Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[C:6]([CH2:8][NH:9][C:10]([C@@H:12]2[CH2:16][CH:15]=[N:14][N:13]2[C:17](=[O:27])[C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[OH:19])=[O:11])[CH:7]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:39]([O:19][C@H:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:17]([N:13]1[C@H:12]([C:10](=[O:11])[NH:9][CH2:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:28]2[CH:32]=[N:31][N:30]=[N:29]2)[CH2:16][CH:15]=[N:14]1)=[O:27])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CC=NN1C(=O)[C@H](O)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O[C@@H](C(=O)N1N=CC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1)c1ccc(F)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 13 %

Procedure:
To a mixture of (3S)—N—[[5-chloro-2-(tetrazol-1-yl)phenyl]methyl]-2-[(2R)-2-(4-fluorophenyl)-2-hydroxy-acetyl]-3,4-dihydropyrazole-3-carboxamide (0.48 g, 1.05 mmol), pyridine (6 mL, 74 mmol), and DMAP (0.023 g, 0.188 mmol) in CH2Cl2 (8 mL) at −10° C. was added benzoyl chloride (135 μL, 1.15 mmol). The reaction mixture was allowed to attain rt and was stirred for 5 h. Another portion of benzoyl chloride (400 μL, 3.4 mmol) was added. The mixture was stirred for 60 h. LCMS analysis indicated only a trace amount of product. The solvents were removed by evaporation and pyridine (5 mL, 62 mmol) was added followed by another portion of benzoyl chloride (400 μL, 3.4 mmol). The reaction mixture was heated to 70° C. overnight. LCMS analysis indicated approximately 20% conversion of starting material. The solvent was evaporated of and the residue was purified by HPLC (MeCN gradient 0 to 100% in 0.1 M NH4OAc buffer containing 5% MeCN). The relevant fractions were combined and lyophilized to give the title compound (77 mg, 13%) together with 289 mg of unreacted starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][CH:20]=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:21].C([O-])(=O)C.[Na+].[I:27]Cl>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]3[N:18]=[CH:19][C:20]([I:27])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:21]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3nccc3n2)ccc1Cl
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 89.6 %

Procedure:
To a stirred solution of 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (4.57 g, 15.2 mmol) in acetic acid (25 mL) was added at room temperature sodium acetate (1.36 g, 16.6 mmol) and drop wise a solution of iodine monochloride (2.69 g, 16.6 mmol) in acetic acid (10 mL). The reaction mixture was stirred at room temperature for 19 h, diluted slowly with water (up to 100 mL), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 5-(4-chloro-3-methyl-phenyl)-3-iodo-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (5.96 g, 93%) as a yellow solid. MS (EI) 436.9 [(M)+]; mp 151° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[C:13]=1[Cl:21])(=[O:4])=[O:3].[NH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[C:24]=1[Br:29]>>[Br:29][C:24]1[C:25]([CH3:28])=[N:26][O:27][C:23]=1[NH:22][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[C:13]=1[Cl:21])(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccsc1COc1ccc2c(c1Cl)OCO2
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccsc2COc2ccc3c(c2Cl)OCO3)c1Br
Yield: 47 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 9 by reaction of 3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]thiophene with 5-amino-4-bromo-3-methylisoxazole, 47% yield, m.p. 152-154° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:27])/[CH:12]=[CH:13]/[C:14](/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:15]/[C:16]([O:18]CC)=[O:17].C(O)C.C(=O)(O)[O-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:27])/[CH:12]=[CH:13]/[C:14](/[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:15]/[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)/C=C(/C=C/C(=O)c1cc(OC)ccc1OC)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(OC)c(C(=O)/C=C/C(=C/C(=O)O)c2ccccc2)c1

Procedure:
0.45 g (1.22 mmol) of ethyl (2Z, 4E)-6-(2,5-dimethoxyphenyl)-6-oxo-3-phenylhexa-2,4-dienoate, 20 ml of ethanol, 0.206 g (2.44 mmol) of sodium bicarbonate and 20 ml of water are mixed together and refluxed for three hours. After evaporating off the solvents, the residue is poured into water, acidified with normal hydrochloric acid solution and extracted with dichloromethane. The organic phase is dried (Na2SO4), the solvent is evaporated off and the pasty product obtained is purified by flash chromatography (20/80 heptane/ethyl acetate) (yellow solid; diisopropyl ether; m.p.: 165° C.; 170 mg) and recrystallized (10/6 hexane/ethyl acetate) (0.3 g of yellow solid; 22%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].CCO.[ClH:17].[NH3:18]>C(Cl)Cl.CO>[ClH:17].[NH2:18][N:2]=[CH:1][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: N
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: COC(=O)c1cccc(CC=NN)c1
Temperature: 0 °C
Reaction time: 144 h

