Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:15]1[CH:45]=[CH:44][C:18]([O:19][CH2:20][CH:21]([OH:43])[CH2:22][O:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CCO[CH2:49][CH3:50]>CN(C)C=O>[C:49]1([CH2:50][O:43][CH:21]([CH2:22][O:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:20][O:19][C:18]2[CH:17]=[CH:16][C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:45][CH:44]=2)[CH:16]=[CH:15][CH:1]=[CH:2][CH:3]=1
Reactant: CCOCC
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(OCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)cc1
Reaction time: 3 h
Yield: 198.4 %

Procedure:
To a solution of about 13.78 g of 1-(4-tetradecyl phenoxy)-3-(triphenylmethoxy)-2-propanol in about 45 ml of dimethylformamide was added a suspension of about 1.426 g of ether pre-washed sodium hydride in about 10 ml of dimethylformamide, followed by a solution of about 4.06 g of benzylbromide in about 5 ml of dimethylformamide. The mixture was stirred under argon for about 3 hours, quenched very slowly with water and extracted twice with about 50% ether in hexane. The organic layer was dried, filtered and the solvents removed, giving about 15.7 g of the desired title compound.
Reaction SMILES: [C:1]1([C:7]2([CH2:10][NH2:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.[Pt]>[CH:1]1([C:7]([CH3:9])([CH3:8])[CH2:10][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Product: CC(C)(CN)C1CCCCC1

Procedure:
{1-(1-Phenylcyclopropyl)}methylamine (205 mg, 1.1 mmole) was hydrogenated using platinum-black (410 mg) in 20 mL of acetic acid under 4 atmospheres of hydrogen for 3 days. The same conditions were repeated 3 times to complete the reaction. 2-Cyclohexyl-2-methylpropylamine was isolated as an acetic acid salt in quantitative yield. This material (28.5 mg, 0.12 mmole) was coupled with Example 4 (100 mg, 0.1 mmole) by the EDC and HOBT method followed by deprotection and purification to afford pure title compound (51 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].OC1([C:25]([F:28])([F:27])[F:26])C2C(=CC(OC)=CC=2)CC1>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]([OH:6])[C:25]([F:28])([F:27])[F:26]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: COc1ccc2c(c1)CCC2(O)C(F)(F)F
Product: COc1ccc(C(O)C(F)(F)F)c(OC)c1

Procedure:
This compound was prepared from 2,4-dimethoxybenzaldehyde in the same manner of Compound 62.
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH:9](N1C(=O)COC1=O)=[CH2:10]>>[CH:9]([N:4]1[C:3](=[O:8])[CH:2]([CH3:1])[O:6][C:5]1=[O:7])=[CH2:10]
Reactant: CC1OC(=O)NC1=O
Reactant: C=CN1C(=O)COC1=O
Product: C=CN1C(=O)OC(C)C1=O

