Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][NH:6][S:7]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH:15]1OCC[O:16]1)(=[O:9])=[O:8])[CH3:2].Cl>C1COCC1.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][NH:6][S:7]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH:15]=[O:16])(=[O:9])=[O:8])[CH3:2]
Reactant: CCOC(=O)CNS(=O)(=O)c1sccc1C1OCCO1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CNS(=O)(=O)c1sccc1C=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.8 %

Procedure:
To a solution of the product from Step A (31.0 g 97.0 mmol) in THF (100 mL) was added 3N HCl and the mixture stirred for 6 h at room temperature. Brine (100 mL) was added and the mixture extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine (20.0 mL), dried (MgSO4) and evaporated to yield a white solid (22.0 g, 82%): mp 74°-76° C.
Reaction SMILES: [CH:1]1([C:6](=O)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:12][NH2:13]>C(O)C>[CH:1]1([C:6]2[CH:7]=[C:8]([NH2:9])[NH:12][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: N#CCC(=O)C1CCCC1
Solvent: CCO
Solvent: O
Product: Nc1cc(C2CCCC2)n[nH]1
Temperature: 80 °C
Yield: 46.2 %

Procedure:
To a solution of 3-cyclopentyl-3-oxo-propionitrile (1.0 g, 7.3 mmol, 1 eq) in ethanol (10 mL) was added a 64 wt.-% solution of hydrazine hydrate (1.1 mL, 14.6 mmol, 2 eq). The mixture was heated at 80° C. for 16 h and was evaporated to dryness. The residue was purified by flash chromatography using dichloromethane and methanol (100/0 to 90/10) to afford 5-cyclopentyl-2H-pyrazol-3-ylamine as yellow oil (510 mg, 46% yield).
Reaction SMILES: FC1C=CC(C2C(C3C=CC=CC=3)SC(C(C)C)C=2C(OCC)=O)=CC=1.[CH:27]([CH:30]1[C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:33]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[CH:32]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)[S:31]1)([CH3:29])[CH3:28]>>[CH:27]([C:30]1[S:31][C:32]([C:47]2[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=2)=[C:33]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[C:34]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36])([CH3:28])[CH3:29]
Reactant: CCOC(=O)C1=C(c2ccc(F)cc2)C(c2ccc(Cl)cc2)SC1C(C)C
Agent: CCOC(=O)C1=C(c2ccc(F)cc2)C(c2ccccc2)SC1C(C)C
Product: CCOC(=O)c1c(C(C)C)sc(-c2ccc(Cl)cc2)c1-c1ccc(F)cc1

Procedure:
Repeating the procedure described in Step 6 of Prep. 3, above, but using in place of the 4-(4-fluorophenyl)-2,5-dihydro 2-isopropyl-5-phenyl-3-thiophenecarboxylic acid, ethyl ester product thereof, an approximately equivalent amount of the refined product of Step 7 of this preparation, above, there is accordingly obtained the title product of this preparation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](I)=[N:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)CO.[C:34]1([SH:44])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>C(OCC)(=O)C.[Cu]I.CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([S:44][C:34]2[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=2)=[N:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]nc(I)c23)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]nc(Sc4cccc5ccccc45)c23)CC1
Temperature: 25 °C
Yield: 45 %

Procedure:
A mixture of 4-[4-(t-butoxycarbonyl)piperazin-1-yl]-3-iodo-1H-indazole (0.068 g, 0.159 mmol), copper(I) iodide (0.005 g, 0.024 mmol) and potassium carbonate (0.044 g, 0.318 mmol) are added to a screw-capped test tube with a Teflon-lined septum. The tube is evacuated and backfilled with argon and this procedure repeated twice more. The reaction mixture is treated sequentially with 2-propanol (1.5 mL), ethylene glycol (19 μL, 0.318 mmol) and 1-naphthalenethiol (0.051 g, 0.318 mmol), heated at 130°-140° C. for 8 h, cooled to room temperature, diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate is concentrated under reduced pressure. The resultant crude material is purified by flash chromatography (silica gel, 40:60 ethyl acetate/hexanes) to afford the title compound as a colorless oil, 0.033 g (45% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([C:3]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4]1)[CH3:2].[CH:10]([Mg]Br)=[CH2:11]>>[CH2:1]([C:3]1([CH3:9])[CH2:7][CH2:6][C:5]([CH:10]=[CH2:11])([OH:8])[CH2:4]1)[CH3:2]
Reactant: C=C[Mg]Br
Reactant: CCC1(C)CCC(=O)C1
Product: C=CC1(O)CCC(C)(CC)C1
Yield: 59.4 %

