Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[C:10](=[O:12])[CH3:11].C.[CH:14](=[O:16])[CH3:15]>C(O)(=O)C>[OH:16][CH:14]([CH3:15])[CH2:11][C:10]([C:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:12].[CH3:11][C:10](=[O:12])[CH2:3][CH3:2]
Reactant: CC=O
Reactant: CC(=O)C1=C(C)C=CCC1(C)C
Agent: C
Solvent: CC(=O)O
Product: CC1=C(C(=O)CC(C)O)C(C)(C)CC=C1
Product: CCC(C)=O
Temperature: 10 °C

Procedure:
Into a 2-liter reaction flask equipped with a mechanical stirrer, cooling bath, 250 ml addition funnel, nitrogen purge, water-cooled condenser, gas bubbler and thermometer, is placed 427 ml (1.3 moles) of a 3-molar solution of methyl magnesium chloride in tetrahydrofuran. 200 Grams (1.22 moles) of 2,6,6-trimethyl-1-acetylcyclohexa-1,3-diene are added dropwise from the addition funnel at a rate sufficient to produce methane. Cooling is applied as necessary to maintain the reaction temperature between 30° and 35° C. Following completion of the addition of the 2,6,6-trimethyl-1-acetylcyclohexa-1,3-diene, the reaction mass is stirred until no further methane is evolved. The reaction mass is then cooled to a temperature in the range of from 0° C. to 5° C., and 59 grams of acetaldehyde is added dropwise with stirring while maintaining the reaction mass temperature at about 10° C. The reaction is slightly exothermic. 15 Minutes after the completion of the addition of acetaldehyde, acetic acid is added dropwise while maintaining the temperature of the reaction mass at about 10° C. Following the addition of acetic acid, the reaction mass is permitted to reach room temperature. The reaction mass is then washed into a separatory funnel with water to dissolve the salt therein. The resulting organic layer is washed with saturated sodium chloride, saturated sodium bicarbonate, and then saturated sodium chloride. The washed organic layer is then dried over anhydrous magnesium sulfate and concentrated on a rotovap yielding 256 grams of residue.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([CH:16]([NH:18][OH:19])[CH3:17])=[CH:9][CH:10]=3)[S:5][C:4]=2[CH:3]=1.C[Si]([N:24]=[C:25]=[O:26])(C)C.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13]([O:12][C:11]3[CH:10]=[CH:9][C:8]([CH:16]([N:18]([OH:19])[C:25]([NH2:24])=[O:26])[CH3:17])=[CH:7][C:6]=3[S:5]2)=[CH:14][CH:15]=1
Reactant: CC(NO)c1ccc2c(c1)Sc1cc(Cl)ccc1O2
Reactant: C[Si](C)(C)N=C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc2c(c1)Sc1cc(Cl)ccc1O2)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the product from Step 1 (320 mg, 1.09 mmol) in THF (15 mL) there was added 85% trimethylsilyl isocyanate (295 mg, 2.18 mmol) and the mixture was stirred at room temperature for 45 minutes. After addition of water (5 mL) the mixture was stirred a further 10 minutes, then the THF was evaporated, the residual aqueous suspension diluted with water and filtered to afford the title compound as a white solid, m.p.: dec 173° C. (gassing).
Reaction SMILES: N#N.[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([C:18]([OH:20])=O)[N:17]=2)[O:8][CH2:7][CH2:6][O:5]1.CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C1(C)C=CC=CC=1>[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([C:18]([Cl:29])=[O:20])[N:17]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(CCCCc2nc(C(=O)O)co2)OCCO1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC1(CCCCc2nc(C(=O)Cl)co2)OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-oxazole-4-carboxylic acid (489 mg, 1.92 mmol) in toluene (20 mL) was treated with a drop of DMF followed by oxalyl chloride (0.20 mL, 2.30 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-oxazole-4-carbonyl chloride as a yellow oil. LC-MS-conditions 02: tR=0.96 min [M+H]+=274.37.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[N+:19]([C:22]1[N:23]=[C:24]2[N:29]([CH:30]=1)[CH2:28][CH2:27][C@H:26]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]3)=[CH:35][CH:34]=1)[O:25]2)([O-:21])=[O:20].[F:46][C:47]([F:65])([F:64])[O:48][C:49]1[CH:63]=[CH:62][C:52]([CH2:53][O:54][C:55]2[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>C(Cl)Cl.ClCCCl>[N+:19]([C:22]1[N:23]=[C:24]2[N:29]([CH:30]=1)[CH2:28][CH2:27][C@H:26]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][CH:42]([NH:61][C:58]4[CH:57]=[CH:56][C:55]([O:54][CH2:53][C:52]5[CH:62]=[CH:63][C:49]([O:48][C:47]([F:46])([F:64])[F:65])=[CH:50][CH:51]=5)=[CH:60][CH:59]=4)[CH2:41][CH2:40]3)=[CH:35][CH:34]=1)[O:25]2)([O-:21])=[O:20]
Reactant: Nc1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Reactant: O=C1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCC(Nc4ccc(OCc5ccc(OC(F)(F)F)cc5)cc4)CC3)cc1)CC2
Temperature: 25 °C
Reaction time: 120 h
Yield: 67 %

