Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13][CH2:14][C:15]([O:17]CC)=O)[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:20][CH2:21][C@@H:22]([OH:34])[CH2:23][N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1>CCO>[CH2:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33][N:24]1[CH2:23][C@H:22]([OH:34])[CH2:21][NH:20][C:15](=[O:17])[CH2:14][O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2
Reactant: NC[C@@H](O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1cccc2ccc(OC)nc12
Solvent: CCO
Product: COc1ccc2cccc(OCC(=O)NC[C@@H](O)CN3CCc4ccccc4C3)c2n1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
Ethyl 2-((2-methoxyquinolin-8-yl)oxy)acetate (100 mg, 0.383 mmol), (R)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (79.0 mg, 0.383 mmol) and EtOH (1 mL) were combined in a sealed tube. The mixture was stirred at 120° C. for 30 min in a microwave. The EtOH was evaporated and the residue was purified by pre-HPLC to give the desired product (77 mg, yield 48%). 1HNMR (MeOD-d4, 400 MHz) δ: 8.36 (br. s., 1H), 8.16 (d, J=8.8 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.28-7.15 (m, 4H), 7.12 (d, J=6.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 4.82 (s, 2H), 4.23-4.16 (m, 3H), 4.10 (s, 3H), 3.54-3.48 (m, 1H), 3.47-3.40 (m, 1H), 3.38-3.33 (m, 2H), 3.13-2.98 (m, 4H). LCMS (m/z): 422.2 [M+H]+
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=2)[NH:12][C:11](=[O:17])[CH:10]=[CH:9]3)[CH:5]=[N:4][CH:3]=[N:2]1.C>C(O)C>[CH3:16][C:14]1[CH:15]=[C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:17])[CH2:10][CH2:9]2
Reactant: Cc1cc(-n2cncn2)cc2ccc(=O)[nH]c12
Solvent: CCO
Product: Cc1cc(-n2cncn2)cc2c1NC(=O)CC2

Procedure:
A suspension of 6-(1,2,4-triazol-1-yl)-8-methyl-2-(1H)-quinolone (see Example 9) (1.7g) in ethanol (450 cm3) was hydrogenated at 60° and 60 p.s.i. (4.13×105Pa) pressure over 10% palladised charcoal (0.35g) for 72 hours. The cooled mixture waas then filtered through "Solkafloc" (Trademark for a cellulose based filtering agent) and evaporated in vacuo to afford a solid. Chromatography on silica (Merck "MK 60.9385" [Trade Mark]) eluting with chloroform: methanol, 49:1, followed by combination and evaporation of the appropriate fractions in vacuo gave a solid which was recrystallised from ethyl acetate/methanol to give 3,4-dihydro-8-methyl-6-(1,2,4-triazol-1-yl)-2-(1H)-quinolone, m.p. 258°-259° (0.266 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH2:11][CH2:10][C:8]3=2)[CH:3]=[C:2]1C(O)=O.O1C2C=C3C(CCN3)=CC=2C=C1C(O)=O.CCCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH2:11][CH2:10][C:8]3=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1cc2ccc3c(c2[nH]1)CCO3
Agent: O=C(O)c1cc2cc3c(cc2o1)NCC3
Solvent: CCCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: c1cc2ccc3c(c2[nH]1)CCO3
Temperature: 25 °C
Yield: 5.4 %