Procedure:
3-Ethyl-3-methylcyclopentanone (2b, 30.0 g, 0.24 mol) was reacted with vinylmagnesium bromide (0.6M in THF, 285 ml, 0.29 mol), as described in Example 1b, to afford 3b (22.0 g, 2:1 mixture of diastereomers, 60% yield) as a colorless liquid.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.COC1C=C(OC)C=CC=1C[N:21]1[CH2:27][CH2:26][C:25]([F:29])([F:28])[CH2:24][C@@H:23]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=2)(=[O:33])=[O:32])[C:22]1=[O:41]>ClCCl>[F:29][C:25]1([F:28])[CH2:26][CH2:27][NH:21][C:22](=[O:41])[C@H:23]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=2)(=[O:32])=[O:33])[CH2:24]1
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](NS(=O)(=O)c3ccc(Cl)cn3)C2=O)c(OC)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cn1

Procedure:
A mixture containing trifluoroacetic acid/trifluoromethanesulfonic acid (5:2 v/v, 2.44 ml) was added to 5-chloro-pyridine-2-sulfonic acid [(R)-1-(2,4-dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-amide (0.37 g, 0.76 mmol) in dichloromethane (20 ml). After 2 h the reaction mixture was concentrated under reduced pressure and the residue taken up in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine, dried (Na2SO4), filtered, concentrated under reduced pressure and purified over silica gel (heptane-ethylacetate, 1:1-0:1); white solid 0.22 g (84%); MS: m/e=340.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6]O.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][Br:13]
Reactant: COc1ccccc1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccccc1CCBr
Temperature: 0 °C
Yield: 93.5 %

Procedure:
A mixture of 2-methoxyphenethyl alcohol (500 mg) and carbon tetrabromide (1.53 g) in anhydrous dichloromethane (10 mL) was stirred at 0° C. under a nitrogen atmosphere. After adding triphenylphosphine (1.03 g) portionwise, the reaction mixture was stirred for an hour under the same condition. The reaction mixture was evaporated in vacuo and the residue was subjected to a silica gel column chromatography eluting with n-hexane only and then a mixture of n-hexane and ethyl acetate (40:1 to 20:1) to give 2-methoxyphenethyl bromide (661 mg) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH:9]([CH3:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH:28](Br)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C)C=O>[CH2:32]([O:31][C:29]([CH:28]1[O:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[CH3:8])[CH3:19])=[CH:12][C:13]=2[O:18]1)=[O:30])[CH3:33]
Reactant: CC(Cc1ccc(O)c(O)c1)N(C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2ccc(CC(C)N(C)C(=O)OC(C)(C)C)cc2O1
Temperature: 100 °C
Yield: 34.2 %

