Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10]C)[CH:5]=[N:6][C:7]=1[Cl:8].CCN(CC)CC.CC(O[C:23]([CH3:25])=[O:24])=O>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:23](=[O:24])[CH3:25])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CNCc1cnc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cnc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
To a mixture of the amine from step (c) above (1.77 g, 10 mmol) and Et3N (2.78 mL, 20 mmol, Aldrich) was added Ac2O dropwise with stirring at room temperature. The mixture was stirred for 30 min at room temperature, diluted with EtOAc (30 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 80% EtOAc/hexane to give the title compound. MS (ESI, pos. ion) m/z: 219 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[CH:11][C:12]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[C:13]([C:15](=[O:25])[C:16]([NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:37].Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([O:32][CH3:33])=[CH:11][C:12]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[C:13]([C:15](=[O:25])[C:16]([N:18]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH3:37])=[O:17])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)C(=O)NC2CCCCC2)cc1OCc1ccccc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(-c2noc(C)n2)c(C(=O)C(=O)N(C)C2CCCCC2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 2-[5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]N-cyclohexyl-2-oxoacetamide (reference example 14-15) (860 mg) and N,N-dimethylformamide (6 mL) was added sodium hydride (60%, 92 mg). After stirring at room temperature for 20 minutes, iodomethane (0.48 mL) was added to the mixture. After stirring at room temperature for 8 hours, the mixture was poured into a mixture of 2 mol/L hydrochloric acid and ice-water. Ethyl acetate was added to the mixture. The separated organic layer was washed with water, an aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0%-50% ethyl acetate/hexane, gradient elution) to give the title compound (605 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:38]3[CH2:43][CH2:42][CH:41]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[CH2:40][CH2:39]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CC(N2CCOCC2)CCN1
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCOCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-piperidin-4-yl-morpholine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C36H40N4O3F3Cl2 [(M+H)+] 703.2424, observed 703.2419.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.C(Br)C#C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:41][C:37]#[CH:38])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: C#CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: C#CCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 30.2 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), propargyl bromide (0.111 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.061 g (25%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:4][OH:5])[CH3:3].C(=O)(O)[O-].[Na+].Cl[C:12]([O:14][CH3:15])=[O:13]>C1COCC1.O>[OH:5][CH2:4][C@@H:2]([NH:1][C:12](=[O:13])[O:14][CH3:15])[CH3:3]
Reactant: COC(=O)Cl
Reactant: C[C@H](N)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](C)CO
Temperature: 25 °C

Procedure:
To a solution of (S)-alaninol (10 g, 130 mmol) and sodium bicarbonate (32.8 g, 390 mmol) in THF-H2O (1:1, 650 mL) at 0° C. was added dropwise methyl chloroformate (11.4 mL, 143 mmol). The mixture was stirred and allowed to warm to rt over 4 h, and was then extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and brine, and was then dried over sodium sulfate, filtered and concentrated to give the crude title compound, which was used without further purification. MS m/z 134.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][C@@H:23]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[CH:25]([CH2:26][CH2:27][C@@H:28]3[C@@H:44]2[CH2:43][CH2:42][C@@:41]2([CH3:49])[C@H:29]3[CH2:30][CH2:31][C@@H:32]2[C@H:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:24]1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([NH:22][C@@H:23]1[CH2:47][CH2:46][C@@:45]2([CH3:48])[CH:25]([CH2:26][CH2:27][C@@H:28]3[C@@H:44]2[CH2:43][CH2:42][C@@:41]2([CH3:49])[C@H:29]3[CH2:30][CH2:31][C@@H:32]2[C@H:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:24]1)=[O:21])[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@H](NC(=O)[C@H](COCc5ccccc5)NC(=O)OC(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 90.4 %

