Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=CC(C(C)(CCCCC(=O)CCCCC(C2C=CC(CC(C)C)=CC=2)(C)C(O)=O)C(O)=O)=CC=1)C(C)C.C([O:43][C:44](=[O:74])[C:45]([CH3:73])([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH2:46][CH2:47][CH2:48][C:49](=[O:66])[CH2:50][CH2:51][CH2:52][C:53]([CH3:65])([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:54]([O:56]CC)=[O:55])C.[OH-].[K+]>O.C(O)C>[CH3:65][C:53]([C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1)([CH2:52][CH2:51][CH2:50][C:49](=[O:66])[CH2:48][CH2:47][CH2:46][C:45]([CH3:73])([C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=1)[C:44]([OH:74])=[O:43])[C:54]([OH:56])=[O:55]
Reactant: CCOC(=O)C(C)(CCCC(=O)CCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Agent: CC(C)Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(CC(C)C)cc2)C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CCCC(=O)CCCC(C)(C(=O)O)c1ccccc1)(C(=O)O)c1ccccc1
Yield: 31.3 %

Procedure:
According to the procedure given for 210f, 209b (14.5 g, 31.1 mmol) was saponified with KOH (85%, 7.2 g, 108.6 mmol) in water (15 mL) and ethanol (45 mL) at reflux for 6 h. After the usual extractive workup, the crude material was purified by flash chromatography (silica gel; ethyl acetate/hexanes=1/20, 1/10, 1/2) to give 210b (4.0 g, 31%) as a white solid. Mp 44-46° C. 1H NMR (CDCl3): 10.25 (br., 2H), 7.35-7.22 (m, 10H), 2.32 (m, 4H), 1.94-1.86 (m, 4H), 1.57 (s, 6H), 1.51-1.22 (m, 4H). 13C NMR (CDCl3): δ 210.64, 182.66, 142.69, 128.66, 127.18, 126.29, 50.07, 42.97, 38.62, 22.20, 19.11. HRMS (LSIMS, gly): Calcd for C25H31O5 (MH+): 411.2171, found: 411.2144. HPLC: 95.2% pure.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:15]C)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1.C1(=O)[O:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.O>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[O:15])[CH:9]=1
Reactant: O=C1CCCCO1
Reactant: COC(=O)c1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCCO)c1cccnc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A solution of potassium tert-butoxide (83.55 g) in tetrahydrofuran (500 ml) at 22° C. is treated, dropwise, with a solution of methyl nicotinate (68.5 g) and delta-valerolactone (75.0 g) in tetrahydrofuran (125 ml) during a period of 1 hour. The solution is then stirred at 23° C. for 2 hours. The reaction mixture is diluted with water and washed with toluene (125 ml). The organic phase is discarded and the aqueous phase is treated dropwise with concentrated hydrochloric acid (400 ml; 37% w/v). The solution is stirred for a further 2 hours. The solution is then washed with dichloromethane (250 ml). The organic phase is discarded and the aqueous phase is treated with aqueous sodium hydroxide solution to bring it to between pH8 and pH9. The aqueous phase is then washed with toluene (125 ml) and the organic phase is back washed with water (3×100 ml). The two aqueous phases are combined and extracted with dichloro- methane. The dichloromethane extract is dried over magnesium sulphate, and evaporated to dryness, to give 4-hydroxybutyl 3-pyridyl ketone (61.1 g) in the form of an oil which crystallises to form a pale brown solid, m.p. 36°-38° C. [NMR (CDCl3): 1.7(m,2H), 1.9(m,2H), 3.1(t,2H), 3.7(t,2H), 7.4(m,1H), 8.2(dt,1H), 8.8(m, 1H), 9.2(m, 1H)].
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([C:29]5([CH2:35][OH:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.CCN(C(C)C)C(C)C.[CH:46]([S:48]([CH:51]=C)(=[O:50])=[O:49])=[CH2:47]>>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([C:29]5([CH2:35][OH:36])[CH2:30][CH2:31][N:32]([CH2:47][CH2:46][S:48]([CH3:51])(=[O:50])=[O:49])[CH2:33][CH2:34]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: C=CS(=O)(=O)C=C
Reactant: OCC1(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCN1CCC(CO)(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Yield: 57.5 %