Procedure:
Sodium triacetoxyborohydride (0.32 g) and acetic acid (1 ml) were added to a 1,2-dichloroethane solution (8 ml) of 1-[4-((R)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-one (0.40 g) and 4-(4-trifluoromethoxybenzyloxy)phenylamine (0.33 g), and the mixture was stirred at room temperature for 5 days. The reaction mixture was diluted with methylene chloride. The result was washed with a potassium carbonate aqueous solution and water in this order, and then dried over magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=1:0→methylene chloride:methanol=9:1) to afford the title compound as a yellow powder (0.46 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O[CH:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:35]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[O:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: OC1Cc2ccccc2C1
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OC1Cc2ccccc2C1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A 0.26 g quantity of 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained in Example 136 was dissolved in 10 ml of tetrahydrofuran. To the obtained solution were added 0.2 g of 2-hydroxyindane, 0.75 ml of diisopropyl azodicarboxylate (40% toluene solution) and 0.31 g of tri(n-butyl)phosphine, and the mixture was stirred at 50° C. After 3 hours, 0.2 g of 2-hydroxyindan, 0.75 ml of diisopropyl azodicarboxylate (40% toluene solution) and 0.31 g of tri(n-butyl)phosphine were further added thereto, and the mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate:dichloromethane=1:1:1), and recrystallized from acetone/diisopropyl ether to give 0.13 g of colorless powdery 3-{2-[3-(indan-2-yloxy)-4-methoxyphenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([N:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)[N:10]=1)[CH2:2]2.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(O)C.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].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>[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:13]2[N:14]=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:10]=[C:11]([N:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)[N:12]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: O=C1CCN(c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)CC1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2nc(N3CCC(=O)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
A suspension of 1-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)piperidin-4-one (1.0 g, 3.1 mmol), 4-aminophenylboronic acid, pinacol ester (1.0 g, 4.7 mmol), and tetrakis(triphenylphosphine)palladium (0.20 g, 0.17 mmol) in aqueous 2 M sodium carbonate solution (3 mL) and 1:1 ethanol/toluene (12 mL) was irradiated in the microwave at 120° C. for 1 hour. After cooling, the biphasic mixture was extracted thrice with ethyl acetate. The extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound as a golden yellow foam.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:14]=1)[C:9]([OH:11])=O)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:30]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:31]([CH3:33])[CH3:32]>C(Cl)Cl.C(Cl)(Cl)Cl.CN(C)C=O>[CH2:16]([O:15][C:13]1[CH:12]=[C:8]([CH:7]=[C:6]([O:5][CH2:1][CH:2]([CH3:3])[CH3:4])[CH:14]=1)[C:9]([C:38]1[CH:39]=[CH:40][C:35]([O:34][CH2:30][CH:31]([CH3:32])[CH3:33])=[C:36]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:37]=1)=[O:11])[CH:17]([CH3:19])[CH3:18]
Reactant: CCOC(=O)CCc1ccccc1OCC(C)C
Reactant: CC(C)COc1cc(OCC(C)C)cc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cc(C(=O)c2cc(OCC(C)C)cc(OCC(C)C)c2)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
In 11 ml of methylene chloride is dissolved 1.11 g of 3,5-diisobutoxybenzoic acid. To the solution thus obtained, 0.44 ml of oxalyl chloride is added at ambient temperature, and then 20 μl of N,N-dimethylformamide is added and stirred at ambient temperature for 2 hours. Then, at −20° C., 1.67 g of aluminum chloride is added and thereafter 1.15 g of ethyl 3-(2-isobutoxyphenyl)propanoate is added, and the mixture thus obtained is stirred at 5-10° C. for 10 minutes. The reaction mixture is added to a mixture of chloroform and ice water, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 1.75 g of ethyl 3-[5-(3,5-diisobutoxybenzoyl)-2-isobutoxyphenyl]propanoate as a yellow-colored oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:22].CO>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:22])[C:13](=[O:18])[CH2:12][CH2:11]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C1CCc2cc(-c3cccc(F)c3)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)CCc2cc(-c3cccc(F)c3)ccc21
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.) solution of 6-(3-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one (48 mg, 0.20 mmol) in anhydrous tetrahydrofuran (2 mL) was added 95% sodium hydride (10 mg, 0.40 mmol). The reaction mixture was stirred for 5 minutes, then warmed to 40° C. for 15 minutes under an atmosphere of dry N2. Iodomethane (142 mg, 1.00 mmol) was added, and the resulting mixture was stirred at room temperature for 15 hours. Methanol (2 mL) was added, and the mixture stirred for 10 minutes. Solvent was removed from the reaction mixture under reduced pressure, ethyl acetate (30 mL) and 30% ammonium chloride (10 mL) were added, the organic phase was washed with water (10 mL), 30% ammonium chloride (15 mL) and brine (15 mL), and the organic layer was concentrated under reduced pressure to give 6-(3-fluorophenyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. MS mz 256.1 (M+H), anal HPLC 92% in purity. 1H NMR (400 MHz; CDCl3) δ 7.46 (dd, J=8.6 Hz, 2.3 Hz, 1H); 7.30-7.42 (m, 3H); 7.25 (m, 1H); 6.98-7.10 (m, 2H); 3.39 (s, 3H); 2.97 (t, J=7.4 Hz, 2H); 2.70 (t, J=7.4 Hz, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23](=[O:27])[CH2:24][CH2:25]Br.[CH2:28](N(CC)CC)C>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:27])[CH2:24][CH2:25][CH2:28][N:16]1[CH2:15][CH2:14][CH:13]([O:12][C:11]2[CH:19]=[CH:20][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:18][CH2:17]1
Reactant: COC(=O)CCBr
Reactant: CCN(CC)CC
Reactant: c1ccc(Oc2ccc(OC3CCNCC3)cc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCN1CCC(Oc2ccc(Oc3ccccc3)cc2)CC1
Reaction time: 48 h
Yield: 67.7 %