Procedure:
3-Vinyl-5-methyl-2,4-oxazolidinedione was prepared from 5-methyl-2,4-oxazolidinedione by the procedure for making 3-vinyl-2,4-oxazolidinedione in Example 9 hereinafter.
Reaction SMILES: [Br-].[Br:2][CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:25][NH:26][CH3:27].C(Br)(=O)C>C(O)C>[Br-:2].[CH3:25][N:26]([CH3:27])[CH2:3][CH2:4][CH2:5][P+:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNC
Reactant: BrCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)Br
Agent: [Br-]
Solvent: CCO
Product: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 3-bromopropyltriphenylphosphonium bromide (Olo-IM3) (420 g, 0.90 mol) in absolute ethanol (664 g) a solution of dimethylamine in absolute ethanol (368 g, 2.69 mol, assay: 33%) was added slowly within 30 minutes at room temperature. After complete addition the suspension was stirred 1 hour at reflux whereupon a solution was obtained. The solution was cooled to a temperature of 0-10° C. and acetyl bromide (202.7 g, 1.65 mol) was added dropwise until the pH was ≦1, and the resulting suspension was allowed to warm to 20-25° C. After the white suspension was filtered the wet product washed with absolute ethanol (237 g) and then dried under vacuum (15 h, 70° C.) to give 3-dimethylaminopropyltriphenylphosphonium bromide*HBr (Olo-IM4) as a white solid (yield: 471.2 g, 0.77 mol, 85.1%; HPLC assay: 83.2%, HPLC purity: 98.72%).
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[C:6]1[N:10]=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)[N:8]([CH3:17])[N:7]=1)C.C(=O)([O-])[O-].[K+].[K+]>>[CH3:17][N:8]1[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[N:10][C:6]([CH:5]=[O:4])=[N:7]1
Reactant: CCOC(OCC)c1nc(-c2ccnn2C)n(C)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1nccc1-c1nc(C=O)nn1C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a 4 N solution of HCl (185 mL, 0.74 mol) was added 3-(diethoxymethyl)-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-1,2,4-triazole (40.1 g, 0.151 mol), and the reaction mixture was left to stir overnight. To the resulting mixture was added potassium carbonate (166 g) in portions under vigorous stirring, and the resulting mixture was extracted with ethyl acetate (5×300 mL). The organic layer was dried with anhydrous sodium sulfate, and the solvents were removed under vacuum on a rotary evaporator. To the residue was added absolute ether (4×100 mL) to give 27.3 g (94.5%) of the title product as a light-beige powder. Satisfactory C,H,N-analysis was obtained. 1H NMR (400 MHz, DMSO-d6): δ 4.04 (s, 3H), 4.08 (s, 3H), 6.98 (d, J=2 Hz, 1H), 7.67 (d, J=2 Hz, 1H), 9.95 (s, 1H). LC/MS (API-ES) calcd for C8H9N5O: 191.08, found (M+H+): 192.0 m/z.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[C:6]([CH3:21])[CH:5]=[CH:4][N:3]=1.[H-].[Na+]>>[CH3:21][C:6]1[CH:5]=[CH:4][N:3]=[C:2]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:9](=[O:10])[NH:8][C:7]=12
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1NC1CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1

Procedure:
3-Amino-2-chloro-4-methylpyridine of Formula A is condensed with 2-chloronicotinoyl chloride of Formula B to give 2-chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide of Formula II, which is then reacted with cyclopropylamine to give N-(2-chloro-4-methyl-3-pyridyl)-2 -cyclopropylamino) -3-pyridine carboxamide of Formula III. Then N-(2-chloro-4-methyl-3-pyridyl)-2-(cyclopropylamino)-3-pyridine carboxamide was cyclized in the presence of sodium hydride to give nevirapine of Formula I. The disadvantage of the above process is use of large excess of cyclopropylamine. Further, with the above process undesirable side products are obtained during the reaction, which makes the product impure.
Reaction SMILES: [N+:1]([C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2)([O-])=O.O.O.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[NH:10][C:9](=[O:15])[C:8](=[O:16])[NH:7]2
Reactant: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])c(Cl)c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)cc2[nH]c(=O)c(=O)[nH]c2c1Cl
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a stirred mixture of 6-nitro-5,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (81 mg, 0.295 mMol) in ethanol (3 mL) was added SnCl2.2H2O (331 mg, 1.47 mMol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) with stirring to 0.5 h, to form a clear solution and continually refluxed for another 0.5 h. It was then cooled to room temperature and the yellow precipitate was collected by filtration, followed by washing with cold ethanol (2×1 mL) to give 70 mg (97%) of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 32 mg of pure title compound as bright yellow needles; mp: 342°-5° C. (dec. from 335° C.), changed color from 325° C. IR (KBr, cm-1): 3468, 3362, 3193, 1693, 1631, 1493, 1375; NMR (1H, DMSO-d6): δ5.418 (s, 2H); 6.999 (s, 1H); 11.238 (s, 1H); 11.776 (s, 1H). HRMS: calcd for C8H5N3O2Cl2 (M+) m/z: 244.9757; found 244.9769. Potency relative to DCK: 8.6%.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([S:7]([N:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=3)[CH2:30][CH2:29]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)s1)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of (5-bromo(2-thienyl))chlorosulfone (1.09 g, 4.16 mmol) in CH2Cl2 (30 mL) was added triethylamine (0.4 mL, 3.052 mmol), followed by (4-fluorophenyl)piperazine (500 mg, 2.77 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was treated with a saturated NaHCO3 solution (1 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with a saturated NaCl solution (10 mL), dried (MgSO4) and concentrated under reduced pressure to give a brown solid. The crude product was purified flash chromatography (10% EtOAc/hex) to give 5-bromo-2-{[4-(4-fluorophenyl)piperazinyl]sulfonyl}thiophene (1.12 g, 100%) as a white solid: mp 123-124° C.; TLC (EtOAc) Rf 0.44; HPLC ES-MS m/z 406 (MH+).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([Br:9])[CH:8]=1.Cl[CH2:12][CH:13]([O:16][CH3:17])[O:14][CH3:15].[Cl-].[NH4+]>O.CN(C)C=O>[CH3:15][O:14][CH:13]([O:16][CH3:17])[CH2:12][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([Br:9])[CH:8]=1
Reactant: Oc1cc(O)cc(Br)c1
Reactant: COC(CCl)OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1cc(O)cc(Br)c1)OC
Temperature: 90 °C