Procedure:
A stirred solution of 7,8-dihydrofuro[2,3-g]indole-2-carboxylic acid and 5,6-dihydrofuro[3,2-f]indole-2-carboxylic acid (1:1) (5.46 g, 26.9 mmol) in phenyl ether (250 mL) was heated at reflux for 45 min, then allowed to cool to ambient temperature. Heptane (500 mL) was added and the mixture was passed through a heptane-packed SiO2 column under pressure. The column was eluted with heptane (1.5 L), then heptane-dichloromethane (1:1, 1L) and finally dichloromethane to afford 7,8-dihydrofuro[2,3-g]indole (230 mg, 5.4%) as a white solid. IR νmax (Nujol)/cm−1 3382, 2925, 2854, 1644, 1618, 1497, 1463, 1441, 1435, 1368, 1326, 1234, 1140, 1021, 970, 793, 719, 622, 533 and 475; NMR (400 MHz, CDCl3) δH 3.31 (2H, t, J 8.5 Hz), 4.66 (2H, t, J 8.5 Hz), 6.51 (1H, dd, J 2, 3.5 Hz), 6.73 (1H, d, J 8 Hz), 7.06 (1H, dd, J 2, 3.5 Hz), 7.39 (1H, d, J 8.5 Hz) and 7.83 (1H, brs). Also collected were 5,6-dihydrofuro[3,2-f]indole (667 mg, 15.6%) and mixed fractions (2.94 g, 68.7%). The mixed isomers were further separated by flash column chromatography [SiO2; ethyl acetate-heptane (1:3)] to afford afford 7,8-dihydrofuro[2,3-g]indole (408 mg, 9.5%) as a white solid and 5,6-dihydrofuro[3,2-f]indole (690 mg, 16%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C1COc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.9 %

Procedure:
To a stirred solution of 6-hydroxy-3-oxo-2,3-dihydrobenzofuran of Example 10(a) (32 kg, 213 moles) in DMF (192 L) was added potassium carbonate (31.0 kg, 224 moles). After stirring for 5 min. at room temperature, benzyl bromide (45.2 kg, 264 moles) was added and the resulting mixture was stirred for 2 hours at room temperature. The mixture was poured into water (651 L), stirred for 30 minutes and the product collected by centrifugation. The crude solid was washed with water (580 L), 80% ethanol (100 L) and dried under vacuum to afford the desired product (49.1 kg, 95%) which was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([OH:13])=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:20]1(Br)[CH2:22][CH2:21]1>CN(C=O)C.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([O:13][CH:20]2[CH2:22][CH2:21]2)=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)c2cc(F)ccc12
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc2c(OC3CC3)cnc(Cl)c2c1
Temperature: 145 °C
Yield: 20 %

Procedure:
To a solution of 1-chloro-7-fluoroisoquinolin-4-ol (1 g, 5.06 mmol) in DMF (5 mL) was added Cs2CO3 (4.95 g, 15.18 mmol) followed by cyclopropyl bromide (1.2 mL, 15.18 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.24 g, 20%) as a yellow solid.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH:12][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccn(-c2ccccc2)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccn(-c2ccccc2)n1)C(=O)OCC

Procedure:
1-phenyl-3-amino-pyrazole, m.p. 90°-91° C. (18 g) was reacted with diethyl ethoxymethylenemalonate (29.3 g) in anhydrous ethanol (180 ml) at the reflux temperature for 15 hours. After cooling the solution was evaporated in vacuo to dryness: the residue was dissolved in isopropyl ether (200 ml) and decolorized by charcoal. Crystallization obtained by dilution with hexane gave diethyl N-(1-phenyl-pyrazol-3-yl)-aminomethylenemalonate, m.p. 81°-82° C. (31 g), which was reacted with polyphosphoric acid (13 g; 6.1 g of P2O5 and 6.9 g of H3PO4) and POCl3 (57 g) under stirring at the reflux temperature for 30 minutes. After cooling the reaction mixture was diluted with ice water and then the solution was decolorized, with charcoal: neutralization with 35% NaOH gave a precipitate which was filtered and washed with water. Washing with hexane gave 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid, ethyl ester, m.p. 187°-190° C. (24.2 g), which was hydrolized by heating with a mixture 1:1 of 37% HCl:acetic acid (1.2 l) at the reflux temperature for 4 hours. After cooling the reaction mixture was neutralized to pH=6 with 35% NaOH and the precipitate was filtered and washed with water: crystallization from isopropyl alcohol gave 9.7 g of 1-phenyl-7-oxo-1H,7H-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid m.p. 185°-190° C. dec., N.M.R. (DMSO-d6) δ p.p.m.: 6.94 (d) (1H, C-3 proton), 7.59 (s) (5H, phenyl protons), 8.74 (d) (1H, C-2 proton), 8.81 (s) (C-5 proton).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14]C(=O)C)[CH:9]=2)[C:5](=[O:18])[N:4]([C:19]2[CH:24]=[CH:23][C:22]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[C:3]1=[O:30].C[O-].[Na+]>CO>[NH2:14][C:10]1[CH:9]=[C:8]([CH2:7][N:6]2[C:2]([CH3:31])([CH3:1])[C:3](=[O:30])[N:4]([C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[C:5]2=[O:18])[CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)Nc1cc(CN2C(=O)N(c3ccc(SC(F)(F)F)cc3)C(=O)C2(C)C)ccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)C(=O)N(c2ccc(SC(F)(F)F)cc2)C(=O)N1Cc1ccnc(N)c1
Yield: 74.6 %

