Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:2]=[O:3].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH2:27][CH:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[NH:25][N:24]=2)[CH:18]=1>CN(C=O)C.ClCCCl.C(=O)(O)[O-].[Na+]>[OH:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH:26]1[N:25]([C:2]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:3])[N:24]=[C:23]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[CH2:27]1
Reactant: O=C=Nc1ccccc1Oc1ccccc1
Reactant: Oc1ccccc1C1CC(c2cccnc2)=NN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccccc1Oc1ccccc1)N1N=C(c2cccnc2)CC1c1ccccc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 12.9 %

Procedure:
To a solution of 1-isocyanato-2-phenoxybenzene (29.14 mg, 0.138 mmol) in DMF (0.5 mL) was added a solution of 2-(3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (29.9 mg, 0.125 mmol) in DMF (0.5 mL) and DCE (0.5 mL) at rt. The reaction mixture was shaken at rt for 20 h. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (2 mL) and extracted with DCM. The organic solutions were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by RP-HPLC to give 5-(2-hydroxyphenyl)-N-(2-phenoxyphenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazole-1-carboxamide (I-85) (7.24 mg, 12.8%). LCMS: (FA) ES+ 451.3.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)(O)[O-].[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>C(#N)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1c(N)cccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(Br)cccc1NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
Step 1 A mixture of 3-bromo-2-methylaniline (0.620 mL, 5.03 mmol) and sodium bicarbonate (565 mg, 6.73 mmol) in acetonitrile (4.5 mL) was treated with 2-bromo-1-phenylethanone (500 mg, 2.51 mmol) and the mixture was stirred at rt. After 24 h, the suspension was filtered and the precipitate was suspended and sonicated in water, collected again by filtration, washed with water and dried to provide 2-(3-bromo-2-methylphenylamino)-1-phenylethanone as an off-white solid (508 mg, 67%). 1H NMR (400 MHz, chloroform-d) δ8.00-8.06 (2H, m), 7.61-7.68 (1H, m), 7.53 (2H, t, J=7.6 Hz), 6.94-7.01 (2H, m), 6.51-6.58 (1H, m), 5.06 (1H, t, J=4.1 Hz), 4.62 (2H, d, J=4.4 Hz), 2.40 (3H, s). Mass spectrum m/z 304, 306 (M+H)+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].C([N-]C(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.[CH:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[CH:30]=[C:29]2[CH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=1[O:49][CH3:50])=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([CH:2]([CH2:3][CH3:4])[CH:24]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH2:35][CH2:36][CH3:37])[CH:30]=[C:29]2[CH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][C:40]=1[O:49][CH3:50])[OH:25])([OH:6])=[O:5]
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C=O)ccc21
Reactant: CCCC(=O)O
Agent: CC(C)[N-]C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(C(O)C(CC)C(=O)O)ccc21
Temperature: 25 °C

Procedure:
A solution of the dianion of butyric acid (5.6 mmol) [prepared from butyric acid (5.6 mmol) and lithium di-isopropylamide (5.6 mmol) in tetrahydrofuran (THF) (30 ml) and dimethylpropyleneurea (11.2 mmol)]was added to a solution of methyl 4-[5-formyl-1-propylindol-3-ylmethyl]-3-methoxybenzoate (2.0 g) in THF (15 ml) cooled in an ice-bath, under a nitrogen atmosphere, at such a rate as to maintain the temperature of the reaction below 10°. The mixture was allowed to warm to room temperature, stirred for an additional hour, poured into 20% (w/v) citric acid solution (150 ml), and extracted with ethyl acetate. The organic extracts were washed (water (twice), brine), dried (MgSO4) and evaporated to give a yellow oil. The product was purified by flash chromatography, eluting with 80:20:2 toluene:ethyl acetate:acetic acid, to give methyl 4-[5-(2-carboxy-1-hydroxybutyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (1.25 g, 48%, as a separable mixture of diastereomers), as a foam; isomer A partial NMR (300 Mz, DMSO-d6): 0.66(t, 3H, CH3), 0.81 (t, 3H, CH3), 3.83(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.53(d, 1H, CHOH), 5.23(br s, 1H, CHOH); isomer B partial NMR (300 Mz, DMSO-d6): 0.85(m, 6H, 2×CH3), 3.83(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.62(d, 1H, CHOH), 5.20(br s, about 1H, CHOH).
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[CH3:6][O:7][C:8]([CH2:10][C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=O)=[O:9].C([O-])(=O)C.[Na+]>O>[Br:2][CH2:3][CH2:4][NH:5][C:11]([CH2:10][C:8]([O:7][CH3:6])=[O:9])=[CH:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: NCCBr
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)C=C(CC(=O)OC)NCCBr
Reaction time: 0.12 h
Yield: 87.1 %