Procedure:
The monosodium salt of 3-hydroxy-5-bromophenol (0.05 mole) and dimethylformamide (75 ml) are charged under nitrogen gas into a glass reaction vessel equipped with a mechanical stirrer, thermometer and additional funnel. The mixture is stirred until dissolved, and 1-chloro-2,2-dimethoxyethane (0.05 mole) is added dropwise over a period of about 20 minutes. After the addition is completed, the reaction mixture is heated at about 90° C. with stirring for a period of about 48 hours. After this time water (200 ml) is added, and the reaction mixture is neutralized with ammonium chloride. The reaction mixture is then extracted with chloroform, and the organic phase is separated from the aqueous phase. The organic phase is then stripped of solvent, leaving an oil. This oil is distilled under reduced pressure to yield the desired product 3-(2,2-dimethoxyethoxy)-5-bromophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[O:18])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCN1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCN1C(=O)NCCN1CC=C(c2ccc(Cl)cc2)CC1
Yield: 98.3 %

Procedure:
A solution of 1.68 g (4.59 mmol) of 1-[[2-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]ethyl]carbamoyl]-2-oxopyrrolidine (Ia-25) and 1.05 g (5.5 mmol) of p-toluenesulfonic acid monohydrate in 75 ml of toluene was refluxed for 25 hr. using a Dean-Stark trap containing 10 g of Molecular Sieves-4A. By proceeding as in Example 67, 1.57 g of the objective compound (Ia-29) was obtained.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH3:17])([CH3:16])[C:13]([NH2:15])=[O:14])[O:11][C:7]=2[C:6](F)=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:4]=1[CH3:25])#[N:2].C(N(CC)CC)C.[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1.C(OCC)(=O)C>CS(C)=O.O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH3:17])([CH3:16])[C:13]([NH2:15])=[O:14])[O:11][C:7]=2[C:6]([N:37]2[CH2:38][CH2:39][C@H:35]([N:34]([CH3:40])[CH3:33])[CH2:36]2)=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:4]=1[CH3:25])#[N:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)C(N)=O)nc2c1C#N
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(C)(C)C(N)=O)nc2c1C#N
Temperature: 90 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
2-(4-Cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)-2-methylpropanamide (I-96) (58 mg, 0.17 mmol) was dissolved in dimethyl sulfoxide (1.2 ml), triethylamine (33 μl, 0.24 mmol) and (3S)-3-(dimethylamino)pyrrolidine (26 μl, 0.21 mmol) were added, followed by stirring at 90° C. for 3 hours under nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated away and the resulting residue was subjected to preparative silica gel column chromatography, eluted with a mixed solvent of chloroform/methanol (10:1, v/v) to obtain the entitled compound (41 mg, 0.09 mmol, 55%) as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][N:20]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:29](OC)=[O:30])[C:23]=2[CH:22]=[CH:21]1.O.[OH-].[Na+]>O1CCCC1>[OH:30][CH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[CH:22]=[CH:21][N:20]2[CH2:19][C:9]1[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:12][C:8]=1[CH3:7]
Reactant: COC(=O)c1cccc2c1ccn2Cc1nc(-c2ccccc2)oc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1Cn1ccc2c(CO)cccc21
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a suspension of 114 mg of lithium aluminum hydride in 5 ml of tetrahydrofuran, there was dropwise added a solution obtained by dissolving, in 5 ml of tetrahydrofuran, 1.04 g of methyl 1-[(5-methyl-2-phenyloxazol-4-yl)methyl]indole-4-carboxylate prepared in Example 28 over 30 minutes, with ice-cooling and under an argon gas atmosphere. After stirring the reaction solution for one hour, there were, in order, added 0.11 ml of water, 0.11 ml of a 15% aqueous sodium hydroxide solution and 0.33 ml of water to the reaction solution, followed by stirring the mixture for 2 hours. The insolubles were filtered off, the resulting filtrate was concentrated and the residue was dried under reduced pressure to give 949 mg of 4-hydroxymethyl-1-[(5-methyl-2-phenyloxazol-4-yl)methyl]indole as colorless crystals. The yield thereof was found to be 99%.
Reaction SMILES: [CH3:1]OC1C=CC=CC=1CCN.C(N)CC1C=CC=CC=1.[CH3:21][S:22][C:23]1[NH:28][C:27](=[O:29])[N:26]=[C:25]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:24]=1>>[CH3:1][N:28]1[C:23]([S:22][CH3:21])=[N:24][C:25]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[N:26][C:27]1=[O:29]
Reactant: CSc1nc(-c2ccncc2)nc(=O)[nH]1
Reactant: COc1ccccc1CCN
Agent: NCCc1ccccc1
Product: CSc1nc(-c2ccncc2)nc(=O)n1C