Procedure:
To 2.5 g (8.8 mmol) of 1C was added 20 mL of anhydrous N,N-dimethylformamide (DMF) followed by 3.68 g (26 mmol) of anhydrous K2CO3 and 3 mL (23 mmol) of ethyl dibromoacetate. The reaction mixture was heated to 100° C. for 4.5 hours and then allowed to cool to room temperature. This was concentrated to dryness under reduced pressure, and 50 mL of water was added to the residue. The mixture was adjusted to pH 3 using 1N HCl and extracted with 4×50 mL of dichloromethane. Organic layers were combined, dried (anhydrous Na2SO4), and concentrated to dryness. The residue was purified by flash column silica gel chromatography using 15% ethyl acetate in hexane to give 1.1 g (3.01 mmol, 34%) of 1D as a colorless oil (M+Na, 388).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][N:29]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:30]=3)=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][N:29]([C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:30]=3)=[CH:18][CH:19]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To the reaction mixture of Example 6 was added sodium borohydride (0.1 m=3.9 g) along with some water (8.7 mL). After stirring at room temperature for 3 hours, the reaction mixture was slowly added to excess amount of water (540 ml) with stirring. The wet filter cake was washed with 270 mL of water, then crystallized from 355 g of butyl chloride to give a crude product. Recrystallization from 300 g of ethyl acetate and dried in a vacuum oven to give 49.3 g of pure title compound in 72% yield for two steps, mp 168°-169° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7]([CH2:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.[NH2:14][CH:15]1[C:29](=[O:30])[N:17]2[C:18]([C:26]([OH:28])=[O:27])=[C:19]([CH2:22][N:23]=[N+:24]=[N-:25])[CH2:20][S:21][C@H:16]12>>[N:1]1[CH:2]=[CH:3][C:4]([S:7]([C:9]#[C:10][C:11]([NH:14][CH:15]2[C:29](=[O:30])[N:17]3[C:18]([C:26]([OH:28])=[O:27])=[C:19]([CH2:22][N:23]=[N+:24]=[N-:25])[CH2:20][S:21][C@H:16]23)=[O:13])=[O:8])=[CH:5][CH:6]=1
Reactant: O=C(O)CCS(=O)c1ccncc1
Reactant: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)C#CS(=O)c3ccncc3)[C@H]2SC1

Procedure:
398 mg. of 3-(4-pyridylsulfinyl)propionic acid and 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 143 mg. of 7-[3-(4-pyridylsulfinyl)propinamido]-3-azidomethyl-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:27]([O:30][C@@H:31]1[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:35]([O:41][C:42](=[O:44])[CH3:43])[C@@H:34]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[O:33][C@H:32]1[C:50]1[CH:55]=[C:54]([CH3:56])[CH:53]=[CH:52][C:51]=1[O:57][CH2:58][CH3:59])(=[O:29])[CH3:28]>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[C:27]([O:30][C@@H:31]1[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:35]([O:41][C:42](=[O:44])[CH3:43])[C@@H:34]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[O:33][C@H:32]1[C:50]1[CH:55]=[C:54]([CH2:56][Br:1])[CH:53]=[CH:52][C:51]=1[O:57][CH2:58][CH3:59])(=[O:29])[CH3:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccc(C)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(CBr)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 32.4 %

Procedure:
N-bromosuccinimide (1.7 g) and benzoyl peroxide (0.1 g) were added to a solution of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(2-ethoxy-5-methylphenyl)-D-glucitol (3.7 g) in carbon tetrachloride (30.0 ml) and the mixture was refluxed with heating for one hour. The reaction mixture was diluted with chloroform and the diluted product was washed with saturated aqueous solution of sodium hydrogencarbonate, saturated aqueous solution of sodium thiosulfate, and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The resulting precipitates were collected by filtration to obtain (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-(bromomethyl)-2-ethoxyphenyl]-D-glucitol (1.4 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:13]=2)[C:8]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>O1CCCC1.O>[CH2:31]([N:33]([CH2:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:13]=2)[C:8]1=[O:21])[CH2:34][CH3:35])[CH3:32]
Reactant: COC(=O)c1ccc2ccn(Cc3cccc(CBr)c3)c(=O)c2c1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)Cc1cccc(Cn2ccc3ccc(C(=O)OC)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of methyl 2-[3-(bromomethyl)benzyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.10 g, 0.26 mmol) in tetrahydrofuran (7 mL) was added cesium carbonate (0.25 g, 0.78 mmol) and diethylamine (40 μL, 0.39 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 5% MeOH/DCM) to afford methyl 2-{3-[(diethylamino)methyl]benzyl}-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (71 mg, 72%). LC-MS: (FA) ES+ 379.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[NH:5][C:6]=1[CH2:7][O:8]CC1C=CC=CC=1.CS(O)(=O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[NH:5][C:6]=1[CH2:7][OH:8]
Reactant: CCc1nc(Cl)c(COCc2ccccc2)[nH]1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc(Cl)c(CO)[nH]1
Temperature: 0 °C