Procedure:
2-Bromoethylamine hydrobromide (12.35 g, 60 mmol) was dissolved in water (30 mL) at room temperature (20° C.) with stirring, and dimethyl 1,3-acetonedicarboxylate (10.0 g, 57 mmol) was added. After 5-10 minutes, solid anhydrous sodium acetate (14.35 g, 175 mmol) was added, and stirring continued. After approximately 80 minutes, precipitation of dimethyl 3-(2-bromoethylamino)-2-pentenedioate began, and the solution was stirred for 17 hours at room temperature. The thick slurry was diluted with cold water (20 mL), and aged at 0°-5° C. for 30 minutes and filtered, and the precipitate washed with cold (0°-5° C.) water (50 mL) and dried to constant weight, to afford 13.9 g (86% yield) of dimethyl 3-(2-bromoethylamino)-2-pentenedioate as a white solid, m.p. 71°-72° C.,
Reaction SMILES: [N:1]1([C:7]2[S:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27].CCN(C(C)C)C(C)C>CN1CCCC1=O>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[S:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:8]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1ccccc1CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2nsc(N3CCN(Cc4ccccc4C)CC3)n2)cc1
Temperature: 165 °C

Procedure:
A mixture of 5-(piperazin-1-yl)-3-p-tolyl-1,2,4-thiadiazole (17.3 mg, 66.4 μmol), 1-(chloromethyl)-2-methylbenzene (14.0 mg, 99.7 μmol) and DIPEA (42.9 mg, 58.0 μl) in 0.8 mL N-Methyl-2-pyrrolidinone was heated in the microwave oven 165° C. for 12.5 min. The resulting reaction mixture solution was purified by preparative HPLC on reversed phase eluting with a gradient formed from MeCN, water and NEt3 to yield after evaporation of the product containing fractions 17.5 mg (72%) of the title compound as yellow viscous oil. MS (m/e): 365.3 (MH+).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[O:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21]1>[OH-].[K+].CCO>[O:20]1[CH:24]=[CH:23][C:22]([CH:25]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])=[CH:21]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccoc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccoc2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 69.8 %

Procedure:
According to the method of Example 8, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.20 g, 0.78 mmol) was reacted with 3-furaldehyde (0.083 g, 0.86 mmol) in 2 mL of 4% KOH in EtOH for 48 hours at room temperature to afford 0.182 g (70%) of the title compound, mp 116-117° C.: APCI-MS m/e 335.3 (M+ +1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(COC)OC.C(=O)(O)[O-].[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>[C:13]1([C:2]2[CH:3]=[C:4]([CH:11]=[O:12])[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1cc(Br)cc2ccoc12
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: COCCOC
Product: O=Cc1cc(-c2ccccc2)cc2ccoc12
Yield: 36.1 %