Procedure:
By analogy with the method described in example 1 (step 1.2), using 2-(2-Methoxy-phenyl)-ethylamine (commercially available) in place of phenethylamine and 6-Methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one (synthesis as described in U.S. Pat. No. 4,406,897) in place of 1-Methyl-6-methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one, to afford the product which was transformed into the hyrdochloride salt in the usual manner to give 0.11 g (51%) of a white solid.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])C.Cl>C1COCC1>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14](=[O:15])[N:6]1[CH2:5][CH:4]=[O:3]
Reactant: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCN1C(=O)c2ccccc2C1=O
Reaction time: 20 h

Procedure:
A solution of 2-[2,2-bis(ethyloxy)ethyl]-1H-isoindole-1,3(2H)-dione (24.60 g, 93 mmol) in THF (150 mL) under nitrogen was treated with 1N HCl (aq) (75 mL, 75 mmol) and brought to reflux. After stirring for 20 h, the reaction was evaporated in vacuo and the residue was triturated with 1N HCl (100 mL). The resulting solid was collected by filtration, washed with 1N HCl, water, and Et2O and dried under high vacuum to provide the desired product as a white solid: 1H NMR (d6-DMSO, 300 MHz) δ 9.60 (1H, s), 7.87-7.95 (4H, m), 4.6 (2H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([C:17]3[N:18]=[C:19]4[C:25]([C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:24][N:23]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:20]4=[N:21][CH:22]=3)[CH:10]=[C:11]([O:13][CH2:14]OC)[CH:12]=2)[CH2:3]1.[CH3:41][N:42]([CH3:46])[CH2:43]CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:41][N:42]([CH3:46])[CH2:43][CH2:14][O:13][C:11]1[CH:10]=[C:9]([C:17]2[N:18]=[C:19]3[C:25]([C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:24][N:23]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[C:20]3=[N:21][CH:22]=2)[CH:8]=[C:7]([N:4]2[CH2:5][CH2:6][C:2]([CH3:40])([CH3:1])[CH2:3]2)[CH:12]=1
Reactant: COCOc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc(N2CCC(C)(C)C2)c1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc(N2CCC(C)(C)C2)c1

Procedure:
A flask was charged with 1-[2-[3-(3,3-dimethyl-pyrrolidin-1-yl)-5-methoxymethoxy-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (90 mg, 0.17 mmol), 2-dimethylamino-ethanol (reagent A, 0.04 ml, 0.34 mmol) and triphenylphosphine (reagent B, 90 mg, 0.34 mmol). THF (2 ml) was added under nitrogen atmosphere. Diisopropyl azodicarboxylate (reagent C, 0.07 ml, 0.34 mmol) was added via syringe and the material was stirred. After 1 hour a further 2 equivalents each of reagents A, B and C were added. The mixture was stirred overnight. The crude was loaded onto 2 preparative TLC plates eluting with 3% MeOH in dichloromethane. The plates were dried and re-developed with the solvent system. This process was repeated once more and then product band was collected providing 1-[2-[3-(2-dimethylamino-ethoxy)-5-(3,3-dimethyl-pyrrolidin-1-yl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one, 56 mg, as a golden yellow viscous oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[NH2:17][NH2:18]>C(O)C>[NH:17]([C:4]1[N:5]=[N:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[N:3]=1)[NH2:18]
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1nc(NN)nnc1-c1ccccc1

