Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1.Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>CN(C)C=O>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[CH2:16][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C1CCCc2ccc(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCCc2ccc(OCc3ccc4ccccc4n3)cc21
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a slurry of NaH (0.29 g, 12.25 mmol) in 25 mL dimethylformamide under nitrogen at 0° C. is added portionwise 7-hydroxy-1-tetralone (2.0 g, 12.33 mmol) over 5 minutes. After half an hour, 2-(chloromethyl)quinoline (2.2 g, 12.43 mmol) is added in 10 mL dimethylformamide. The ice bath is removed and the reaction mixture is stirred overnight. The solvent is then removed in vacuo and the residue is partitioned between 1N sodium hydroxide and methylene chloride. The organic layer is separated, dried over magnesium sulfate, evaporated down to an oil, and chromatographed on silica gel. Elution with 9-1 methylene chloride/ethyl acetate gives 2.0 g(54%). This material is recrystallized from acetonitrile to afford 1.3 g (35%) of yellow crystals, m.p. 98.5°-101.5° C.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[Br:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1>ClCCl>[CH3:8][C:3]1[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:14])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10].[NH2:13][N+:20]1[CH:21]=[C:16]([Br:15])[CH:17]=[CH:18][C:19]=1[NH2:22]
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Nc1ccc(Br)c[n+]1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
O-(Mesitylsulfonyl)hydroxylamine (3.84 g) dissolved in dichloromethane (150 mL) was added over a period of 1 h to a stirred solution of 5-bromo-pyridin-2-ylamine (3.00 g) in dichloromethane (100 mL) chilled in an ice bath. The cooling bath was removed and the mixture was stirred at room temperature for 15 min. The precipitate was separated by filtration, washed with dichloromethane, and dried to give the title compound as a colorless solid. Yield: 5.04 g (75% of theory); Mass spectrum (ESI+): m/z=188/200 (Br) [M1+H]+; Mass spectrum (ESI): m/z=199 [M2−H]−.
Reaction SMILES: N1C=CC=CC=1.S(Cl)(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([C:23]1[C:24]([O:29][CH3:30])=[N:25][CH:26]=[CH:27][CH:28]=1)O.[Cl-:31].[NH4+]>ClCCl>[Cl:31][C:15]1([C:23]2[C:24]([O:29][CH3:30])=[N:25][CH:26]=[CH:27][CH:28]=2)[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([Cl:11])[CH:13]=2)[NH:17][C:16]1=[O:21]
Reactant: COc1ncccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Reactant: [Cl-]
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyridine (0.33 ml) and thionyl chloride (0.30 ml) were added successively to an ice-cold solution of the intermediate from step A (1.1 g, 3.44 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at 0° C. for 1 h and then saturated ammonium chloride solution was added. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude intermediate was rapidly employed without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([OH:13])=O)[S:8][C:6]=2[N:7]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)=[O:13])[S:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: O=C(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C1CCN(C(=O)c2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carboxylic acid (200 mg, 0.67 mmol), 2-piperidin-4-ylpropan-2-ol (105 mg, 0.73 mmol), HATU (278 mg, 0.73 mmol) and DIPEA (130 μL, 0.75 mmol) in DCM (7 mL) was allowed to stir at r.t. for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, MeOH:DCM, 0-2%) affording the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ 5.15 (1 H, d, J=13.36 Hz), 4.79 (1 H, d, J=13.25 Hz), 4.35 (4 H, brd s), 3.85 (4 H, t, J=4.75 Hz), 3.16-3.13 (1 H, m), 1.92 (2 H, t, J=15.39 Hz), 1.75-1.60 (1 H, m), 1.49-1.38 (4 H, m), 1.22 (6 H, d, J=6.97 Hz).