Procedure:
A sample of methyl 3-(cyanomethyl)benzoate (1.87 g, 0.011 mol) was dissolved in anhydrous CH2Cl2 (100 mL) containing absolute EtOH (15 mL). The mixture was cooled to 0° C. and a stream of HCl gas passed through the solution for 10 min. The mixture was then refrigerated for 6 days. The mixture was transferred to a 500-mL flask and concentrated in vacuo (0.05 mm Hg) at 0° C. to give a white solid. The solid material was dissolved in anhydrous methanol (200 mL) and anhydrous ammonia passed through the solution for 20 min. The mixture was warmed to 50° C. for 18 h. The solution was cooled and filtered to remove solids. The filtrate was concentrated at room temperature in vacuo to give a white foam (2.5 g, quantitative). A portion (ca. 1 g) of the material was dried over toluene to give methyl 3-[(aminoiminomethyl)methyl]benzoate hydrochloride, mp 139°-140° C.
Reaction SMILES: Br[C:2]1[N:6]2[C@@H:7]([CH3:14])[CH2:8][N:9]([CH2:12][CH3:13])[C:10](=[O:11])[C:5]2=[C:4]([O:15][CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[Li]CCCC.CCCCCC.[C:33](OC)(=[O:38])[C:34]([O:36][CH3:37])=[O:35].S(=O)(=O)(O)O>C1COCC1>[CH2:12]([N:9]1[CH2:8][C@H:7]([CH3:14])[N:6]2[C:2]([C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35])=[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:4]([O:15][CH3:16])=[C:5]2[C:10]1=[O:11])[CH3:13]
Reactant: COC(=O)C(=O)OC
Reactant: CCOC(=O)c1c(OC)c2n(c1Br)[C@@H](C)CN(CC)C2=O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OC)c2n(c1C(=O)C(=O)OC)[C@@H](C)CN(CC)C2=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of ethyl (4S)-6-bromo-2-ethyl-8-methoxy-4-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-carboxylate (8.51 g, 23.7 mmol) in anhydrous THF (800 mL) under an atmosphere of dry nitrogen, a solution of n-BuLi in hexane (10.5 mL, 26.3 mmol, 2.5 M) was added. The resultant mixture was stirred at −78° C. for 20 minutes. A solution of dimethyl oxalate (6.4 g, 53.8 mmol; dried from concentration from benzene under vac) in anhydrous THF (30 mL) was added. The reaction mixture was stirred at −78° C. for 1 hour and cannulated into a mixture of aqueous sulfuric acid (240 mL, 2M) and THF (200 mL) maintained between at −5 to −35° C. The mixture was extracted with ethyl acetate (3 times). The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 40 to 100% ethyl acetate-hexane gradient. Collection and concentration of appropriate fractions provided the titled compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH2:12][C:13]#[N:14])[C:7]([CH3:11])=[N:8][C:9]=1[CH3:10])#[N:2].Cl.N[C:17]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[C:19]([F:25])[C:18]=1[SH:26].C(O)(=O)C.C(=O)(O)[O-].[Na+]>FC(F)(F)CO.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH3:10][C:9]1[C:4]([CH2:3][C:1]#[N:2])=[CH:5][C:6]([CH2:12][C:13]2[S:26][C:18]3[C:19]([F:25])=[CH:20][C:21]([F:24])=[C:22]([F:23])[C:17]=3[N:14]=2)=[C:7]([CH3:11])[N:8]=1
Reactant: Cc1nc(C)c(CC#N)cc1CC#N
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])O
Solvent: OCC(F)(F)F
Solvent: CC(=O)O
Product: Cc1nc(C)c(Cc2nc3c(F)c(F)cc(F)c3s2)cc1CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
In a teflon screwcap glass pressure vessel a solution of 5-cyanomethyl-2,6-dimethyl-pyridin-3-yl-acetonitrile (1.5 g, 8.1 mmol), 2-amino-3,4,6-trifluoro-benzenethiol hydrochloride (2.6 g, 12.2 mmol), 2,6-di-tert-butyl-4-methylphenol (BHT) (20 mg) and acetic acid (0.56 mL, 9.8 mmol) in 2,2,2-trifluoroethanol (10 mL, 0.8 M, degassed with nitrogen) is warmed to 90° C. and stirred overnight. The mixture is cooled to room temperature, added to saturated aq sodium bicarbonate (30 mL), extracted with ethyl acetate (2×30 mL) and dried over sodium sulfate. Purification by medium-pressure liquid chromatography (MPLC) on silica (10-90% ethyl acetate in heptane) afford 2,6-dimethyl-5-(4,5,7-trifluorobenzothiazole-2-yl-methyl)-pyridin-3-yl-acetonitrile as a white solid (1.1 g, 38%); Rf 0.37 (20% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 7.71 (ddd, J=10.3, 8.5, 5.4 Hz, 1H), 7.67 (s, 1 H), 4.61 (s, 2 H), 4.03 (s, 2 H), 2.44 (s, 3 H), 2.43 (s, 3 H). ESI-LCMS m/z calcd for C17H12F3N3S: 347.1; found 348.0 (M+1)+.
Reaction SMILES: CO[C:3]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:4]=1[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=[O:6].Cl.FC(F)(F)C1N=CC(N[C@H]2CCC[C@@H]2N)=NC=1.CC1C=CC([N:57]2[CH:61]=[CH:60][N:59]=[N:58]2)=C(C=1)C(O)=O>>[CH3:28][C:25]1[CH:26]=[CH:27][C:3]([N:57]2[CH:61]=[CH:60][N:59]=[N:58]2)=[C:4]([CH:24]=1)[C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[NH:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)=[O:6]
Reactant: Cc1ccc(-n2ccnn2)c(C(=O)O)c1
Reactant: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Product: Cc1ccc(-n2ccnn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2cnc(C(F)(F)F)cn2)c1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol) and 5-methyl-2-(1H-1,2,3-triazol-1-yl)benzoic acid (CAS number 1149352-55-5; 65 mg, 0.32 mmol) to afford the title compound.
Reaction SMILES: [C:1]([O:10][CH2:11][CH2:12][OH:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[C:20](Cl)(=[O:23])[CH:21]=[CH2:22].CCOCC>C1C=CC=CC=1>[C:20]([O:13][CH2:12][CH2:11][O:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:23])[CH:21]=[CH2:22]
Reactant: C=CC(=O)Cl
Reactant: CCCCCCCC(=O)OCCO
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: C=CC(=O)OCCOC(=O)CCCCCCC
Reaction time: 2 h

