)phenoxyacetyl]-1-[N-(3-phenylpropionyl)-L-prolyl]pyrrolidine (1.44 g) in a mixture of methanol (50 ml), water (30 ml) and acetic acid (20 ml) was added Pd-Black (300 mg), and the mixutre was stirred at room temperature under hydrogen atmosphere for 4 hours. The reaction mixture was concentrated, and the concentrate was poured into saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 0.71 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([N:21]=[C:22]([N:24](C)C)[CH3:23])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Cl.N[OH:29]>CO>[Br:1][C:2]1[N:3]=[C:4]([N:21]=[C:22]([NH:24][OH:29])[CH3:23])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: CC(=Nc1nc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1)N(C)C
Reactant: NO
Agent: Cl
Solvent: CO
Product: CC(=Nc1nc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1)NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.9 %

Procedure:
A 100 mL round bottom flask was charged with tert-butyl 4-(5-bromo-3-((1-(dimethylamino)ethylidene)amino)pyrazin-2-yl)piperazine-1-carboxylate (2.8 g, 6.6 mmol) and methanol (25 mL). To the above solution was added hydroxylamine hydrochloride (0.76 g, 10.9 mmol) in one portion. The mixture was stirred at room temperature for 16 h. Work-up: the solvent was evaporated. The resulting crystalline solid was washed with water and collected by filtration. The solid was washed with ethanol (100 mL) and dried, to afford 2.3 g (84%) of the product as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][NH:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])=[O:13].C(Cl)Cl>CN(C=O)C>[O:19]=[C:15]1[CH2:16][CH2:17][CH2:18][N:14]1[C:12](=[O:13])[NH:11][CH2:10][CH2:9][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=C1CCCN1C(=O)NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCCN1C(=O)NCCn1cncn1
Temperature: 90 °C
Yield: 55.6 %

Procedure:
To a solution of 1.9 g (27.5 mmol) of 1,2,4-triazole in 15 ml of DMF was added 1.1 g (27.5 mmol) of 60% NaH, and the mixture was heated at 90° C. for about 2 hr. Then, 13 ml of DMF containing 3.50 g (18.4 mmol) of 1-[(2-chloroethyl)carbamoyl]-2-oxopyrrolidine (III-1) was added to the mixture, which was heated at 90° C. for 4.5 hr. The reaction solution was poured into CH2Cl2, and the insoluble material was removed by filtration. After evaporating the solvent, the CH2Cl2 layer was refined by silica gel column chromatography, whereby 2.28 g (55.6%) of the objective compound (Ia-34) was obtained from the eluate with CH2Cl2 - methanol (20/1 v/v). The crystals melting at 106.0°-107.0° C. were obtained by recrystallizing from ethanol.
Reaction SMILES: C(O)=O.[C:4](=[O:11])([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[NH2:5].[CH:12]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[S:22][CH3:23])=O.[C:24]1([S:30]([O-:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+]>C1COCC1.O>[C:7]([O:6][C:4](=[O:11])[NH:5][CH:12]([S:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:32])=[O:31])[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[S:22][CH3:23])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=S([O-])c1ccccc1
Reactant: CSc1cc(C#N)ccc1C=O
Reactant: CC(C)(C)OC(N)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=CO
Solvent: O
Product: CSc1cc(C#N)ccc1C(NC(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Formic acid (3.0 mL, 79 mmol) is added to a solution of tert-butyl carbamate (1.436 g, 12.3 mmol), 4-formyl-3-methylsulfanyl-benzonitrile (INTERMEDIATE 1; 1.975 g, 11.1 mmol) and sodium benzenesulfinate (2.012 g, 12.2 mmol) in a mixture of THF (3.0 mL) and water (7 mL), and the mixture is stirred at room temperature for 3 days. Water is added, the precipitate is filtered off and washed with water. The precipitate is treated with tert-butyl methyl ether, and the mixture is stirred for 30 min. The precipitate is filtered off, washed with tert-butyl methyl ether and dried. Yield: 3.5 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=2[O:26][CH3:27])[C:13]([F:28])=[CH:12][N:11]=1>>[Cl:25][C:20]1[C:21]([O:23][CH3:24])=[CH:22][C:17]([NH:16][C:14]2[C:13]([F:28])=[CH:12][N:11]=[C:10]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=3)[N:15]=2)=[C:18]([O:26][CH3:27])[CH:19]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1cc(Nc2nc(Cl)ncc2F)c(OC)cc1Cl