Reaction SMILES: [CH:1]1([S:7]([CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O.O>[CH:1]1([S:7]([CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:33][CH2:32][C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[O:23])=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])(=[O:8])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)C1CCCCC1
Reactant: NCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCCCC1
Yield: 39.9 %

Procedure:
A solution of 4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)benzoic acid (500 mg, 1.38 mmol, 1.00 equiv), pyridin-3-ylmethanamine (180 mg, 1.67 mmol, 1.20 equiv), EDCI (320 mg, 1.68 mmol, 1.20 equiv), HOBt (220 mg, 1.63 mmol, 1.20 equiv) and triethylamine (420 mg, 4.16 mmol, 3.00 equiv) in N,N-dimethylformamide (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with 15 mL of water and ice. The precipitate was collected by filtration, washed with water and dried in a vacuum oven to give 0.25 g (40%) of 4-(4-(cyclohexylsulfonylmethyl)-5-methyloxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid LC-MS: (ES, m/z): 454 [M+H]+, 347, 306, 238, 120 1HNMR (400 MHz, CDCl3, ppm) δ 8.97 (s, 1H), 8.57 (s, 2H), 8.21-8.05 (t, 4H), 7.54 (s, 2H), 4.73 (s, 2H), 4.17 (s, 2H), 3.02-2.98 (d, 2H), 2.90-2.50 (m, 6H), 2.31-2.20 (d, 2H), 1.95 (s, 2H), 1.74-1.61 (m, 3H), 1.29 (s, 3H
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][NH:6][CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:15])C.[N+]([O-])(O)=O.C[C:22]1C=C(C)N(C(N)=N)[N:23]=1>C(O)C>[CH3:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[CH2:7][N:6]1[CH2:5][C:4](=[O:16])[NH:23][C:22]1=[N:15]2
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: CCOC(=O)CNCc1c(C)cccc1N
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: Cc1cccc2c1CN1CC(=O)NC1=N2
Yield: 61.9 %

Procedure:
A mixture of N-(2-amino-6-methylbenzyl)glycine ethyl ester (1.097 g, 0.0049 mole) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (0.993 g, 0.0049 mole) in absolute ethanol (15 ml) was heated at reflux for 64 hours. The mixture then was filtered and the product washed with hot ethanol to yield the title compound (0.610 g, 61%); identical (ir, nmr) with authentic material prepared according to the procedure of J. Med. Chem., 18, 224 (1975)).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:15].[CH3:16]O.[CH:18]([O:21]C(C)C)(C)C>CO>[ClH:15].[CH3:18][O:21][C:11]1([O:14][CH3:16])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)OC(C)C
Agent: Cl
Product: COC1(OC)CCNCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidinone (400 mg, 2.01 mmol) was dissolved in methanol (4 mL), and the solution was added with 10% hydrogen chloride-methanol solution (4 mL), followed by stirring at 50° C. for 2 hours. The reaction mixture was added with diisopropyl ether and the precipitated solid was collected by filtration, washed with diisopropyl ether and then dried under reduced pressure to obtain 4,4-dimethoxypiperidine hydrochloride (238 mg, yield 65%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([CH3:13])=[CH:11][C:6]2[C:7]([CH3:10])=[CH:8][O:9][C:5]=2[CH:4]=1.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1>O1CCOCC1>[CH3:10][C:7]1[C:6]2[CH:11]=[C:12]([CH3:13])[C:3]([N:2]3[CH:16]=[CH:20][CH:19]=[CH:18]3)=[CH:4][C:5]=2[O:9][CH:8]=1
