Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1)#[N:3].C([O-])(=O)C.[Na+].[C:17]1(=[O:34])[N:21]([CH:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)[C:20](=[O:29])[C:19]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:18]12>C(O)(=O)C>[C:20]1(=[O:29])[N:21]([CH:22]2[CH2:23][C:24]3[C:8]4[C:7](=[CH:6][CH:5]=[C:4]([C:2]#[N:3])[CH:9]=4)[NH:10][C:25]=3[CH2:26][CH2:27]2)[C:17](=[O:34])[C:18]2=[CH:33][CH:32]=[CH:31][CH:30]=[C:19]12
Reactant: N#Cc1ccc(NN)cc1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)CC3

Procedure:
4-Cyanophenyl hydrazine hydrochloride (4.41 g, 0.026 mole) was dissolved in acetic acid (100 ml) and sodium acetate (2 g) was added. 4-Phthalimido cyclohexanone (6.4 g, 0.026 mole) was added and the mixture heated under reflux overnight. The solvent was removed in vacuo and the residue triturated with methanol to give 3-phthalimido-6-cyano-1,2,3,4-tetrahydrocarbazole as a beige solid, (5.3 g).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:12]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([NH2:22])[CH:13]=1>>[F:1][C:2]1[C:7]([C:12]2[N:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[N:15]=[C:14]([NH2:22])[CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1cccnc1F
Reactant: Nc1cc(Cl)nc(C(F)(F)F)n1
Product: Nc1cc(-c2cccnc2F)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in an analogous manner to that described above in Example 4 using 2-fluoropyridin-3-ylboronic acid and 6-chloro-2-(trifluoromethyl)pyrimidin-4-amine (SynChem. Inc., Elk Grove Village, Ill.), and the desired product 6-(2-fluoropyridin-3-yl)-2-(trifluoromethyl)pyrimidin-4-amine was isolated as a white solid (34%). LCMS (API-ES) m/z 259 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 8.57 (t, J=8.80 Hz, 1H) 8.38 (d, J=3.91 Hz, 1H) 7.83 (br. s., 2H) 7.46-7.63 (m, 1H) 7.15 (s, 1H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]([NH:23][CH3:24])=[O:22])=[CH:16][N:17]2[CH3:20])=[CH:13][CH:12]=1>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[CH3:24][NH:23][C:21]([C:15]1[C:14]2[C:18](=[CH:19][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[N:17]([CH3:20])[C:16]=1[Cl:1])=[O:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNC(=O)c1cn(C)c2cc(OC)ccc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(Cl)n(C)c2cc(OC)ccc12
Temperature: 60 °C
Yield: 86.6 %

Procedure:
N-Chlorosuccinimide (0.150 g, 1.12 mmole) was added to a solution of 6-methoxy-N,1-dimethyl-1H-indole-3-carboxamide 75a (0.243 g, 1.11 mmole) in CCl4 (10 ml) and DMF (3 ml). The reaction mixture was heated to 60° C. for 3 h and concentrated. The residue was purified by reverse phase chromatography eluting with 0–1% CH3OH in 1:1 EtOAc and CH2Cl2 to give a brown colored oil (0.243 g, 87% yield); 1H NMR (300 MHz, CDCl3) δ 7.61 (1H, d, J=8.6 Hz), 6.38 (1H, d, J=8.6 Hz), 6.19 (1H, s), 3.35 (3H, s), 2.96 (3H, s), 2.52 (3H, s); ESIMS (MH+): 253.05.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>CO.C(Cl)Cl>[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-proline methyl ester hydrochloride (Bachem), the title compound was prepared as a viscous solid. The reaction was monitored by tlc (Rf=0.57 in 10% MeOH/DCM) and the product was purified by acid/base washes.
Reaction SMILES: C(C1[S:7][C:6]([C:8](=[O:19])[CH2:9][C:10](=[O:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1)#N.S(=O)(=O)(O)O.[C:25]([OH:28])(=[O:27])[CH3:26]>O>[C:25]([C:26]1[S:7][C:6]([C:8](=[O:19])[CH2:9][C:10](=[O:18])[C:11]([F:17])([F:16])[C:12]([F:13])([F:14])[F:15])=[CH:5][CH:4]=1)([OH:28])=[O:27]
Reactant: N#Cc1ccc(C(=O)CC(=O)C(F)(F)C(F)(F)F)s1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(C(=O)CC(=O)C(F)(F)C(F)(F)F)s1