Procedure:
500 mg (1.11 mmol) of N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}acetamide are dissolved in MeOH, 1.5 mmol of NaOMe are added and the resulting mixture is refluxed for 4 hours. The solvent is removed, the residue is taken up in CH2Cl2 and washed twice with 10% NaHCO3 solution and with water, and the organic phase is evaporated off. 340 mg (75%) of 1-(2-aminopyrid-4-yl-methyl)-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione are isolated in this manner.
Reaction SMILES: [Si]([N:5]=[N+:6]=[N-:7])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:26]([C:28]1[CH:29]=[C:30]([C:34]2([OH:61])[CH2:39][CH2:38][CH:37]([N:40]3[CH2:43][CH:42]([NH:44][C:45]([CH2:47][NH:48][C:49](=[O:60])[C:50]4[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=4)=[O:46])[CH2:41]3)[CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1)#[N:27].O>C1COCC1.C(OCC)(=O)C.N.CO>[OH:61][C:34]1([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([C:26]3[NH:27][N:7]=[N:6][N:5]=3)[CH:29]=2)[CH2:39][CH2:38][CH:37]([N:40]2[CH2:41][CH:42]([NH:44][C:45]([CH2:47][NH:48][C:49](=[O:60])[C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:58])([F:59])[F:57])[CH:51]=3)=[O:46])[CH2:43]2)[CH2:36][CH2:35]1
Reactant: N#Cc1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cccc(-c4nnn[nH]4)c3)CC2)C1

Procedure:
TMSN3 (Fluka, 50 mg, 0.42 mmol), TBAF (Aldrich, 1.0 N in THF, 0.5 mL, 0.5 mmol) and N-({1-[4-(3-cyano-phenyl)-4-hydroxy-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 48, less polar isomer, 70 mg, 0.14 mmol) were dissolved in THF (2 mL) and water (0.5 mL) mixed solvent. The reaction mixture was subjected to microwave irradiation at 120° C. for 20 min. The crude reaction mixture was loaded on a silica gel column using a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[Li+].[Cl-].I[C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1.[NH4+].[Cl-]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:1][C:2]1[C:7]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: Clc1cncc(Cl)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ncc(Cl)nc2Cl)cc1
Yield: 84.5 %

Procedure:
2,6-Dichloropyrazine (9) (149 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25° C. and the reaction mixture was then stirred at this temperature for 30 min according to TP 2. Pd(dba)2 (17 mg, 3 mol %) and P(o-furyl)3 (14 mg, 6 mol %) dissolved in THF (2 mL), followed by the addition of ethyl 4-iodobenzoate (359 mg, 1.3 mmol), were then transferred via cannula to the reaction mixture. The reaction mixture was stirred at 25° C. for 1.5 h. with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:2) furnished compound 11b (251 mg, 87%) as a colourless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][N:4]=1)#[N:2].[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)Cl>[Br:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(CBr)cn1
Temperature: 60 °C
Reaction time: 6 h
Yield: 53.3 %