Procedure:
A mixture of 5-bromo-benzofuran-7-carbaldehyde (600 mg), phenylboronic acid (326 mg) and tetrakis(triphenylphosphine)palladium (O) (176 mg) in dimethoxyethane (20 ml) and 8% sodium bicarbonate (10 ml) was heated at reflux for 16 h. Solvent was removed in vacuo, the residue was partitioned between chloroform (40 ml) and water (40 ml). The organic phase was washed with brine (50 ml), dried, filtered and the filtrate evaporated in vacuo to give a yellow oil. Purification by FCC eluted with hexane:ethyl acetate (1:0→10:1) gave the title compound as a pale yellow solid (214 mg).
Reaction SMILES: [C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:21])[N:19]=2)[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[O:21])[N:19]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(Cc1nc(C(=O)NCCNc2ccccn2)co1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(Cc1nc(C(=O)NCCNc2ccccn2)co1)c1ccccc1
Reaction time: 24 h
Yield: 32.9 %

Procedure:
To a solution of ethyl(±)-3-phenyl-4-[4-[[[2-(pyridin-2-yl)amino-1-ethyl]amino]carbonyl]-1,3-oxazol-2-yl]butanoate (157 mg, 0.37 mmole) in 1:1 THF/H2O (4 mL) was added 1.0 N LiOH (0.56 mL, 0.56 mmole). After 24 hr, the mixture was washed with Et2O (2×2 mL), and the pH of the aqueous layer was adjusted to 6 using 10% HCl. The solution was chromatographed on a C-18 Mega Bond Elut® column (50 mL H2O then 50 mL 10% CH3CN/H2O). Fractions containing the product were pooled and lyophilized to give the title compound (48 mg, 33%) as a white powder: MS (ES) m/e 395 (M+H)+. Anal. Calcd for C21H22N4O4. 0.75 HCl: C, 59.80; H, 5.44; N, 13.28. Found: C, 59.89; H, 5.50; N, 12.98.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]1[CH3:19])(=[O:3])N.C(=O)([O-])[O-:21].[Na+].[Na+]>Cl>[C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]1[CH3:19])([OH:21])=[O:3]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(C)C2)cc1
Agent: Cl
Agent: [Na+]
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
15.16 g of (2S,4S)-2-carbamoyl-4-(4-methoxybenzylthio)-1-methylpyrrolidine [prepared as described in step (i) above] were dissolved in 170 ml of 2N aqueous hydrochloric acid, and the solution was stirred in a bath kept at 110° C. for 3.5 hours. At the end of this time, the reaction mixture was cooled to room temperature, and its pH was adjusted to a value of by the addition of sodium carbonate. The mixture was then concentrated by evaporation under reduced pressure, after which it was allowed to stand in a refrigerator precipitate crystals. The precipitated crystals were collected by filtration and washed with a small amount of cold water. They were then dried, to give 10.4 g of the title compound. The mother liquor was then concentrated by evaporation under reduced pressure, and the residue was subjected to column chromatography through CHP20P (75-150μ, Mitsubishi Chemical Industries, Ltd.), using 50% v/v aqueous methanol as the eluent, to afford a further 3.7 g of the title compound, as crystals melting an 185°-187.5° C.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:37])([F:36])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(O)C>[Br:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:33]2[CH2:34][CH2:35][N:30]([CH:27]3[CH2:26][CH2:25][N:24]([C:21]4[CH:20]=[CH:19][C:18]([O:17][C:16]([F:37])([F:15])[F:36])=[CH:23][CH:22]=4)[CH2:29][CH2:28]3)[CH2:31][CH2:32]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Reactant: FC(F)(F)Oc1ccc(N2CCC(N3CCNCC3)CC2)cc1
Solvent: CCO
Product: C[C@](O)(CN1CCN(C2CCN(c3ccc(OC(F)(F)F)cc3)CC2)CC1)Cn1cc([N+](=O)[O-])nc1Br
Temperature: 50 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A mixture of (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (485 mg, 1.75 mmol), 1-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]piperazine (720 mg, 2.19 mmol) and ethanol (10 ml) was stirred at 50° C. for 8 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to obtain (S)-1-(2-bromo-4-nitroimidazol-1-yl)-2-methyl-3-{4-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]piperazin-1-yl}propan-2-ol (792 mg, yield 77%) as a yellow amorphous form.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[S:17]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:19])(=[O:18])[CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCCO1
Reaction time: 0.5 h
Yield: 102 %