Procedure:
To a stirring mixture of (4-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidin-4-yl)-methanol hydrochloride 75 (97 mg, 0.1873 mmol) in IMS (3 mL) was added DIPEA (165 L, 0.94 mmol) followed by vinyl sulfone (18 ul, 0.206 mmol) at RT, as illustrated in FIG. 16. After 3 h the solvent was removed in vacuo and the residue was subjected to HPLC (Gemini C6-Phenyl column, gradient 10 to 60%, 20 min ramp) to afford 188 (63 mg, 53%). 1H NMR δ ppm (DMSO-d6): 8.42-8.39 (1 H, m), 8.23 (1 H, s), 8.19 (1 H, s), 7.80 (1 H, td, J=8.77, 5.87 Hz), 7.53 (1 H, ddd, J=10.34, 8.85, 2.77 Hz), 7.36 (1 H, d, J=2.40 Hz), 7.33-7.27 (1 H, m), 7.12 (1 H, dd, J=8.59, 2.48 Hz), 6.85 (1 H, dd, J=8.55, 4.83 Hz), 4.17 (2 H, t, J=5.04 Hz), 3.22-3.14 (6 H, m), 3.02 (2 H, t, J=5.09 Hz), 2.98 (3 H, s), 2.02 (2 H, s), 1.72 (4 H, s). 2 Protons obscured by water peak. LCMS: RT=6.57 min, M+H+=585
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[H-].[Na+].Cl[CH2:24][O:25][CH2:26][CH3:27].ClCCl>CO>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:24][O:25][CH2:26][CH3:27])=[CH:13][CH:14]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOCOc1ccc(NC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1
Temperature: 0 °C
Yield: 81 %

Procedure:
4-Chloro-N-(4-hydroxy-phenyl)-3-nitro-benzamide (14.6 g, 0.05 mol) was placed in an oven dried 2-necked 500 ml round-bottomed flask and flushed with N2. Enough Dimethoxyethane (DME, 100 ml) was added to dissolve the amide. The mixture was cooled in ice bath and sodium hydride (NaH, 50% in oil, 3.6 g total, 0.075 mol) added in small portions with vigorous stirring. An hour after addition was complete, chloromethoxy-ethane (7.13 g, 0.075 mol, commercially available) was added drop wise via a pressure-equalising dropping funnel. The reaction was followed by TLC (dichloromethane, DCM:methanol, MeOH, 95:5). The reaction mixture was poured into ice water and extracted with EtOAc (3×50 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was recrystallised form Hexane/ethyl acetate, 1:4. to give 81% of the title compound.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)(=[O:13])[CH3:12].C(O)C>O1CCCC1>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:11]([CH2:12][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[O:13]
Reactant: CC(=O)c1ccco1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccco1
Temperature: 0 °C
Yield: 60.6 %

Procedure:
Sodium hydride (4.4 grams) and 10.7 grams of diethyl carbonate are suspended in 60 ml of tetrahydrofuran and 10 grams of 2-acetylfuran is gradually added thereto by keeping the inner temperature at 40°to 50° C. A small amount of ethanol is added thereto, heated to reflux for three hours, and the reaction is made stopped by addition of 20 ml of ethanol. The mixture is poured into ice water, extracted with ether, the ether extracts are combined, washed with water, dried with anhydrous magnesium sulfate, and ether is evaporated therefrom. The resulting oil is purified by distilling in vacuo to give 10 grams of pale yellow oily product, b.p. 90° C./3 mmHg.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([CH3:19])=[CH:14][N:13]=1>O.CO>[Cl:11][C:12]1[N:17]=[C:16]([S:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)[C:15]([CH3:19])=[CH:14][N:13]=1
Reactant: Nc1ccc(S)cc1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cnc(Cl)nc1Sc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1124.2 %

Procedure:
Sodium hydroxide (2.38 g, 5.9 mmol) was dissolved in water (10 mL), 4-aminothiophenol (6.77 g, 5 4 mmol) was added as a solution in methanol (25 mL) and the reaction was stirred at room temperature for 30 minutes. 2,4-Dichloro-5-methylpyrimidine (7.05 g, 4 3 mmol) was slowly added as a solution in methanol (25 mL) and the reaction was stirred at room temperature for a further 1 hour during which time a precipitate formed. This precipitate was isolated by filtration, washed with minimum ice cold diethyl ether and dried under vacuum to give 4-[(2-chloro-5-methylpyrimidin-4-yl)thio]aniline (8.49 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH:11]2[C:16](=O)[CH2:15][CH2:14][S:13][CH2:12]2)=O)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:20]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[CH:26][CH:25]=2)[CH:21]=[CH:22][N:23]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:11]3[CH2:12][S:13][CH2:14][CH2:15][C:16]=3[N:33]=[C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([N:20]4[CH:21]=[CH:22][N:23]=[C:19]4[CH3:18])=[CH:25][CH:26]=3)[N:32]=2)=[CH:4][CH:3]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: O=C1CCSCC1C(=O)Cc1ccc(F)cc1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CSCC3)cc1
Yield: 78 %