Reactant: COC1CCC(OC)O1
Reactant: Cc1cc2c(C)coc2cc1N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc2c(C)coc2cc1-n1cccc1

Procedure:
5 ml of 6N hydrochloric acid are added to a mixture of 7.5 g (46.5 mmole) of 6-amino-3,5-dimethylbenzofuran, 7.5 ml (58 mmole) of 2,5-dimethoxytetrahyrofuran and 150 ml of dioxane and the whole is boiled under reflux for 40 minutes. The whole is concentrated by evaporation in vacuo and the residue is taken up in methylene chloride and washed three times with water. The crude product obtained after drying and concentration by evaporation of the organic phase is chromatographed over silica gel with petroleum ether/ether. Subsequent distillation of the pure fractions in a bulb tube (120°/4.10-2 torr) yields 3,5-dimethyl-6-(pyrrol-1-yl)-benzofuran having a melting point of 43°-45°.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:21])[S:13][C@@H:12]2[C@H:14]([NH2:17])[C:15](=[O:16])[N:11]2[C@H:10]1[C:18]([OH:20])=[O:19].C[Si](C)(C)Cl.Cl[C:28]1[C:33]([O:34][C:35](=[O:52])[CH:36]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:37](OC2C=CC=CC=2)=[O:38])=[C:32](Cl)[C:31](Cl)=[C:30](Cl)[C:29]=1Cl.C(=O)(O)[O-].[Na+:61]>C(Cl)Cl>[Na+:61].[O:34]([C:35]([CH:36]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:37]([NH:17][CH:14]1[C:15](=[O:16])[N:11]2[CH:10]([C:18]([O-:20])=[O:19])[C:9]([CH3:21])([CH3:8])[S:13][C@H:12]12)=[O:38])=[O:52])[C:33]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Oc1ccccc1)C(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccccc3)c3ccccc3)C(=O)N2C1C(=O)[O-]
Temperature: 35 °C
Reaction time: 1 h

Procedure:
56 ml. (0.4 moles) of triethylamine are added to a suspension of 42 g. (0.2 moles) of 6-APA in 600 ml. of methylene chloride. Subsequently 430 g. (0.4 moles, 50 ml.) of trimethyl chlorosilane are added to the obtained solution at 10° C., and the mixture is stirred for 60 minutes. Thereafter the mixture is heated to 35° C., 104 g. (0.2 moles) of phenylmalonic acid phenylester pentachlorophenyl ester are added, and subsequently 28 ml. (0.2 moles) of triethylamine are introduced dropwise into the mixture. The reaction mixture is stirred at room temperature for 3 hours, thereafter it is neutralized to pH=7 with 200 ml. of 8% aqueous sodium bi-carbonate solution.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=3)[N:31]=2)=[CH:23][CH:22]=1.[CH3:39][N:40]([CH3:44])[CH2:41][C:42]#[CH:43]>C(NCC)C.C(#N)C.Cl[Pd]Cl.[Cu]I>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([CH2:43][C:42]#[C:41][N:40]([CH3:44])[CH3:39])=[CH:34][CH:33]=3)[N:31]=2)=[CH:23][CH:22]=1
Reactant: C#CCN(C)C
Reactant: Fc1ccc(-c2nc(-c3ccc(Br)cc3)cs2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCNCC
Product: CN(C)C#CCc1ccc(-c2csc(-c3ccc(F)cc3)n2)cc1
Reaction time: 0.25 h

Procedure:
In a 100 ml flask is placed triphenylphosphine (80 mg, 10%), PdCl2 (40 mg, 5%) and 2-(4′-fluorophenyl)-4-(4′-bromophenyl)thiazole (0.98 g, 2.9 mmol) in 20 mL of diethylamine. After stirring for 15 min under N2 atmosphere, CuI (30 mg, 5%) and 1-dimethylamino-2-propyne (0.27 g, 3.18 mmol) in 20 ml of acetonitrile are added to the mixture. After 18 h of heating, the solvent is evaporated under reduced pressure and the residue is filtered through silica gel pad (50 g) using CHCl3 (400 mL) and 2% MeOH in CHCl3(400 mL). A large portion of unreacted 2-(4′-fluorophenyl)-4-(4′-bromophenyl)thiazole is recovered after removal of chloroform filtrate (0.55 g, 56%). The second part of the filtrate (2% MeOH in CHCl3) is concentrated and the residual solid is then purified over silca gel column eluting with 2% MeOH in CHCl3. 