Procedure:
A solution of 2-hydroxyethyl caprylate (HEC) (1 mol; 188.3 g) in pyridine (1.25 mol; 98.9 g; 100.7 ml) was added under continuous stirring at 5°-10° C. into a solution of freshly distilled acryloyl chloride (1.12 mol; 101.4 g) in benzene (300 ml). The mixture was further stirred for 2 hours at the reaction temperature, extracted with 800 ml of 2% hydrochloric acid, the emulsion formed was broken by addition of ether and the aqueous layer was repeatedly extracted with ether until the reaction on capryloyloxyethyl acrylate was negative. The combined ether extracts were washed with water, solution of potassium hydrogencarbonate (KHCO3), and water and dried with magnesium sulfate (MgSO4). Ether was removed by distillation under normal pressure and the product was distilled after addition of octylpyrocatechol as an inhibitor. The overall yield of raw product was 74.9%. The obtained fractions contained 60 to 93% of capryloyloxyethyl acrylate. The product with purity 99.8% was obtained by redistillation; b.p. 111° C./66.7 Pa. Elemental analysis for C13H22O4 theory: 64.44% C, 9.15% H; found 64.23% C; 9.41% H. The infrared and 13C-NMR spectra proved the expected structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C@:19]2([CH2:30][F:31])[CH2:24][C@@H:23]([C:25]([F:28])([F:27])[F:26])[O:22][C:21]([NH2:29])=[N:20]2)[C:15]([F:18])=[N:16][CH:17]=1>>[NH2:29][C:21]1[O:22][C@H:23]([C:25]([F:26])([F:28])[F:27])[CH2:24][C@:19]([C:14]2[CH:13]=[C:12]([NH:11][C:8](=[O:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[CH:17]=[N:16][C:15]=2[F:18])([CH2:30][F:31])[N:20]=1
Reactant: NC1=N[C@](CF)(c2cc(N)cnc2F)C[C@@H](C(F)(F)F)O1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: NC1=N[C@](CF)(c2cc(NC(=O)c3ccc(Cl)cn3)cnc2F)C[C@@H](C(F)(F)F)O1