Procedure:
4-(4-Fluorobenzyl)-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (103 mg, 78%) was synthesised from 3-(2-(4-fluorophenyl)acetyl)dihydro-2H-thiopyran-4(3H)-one and 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (Example 41c) according to the general procedure for the synthesis of pyrimidines. MS (ES+) m/z 432.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C([O-])(=O)C.[Na+]>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: C1=CCCCC1
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(C2=CCCCC2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
2 ml of the stock solution described in Example 23 are added to 18 ml of DMF. 9.26 g (50 mmols) of 4-bromobenzaldehyde, 5.58 ml (55 mmols) of cyclohexene and 4.52 g (55 mmols) of anhydrous sodium acetate are then added and the reaction mixture is stirred for 8 hours at 140° C. in a pressure tube. After working up as described in Example 1, the crude product is distilled in vacuo. 2.05 g (11.0 mmols) of 4-formylphenylcyclohexene are obtained in the form of a yellow liquid of boiling point 140°-150° C./2400 Pa; yield 22% of theory (conversion figure 2200; Pd content 0.01 mol %). The product is a mixture of isomers.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[CH2:10][O:11][CH2:12][C@@H:13]([NH:16][C:17](=[O:28])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[NH2:19])[C:14]#[N:15])=[O:6])[CH:2]=[CH2:3].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[CH2:10][O:11][CH2:12][C@@H:13]([NH:16][C:17](=[O:28])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[NH:19][C:36]1[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=1)[C:14]#[N:15])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@@H](N)Cc2cccc(C)c2)c1
Reactant: OB(O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)c1cccc(COC[C@H](C#N)NC(=O)[C@H](Cc2cccc(C)c2)Nc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-[3-(allyloxycarbonyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-L-phenylalaninamide (0.6 g, 1.42 mmol) in CH2Cl2 (15 mL) is added 4-fluorophenylboronic acid (0.398 g, 2.85 mmol), cupric acetate (0.26 g, 1.4 mmol) and pyridine (0.23 mL, 2.85 mmol), and the dark blue solution is stirred overnight at room temp. The solution is then diluted with CH2Cl2 (35 mL), and washed with 1 N HCl (50 mL) and brine (50 mL), then dried (MgSO4), evaporated and chromatographed (silica, 30% EtOAc/hexane) to yield N-[2-[3-(allyloxycarbonyl)-benzyloxy]-1(S)-cyanoethyl]-3-methyl-Nα-(4-fluorophenyl)-L-phenylalaninamide, as a clear oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH3:12])[CH2:6][CH2:5]2.N1C=CC=CC=1.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[Br:1][C:2]1[C:3]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:26](=[O:28])[CH3:27])[CH:7]([CH3:12])[CH2:6][CH2:5]2
Reactant: CC(=O)Cl
Reactant: CC1CCc2c(ccc(Br)c2Oc2ccccc2)N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(Br)c(Oc3ccccc3)c2CCC1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
A solution of rac-6-bromo-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline (0.022 g, 0.069 mmol) in dichloromethane (1 mL), and pyridine (0.017 mL, 0.207 mmol) was cooled to 0° C. and treated with acetyl chloride (5.41 μL, 0.076 mmol). The reaction mixture was then stirred at rt. After 10 min, additional acetyl chloride (3.93 μL, 0.055 mmol) was added and stirring was continued at rt. After 75 min, the reaction mixture was diluted with dichloromethane and washed with 1 N aqueous hydrochloric acid solution (2×0.5 mL) and 5% aqueous sodium chloride solution (0.5 mL). The dichloromethane layer was concentrated to afford crude rac-1-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.024 g, 96%) as a nearly colorless gum that solidified upon standing. The crude product was used without further purification. MS (ESI, pos. ion) m/z 360, 362 [M+H]+.
Reaction SMILES: [C:1]([C@:9]1([OH:47])[C@@:16]([C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:17])[C@:15]([C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:26])[C@@H:14]([CH:35](S(C2C=CC(C)=CC=2)(=O)=O)[OH:36])[O:13][C@@H:10]1[O:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:48]=[N+:49]=[N-:50].[Na+].O>CN(C=O)C>[C:1]([C@:9]1([OH:47])[C@@:16]([C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([OH:17])[C@:15]([C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:26])[C@@H:14]([CH:35]([N:48]=[N+:49]=[N-:50])[OH:36])[O:13][C@@H:10]1[O:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CO[C@H]1O[C@H](C(O)S(=O)(=O)c2ccc(C)cc2)[C@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@@]1(O)C(=O)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1O[C@H](C(O)N=[N+]=[N-])[C@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@@]1(O)C(=O)c1ccccc1
Reaction time: 24 h