Procedure:
Commercially available 2-cyano-5-methylpyridine (1.90 g, 16.1 mmol) was dissolved in chloroform (100 mL), and the mixture was stirred at 60° C. for 6 hours after adding N-bromosuccinimide (4.29 g, 24.1 mmol) and α,α-azobisisobutyronitrile (0.792 g, 4.82 mmol). After ice-cooling the reaction mixture, the precipitate was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-bromomethyl-2-cyanopyridine (1.69 g, 53%).
Reaction SMILES: C(#N)CC#N.[H-].[Na+].Br[C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=3)[C:12](C)(C)[C:11]=2[SiH:10]=1.BrBr.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[SiH:10]1[C:11]2[CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]=2[CH:20]=[CH:21][CH:9]=1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)[siH]c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: BrBr
Agent: [H-]
Solvent: COCCOC
Solvent: N#CCC#N
Solvent: O
Product: c1ccc2c(c1)Cc1[siH]cccc1-2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
in ice bath, 3.14 g of malononitrile was added to the suspension of 2.45 g of sodium hydride (60% in oil solution) in 50 mL of ethylene glycol dimethyl ether, then the mixture was warmed to room temperature, stirred for 20 minutes and 3.68 g of 2,7-dibromo-9,9-dimethyl silafluorene and 0.54 g of PdCl2(PPh3)2 were added. The mixture was heated to 120° C. for 12 hours, cooled to 0° C., and saturated Br2/H2O solution was added. A water was added, and the resulting mixture was vacuum filtered, washed with water, dried, and column chromatographed to give the product. MALDI-TOF-MS (m/z): 336.4 (M+).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([NH2:21])=[CH:8][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[CH:24]=[C:25]2[CH2:31][CH2:30][NH:29][C:26]2=[N:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:5][C:6]1[C:7]([NH2:21])=[CH:8][C:9]([C:23]2[CH:24]=[C:25]3[CH2:31][CH2:30][NH:29][C:26]3=[N:27][CH:28]=2)=[CH:10][CH:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: Brc1cnc2c(c1)CCN2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1ccc(-c2cnc3c(c2)CCN3)cc1N
Temperature: 110 °C
Yield: 28.3 %