Procedure:
The title compound was synthesized using procedures analogous to those described in Method H Step 2 (Example 66) above, but using 5-chloropicolinic acid and (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (12k, as described in Example 138, method S). MS m/z=449.9 [M+H]+. Calculated for C17H13ClF5N5O2: 449.8
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.C([O-])(=O)C>C(=O)([O-])[O-].[K+].[K+]>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:21][CH:22]=1
Reactant: Cc1ccc(N)cc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.384 g (1.5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.482 g (4.5 mmol) p-toluidine is stirred for 1.5 h at 90° C. under a nitrogen atmosphere. The reaction mixture is then distributed between 30 ml acetate and 20 ml of 20% aqueous potassium carbonate solution. The organic phase washed with water and dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol mixtures (50:1 to 9:1). Title compound is obtained after crystallization of the product-containing fractions from acetonitrile and drying under HV; m.p. 152-153° C.; ESI-MS: (M+H)+=327.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[O:4]1[CH2:5][CH2:6][N:1]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.9 %

Procedure:
To a solution of morpholine (0.5 g, 5.739 mmol, 1.0 eq) in DMF were added K2CO3 (1.98 g, 14.34 mmol, 2.5 eq.) and ethyl 2-chloroacetate (1.05 g, 8.60 mmol, 1.5 eq.). The mixture was stirred at RT for 12 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 73.9% yield (0.735 g). LC-MS (ESI): Calculated mass: 173.21; Observed mass 174.0 [M+H]+ (rt: 0.1-0.4 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2C(=O)[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].CCO.[OH-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:15]2[C:19]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][O:17][N:16]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=c1onc(-c2nonc2COc2ccccc2)n1-c1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: ON=C(Nc1ccc(F)c(Cl)c1)c1nonc1COc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Into a vial was added 4-(3-chloro-4-fluorophenyl)-3-[4-(phenoxymethyl)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one (9 mg, 23 mmol), EtOH (0.5 mL), and 2.0 M of sodium hydroxide in water (35 μL). Reaction was stirred for 2 hrs at rt. The reaction mixture was neutralized with acetic acid and then purified by preparative HPLC to yield the desired compound (7.6 mg, 90%). 1H NMR (400 MHz, DMSO-d6) δ: 11.58 (s, 1H), 9.05 (s, 1H), 7.32 (t, J=7.8 Hz, 2H) 7.19 (dd, J=9.1, 9.1 Hz, 1H), 7.0 (m, 1H), 6.97 (m, 2H) 6.96 (m, 1H), 6.72 (ddd, J=8.8, 4.0, 2.8 Hz, 1H), 5.43 (s, 2H); MF═C16H12ClFN4O3; LCMS calculated for C16H13ClFN4O3(M+H)+: m/z=363.066.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([N:15]1[C:19]2([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[NH:18][C@@H:17]([CH2:32][CH2:33][S:34][CH3:35])[C:16]1=[O:36])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:8]([N:15]1[C:19]2([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[NH:18][C@@H:17]([CH2:32][CH2:33][S:34][CH3:35])[C:16]1=[O:36])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CSCC[C@@H]1NC2(CCN(C(=O)OC(C)(C)C)CC2)N(Cc2ccccc2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@@H]1NC2(CCNCC2)N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
TFA (7.8 g, 68.0 mmol) was added dropwise at 0° C. to a solution of tert-butyl 1-benzyl-3-(S)-(2-methylsulfanylethyl)-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate (1.5 g, 3.5 mmol) in CH2Cl2 (10 ml) and the mixture was stirred at this temperature for 15 min. After warming to RT, the reaction solution was stirred for a further 2.5 h. Subsequently, the reaction solution was adjusted to pH 7-8 using aqueous saturated NaHCO3 solution, the organic phase was separated off and the aqueous phase was extracted with CH2Cl2 (2×10 ml). The combined organic phase was dried over Na2SO4, filtered and the solvent was distilled off. The workup was carried out by means of column chromatography and afforded 1-benzyl-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5]decan-2-one in a yield of 655 mg (58%).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6](O)[CH:5]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:17]>C1(C)C=CC=CC=1>[Cl:17][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CC(C)c1cc(O)nc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Cl)nc2ccccc12
Yield: 84 %