2-(4′-fluorophenyl)-4-[4′-(3-dimethylamino-2-propyn-1-yl)phenyl]thiazole is obtained after concentration and trituration with hexane (0.25 g, 27% yield), mp. 98-9° C. 1H NMR (CDCl3): δ 2.39 (s, 6H), 3.50 (s, 2H), 7.16 (t, 2H), 7.48 (s, 1H), 7.51 (d, 2H), 7.93 (d, 2H), 8.03 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[Cl:37][C:38]1[CH:39]=[C:40](CO)[CH:41]=[CH:42][CH:43]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:37])[CH:43]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCc4cccc(Cl)c4)cc3C)c2cc1OC
Yield: 77 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (3-chlorophenyl)methanol (67 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (117 mg, yield 71%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[CH:3]=1.Br[CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:16][CH2:15][N:10]3[C:9](=[N:13][CH:12]=[CH:11]3)[C:4]=2[CH:3]=1
Reactant: Oc1ccc(Br)cc1-c1ncc[nH]1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)-c1nccn1CCO2
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
Into a 20 L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 4-bromo-2-(1H-imidazol-2-yl)phenol (835 g, 3.49 mol, 1.00 equiv) in N,N-dimethylformamide (8.5 L), 1,2-dibromoethane (2366 g, 12.59 mol, 3.60 equiv), potassium carbonate (1930 g, 4.00 equiv), and Cs2CO3 (1160 g, 1.00 equiv). The resulting solution was stirred at 100° C. overnight, quenched by the addition of 20 L of water/ice and extracted with 4×10 L of ethyl acetate. The combined organic layers were washed with 4×5 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from EA:PE (1:2) to afford 350 g (38%) of 9-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]([CH3:28])([CH3:27])[CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:15]=2[N:16]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:39])(=O)=O)=CC=1>O1CCCC1>[CH3:9][C:10]([CH3:27])([CH3:28])[CH2:11][C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]([F:39])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:17][C:15]=2[N:16]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)C(C)c1ccc2oc(CC(C)(C)C)nc2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(F)c1ccc2oc(CC(C)(C)C)nc2c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of lithium diisopropylamide (2.0M solution in tetrahydrofuran/ethylbenzene/heptane, 4.55 ml, 0.009 mol) was added, dropwise, to a solution of methyl 2-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]propionate (2.5 g, 0.009 mol) in tetrahydrofran (65 ml) at −70° C. under a nitrogen atmosphere and the mixture was stirred at −70° C. for 1 hour. A solution of N-fluorobenzensulfonimide (2.9 g. 0.009 mol) in tetrahydrofuran (15 ml) was added and the mixture was stirred at −70° C. for a further 1 hour. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature, with stirring over 1½ hours. The mixture was quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:dichloromethane 1:99, to give methyl 2-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]-2-fluoropropionate (2.06 g).