Procedure:
By using N-tert-butyloxycarbonyl-O-benzyl-L-serine (2.28 g, 7.72 mmol) and 3α-aminocholestane (3.00 g, 7.74 mmol), the title compound was obtained in the same manner as in Synthetic Example BB1 (4.64 g, yield; 90.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:15][C@H:16]([C:21]([O:23]C)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:10]([N:12]([CH3:14])[CH3:13])=[O:11].[OH-].[Li+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:15][C@H:16]([C:21]([OH:23])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:10]([N:12]([CH3:13])[CH3:14])=[O:11]
Reactant: COC(=O)[C@H](CC(C)C)NC(C(=O)N(C)C)c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(C(=O)N(C)C)c1ccc(F)cc1F)C(=O)O
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a solution of methyl N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucinate (100 mg) in methanol (3 ml) was added a solution of lithium hydroxide (15.4 mg) in water (1 ml). After stirring vigorously for 4 hours the solvent was removed in vacuo. The residue was diluted with water (10 ml) then neutralised with 2N hydrochloric acid. This solution was applied to an Oasis™ cartridge (6 g) and eluted with water (×2) and methanol (×2). The required fractions were combined and evaporated to afford N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (95 mg).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][N:20]=1)[C:13]([O:15]CC)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][N:20]=1)[C:13]([OH:15])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccnc(NC(=O)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A solution of ethyl 2-benzamidoisonicotinate (1.38 g, 5.09 mmol) and lithium hydroxide monohydrate (1.07 g, 24.45 mmol) in a mixture of tetrahydrofuran (30 mL) and water (15 mL) was stirred at ambient temperature for 4 hours and the organic solvent was removed in vacuo. The aqueous solution was acidified with 10% aqueous hydrochloric acid solution until pH 7. The colorless solid was collected and dried in vacuo to give 2-benzamidoisonicotinic acid as a colorless solid (1.10 g, 89%): 1H NMR (300 MHz, DMSO-d6) δ 13.69 (s, 1H), 11.95 (s, 1H), 8.71 (s, 1H), 8.57-8.56 (m, 1H), 8.05-8.03 (m, 2H), 7.61-7.50 (m, 4H); MS (ES+) m/z 243.1 (M+1).
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][O:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1>>[ClH:1].[CH3:8][O:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: COCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COCC1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A solution of 4M hydrogen chloride in 1,4-dioxane (807 μL, 3.23 mmol) was added to tert-butyl 4-(methoxymethyl)piperidine-1-carboxylate (Intermediate 176, 74 mg, 0.323 mmol) and the mixture was stirred at room temperature for 18 h before being evaporated to dryness to provide the title compound (47.7 mg, 89%). Method B HPLC-MS: MH+ requires m/z=130 Found: m/z=130, Rt=0.24 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.C([Si]([O:26][CH2:27][C:28]([CH3:32])([CH3:31])[C:29]#[CH:30])(C)C)(C)(C)C.[Si](O[Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C>CC#N>[OH:26][CH2:27][C:28]([CH3:32])([CH3:31])[C:29]#[C:30][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#CC(C)(C)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C
Solvent: CC#N
Product: CC(C)(C#Cc1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2)CO
Yield: 28 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with tert-butyl[(2,2-dimethylbut-3-yn-1-yl)oxy]dimethylsilane to give the titled compound as a off-white solid (35 mg, 28%) after deprotection of the tert-butyldimethylsilyl ether (HF/MeCN).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12]OC.FC1C(C)=C(C2C=CC(C(O)=O)=CC=2COC)C=CC=1.[C:35]([O-:38])(=[O:37])[CH3:36].[Na+]>CC(O)=O>[C:35]([O:38][CH2:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])(=[O:37])[CH3:36]
Reactant: CC(=O)[O-]
Reactant: COCc1cc(C(=O)OC)ccc1Br
Agent: COCc1cc(C(=O)O)ccc1-c1cccc(F)c1C
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Br)c(COC(C)=O)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 79.3 %

Procedure:
To a solution of methyl 4-bromo-3-(bromomethyl)benzoate (Intermediate 1 Step 1, 6.5 g, 21 mmol) in AcOH (32.5 mL) was added sodium acetate (3.46 g, 42 mmol) and the reaction mixture was stirred at 100° C. for 15 hours. After concentration in vacuo, the residue was partitioned between EtOAc and water. The organic layer was washed with a 5% aqueous solution of NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. Purification by chromatography (silica, chex/EtOAc) afforded the title compound as a white solid (4.78 g, 79%). 1H NMR (DMSO-d6) δ 8.03 (m, 1H), 7.85 (m, 2H), 5.18 (s, 2H), 3.87 (s, 3H), 2.11 (s, 3H). HPLC (Method A) Rt 4.37 min (purity 98.1%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([OH:30])=[C:24]([O:31][CH3:32])[CH:23]=1>>[OH:30][C:25]1[C:24]([O:31][CH3:32])=[CH:23][C:22]([CH2:21][CH2:20][NH:19][C:2]2[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:27][C:26]=1[O:28][CH3:29]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: COc1cc(CCN)cc(OC)c1O
Product: COc1cc(CCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)C)C2=O)cc(OC)c1O