Procedure:
10 g of compound 2 and 3 g of NaN3 were dissolved in 100 cc of DMF. Reaction was allowed to proceed for 24 hrs at 70° C. after which the reaction mass was poured into 1 liter of water. Compound 5, obtained as a solid, was recrystallized from acetone giving 8 g (quant.) after drying over P2O5. M.p. 111° C.; 1H NMR (CDCl3): δ 8.22, 8.07, 7.92 (d,d,d, 2H each, benzoyl), 7.38-7.66 (m, 9H, benzoyl), 6.0—5.96 (m, 2H, H2,3), 5.8 (m, 1H, H4), 5.13 (d, 1H, H1), 4.47 (m, 1H, H5), 3.69 (s, 3H, OMe), 3.62 (AB, 2H, H6.6′).
Reaction SMILES: [NH2:1][NH2:2].O[CH:4]=[C:5]1[C:15](=O)[C:10]2[CH:11]=[N:12][N:13]([CH3:14])[C:9]=2[CH2:8][CH2:7][CH2:6]1>CO>[CH3:14][N:13]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5]3[CH:4]=[N:2][NH:1][C:15]=3[C:10]=2[CH:11]=[N:12]1
Reactant: NN
Reactant: Cn1ncc2c1CCCC(=CO)C2=O
Solvent: CO
Product: Cn1ncc2c1CCCc1cn[nH]c1-2
Yield: 96 %

Procedure:
Hydrazine (0.5 ml) was added slowly to a warm solution of 3 g of 5,6,7,8-tetrahydro-5-hydroxymethylene-1-methyl-4(1H)-cycloheptapyrazolone in 90 ml of methanol. The reaction was heated at reflux for 30 minutes and the solvent was removed under reduced pressure. The residue was triturated in warm ether to give 4,5,6,7-tetrahydro-7-methyl-1H-cyclohepta[1,2-c:3,4 c']dipyrazole as a tan powder (96% yield) melting at about 153°-155° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:5][C:6](=[O:8])[CH:7]=1.O.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:5][C:6](=[O:8])[C:7]=1[N:16]=[O:17]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)[nH]c(C2CCCCC2)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(C2CCCCC2)[nH]c(=O)c1N=O
Temperature: 70 °C

Procedure:
A mixture of 4-amino-2-cyclohexylpyrimid-6-one (18 g.) and water (150 ml.) was stirred and heated to 70° C, and treated slowly with sodium nitrite (8 g.), followed by an excess of glacial acetic acid. The mixture was stirred for a further 1 hour and the blue solid (25 g.) filtered off and used directly for the next stage. A sample recrystallised from glacial acetic acid gave pure 4-amino-2-cyclohexyl-5-nitrosopyrimid-6-one, m.p. 233°-234° C. (with decomposition).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([C:15]([CH3:19])([CH3:18])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>C1C=CC=CC=1>[F:22][C:2]([F:1])([F:21])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[CH3:30])[CH2:12][CH2:11][N:10]([C:15]([CH3:18])([CH3:19])[C:16]#[CH:17])[C:9]2=[O:20])=[N:5][N:4]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: C#CC(C)(C)N1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C#CC(C)(C)N1CCC(OC(=O)c2ccccc2C)N(c2nnc(C(F)(F)F)s2)C1=O

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol- 2-yl)-3-(1,1-dimethylprop-2-ynyl)-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Methylbenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1 -(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-(1,1-dimethylprop- 2-ynyl)-6-(2-methylbenzoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][O:10][C:9]3[CH:12]=[C:13]4[O:18][CH2:17][O:16][C:14]4=[CH:15][C:8]=3[C:7](=[O:19])[C:6]=2[CH:20]=1.[CH3:21][N:22](C)C=O.C(Cl)(Cl)Cl.[C-]#N.[Na+]>O>[CH2:17]1[O:18][C:13]2[C:14](=[CH:15][C:8]3[C:7](=[O:19])[C:6]4[CH:20]=[C:2]([C:21]#[N:22])[CH:3]=[CH:4][C:5]=4[CH2:11][O:10][C:9]=3[CH:12]=2)[O:16]1
Reactant: CN(C)C=O
Reactant: O=C1c2cc(Br)ccc2COc2cc3c(cc21)OCO3
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ccc2c(c1)C(=O)c1cc3c(cc1OC2)OCO3