Procedure:
A stirred solution of 13.9 g of tetrahydro-2-pyranylmethanol and 18.2 g of triethylamine in 250 ml of methylene chloride was cooled to -10° C. and 15.1 g of methansulfonyl chloride was added dropwise over 5 minutes while maintaining the temperature at -10° C. to 0° C. using a cooling bath. The bath was removed and the mixture was stirred for 1/2 hour while the temperature reached 16° C. The reaction mixture was washed successively with 150 ml of ice water, 150 ml of 10% hydrochloric acid solution, 150 ml of saturated sodium bicarbonate solution and 150 ml of saturated sodium chloride solution, then dried (MgSO4) and evaporated under vacuum at 50° C. to give 23.7 g of a yellow oil, which was Claisen distilled to yield 19.7 g of the desired product; b.p. 110° C. (0.2 mm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[I-].[K+].[CH2:27]([NH2:30])[CH:28]=[CH2:29]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][NH:30][CH2:27][CH:28]=[CH2:29])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: C=CCN
Reactant: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCNCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 31, 8-fluoro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide and allylamine in tetrahydrofuran are reacted to give 8-fluoro-1-[(allyl-amino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([C:5]1(O)[C:10]([CH3:12])(C)[CH2:9][C:8](=[O:13])[CH:7]=[C:6]1[CH3:14])[CH2:2][CH2:3][CH3:4].Cl.[C:17]1(=O)C=CCC=C1>CCCCCC>[CH2:1]([C:5]1([CH3:17])[C:6]([CH3:14])=[CH:7][C:8](=[O:13])[CH:9]=[C:10]1[CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(O)C(C)=CC(=O)CC1(C)C
Reactant: O=C1C=CCC=C1
Agent: Cl
Solvent: CCCCCC
Product: CCCCC1(C)C(C)=CC(=O)C=C1C

Procedure:
A solution of 7 g of 4-butyl-4-hydroxy-3,5,5-trimethyl-2-cyclohexen-1-one (prepared by the procedure of Example IV) in hexane is stirred overnight with 10 ml of a 5% solution of HCl. The hexane is separated and evaporated, and the residue is distilled through a micro column using triethanolamine as a still base. The product obtained is 4-butyl-3,4,5-trimethyl-(2,5-cyclohexadien-1-one, boiling point 112°-119° C. at 0.1 mm Hg. The compound exhibits the following spectral characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:20])[C:10]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)([OH:13])[CH2:11][OH:12].[H-].[Na+].[CH2:23](I)[CH3:24].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:23]([O:12][CH2:11][C:10]([CH:9]([CH3:20])[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[OH:13])[CH3:24]
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(CO)c1cccnc1
Reactant: CCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC(O)(c1cccnc1)C(C)c1ccc(Cl)cc1Cl
Reaction time: 6 h

Procedure:
1.2 g of 3-(2,4-dichlorophenyl)-2-(3-pyridyl)-1,2-butanediol are dissolved under argon in 19 ml of N,N-dimethylformamide and treated at -15° C. with 0.12 g of sodium hydride (99%). The mixture is left to come to 0° C. and stirred at this temperature for 6 hours and 0.4 ml of ethyl iodide is added thereto. There thereby results a red-orange colored suspension which, after stirring at 0° C. for 1 hour, is treated with 20 ml of saturated aqueous sodium bicarbonate solution and subsequently evaporated under a pressure of 0.1 mmHg in order to remove the solvent. The residue is taken up in water and the aqueous solution extracted with ethyl acetate, and the organic phase is washed with saturated aqueous sodium chloride solution and then evaporated to dryness under reduced pressure. The oily residue is purified by chromatography on silica gel with diethyl ether/n-hexane (17:3) and it is recrystallized from methylene chloride/n-hexane. In this manner there is obtained 0.7 g of α-ethoxymethyl-α-(2,4-dichloro-α-methylbenzyl)-3-pyridinemethanol as colorless crystals, m.p. 86° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.1 %