Procedure:
A solution of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (7 g) and hydrazine hydrate (5 ml) in ethanol (15 ml) was heated under reflux for 8 hours. The reaction mixture was evaporated and the resultant residue was washed with water, dried and recrystallized from a mixture of ethanol and water (5:3) to give crystals of 3-hydrazino-5-methyl-6-phenyl-1,2,4-triazine (3.76 g), m.p. 136.5°~137.5° C.
Reaction SMILES: Cl[CH2:2][CH2:3][OH:4].[CH3:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:2][CH2:3][OH:4])[CH2:8][CH2:7]1
Reactant: CN1CCNCC1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(CCO)CC1
Yield: 77.8 %

Procedure:
2-Chloroethanol (36.0 g, 30 mL, 0.44 mol) was added to 1-methylpiperazine (27.0 g, 30 mL, 0.27 mol) and potassium carbonate (40 g, 0.29 mol) in acetonitrile (100 mL) with stirring. The reaction mixture was heated under reflux for 48 h, then filtered, and the solids were washed with acetonitrile. The combined filtrates were evaporated under reduced pressure and the resulting oil was distilled at 12 mm Hg to give the title compound (31 g, 0.21 mol) as a light tan oil. Electrospray MS m/z 145 [M+H]+.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[Br:19]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl>[Br:19][C:11]1[CH:10]=[C:9]([CH2:8][N:4]2[CH2:5][CH2:6][CH2:7][O:1][CH2:2][CH2:3]2)[N:17]2[C:12]=1[C:13]([NH2:18])=[N:14][CH:15]=[N:16]2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Nc1ncnn2c(CN3CCCOCC3)ccc12
Solvent: ClC(Cl)Cl
Product: Nc1ncnn2c(CN3CCCOCC3)cc(Br)c12
Temperature: -25 °C

Procedure:
7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (1.90 g, 7.68 mmol) was suspended in chloroform (76 mL). The solution was cooled to −20 to −30° C. 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione ( 989 g, 3.46 mmol) was added. The reaction was maintained at −20° C. for 20 minutes then warmed to room temperature. An LC taken at that time showed the reaction to be essentially complete. The reaction was then quenched by the addition of saturated aqueous sodium sulfite. The resultant slurry was partitioned between ethyl acetate (300 mL) and saturated bicarbonate (100 mL). The organic layer was washed (3×100 mL) with bicarb then dried with Na2SO4 and concentrated under vacuum.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:31][CH2:32][CH3:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([OH:29])=O)([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:30])[CH3:2].[NH2:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][OH:40])=[CH:37][CH:36]=1.Cl.C(N=C=NCCCN(C)C)C.O>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][CH:4]([O:31][CH2:32][CH3:33])[CH2:5][N:6]1[C:14]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@:8]([CH2:26][C:27]([NH:34][C:35]2[CH:42]=[CH:41][C:38]([CH2:39][OH:40])=[CH:37][CH:36]=2)=[O:29])([NH:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:17])[C:7]1=[O:30])[CH3:2]
Reactant: Nc1ccc(CO)cc1
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOC(CN1C(=O)[C@](CC(=O)Nc2ccc(CO)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
(+)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N′-(4-methylphenyl)ureido)indolin-2-one (compound described in “Example 174(1)” of Japanese Patent Application Laid-Open No. 7-48349, 300 mg) was dissolved in acetonitrile (10 mL), and after adding p-aminobenzylalcohol (100 mg) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (151 mg) in that order, the mixture was stirred at 15-30° C. for 18 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off. The resulting reaction mixture was purified by column chromatography to obtain 324 mg of the title compound (yield: 88%).