Procedure:
To a solution of 4-(4-Phenoxy-phenoxy)-piperidine (152 mg, 0.5 mmol) in anhydrous CH2Cl2 (0.5 mL) was added methyl-3-bromopropionate (99 mg, 0.55 mmol) in CH2Cl2 (0.5 mL) and triethylamine (101 mg, 1.0 mmol). The resulting mixture was purged with nitrogen and stirred at if for 48 h. CH2Cl2 was removed in vacuo and crude mixture was partioned between EtOAc and water. EtOAc layer was removed, washed with brine, dried over anhydrous MgSO4 and concentrated. The crude mixture was purified by silica gel flash chromatography (40-70% EtOAc/Hexane) to obtain the product as yellow oil (125 mg, 68%): 1H NMR (400 MHz, DMSO-d6); δ 1.54-1.69 (m, 4H), 1.89-1.92 (m, 2H), 2.14-2.18 (m, 2H), 2.26-2.33 (m, 4H), 2.64-2.67 (m, 2H), 3.58 (s, 3H), 4.27-4.31 (m, 1H), 6.91-6.96 (m, 6H), 7.04-7.08 (m, 1H), 7.32-7.36 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12]([CH:14]2[CH2:17][CH2:16][CH2:15]2)=O)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.N>C(#N)C>[CH:14]1([C:12]2[C:7]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=3)[CH2:9][CH2:10][N:11]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(CCNC(=O)C2CCC2)cc1
Agent: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(C1CCC1)=NCC2
Yield: 48.2 %