Product: COc1cc(Nc2nc(Nc3cccc(O)c3)ncc2F)c(OC)cc1Cl

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-N4-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine gave N4-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.96 (d, 1H, J=4.8 Hz), 7.66 (s, 1H), 7.13 (s, 1H), 7.07 (t, 1H, J=8.7 Hz), 8.86 (m, 2H), 6.57 (dd, 1H, J=3.2 and 8.1 Hz), 3.48 (s, 3H), 3.66 (s, 3H); 19F NMR (CD3OD): −46968.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:26][NH:25][C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4]1.CCN(C(C)C)C(C)C.O=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH3:1][O:2][CH:3]1[CH2:26][N:25]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4]1
Reactant: CCOC(=O)CCCCCC=O
Reactant: COC1CNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)CCCCCCN1CC(OC)Cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
rac-7-Methoxy-2,3-dip-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate K) (80 mg, 0.232 mmol) in dry DCE (4 ml) at RT under nitrogen was treated with DIPEA (0.044 ml, 0.255 mmol) followed by ethyl 7-oxoheptanoate (80 mg, 0.463 mmol). The resulting mixture was stirred at RT for 10 minutes and treated with sodium triacetoxyborohydride (245 mg, 1.158 mmol). The mixture was heated at 60° C. for 16 hours. A further portion of sodium triacetoxyborohydride (245 mg, 1.158 mmol) was added and the mixture was heated at 50° C. for 3 days. After cooling to RT, the reaction mixture was diluted with DCM (50 ml) and washed with water (×2). The organic portion was isolated using a phase separating cartridge and the solvent was removed in vacuo. Purification of the crude product by chromatography on silica eluting with 0-20% EtOAc/iso-hexane afforded the title compound.
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[C:24]1(/[CH:30]=[CH:31]/B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([CH:31]=[CH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)/C=C/c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3C=Cc3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 66.9 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), trans-2-phenylvinylboronic acid (148 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography using methanol-chloroform to give the title compound (53 mg, yield 67%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]>C(Cl)Cl>[CH2:10]([O:9][C:7]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCO
Solvent: ClCCl
Product: O=C(NCCCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of 3-amino-1-propanol (3.75 g, 50 mmol) in methylene chloride (40 mL) was slowly added benzyl chloroformate (3.4 g, 20 mmol) in methylene chloride (10 mL) at 0° C. and the mixture was stirred at 0° C. for 3 h. Additional methylene chloride (50 mL) was added, the solution washed with 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by filtration through silica gel (1:1 ethyl acetate:hexane) to give the title compound as a white solid (4.05 g, 97%). 1H-NMR (300 MHz, CDCl3) δ 7.34 (m, 5H), 5.17 (br s, 1H), 5.10 (s, 2H), 3.66 (t, J=5.8 Hz, 2H), 3.33 (t, J=6.1 Hz, 2H), 2.63 (br s, 1H), 1.69 (pentet, J=6.1 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1.[O:20]1[CH2:24]CCC1.C[N:26](C)[CH:27]=[O:28]>O>[CH:27]([N:26]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1)[CH:24]=[O:20])=[O:28]
Reactant: CC(=O)Nc1nc(CCc2ccc(CBr)cc2)cs1
Reactant: C1CCOC1
Reactant: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(CCc2ccc(CN(C=O)C=O)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-(4-{2-[4-(bromomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (100 mg), tetrahydrofuran (2 ml) and N,N-dimethylformamide (2 ml) was added sodium diformylimide (42 mg), and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with water (3 ml), and the precipitated solid was filtered and washed with water to give N-[4-(2-{4-[(diformylamino)-methyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide (80 mg).