Procedure:
A mixture of 1-(5-cyano-2-thienyl)-4,4,5,5,5-pentafluoro-1,3-pentanedione (0.78 g), sulfuric acid (9 ml) and acetic acid (10 ml) was refluxed for 2 hours. The cooled mixture was poured into 100 ml of water. The precipitation was filtered and washed with water. 1H NMR (CDCl3): 6.53 (s, 1 H); 7.57 (d, 1 H, J=4.1 Hz); 7.78 (d, 1 H, J=4.1 Hz).
Reaction SMILES: O[C:2]1([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9](=[O:16])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)([Cl:26])=O>C(Cl)Cl>[Cl:26][C:2]1([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9](=[O:16])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C2(O)c3ccccc3C(=O)c3ccccc32)cc1
Solvent: ClCCl
Product: Cc1ccc(C2(Cl)c3ccccc3C(=O)c3ccccc32)cc1
Yield: 81.1 %

Procedure:
42 g (0.14 mol) of 9,10-dihydro-9-hydroxy-9-(4-methylphenyl)-10-oxo-anthracene and 20.2 g (107 mol) of thionyl chloride in 500 ml of methylene chloride are heated under reflux for 8 hours. Thereafter, the solvent is distilled off in vacuo and the solid which remains is recrystallised from petroleum ether. 36.2 g (70.9% of theory) of 9-chloro-9,10-dihydro-9-(4-methylphenyl)-10-oxo-anthracene of melting point 136°-140° C. are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8]C(=O)OC(C)(C)C)[C:3]1=[O:16].O1CCOCC1.[ClH:23]>>[ClH:23].[NH2:8][C@H:4]1[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]1=[O:16]
Reactant: CN1CCC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCC[C@H](N)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
(S)-tert-Butyl 1-methyl-2-oxopiperidin-3-ylcarbamate (prepared according to Example 12; 78 mg, 0.34 mmol) was dissolved in 4M hydrogen chloride in dioxane (1.7 mL, 6.8 mmol), and the reaction was allowed to stir at ambient temperature for 16 hours. The reaction mixture was concentrated to yield (S)-3-amino-1-methylpiperidin-2-one hydrochloride (56 mg, 100%), which was taken on to the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:49])[C@H:4]([NH:27][S:28]([C:31]1[CH:48]=[CH:47][C:34]2[N:35]=[C:36]([S:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[S:37][C:33]=2[CH:32]=1)(=[O:30])=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.O>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([S:38][C:36]2[S:37][C:33]3[CH:32]=[C:31]([S:28]([NH:27][C@H:4]([CH2:5][C:6]4[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]5[C:20](=[O:21])[C:19]6=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]6[C:17]5=[O:26])=[CH:8][CH:7]=4)[C:3]([OH:49])=[O:2])(=[O:29])=[O:30])[CH:48]=[CH:47][C:34]=3[N:35]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](Cc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1)NS(=O)(=O)c1ccc2nc(Sc3ccc(OC)cc3)sc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Sc2nc3ccc(S(=O)(=O)N[C@H](Cc4ccc(OCCCN5C(=O)c6ccccc6C5=O)cc4)C(=O)O)cc3s2)cc1