Procedure:
The title compound was prepared from 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-(2-aminoethyl)-2,6-dimethoxyphenol in a similar manner as described for Example 118. 1H NMR (THF-d8, 500 MHz): δ 1.53 (d, 6H), 2.45 (t, 2H), 3.11 (q, 2H), 3.73 (s, 6H), 4.31-4.39 (m, 1H), 6.03 (s, 2H), 6.47 (t, 1H), 7.22 (s, 1H), 7.46-7.50 (m, 3H), 7.55-7.57 (m, 2H); 13C NMR (125 MHz, THF-d8): δ 19.57, 35.92, 45.47, 46.98, 55.93, 106.13, 106.56, 126.64, 127.87, 128.56, 129.34, 131.86, 135.49, 135.64, 148.12, 158.61; Mass Spectrum: M+H+ 447.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6](=[N:18][NH2:19])[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ClS([N:26]=[C:27]=[O:28])(=O)=O.C(OCC)(=O)C.O>CCCCCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6](=[N:18][NH:19][C:27]([NH2:26])=[O:28])[C:7]2[CH:8]=[CH:9][C:10]([CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CS(=O)(=O)Cc1ccc(C(=NN)c2ccc(Cl)cc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CS(=O)(=O)Cc1ccc(C(=NNC(N)=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
4-chloro-4'-methylsulfonylmethylbenzophenone-hydrazone (1.3 g) and chlorosulfonyl isocyanate (0.63 g) were added to ethyl acetate (100 ml), and the mixture was stirred for one hour at room temperature. Then, water (100 ml) was added, and the mixture was further stirred for 16 hours at room temperature. The reaction mixture was subjected to liquid separation, and the ethyl acetate layer was washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. The residual solid was washed with a solvent mixture of ethyl acetate:n-hexane=4:1, to obtain the desired product (1.2 g, melting point: 189° to 191° C., yield: 80%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[CH:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[N:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH:25]([C:27]([NH2:29])=[O:28])[NH2:26]>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[CH:17]=[C:18](/[C:21](=[N:26]/[NH:25][C:27]([NH2:29])=[O:28])/[CH3:22])[CH:19]=[N:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1cnc2ncc(Cc3ccc4ncccc4c3)n2c1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Product: C/C(=N\NC(N)=O)c1cnc2ncc(Cc3ccc4ncccc4c3)n2c1
Yield: 8.9 %

Procedure:
A solution of 1-(3-(quinolin-6-ylmethyl)imidazo[1,2-a]pyrimidin-6-yl)ethanone (40 mg, 0.132 mmol) and hydrazinecarboxamide hydrochloride (14.9 mg, 0.198 mmol) in methanol (3 mL) was stirred at 40° C. for 2 h. The solvent was removed in vacuo and the residue was purified by HPLC to afford 4.2 mg (8.8%) of the title compound as white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.45 (s, 1H), 9.24 (d, 1H), 8.91 (d, 1H), 8.86 (dd, 1H), 8.30 (d, 1H), 7.98 (d, 1H), 7.89 (s, 1H), 7.72 (dd, 1H), 7.52-7.49 (m, 2H), 6.65 (s, 2H), 4.59 (s, 2H), 2.18 (s, 3H). LCMS (method A): [MH]+=360, tR=2.95 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[NH:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COC(=O)c1ccc(OCC2CCCN2)nc1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (351.7 mg, 0.732 mmol), methyl 2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate (173.0 mg, 0.732 mmol), Et3N (122.4 μl, 0.878 mmol) in DMF (5.2 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane:EtOAc (1:5, v/v) as eluent to afford methyl 2-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate (338.4 mg, 87%) as an oil. To a stirred solution of this compound in THF (5.6 mL) and H2O (1.4 mL) was added LiOH (45.7 mg, 1.91 mmol), and the reaction mixture was stirred at room temp overnight. The mixture was diluted with CHCl3, and treated with sat. NH4Cl, washed with brine, dried over Na2SO4. The solvent was removed under a reduced pressure, and the obtained crude solid was recrystallized from n-hexane-Et2O—CHCl3—MeOH to afford 193.8 mg (59%) 40 as a white crystalline powder. mp 125-128; IR (KBr) 1716, 1600, 1533, 1255 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ1.67-2.03 (m, 4H), 2.50 (s, 3H), 3.33-3.42 (m, 1H), 3.52 (m, 2H), 3.58 (d, J=4.4 Hz, 1H), 3.83 (s, 3H), 4.27-4.31 (m, 2H), 4.42-4.47 (m, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.87-6.95 (m, 3H), 7.11-7.17 (m, 2H), 7.79 (d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 8.14 (dd, J=2.0, 8.8 Hz, 1H), 8.46 (s, 1H), 8.56 (s, 1), 8.69 (d, J=2.0 Hz, 1H), 13.06 (br s, 1H); MS (FAB) m/z 519 (M++1); Anal. Calcd. for C28H30N4O6.1/2H2O: C, 63.75; H, 5.92; N, 10.62. Found: C, 63.61; H, 5.94; N, 10.27.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[C:21]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>ClCCl.N1C=CC=CC=1>[CH3:23][C:21]([C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:29][C:28]2[CH:30]=[CH:31][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:26][CH:27]=2)=[O:13])=[CH:30][CH:31]=1)([CH3:24])[CH3:22]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Temperature: 23 °C
Reaction time: 18 h
Yield: 12.1 %