Procedure:
4-Isopropylquinolin-2-ol (1.95 g, 10.43 mmol) and 1.14 mL (1.2 eq) of POCl3 in toluene were reacted as outlined in Scheme 1 above to yield 1.8 g (84%) of the desired title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.40 (d, J=6.74 Hz, 6 H) 3.71 (quin, J=6.81 Hz, 1 H) 7.28 (s, 1 H) 7.48-7.63 (m, 1 H) 7.65-7.78 (m, 1 H) 7.98-8.10 (m, 2 H).
Reaction SMILES: [Cl-].[NH4+].Cl.[N+:4]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:23](=[O:26])(=[O:25])[NH2:24])[C:15]=1[S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([OH:12])=[O:11])([O-])=O.[OH-].[Na+]>[Fe].O>[NH2:4][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:23](=[O:25])(=[O:26])[NH2:24])[C:15]=1[S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]([OH:12])=[O:11]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Sc1ccccc1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccccc1
Temperature: 90 °C

Procedure:
A mixture of ammonium chloride (2.4 g), metallic iron powder (24 g), concentrated hydrochloric acid (0.1 ml), and water (60 ml) was heated to 90° C with stirring, and 3-nitro-4-phenylthio-5-sulphamyl-benzoic acid (10 g) was added in small portions during 2 hours. The reaction mixture was stirred on a steam bath for an additional 2 hours. After the addition of dilute sodium hydroxide until the pH was 8, the hot reaction mixture was filtered, and the filter-cake was washed with warm dilute sodium hydroxide. After the addition of 4N hydrochloric acid to the filtrate until its pH was 2and cooling the resulting precipitate, consisting of 3-amino-4-phenylthio-5-sulphamyl-benzoic acid, was filtered off and dried at 78° C in vacuo. The melting point was 285° C.
Reaction SMILES: C[Li].C(NC(C)C)(C)C.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][N:17]=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[CH:29]=1.[CH3:30][Si:31]([CH3:34])([CH3:33])Cl>C(OCC)C.O1CCCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]([CH3:21])[C:19]([O:22][Si:31]([CH3:34])([CH3:33])[CH3:30])=[CH:18][N:17]=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:15]=2[CH:29]=1
Reactant: C[Si](C)(C)Cl
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1C(O[Si](C)(C)C)=CN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: -70 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
A solution of methyllithium in diethyl ether (0.0275 mol, 15.3 ml of 1.8 M solution) was added dropwise to a solution of 3.04 g (0.03 mol) of diisopropylamine in 25 ml of diethyl ether. The reaction mixture was cooled to -70° C. and a solution of 7.12 g (0.025 mol) of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one in 40 ml of tetrahydrofuran was added dropwise. The reaction mixture became dark red. Trimethylchlorosilane (11.4 ml; 0.09 mol) was added dropwise, after which the reaction mixture was warmed to room temperature, stirred for 3 hours and then filtered. The filtrate was evaporated to dryness and the residue was dissolved in 150 ml of trichlorofluoromethane. This solution was filtered to remove undissolved solid; the filtrate was evaporated to dryness under reduced pressure to give 8.52 g of 7-chloro-1-methyl-5-phenyl-2-trimethylsiloxy-1H-1,4-benzodiazepine as a light orange glass: 1H NMR (CCl3F) δ 0.0 ppm (s, 9H), 2.62 ppm (s, 3H), 5.76 ppm (s, 1H) and 6.4-7.6 ppm (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:22])[C:9]=2[CH3:30])=[CH:4][CH:3]=1.Cl[C:32]([O:34][C:35]1C=CC([N+]([O-])=O)=C[CH:36]=1)=[O:33].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]3)=[O:22])[C:9]=2[CH3:30])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1c(C(=O)NC2CCNCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(NC(=O)c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)CC1
Yield: 87.7 %

Procedure:
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-4-yl)-1H-pyrazole-3-carboxamide (1 eq, 61 mg, 0.132 mmol), p-nitrophenyl chloroformate (1.1 eq, 29 mg, 0.144 mmol), and triethylamine (3 eq, 0.06 mL, 0.395 mmol) were stirred for 16 h in THF (2 mL). The reaction was concentrated in vacuo. The crude material was purified by column chromatography 0-100% ethyl acetate/hexanes to yield 62 mg (75%) of desired product 4-nitrophenyl 4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.54-1.74 (m, 2H) 2.18 (br s, 2H) 2.42 (s, 3H) 3.04-3.38 (m, 2H) 4.21-4.43 (m, 3H) 6.95 (d, J=7.91 Hz, 1H) 7.10 (d, J=8.29 Hz, 2H) 7.30-7.41 (m, 5H) 7.47 (s, 1H) 8.29 (d, J=9.04 Hz, 2H); [M+H]+ 628.7.