Reaction SMILES: [CH3:1]N(C)CCCN.CO.C(Cl)(Cl)Cl.[O:14]=[C:15]1[CH:18]([N:19]2C(=O)C3=CC=CC=C3C2=O)[CH2:17][N:16]1[CH:30]([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)[C:31]([O-:33])=[O:32]>C(OCC)(=O)C>[NH2:19][CH:18]1[CH2:17][N:16]([CH:30]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)[C:31]([O:33][CH3:1])=[O:32])[C:15]1=[O:14]
Reactant: CN(C)CCCN
Reactant: O=C([O-])C(c1cccs1)N1CC(N2C(=O)c3ccccc3C2=O)C1=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C(c1cccs1)N1CC(N)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
N,N-Dimethyl-1,3-propanediamine (1.32 g.) was added to a mixture of methanol (30 ml.) and chloroform (18 ml.) containing 2-(2-oxo-3-phthalimido-1-azetidinyl)-2-(2-thienyl)-acetate (2.22 g.), whereafter the mixture was stirred at ambient temperature overnight. After the reaction, the reaction mixture was evaporated to dryness under reduced pressure to give a residue, which was dissolved in ethyl acetate. The solution was extracted with three portions of an aqueous solution consisting of 1N hydrochloric acid (6.4 ml.) and water (10 ml.). The combined aqueous extracts were adjusted to pH8 with sodium bicarbonate and then saturated with sodium chloride. The solution was extracted with ethyl acetate and the extract was washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. The solution was evaporated to dryness under reduced pressure to give a residue (1.57 g.), which was subjected to column chromatography on silica gel (25 g.). Elution was carried out with chloroform and the fractions containing a desired compound were collected. The solvent was removed by distillation from the solution under reduced pressure to give methyl 2(3-amino-2-oxo-1-azetidinyl)-2-(2-thienyl)acetate (0.96 g.).
Reaction SMILES: C(OC1([CH2:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)C2C(=CC=C(C)C=2)N(CC)C1=O)(=O)C1C=CC=CC=1.[C:36]([O:44][CH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([Cl:54])[CH:52]=2)[N:47]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:46]1=[O:59])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:44][C:45]1([CH2:23][C:24]2[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=2)[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([Cl:54])[CH:52]=2)[N:47]([CH2:55][CH:56]([CH3:57])[CH3:58])[C:46]1=[O:59])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)CN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Reactant: CCN1C(=O)C(Cc2cc(OC)c(OC)c(OC)c2)(OC(=O)c2ccccc2)c2cc(C)ccc21
Product: COc1cc(CC2(OC(=O)c3ccccc3)C(=O)N(CC(C)C)c3ccc(Cl)cc32)cc(OC)c1OC

Procedure:
This compound was prepared in an analogous fashion to 1-ethyl-5-methyl-2-oxo-3-(3,4,5-trimethoxybenzyl)indolin-3-yl benzoate using 5-chloro-1-isobutyl-2-oxoindolin-3-yl benzoate.
Reaction SMILES: CON(C)[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][S:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][Mg]Cl)=[CH:17][CH:16]=1>C1COCC1>[C:5]1([C:4](=[O:11])[CH2:19][C:18]2[CH:22]=[CH:23][C:15]([S:14][CH3:13])=[CH:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CSc1ccc(C[Mg]Cl)cc1
Reactant: CON(C)C(=O)c1ccccc1
Solvent: C1CCOC1
Product: CSc1ccc(CC(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution of N-methoxy-N-methylbenzamide (409 mg, 2.27 mmol) in THF (22mL) was added a THF solution (5.0 mL, 0.5M) of 4-(methylthio)benzylmagnesium chloride (J.Org. Chem. 42, 1914, 1977). The mixture was stirred at 0 ° C. for 3 h. NH4OAc was added and the mixture was extracted with EtOAc. The EtOAc extracts were washed with brine, dried over MgSO4, filtered and concentrated to an oil. Chromatography of the oil on silica gel (eluted with 2.5 % EtOAc/toluene) gave 501 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29].C(OC(=O)C)C>CN(C)C=O.O>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:28][CH3:29])[C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1
Reactant: CCI
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (1.3 g, 5 mmol) in dimethylformamide (25 ml) was added potassium carbonate (1 g, 7.5 mmol), and iodoethane (0.4 ml, 5.1 mmol), and the mixture was stirred at room temperature for 3 hours. Ethylacetate and water were added, the ethylacetate layer was separated, dried over magnesium sulfate, and concentrated in vacuo. The residue was recrystallized from ethylacetate/hexane to afford the title compound, m.p. 200-202° C. (0.4 g, 27%); 1H-NMR (DMSO-d6) δ 1.25 (t, J=7.2 Hz, 3H), 1.64 (s, 6H), 4.07 (q, J=7.2 Hz, 2H), 6.29 (d, J=4.1 Hz, 1H), 7.0 (d, J=8 Hz, 1H), 7.05 (d, J=4.1 Hz, 1H), 7.34 (m, 2H), 10.42 (s, 1H). MS (ESI (−)) m/z 294 (M−H)−