Procedure:
A solution of 2,2'-dithiobisbenzoyl chloride (1.20 g, 3.50 mmol) in 25 mL of dichloromethane was added to a solution of 4-tert-butylaniline (1.04 g, 6.99 mmol) in 8 mL of pyridine at 23° C. The reaction mixture was stirred for 18 hours at 23° C. under nitrogen atmosphere. The mixture was concentrated, the residue triturated with 5% aqueous HCl, and the resulting solid was collected by filtration and washed with water to yield the crude product. The crude material was recrystallized from ethyl ether-ethanol to yield 0.24 g of the title compound, mp 135°-138° C.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16])([CH3:4])[CH3:3].[NH:18]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([CH:27]=O)[C:21]=2[CH:20]=[CH:19]1.[OH-].[Na+]>C(O)C.O>[CH3:4][C:2]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH:16]=[CH:27][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[CH:20]=[CH:19][NH:18]2)([CH3:1])[CH3:3]
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CC(=O)c1ccccc1OCCNC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)NCCOc1ccccc1C(=O)C=Cc1cccc2[nH]ccc12
Reaction time: 4 h
Yield: 89.1 %

Procedure:
A solution of 5.4 g of 1-[2-{2-(1,1-dimethylethylamino)-ethoxy}-phenyl]-ethanone in 75 ml of ethanol was added with stirring under an inert atmosphere to a mixture of 3.339 g of indole-4-carboxaldehyde and 6 ml of 50% sodium hydroxide solution and after stirring for 4 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with aqueous sodium chloride solution, dried over a deshydrant and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 7.41 g of 1-[2-{2-(1,1-dimethylethylamino)-ethoxy}-phenyl]-3-[1H-indol-4-yl]-2-propen-1-one (E).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][F:20].[Na].N.[Cl-].[NH4+]>O1CCCC1>[F:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]/[CH2:9][CH2:8][OH:7]
Reactant: FCCCCCCCCC#CCCOC1CCCCO1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCC/C=C/CCCCCCCCF

Procedure:
A solution of 12-fluoro-3-dodecyn-1-yl tetrahydropyranyl ether (1.42 g, 5 mmol) in dry tetrahydrofuran (50 ml.) is added slowly to a solution of sodium (920 mg., 40 mmol) in liquid ammonia (300 ml), the colour changing from blue through violet and red to a dull orange. More sodium (1.84 g, 80 mmol) is then added, the mixture becoming green then blue. The volume is increased to 500 ml. with liquid ammonia and the mixture stirred for two hours, after which dry ammonium chloride is added slowly until the color changed to pale yellow. After evaporation of the ammonia the residue is treated with dilute hydrochloric acid (6N., 50 ml.) and thoroughly extracted with ether. The neutral fraction is chromatographed on alumina (grade III, 30 g.). Elution with light petroleum yields 12-fluoro-(E)-3-dodecen-1-ol as a colourless oil, IR (film) 966 cm-1 (Trans C=C).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]2[C:13]3[N:17]([CH2:18][CH2:19][C:20](=[O:21])[C:11]=2[CH:10]=1)[C:16]1[N:22]=[C:23]([C:26]([O:28]CC)=[O:27])[CH:24]=[CH:25][C:15]=1[C:14]=3[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]2[C:13]3[N:17]([CH2:18][CH2:19][C:20](=[O:21])[C:11]=2[CH:10]=1)[C:16]1[N:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=[CH:25][C:15]=1[C:14]=3[CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc2c(C3CCCCC3)c3n(c2n1)CCC(=O)c1cc(OCc2ccccc2)ccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2n1)CCC(=O)c1cc(OCc2ccccc2)ccc1-3
Temperature: 60 °C
Yield: 43.7 %

Procedure:
To a solution of ethyl 3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azulene-9-carboxylate (50 mg, 0.10 mmol) in tetrahydrofuran (2 ml) and methanol (2 ml) was added 4N aqueous sodium hydroxide solution (1 ml), and the mixture was stirred with heating at 60° C. for 1 hr. The reaction mixture was allowed to cool to room temperature. 2N Hydrochloric acid (2 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the precipitated solid was collected by filtration and dried in vacuo to give 3-benzyloxy-12-cyclohexyl-6,7-dihydro-5-oxo-7a,8-diazadibenzo[a,e]azulene-9-carboxylic acid (21 mg, yield 41%).