Procedure:
In a microwave vial are added N1-tert-Butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzene-1,2-diamine (100 mg, 0.5 mmol) and 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (180 mg, 0.62 mmol), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) and K2CO3 (139 mg, 1 mmol) in DMF (4 mL) and H2O (0.2 mL). The reaction mixture is heated at 110° C. in a microwave reactor for 1 hour. The reaction is cooled down to room temperature, poured into H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title intermediate (40 mg, 28%). LCMS (ESMS): m/z 283.20 (M++1)
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([OH:35])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].N1C=CC=CC=1.C(Cl)Cl.[C:45](Cl)(=[O:48])[O:46][CH3:47]>C(OCC)(=O)C.CCCCCC>[C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([O:35][C:45]([O:46][CH3:47])=[O:48])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][C:20]([CH3:23])([CH3:24])[CH2:21][O:22]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a mixture of 49.0 mg (0.1 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7αhydroxypregn-5-en-3β-yl acetate, 0.24 ml (3 mmoles) of pyridine and 10 ml of dry methylene chloride was added 0.1 ml (1.3 mmoles) of methyl chlorocarbonate dropwise at a temperature of 0° C. and the mixture was stirred at room temperature for 8 hours. The reaction mixture was washed with cold 1N-hydrochloric acid and the aqueous layer (washings) was extracted with methylene chloride. The extract was combined with the organic layer and the resulting mixture was washed successively with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:10, v/v) to recover 43.7 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate (yield: 80%).
Reaction SMILES: [NH2:1][C:2]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.N1C=CC=CC=1.[SH2:26]>CN(C)C=O>[NH2:1][C:2]([N:8]([CH2:9][CH3:10])[CH2:11][CH3:12])=[C:3]([C:4]#[N:5])[C:6](=[S:26])[NH2:7]
Reactant: CCN(CC)C(N)=C(C#N)C#N
Reactant: S
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCN(CC)C(N)=C(C#N)C(N)=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 72.6 g of 3-amino-2-cyano-3-(diethylamino)propenenitrile, 44.7 g of triethylamine, 200 ml of pyridine, and 50 ml of dimethylformamide was saturated at 60° with hydrogen sulfide. The temperature was increased to 75° while hydrogen sulfide was passed through the solution. After heating at 75° for 2 hours, thin-layer chromatographic analysis indicated the reaction was incomplete. After about 60 hours at room temperature the mixture was heated at 75° for an additional 4 hours. The mixture was allowed to cool to ambient temperature, then was poured into 1750 ml of ice-water mixture. The cold slurry was stirred for 1 hour and the solid was isolated by filtration. The solid was washed with ice-water and recrystallized from 250 ml of ethanol to give 56 g of 3-amino-2-cyano-3-(diethylamino)propenethioamide, m.p. 151°-152°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=2)[N:26]=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:23]4[C:32]5[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=5)[N:26]=[CH:25][CH:24]=4)=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: Fc1ccc(N2CCN(Cc3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)cc1

Procedure:
In the manner given in Example 1C, 1-(p-fluorophenyl)-4-[(4-aminophenyl)methyl]piperazine and 4,7-dichloroquinoline are reacted together at reflux to give 4-[[4-[[4-(p-fluorophenyl)-1-piperazinyl]methyl]phenyl]amino]-7-chloroquinoline.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:21])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([F:20])[CH:13]=2)=[O:8])C.[OH-].[Na+]>O1CCCC1.CO>[F:20][C:14]1[CH:13]=[C:12]2[C:17]([C:18]([OH:19])=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:22])=[O:3])=[O:8])[C:10](=[O:21])[S:11]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)CNC(=O)c1c(O)c2ccc(F)cc2sc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1c(O)c2ccc(F)cc2sc1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
[(7-Fluoro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (150 mg, 0.461 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (5 mL). 1N Sodium hydroxide (1.85 mL) was added to the solution and the reaction was stirred overnight (18 h) at ambient temperature. The reaction was concentrated in vacuo and the residue dissolved in water, treated with 1N HCl to pH 3 to precipitate the product, which was collected via filtration and dried to yield [(7-fluoro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (100 mg, 75%.) MS ESI(−) m/e: 296.23 (M−1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[C:7]([F:15])[CH:6]=1)=O.[C:16]([NH:19][C:20]([NH2:22])=[NH:21])(=[O:18])[CH3:17]>C(#N)C.C(OCC)(=O)C.O>[F:15][C:7]1[CH:6]=[C:5]([C:3]2[N:21]=[C:20]([NH:19][C:16](=[O:18])[CH3:17])[NH:22][CH:2]=2)[CH:10]=[CH:9][C:8]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c(F)c1
Reactant: CC(=O)NC(=N)N
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)c[nH]1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
To a stirred solution of 2-bromo-1-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone (4.5 g, 15.73 mmol) in acetonitrile (45 ml) was added acetyl guanidine (2.38 g, 23.60 mmol) at room temperature. After refluxing for 4 h the reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The layers were separated. The aqueous layer was extracted 2-3 times with ethyl acetate and the combined organic layers were washed with water, followed by brine, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 2% methanol in chloroform to obtain 1.15 g of the product as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 2.07 (s, 3H), 7.58 (s, 1H), 7.69-7.78 (m, 3H), 11.31 (br s, 1H), 11.91 (br s, 1H).