Procedure:
A solution of this amide (9 g) in dry acetonitrile (170 ml) containing phosphorus oxychloride (23.7 ml) was heated under reflux for 43 hours. The cooled mixture was then poured onto dilute ammonia solution and this mixture extracted with ethyl acetate (3×150 ml). The ethyl acetate solution was then extracted with dilute hydrochloric acid (3×100 ml). The aqueous acid extracts were basified by addition of aqueous ammonia solution and the mixture extracted with ethyl acetate. The organic extracts were washed with brine and concentrated to give an oil which was distilled at 190° C./0.2 mbar to give 1-cyclobutyl-7-methoxy-3,4-dihydroisoquinoline as a colourless solid (4 g), mp 44°-46° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:8]=[C:7]3[C:20]4[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][C:21]=4[S:22][C:5]=1[C:6]=23.B(Br)(Br)[Br:30].CO.[BrH:35]>ClC(Cl)C>[BrH:30].[BrH:35].[NH2:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:8]=[C:7]3[C:20]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:21]=4[S:22][C:5]=1[C:6]=23
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1cc(OC)ccc1-2
Reactant: BrB(Br)Br
Agent: Br
Agent: Cl
Solvent: CO
Solvent: CC(Cl)Cl
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1cc(O)ccc1-2
Temperature: 78 °C
Yield: 96 %

Procedure:
A 25° C. suspension of 75 g (0:17 mol) of 5-amino-N,N-diethyl-8-methoxy-2H-[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine, dihydrochloride (1) in 1.35 L of dichloroethane was treated dropwise with 213 g (0.85 mol) of boron tribromide. The mixture was heated at 78° C. for 16 hr, treated cautiously with 1.5 L of methanol, then heated at reflux for 6 hr. After cooling to 25° C., then chilling at -5° C. overnight, the precipitated solids were collected by filtration, washed with cold methanol, and dried at 2 mm/48° C./24 hr to give 84.3 g (96%) of 7 as a salt with 2.0 equivalents of hydrogen bromide, mp 318° C. (dec), 98.3% pure by HPLC.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[S:10](=[O:14])(=[O:13])([OH:12])[OH:11].S(O)(O)(=O)=O.[CH2:20]([S:27]SCCC(N)C(O)=O)CC(N)C(O)=O>O>[NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[S:10]([O-:14])([O-:13])(=[O:12])=[O:11].[CH3:20][SH2+:27].[CH3:4][SH2+:5]
Reactant: NC(CCSSCCC(N)C(=O)O)C(=O)O
Reactant: O=S(=O)(O)O
Agent: CSCCC(N)C(=O)O
Solvent: O
Product: C[SH2+]
Product: O=S(=O)([O-])[O-]
Temperature: 135 °C
Yield: 200.8 %

Procedure:
A 50 ml capacity glass reaction flask was charged with 5 g (33.56 mmol) of DL-methionine, 30.20 g (302.04 mmol) of concentrated sulfuric acid and 16.4 g of water and then the contents were heated under reflux for 3.5 hours at 135° C. in a stream of nitrogen. The reaction solution was analyzed by liquid chromatography. As a result, it was found that 2.92 g (7.97 mmol) of DL-homocystine sulfate and 4.96 g (16.00 mmol) of DL-methionine-S-methylsulfonium sulfate were formed. The conversion ratio was 100% and the selectivity was 48%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C:9]([C:14](=[O:20])[N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])([CH2:12][CH3:13])[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:22][N:23]([CH:25](N(C)C)N(C)C)[CH3:24]>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:21])[O:8][C:9]([C:14](=[O:20])[N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])([CH2:12][CH3:13])[C:10]=1/[CH:11]=[CH:22]/[N:23]([CH3:25])[CH3:24])=[O:5])[CH3:2]
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: CCOC(=O)C1=C(C)C(CC)(C(=O)N(CC)CC)OC1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(/C=C/N(C)C)C(CC)(C(=O)N(CC)CC)OC1=O
Reaction time: 17 h
Yield: 90.2 %