Procedure:
Heat a mixture of 9.26 gm. (0.0278 mole) of 9-bromo-6,11-dihydro-2,3-methylenedioxy-11-oxodibenz[b,e]oxepin, 5.23 (0.0584 mole) of cuprous cyanide and 33 ml. of dimethylformamide under reflux for 9 hours with vigorous stirring. Cool the reaction mixture and shake with a mixture of 45 ml. of chloroform, 32 ml. of saturated sodium cyanide solution and 32 ml. of water until all solids have dissolved. Separate the organic layer, wash with aqueous sodium cyanide solution and water and dry over anhydrous magnesium sulfate. Remove the solvent under vacuum to obtain the title product (yield 7.76 gm., m.p. 217°-220° C.). Recrystallize from acetic acid to obtain pure product as tan prisms [m.p. 224°-225° C., pmr (CDCl3) 5.03 (2H,s, CH2O), 617(2H,s,OCH2O--)].
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][CH:26]([S:37][CH3:38])[C:27]([NH:29][C:30]([CH2:34][O:35][CH3:36])([CH3:33])[CH:31]=O)=[O:28])=[CH:20][CH:19]=2)#[CH:14].C([O-])([O-])=O.[K+].[K+]>CO.C(OCC)(=O)C>[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][CH:26]([S:37][CH3:38])[C:27]([NH:29][C:30]([CH2:34][O:35][CH3:36])([CH3:33])[C:31]#[CH:1])=[O:28])=[CH:20][CH:19]=2)#[CH:14]
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C=O)COC)cc2c1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C#C)COC)cc2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
A mixture of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (Bestmann's reagent) (43 mg) and 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-methoxymethyl-1-methyl-2-oxo-ethyl)-2-methylsulfanyl-acetamide (60 mg) in MeOH (6 ml) was cooled to 0° C. Solid K2CO3 (40 mg) was added and the mixture stirred during 16 hour allowing the temperature raising to 25° C. The reaction mixture was diluted with ethyl acetate and poured onto brine. The water phase was extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography to give 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-methoxymethyl-1-methyl-prop-2-ynyl)-2-methylsulfanyl-acetamide (52 mg) as a light brown oil as a mixture of diastereoisomers.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[S:5][CH:6]=1.CI.[C:18]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:18][O:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cc1nc(O)cs1)c1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1csc(CC(=O)c2ccccc2)n1
Temperature: 25 °C
Yield: 8014 %

Procedure:
To a suspension of 2-(4-hydroxy-1,3-thiazol-2-yl)-1-phenylethan-1-one (0.5 g, 2.3 mmol) in acetone (10 mL) at r.t. was added MeI (0.17 mL, 2.7 mmol), followed by K2CO3 (315 mg, 2.3 mmol). After stirring ON at r.t., the solvent was removed and the residue was taken up in Et2O/H2O. The organic layer was dried (MgSO4), filtered, and evaporated to yield o.43 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C([O:12][C:13]([C:15]1[C:16]([OH:30])=[N:17][C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=2)=O)C.C(Cl)Cl>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:13]([C:15]1[C:16]([OH:30])=[N:17][C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([C:26]([F:29])([F:27])[F:28])[CH:19]=2)=[O:12]
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1O
Reactant: NCc1cccc(F)c1
Solvent: CCO
Solvent: ClCCl
Product: O=C(NCc1cccc(F)c1)c1c(O)nc2cc(C(F)(F)F)ccc2c1O
Temperature: 90 °C
Yield: 97.7 %

Procedure:
2.0 ml (17.3 mmol) 3-fluorobenzylamine was added to a suspension of 1.3 g (4.3 mmol) 2,4-dihydroxy-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in EtOH (50 ml) and the mixture was heated to 90° C. for 3 h. Concentration in a vacuum was subsequently carried out. After CC (DCM) of the residue, 1.6 g (4.2 mmol, 98%) N-(3-fluorobenzyl)-2,4-dihydroxy-7-(trifluoromethyl)quinoline-3-carboxylic acid amide was obtained.