Procedure:
A solution of 4-chloro-2-ethyl-5-{[(phenylmethyl)oxy]methyl}-1H-imidazole (2.51 g, 10.0 mmol) and methanesulfonic acid (25 mL, 385 mmol) in chloroform (56 mL) was stirred at RT for 1 h. The reaction mixture was poured into ice (˜100 g) and the solution was neutralized by addition of 5N NaOH until the pH was 10. The solution was extracted with methyl tert-butyl ether (2×100 mL) and then with n-butanol (3×100 mL). The combined n-butanol extracts were concentrated, azeotroped with toluene, and dried in vacuo to provide the title compound in quantitative yield as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.10 (br. s., 1H), 5.10 (br. s., 1H), 4.32 (s, 2H), 2.54 (q, 2H), 1.15 (t, 3H).
Reaction SMILES: O1CCOCC1.C(OC(=O)[NH:13][C:14]([C:26]1[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1)([CH3:25])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=1)=[O:16])(C)(C)C.Cl.O1CCOCC1>O>[NH2:13][C:14]([C:26]1[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1)([CH3:25])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NC(C)(C(=O)c1ccc(Cl)c(F)c1)c1ccc(Cl)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(N)(C(=O)c1ccc(Cl)c(F)c1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A dioxane (1 ml) solution of the compound (1.23 g, 2.55 mmol) obtained in Step 5 above was added to a 4 N hydrochloric acid/dioxane solution (5 ml) under ice cooling and the resulting mixture was gradually warmed and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and washed with an n-hexane/ethyl acetate mixed solvent and then the aqueous layer was made alkaline by the addition of 15% aqueous sodium hydroxide solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=1:1 (v/v)] to give the title compound (0.75 g, 95%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.C1COCC1.CN(C=O)C>[Ni].O>[F:17][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(N2CCC(F)(F)CC2)nc1
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(N2CCC(F)(F)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
The product from Example 135A (4.56 g, 18.75 mmol) and solvent THF (20 mL)/DMF were added to Ra-Ni 2800, water slurry (4.56 g, 78 mmol) in a 250 mL SS pressure bottle and stirred for 2 hr at 30 psi and ambient temperature. The mixture was filtered through a nylon membrane and washed with MeOH. The filtrate was concentrated and dried under vacuum to afford the title compound (3.40 g, 85%). 1H NMR (400 MHz, DMSO-D6) δ 2.03-1.88 (m, 4H), 3.49-3.38 (m, 4H), 4.61 (s, 2H), 6.73 (d, J=8.8, 1H), 6.93 (dd, J=2.9, 8.8, 1H), 7.61 (d, J=2.6, 1H). MS (ESI) m/z 214 (M+H+).
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3[C:29]2[N:34]=[C:33]([C:35](O)=[O:36])[CH:32]=[CH:31][CH:30]=2)=[N:7][N:6]=1)([CH3:3])[CH3:2].C1C[N:41]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:40]C1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[CH:1]([NH:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3[C:29]2[N:34]=[C:33]([C:35]([NH:41][CH3:40])=[O:36])[CH:32]=[CH:31][CH:30]=2)=[N:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(C(=O)O)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)C)o4)cc23)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To a solution of 6-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)picolinic acid (150 mg, 0.29 mmol) in DMF (3 mL) was added PyBOP (226 mg, 0.439 mmol), HOBt (59 mg, 0.435 mmol) and DIPEA (0.15 mL, 0.87 mmol). Methylamine hydrochloride (23 mg, 0.348 mmol) was added and the reaction was stirred for 2 h under Ar at RT. The reaction was quenched with water (200 mL) to get a brown precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried. The crude product was purified with basic alumina chromatography (eluting with EtOAc) to give 6-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1-tosyl-1H-indol-3-yl)-N-methylpicolinamide (150 mg, 98%). MS (ESI, pos. ion) m/z: 531.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[Cl:19][C:20]([Cl:24])([Cl:23])[CH2:21][OH:22]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([O:22][CH2:21][C:20]([Cl:24])([Cl:23])[Cl:19])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Product: O=C(OCC(Cl)(Cl)Cl)c1csnc1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2.0 g (0.0069 mol) of 3-(α,α,α-trifluoro-m-tolyl-4-isothiazolecarbonyl chloride and 1.22 g (1.18 equivalents) of 2,2,2-trichloroethanol was heated at 70°-140° in an oil bath for 6.5 hours. The reaction mixture was concentrated under vacuum to give 1.78 g of oil, nD23 =1.5499 (yield 63.8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:20][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:26]3[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: CC1(C)CC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 4-(trifluoromethyl)phenyl boronic acid according to the procedure described in example 21. MS m/z 305; HRMS: calcd for C18H15F3O+H+, 305.11478; found (ESI, [M+H]+), 305.1145.
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C>[OH:31][C:30]1[C:25](=[O:24])[NH:26][N:27]=[C:28]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:48])([F:47])[F:49])[CH:41]=2)[CH:29]=1
Reactant: FC(F)(F)c1cccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cc2cccc(C(F)(F)F)c2)cc1O