Procedure:
To a solution of 500.0 mg of compound (12) as obtained from example 5 (22.73 mmol) in 3.0 mL dimethyl formamide were added at room temperature 3.0 mL tris(dimethylamino)methane (17.3 mmol, 10.3 eq). The color of the reaction mixture changed from orange to brown and further to green. After 17 h, the mixture was diluted with 50 mL dichloromethane, washed with 25mL aqueous hydrochloric acid (1.0 M) and washed again three times with 50 mL brine. The organic phase was dried over 2 g sodium sulfate and was filtered. The filter cake was washed with 4 mL dichloromethane. After evaporation of the solvent in a rotary evaporator (50° C., 5 mbar), the crude product was obtained as an orange oil (627.0 mg, 106% by weight), which was liberated from residual dimethyl formamide in a high vacuum rotary evaporator (50° C., 0.5 mbar) yielding the title product (536.0 mg, 1.517 mmol, 90% by weight) as orange crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CN(C)C=O>[CH2:24]([N:26]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)no1
Yield: 81.9 %

Procedure:
0.99 g (3 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature overnight in 1.2 g (16 mmol) of diethylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 9/1 there was obtained 0.9 g (81%) of 3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 153°-154°, which was converted into the hydrochloride.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[I-].[CH3:26][CH3:27].[CH3:28][C:29](CC)=O>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:28][CH3:29])=[C:13]([O:18][CH2:26][CH3:27])[CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)c(O)c2)cc1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1OCC
Temperature: 100 °C
Yield: 67 %

Procedure:
4′-methanesulfonyl-biphenyl-3,4-diol (30 mg) and potassium carbonate (38 mg) were dissolved in methylethylketone. Afterward, ethane iodide (0.027 ml) was added and refluxed for 3 hours at 100° C. After filtering just potassium carbonate, the residue was separated through a silica gel attributed chromatography (an eluting agent: ethylacetate/n-hexane=1/1, v/v). As a result, the present compound (20 mg, productive yield 67%) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CCN(CC)CC.[N:16]1([S:22](Cl)(=[O:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(#N)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)(=[O:24])=[O:23])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: Nc1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=S(=O)(Nc1ccc(I)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 10 g of 4-iodoaniline (45.6 mmol) in 200 ml of acetonitrile there are added 6.41 ml of Et3N (45.6 mmol) and 8.47 g of morpholine-4-sulphonyl chloride (45.6 mmol). The reaction mixture is stirred for 16 hours at ambient temperature. The acetonitrile is evaporated off in vacuo, and the residue is taken up in 1N HCl and extracted with CH2Cl2. The organic phases are combined, washed with brine, dried (MgSO4) and treated with animal charcoal to yield the title product.
Reaction SMILES: FC1C=CC(CN2C(=O)N(C3SC(C(OCC)=O)=C(C)C=3)C=N2)=CC=1.[CH3:26][C:27]1[CH:31]=[C:30]([N:32]2[C:36](=[O:37])[N:35]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=3)[N:34]=[CH:33]2)[S:29][C:28]=1[C:49]([O:51]CC)=[O:50]>>[CH3:26][C:27]1[CH:31]=[C:30]([N:32]2[C:36](=[O:37])[N:35]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:47])([F:48])[F:46])=[CH:43][CH:44]=3)[N:34]=[CH:33]2)[S:29][C:28]=1[C:49]([OH:51])=[O:50]
Reactant: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)cc1C
Agent: CCOC(=O)c1sc(-n2cnn(Cc3ccc(F)cc3)c2=O)cc1C
Product: Cc1cc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Yield: 78 %

Procedure:
Following the procedure as described in Example 30, making variations as required to replace ethyl 5-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-3-methylthiophene-2-carboxylate with ethyl 3-methyl-5-(5-oxo-1-(4-(trifluoromethyl)-benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 78% yield: 1H NMR (300 MHz, DMSO-d6) δ 12.98 (br s, 1H), 8.78 (s, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.28 (s, 1H), 5.09 (s, 2H), 2.47 (s, 3H); MS (ES−) m/z 382.2 (M−1).