Procedure:
To a solution of tert-butyl {[5-(2-chloropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (259 mg) in ethanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 124 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[I:10]I>O.OO>[Cl:1][C:2]1[C:3]([I:10])=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: II
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: OO
Solvent: O
Product: Oc1cc(Cl)cc(Cl)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.9 %

Procedure:
To a suspension of 3,5-dichlorophenol (0.6 g; 3.68 mmol) in H2O (15 ml), 30% H2O2 was added followed by I2 (0.47 g; 1.85 mmol). The resulting mixture was vigorously stirred for 8 h at room temperature, then extracted with CH2Cl2 (15 ml) and the organic phase was dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2) to give the title compound (0.55 g; 52%) as colourless solid. 1H-NMR (CDCl3) 5.58 (s, 1H); 6.89 (s, 1H); 7.06 (s, 1H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:5]=[C:6]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[S:7][C:8]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].C(=O)(O)[O-].[Na+].[Cl:28][C:29]1[CH:40]=[CH:39][C:32]([CH:33]=[CH:34][S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH:33]=[CH:34][S:35]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:8]3[S:7][C:6]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[N:5][C:4]=3[CH3:3])=[O:10])[CH2:12][CH2:13]2)(=[O:37])=[O:36])=[CH:39][CH:40]=1
Reactant: Cc1nc(-c2ccncc2)sc1C(=O)N1CCNCC1
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(S(=O)(=O)C=Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a solution of 1-[4-methyl-2-(4-pyridyl)-5-thiazolecarbonyl]piperazine dihydrochloride (200 mg) in ethyl acetate (10 ml)/sodium bicarbonate (10 ml) was added 4-chlorostyrene-β-sulfonylchloride (275 mg), and the mixture was stirred at room temperature for 1 hour. The ethyl acetate layer was separated, washed with brine, dried and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of the title compound (169 mg).
Reaction SMILES: Cl[C:2]([CH3:12])([CH3:11])[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.[C:13]([NH2:16])(=[S:15])[CH3:14]>C(O)C>[CH2:9]([O:8][C:6]([C:5]1[S:15][C:13]([CH3:14])=[N:16][C:3]=1[CH:2]([CH3:12])[CH3:11])=[O:7])[CH3:10]
Reactant: CCOC(=O)CC(=O)C(C)(C)Cl
Reactant: CC(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(C)nc1C(C)C
Yield: 62.9 %

Procedure:
To a solution of ethyl 2-chloroisobutyrylacetate from step A (1.58 g, 8.2 mmol, ˜66% pure) in ethanol (20 mL) at 25° C. was added thioacetamide (617 mg, 8.2 mmol) and the reaction mixture was stirred at reflux for 24 h. After the solvents were removed under reduced pressure, the residual oil was diluted with ethyl acetate (100 mL), washed in turn with water (75 mL) and brine (75 mL), then was dried (MgSO4), filtered and concentrated in vacuo. The residue was flash chromatographed over silica gel (5% diethyl ether in hexanes) to yield 4-(1-methylethyl)-2-methylthiazole-5-carboxylic acid ethyl ester (1.1 g, 63% yield) as a yellow oil.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N:6]1[S:7][N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12>>[N:6]1[S:7][N:8]=[C:9]2[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: c1ccc2nsnc2c1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cccc2nsnc12
Temperature: 25 °C

Procedure:
To a stirred solution of 100 mL of chlorosulfonic acid at 0° C. was added 10.0 g of 2,1,3-benzothiadiazole under an inert atmosphere. The resulting mixture was heated at reflux for 30 minutes and cooled to room temperature. The reaction mixture was added dropwise to 1000 mL ice. The precipitate was collected, washed with water, and air dried to give the title compound as a beige solid, m.p. 146°-148° C.