Procedure:
(2R)-2-[(2-(4-Methoxyphenylthio)benzthiazol-6-sulfonyl)amino]-3-(4-(3-phthalimido-1-propyl)oxyphenyl) propionic acid methylester (0.196 g, 0.27 mmol) prepared in Example 61 was dissolved in THF/H2O (2 mL/2 mL), and LiOH(0.057 g, 5 equi.) was added and refluxed for 12 hours. Then, the reaction solution was distilled under reduced pressure to remove the solvent and treated with 1N HCl. The product was extracted with ethylacetate (10 mL). The separated organic phase was washed with NaCl solution, dried over anhydrous MgSO4, distilled under reduced pressure and dried under vacuum to prepare the titled compound, (2R)-2-[(2-(4-methoxyphenylthio)benzthiazol-6-sulfonyl)amino]-3-(4-(3-phthalimido-1-propyl)oxyphenyl) propionic acid (0.15 g, 80%).
Reaction SMILES: [K].[K].[SH:3][C:4]1[S:5][C:6]([SH:9])=[N:7][N:8]=1.Cl[CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O>[N:14]1([CH2:13][CH2:12][CH2:11][S:3][C:4]2[S:5][C:6]([S:9][CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:7][N:8]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: ClCCCN1CCOCC1
Reactant: Sc1nnc(S)s1
Agent: [K]
Solvent: O
Product: C(CSc1nnc(SCCCN2CCOCC2)s1)CN1CCOCC1
Reaction time: 2 h

Procedure:
A mixture of 17.0 grams (0.075 mole) of 2,5-dimercapto-1,3,4-thiadiazole dipotassium salt and 24.5 grams (0.150 mole) of 4-(3-chloropropyl)-morpholine in 170 ml of water was heated under reflux with stirring for two hours. The mixture was then cooled to between 28 and 30° C and extracted with benzene. The benzene extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium carbonate. After removal of the drying agent by filtration, the solution was evaporated to dryness, leaving the 2,5-bis(3-(4-morpholinyl)propylthio)-1,3,4-thiadiazole as a pale yellow oil. The product was recrystallized from methylcyclohexane to give white crystals with a melting point of 65.5°-66° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[C:6](=[C:19](OCC)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1=[O:29])(=O)C.[CH2:30]([N:37]([CH2:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1)[CH3:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([N:37]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([NH:44]/[C:19](=[C:6]2\[C:5](=[O:29])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=3)/[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:45][CH:46]=1)[CH3:38])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN(Cc1ccccc1)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(-c3ccccc3)ccc21)c1ccccc1
Product: CN(Cc1ccccc1)Cc1ccc(N/C(=C2\C(=O)Nc3cc(-c4ccccc4)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-phenyl-2-indolinone and 4-[(N-benzyl-N-methyl-amino)-methyl]-aniline
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[Cl:15][C:16]1[CH:17]=[C:18]([S:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: Clc1ccc(SCCCCBr)cc1Cl
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 4 from 6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichlorophenylmercapto)-butylbromide (B.p. 0.1 mb : 153°-160° C.).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.[C:30]([NH:40][C@H:41]([C:45]([O:47][CH:48]([CH2:58][O:59][C:60](=[O:76])[C@H:61]([CH:73]([CH3:75])[CH3:74])[NH:62][C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[CH2:49][O:50][C:51](=[O:57])[CH2:52][CH2:53][C:54](O)=[O:55])=[O:46])[CH:42]([CH3:44])[CH3:43])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:54](=[O:55])[CH2:53][CH2:52][C:51]([O:50][CH2:49][CH:48]([O:47][C:45](=[O:46])[C@H:41]([CH:42]([CH3:44])[CH3:43])[NH:40][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH2:58][O:59][C:60](=[O:76])[C@H:61]([CH:73]([CH3:75])[CH3:74])[NH:62][C:63]([O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[O:64])=[O:57])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)CCC(=O)O)OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)CCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F)OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (0.538 g, 2 mmole), HOBT (0.327 g, 2.42 mmole), DMAP (29.3 mg, 0.24 mmole) and succinic acid 2,3-bis-(N-CBZ-L-valyloxy)-1-propyl ester (1.6 g, 2.42 mmole) was coevaporated two times with DMF and reduced to about 50 ml. DCC (0.536 g, 2.6 mmole) was added and the mixture was stirred 72 hours at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. 100 ml of ethyl acetate was added and the organic phase washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 0.65 g.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.C(Cl)Cl.[CH3:19][O:20][C:21](Cl)=[O:22]>C(N(CC)CC)C>[N:10]1([C:4]2[N:3]=[C:2]([NH:1][C:21]([O:20][CH3:19])=[O:22])[N+:7]([O-:8])=[C:6]([NH:9][C:21]([O:20][CH3:19])=[O:22])[CH:5]=2)[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1
Reactant: COC(=O)Cl
Reactant: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OC)[n+]1[O-]