Reaction SMILES: O[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[F:14])[N:5]=[C:4]2[CH2:15][CH2:16][S:17][CH2:18][C:3]=12.P(Cl)(Cl)([Cl:21])=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:21][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[F:14])[N:5]=[C:4]2[CH2:15][CH2:16][S:17][CH2:18][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1c2c(nn1-c1ccc(Cl)cc1F)CCSC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Fc1cc(Cl)ccc1-n1nc2c(c1Cl)CSCC2
Reaction time: 16 h

Procedure:
12.4 Parts of 3-hydroxy-2-(4-chloro-2-fluorophenyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole was reacted with 6.7 parts of phosphorus oxychloride at 155° C. for 3 hours, the reaction mixture poured into 250 parts of chloroform and 250 parts of saturated aqueous NaHCO3 and stirred for 16 hours. The aqueous portion was extracted with 200 parts of chloroform, the chloroform portions combined and washed twice with 200 parts of water, dried with anhydrous magnesium sulfate, and evaporated under a reduced pressure of 50 to 300 mm Hg. to give 6.0 parts of 3-chloro-2-(4-chloro-2-fluorophenyl)-2,4,6,7-tetrahydro-thiopyrano[4,3-c]pyrazole as a black-brown oil which when contacted with a mixture of ether and pentane changed into a light brown solid, m.p. 97°-99° C.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([N:18]=[C:19]=[O:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]>C1C=CC=CC=1>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:19]([NH:18][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][CH3:8])[CH:11]=1)=[O:20]
Reactant: CN1CCCC1=N
Reactant: COc1ccc(N=C=O)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)N=C2CCCN2C)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
After dissolving 5.4 g. (0.055 mole) of 2-imino-1-methylpyrrolidine in dry benzene, 9.85 g. (0.055 mole) of 3,4-dimethoxyphenylisocyanate (prepared according to the method of J. G. Lombardino and C. T. Gerber, J. Med. Chem., 7, Jan. 1964, p. 101), dissolved in dry benzene, is added dropwise to the solution. The reaction mixture is stirred at room temperature overnight (about 16 hrs.). The solvent is evaporated in vacuo and the residue, which solidifies on cooling, is triturated with anhydrous methanol. Repeated recrystallization from methanol yields the pure product, 1-(1-methyl-2-pyrrolidylidene)-3-(3,4-dimethoxyphenyl)urea, m.p. = 118°-120° C.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:19]1([C:9]2[C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:11][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:28][C:29]4[CH:34]=[N:33][C:32]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:31][CH:30]=4)=[CH:26][CH:25]=3)[N:8]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClCc1ccc(-c2ccccc2)nc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)nc3)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (600 mg), 5-chloromethyl-2-phenylpyridine (350 mg), potassium carbonate (460 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(6-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (710 mg, yield: 85%). This was recrystallized from acetone-hexane. Melting point: 155–156° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:12]C)(=[O:11])[CH2:4][O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[N:23]([CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)[CH3:24].C(O)(=O)C>C1C=CC=CC=1.O>[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[N:23]([CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31](/[CH:32]=[C:6](\[O:5][CH2:4][C:3]([OH:12])=[O:11])/[C:7]([O:9][CH3:10])=[O:8])=[CH:30][CH:29]=1)[CH3:24]
Reactant: COC(=O)COCC(=O)OC
Reactant: CN(CCOc1ccc(C=O)cc1)c1nc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)/C(=C/c1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of sodium hydride (60% dispersion in mineral oil, 0.30 g), dimethyl diglycolate (0.81 g) and 4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]benzaldehyde (2.22 g) in dry benzene (50 mL) was stirred at room temperature overnight. Acetic acid (1 mL) was added, the mixture was poured onto iced water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried (MgSO4) and evaporated. The resulting oil was chromatographed on silica gel using 2% methanol in dichloromethane, and the product crystallised from ethyl acetate, mp 111-112° C.
Reaction SMILES: [C:1](O)(=O)C.Cl.[NH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[NH:11][CH:10]=1.C(=O)CC>CO>[CH2:1]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:9]=2[CH2:8][CH2:7][NH:6]1
Reactant: CC(=O)O
Reactant: NCCc1c[nH]c2ccc(O)cc12
Agent: Cl
Solvent: CO
Solvent: CCC=O
Product: Oc1ccc2[nH]c3c(c2c1)CCNC3
Temperature: 75 °C

Procedure:
Acetic acid was added dropwise to a solution of 3-(2-amino-ethyl)-1H-indol-5-ol hydrochloride (200 mg) in 7 mL methanol until the pH=4. Propionaldehyde (0.2 mL) was added and the mixture was heated at 75° C. in a sealed tube for 1 h. The tube was cooled to rt and unsealed. The solvent was evaporated to yield 190 mg of 2,3,4,9-tetrahydro-1H-β-carbolin-6-ol.