Procedure:
Prepared in the same way as 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(3-(trifluoromethyl)benzyl)pyridazine (Intermediate 58) except that the solvent used for the hydrogenation was ethyl acetate and the product was recrystallised from a mixture of ethyl acetate and heptanes.
Reaction SMILES: S(=O)(=O)(O)[OH:2].N[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][C:16]#[N:17].N>>[NH2:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:8]2[C:9]=1[CH2:10][CH2:11][CH2:12][C:7]2=[O:2]
Reactant: N#CCCCc1ccccc1N
Reactant: O=S(=O)(O)O
Agent: N
Product: Nc1cccc2c1CCCC2=O
Temperature: 100 °C

Procedure:
In a 20 ml Schlenk vessel, 1 g of 96% sulfuric acid (9.79 mmol) is added to 100 mg of 4-(2-aminophenyl)butyronitrile (0.62 mmol) under argon. The mixture is heated to 100° C. for 66 h, stirring. After cooling, it is neutralised with aqueous ammonia solution (ice cooling), and the product is then extracted with chloroform and identified using GC.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8](Cl)(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:8](=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)NC1CCCCC1
Temperature: 30 °C

Procedure:
10 g of cyclohexylamine was dissolved in 80 ml of toluene. The resulting solution was cooled below 20° C. and 30 g of stearic acid chloride was added to the solution with stirring at temperatures below 20° C. The addition required one hour. The mixture solidified entirely. The solidified mixture was maintained at 30° C. for 2 hours. White crystals contained in the mixture was then filtered off, neutralized with alkaline alcohol and washed with water. The material so obtained was recrystallized from alcohol, from which it separated as white needles melting at 93.5° C. to 94.5° C. The yeild was 86%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13])[CH3:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:20][C:21]#[N:22]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19](/[C:20](=[CH:8]/[C:7]2[CH:10]=[CH:11][C:4]([O:3][CH2:1][CH3:2])=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=2)/[C:21]#[N:22])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: CCOc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: COc1ccc(CC#N)cc1OC
Product: CCOc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1[N+](=O)[O-]
Yield: 39.9 %

Procedure:
4-Ethoxy-3-nitrobenzaldehyde (586 mg) and 3,4-dimethoxybenzyl cyanide (532 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (425 mg, yield: 40%).