Procedure:
45 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide are mixed in 600 ml. of methylene chloride with 90 ml. of triethylamine and cooled to 5° C. 90 Ml. of chloroformic acid methyl ester are added dropwise while stirring. The mixture is stirred at 5° C. for 30 minutes and at room temperature for 18 hours. Then, the mixture is treated with 100 ml. of methanol and subsequently extracted with 400 ml. of methylene chloride, washed with water, dried over sodium sulfate and evaporated under reduced pressure. Recrystallization of the residue from methanol yields dimethyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidinedicarbamate-3-oxide having a melting point of 202°-203° C.
Reaction SMILES: C(N(CC)[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][C:16]([O:18]C)=O)=O)C.[BH4-].[Na+].[CH3:24][OH:25]>O1CCCC1>[CH2:12]([N:13]([CH2:14][CH3:6])[C:24]([CH2:4][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[CH2:15][CH2:16][OH:18])=[O:25])[CH3:11]
Reactant: CCN(CC)C(=O)c1cccc2c(CC(=O)OC)c[nH]c12
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Cc1cccc2c(CCO)c[nH]c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
To a solution of methyl (7-((diethylamino)carbonyl)-1H-indol-3-yl)acetate (1.87 g, 6.48 mmol) in tetrahydrofuran (30 mL) are added sodium borohydride (1.35 g, 35.7 mmol) and methanol (5 mL) under nitrogen atmosphere, and the mixture is stirred at room temperature for 24 hours, and then refluxed for 4 hours. The mixture is cooled to room temperature, and methanol is added to the reaction solution. The solvent is evaporated, and the residue is separated into water and chloroform. The organic layer is washed with a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated, and the obtained crude product is purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→ethyl acetate ethyl acetate:methanol=5:1) to give N,N-diethyl-3-(2-hydroxyethyl)-1H-indole-7-carboxyamide (1.56 g, 5.99 mmol, yield: 92%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][C:27](F)=[CH:28][CH:29]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[N:26][C:27]([N:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]5)=[CH:28][CH:29]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cnc3cc(-c4ccc(F)nc4)ccn23)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(-c3ccn4c(-c5ccc(CNC(=O)OC(C)(C)C)cc5)cnc4c3)cn2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Dissolve {4-[7-(6-fluoro-pyridin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-benzyl}-carbamic acid tert-butyl ester (0.500 g, 1.19 mmol, 1.0 eq.) and N-methyl piperazine (0.53 mL, 4.78 mmol, 4.0 eq.) in DMSO (20 mL). Add K2CO3 (0.330 g, 2.0 eq.). Stir the reaction mixture at 80° C. overnight. Pour the mixture into 20 mL of ice. Filter the solid, and purify by silica gel chromatography with a 0-5% MeOH/DCM gradient to give the title compound 0.408 g (0.82 mmol, 70%) as a slightly yellow solid. Use the solid directly in the reaction B below: MS(ES), m/z 499 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:27]2[CH2:30][CH:29]([OH:31])[CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:38]([C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39].N(C(OCC)=O)=NC(OCC)=O>C(#N)C.O>[C:38]([C:42]1[CH:47]=[CH:46][C:45]([O:31][CH:29]2[CH2:30][N:27]([CH:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:28]2)=[CH:44][CH:43]=1)([CH3:41])([CH3:40])[CH3:39]
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 8 h
Yield: 50.5 %

Procedure:
Triphenylphosphine (13.11 g, 50.0 mmol) was added to a stirred solution of 1-(diphenylmethyl)-3-azetidinol (11.97 g, 50.0 mmol) and 4-tert-butylphenol (7.50 g, 50.0 mmol) in acetonitrile (200 mL). Diethyl azodicarboxylate (7.9 mL, 8.7 g, 50.0 mmol) was added dropwise to the solution with water cooling. The suspension was heated under reflux for 4 h, the solution allowed to cool and concentrated in vacuo. The gum was suspended in ether (200 mL), and the suspension was refrigerated overnight. The precipitated triphenylphosphine oxide was filtered off and washed with ether, and the combined filtrate and washings were concentrated. The solid residue was dissolved in dichloromethane (200 mL), and the solution was washed with 1-N sodium hydroxide (50 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by chromatography [SiO2; ethyl acetate-hexane (1:4)] and triturated with cyclohexane to give the title compound (9.39 g, 51%) as a white solid, m.p. 126-127° C. Found: C, 83.9; H, 7.9; N, 3.75. C26H29NO require C, 84.1; H, 7.9; N, 3.8%.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[C:12](=[O:18])[N:11]([CH2:19][CH2:20][N:21]4[CH:25]=[C:24]([C:26]([O:28]CC)=[O:27])[CH:23]=[N:22]4)[CH:8]3[N:9]=2)=[C:5]([C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)[N:4]=[CH:3]1.[OH-].[Li+]>O1CCCC1.CO>[NH2:1][N:2]1[C:10]2[C:6]([N:7]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[C:12](=[O:18])[N:11]([CH2:19][CH2:20][N:21]4[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[N:22]4)[CH:8]3[N:9]=2)=[C:5]([C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)[N:4]=[CH:3]1
Reactant: CCOC(=O)c1cnn(CCN2C(=O)N(CC3CC3)N3C4=C(c5ccco5)N=CN(N)C4=NC23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NN1C=NC(c2ccco2)=C2C1=NC1N(CCn3cc(C(=O)O)cn3)C(=O)N(CC3CC3)N21
Temperature: 26 °C
Reaction time: 16 h
Yield: 48.2 %

Procedure:
A mixture of ethyl 1-[2-[5-amino-1-(cyclopropylmethyl)-8-(2-furyl)-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl]pyrazole-4-carboxylate obtained in step 1 (0.055 g, 0.115 mmol) was dissolved in solution of tetrahydrofuran (6 ml) and methanol (4 ml). To this reaction mixture a solution of lithium hydroxide (0.013 g, 0.576 mmol, in 2 ml water) was added and stirred at 25-27° C. for 16 hours. The reaction mixture was concentrated and acidified with saturated solution of citric acid to get PH˜2-3 and solid obtained was filtered off and washed with water (10 ml) followed by diethyl ether (15 ml). It was dried to obtain 1-[2-[5-amino-1-(cyclopropylmethyl)-8-(2-furyl)-2-oxo-[1,2,4]triazolo[5,1-f]purin-3-yl]ethyl]pyrazole-4-carboxylic acid (0.025 g, 49%) as an off white solid.
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[S:18][C:19]([CH3:22])=[CH:20][CH:21]=1)[CH2:12][C:13]([OH:15])=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[CH2:6]([O:8][C:9]([C:11]1[CH:12]=[C:13]([O:15][C:1](=[O:3])[CH3:2])[C:21]2[CH:20]=[C:19]([CH3:22])[S:18][C:17]=2[CH:16]=1)=[O:10])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C(=Cc1ccc(C)s1)CC(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC(C)=O)c2cc(C)sc2c1
Yield: 60.4 %

Procedure:
Sodium acetate (10 g, 120 mmol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(5-methyl-2-thienyl)but-3-enoic acid (12.3 g, 48 mmol) in 100 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 250 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture, 3:1 as eluent to give 8.2 g (29 mmol, 61%) of 4-(acetyloxy)-2-methyl-1-benzothiophene-6-carboxylic acid ethyl ester as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[S:23]([CH3:22])(=[O:25])=[O:24])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(NCc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1ccccn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 3.3 g. portion of 2-(4-chlorophenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and 2.7 g. of potassium carbonate and 1.5 ml. of methanesulfonyl chloride were added. The mixture was stirred overnight at ambient temperature, and then was stirred for 1 day under gentle reflux. Another 0.5 ml. of methanesulfonyl chloride was added, and the reflux was continued for several hours. Then the mixture was cooled and filtered, and the filtrate was chromatographed on a silica gel column, eluting with chloroform. The product-containing fractions were combined and evaporated to obtain 1 g. of the desired product.