Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=3[CH2:33][N:34]3[C@@H:38]([CH3:39])[C@@H:37]([C:40]4[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=4)[O:36][C:35]3=[O:54])[C:17]([O:21][CH3:22])=[CH:18][C:19]=2[F:20])[CH2:10][CH2:9]1)=[O:7])(=O)C.C[O-].[Na+].O>CO>[F:53][C:50]([F:51])([F:52])[C:42]1[CH:41]=[C:40]([C@H:37]2[O:36][C:35](=[O:54])[N:34]([CH2:33][C:24]3[CH:25]=[C:26]([C:29]([F:31])([F:32])[F:30])[CH:27]=[CH:28][C:23]=3[C:16]3[CH:15]=[C:14]([CH:11]4[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:13][CH2:12]4)[C:19]([F:20])=[CH:18][C:17]=3[O:21][CH3:22])[C@H:38]2[CH3:39])[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=1
Reactant: COc1cc(F)c(C2CCN(C(=O)COC(C)=O)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(F)c(C2CCN(C(=O)CO)CC2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a stirred solution of 2-{4-[2′-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-fluoro-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]piperidin-1-yl}-2-oxoethyl acetate (24 mg, 0.031 mmol) in MeOH (1 mL) under N2 was added sodium methoxide (6.66 mg, 0.031 mmol). The resultant mixture was stirred at room temperature for 15 min. Water (10 mL) was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic fractions were washed with brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-100% EtOAC/hexanes) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-5′-(1-glycoloylpiperidin-4-yl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one as a yellow gum. LCMS=737.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.87 (s, 1H), 7.69 (s, 2H), 7.68-7.60 (m, 2H), 7.34-7.30 (m, 1H), 6.96-6.91 (m, 1H), 6.72 (d, J=11.9 Hz, 1H), 5.44 (d, J=7.8 Hz, 1H), 4.90 (d, J=15.8 Hz, 1H), 4.78-4.70 (m, 1H), 4.18-4.13 (m, 2H), 3.78 (s, 3H), 3.62-3.54 (m, 1H), 3.15-3.05 (m, 2H), 2.82-2.73 (m, 1H), 1.96-1.84 (m, 2H), 1.70-1.52 (m, 4H), 0.43-0.39 (m, 3H).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2C=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:29](=O)CCC.C[C@H]1CC[C@H](N)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH2:21]([N:7]([C@H:1]1[CH2:6][CH2:5][C@H:4]([CH3:29])[CH2:3][CH2:2]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=1)[CH2:22][CH2:23][CH3:24]
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CCCC=O
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: C[C@H]1CC[C@H](N)CC1
Product: CCCCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using butyraldehyde, trans-4-methyl-cyclohexylamine and (2-aminothiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.COCCCOCCCO>>[CH3:12][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: CCOC(=O)C1CCNCC1
Agent: COCCCOCCCO
Product: CCOC(=O)C1CCN(c2cc(C)nc3ccccc23)CC1
Temperature: 150 °C
Reaction time: 48 h
Yield: 162.9 %

Procedure:
4-Chloroquinaldine (0.888 g, 5 mmol) and ethyl piperidine-4-carboxylate (1.18 g, 7.5 mmol) were mixed together with dipropyleneglycolmonomethylether (5 ml) and stirred at 150° C. for 48 hours. The solvent was removed under reduced pressure and the residue purified by column chromatography (pre-packed silica column, gradient of dichloromethane/ethyl acetate) to give 2.43 g of a brown oil that was used directly in the next step. MS (APCI): m/z=298.9 [M+1]+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])C.Cl.C(Cl)Cl>CCO.[OH-].[Na+]>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)=[O:20])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1CCCN(C(=O)c2ccc(F)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)C1CCCN(C(=O)c2ccc(F)cc2)C1
Yield: 101.8 %

Procedure:
1-(4-Fluoro-benzoyl)-piperidine-3-carboxylic acid ethyl ester (1.15 g, 4.42 mmol) was added in a mixture of EtOH/NaOH 3N:1/1 (8 ml) and the resulting heterogeneous solution was stirred at R.T for 1 h. Fuming HCl was added to the mixture until pH=1. The solution was poured with DCM. The organic layer was separated and the aqueous phase was extracted twice with DCM. The combined organic phase was washed twice with water. The solution was dried over Na2SO4, filtered and concentrated to afford 1.13 g (100%) of 1-(4-Fluoro-benzoyl)-piperidine-3-carboxylic acid as an orange oil which can be used without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([CH2:13][C@@H:14]([NH2:30])[CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:18][CH2:17]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:31][C:32]([CH3:37])([CH3:36])[C:33]([Cl:35])=[O:34]>ClCCl.O>[CH:7]1([CH2:13][C@@H:14]([NH:30][C:33](=[O:34])[C:32]([CH3:37])([CH3:36])[CH3:31])[CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:20][CH2:21]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[ClH:35]
Reactant: COc1ccccc1C1CCN(C[C@H](N)CC2CCCCC2)CC1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1C1CCN(C[C@@H](CC2CCCCC2)NC(=O)C(C)(C)C)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 0.076 g of potassium carbonate (0.54 mmol) in 1 ml. of water was added a solution of 0.18 g of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperidin-1-yl]-ethyl}-amine (0.54 mmol) in 10 mL of dichloromethane. The resulting mixture was cooled to 0° C. and 0.066 g of trimethylacetyl chloride (0.54 mmol) was added. The reaction was allowed to stir overnight at 0° C., and was then diluted with 5 mL of water and 20 mL of dichloromethane and the phases separated. The aqueous phase was extracted with three additional portions of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride.0.75 hydrate salt of the title compound with isopropanolic HCl to yield 0.137 g (56%) of white solid; mp=97-99° C.; MS(+)ESI m/z=415 (M+H)+.
Reaction SMILES: F[C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]2[C:10]=1[O:9][C:8]([N:11]1[CH2:14][CH:13]([CH2:15][OH:16])[CH2:12]1)=[N:7]2.C(N(CC)CC)C.[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O>[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][N:37]([C:2]2[C:3]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]3[C:10]=2[O:9][C:8]([N:11]2[CH2:14][CH:13]([CH2:15][OH:16])[CH2:12]2)=[N:7]3)[CH2:36]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(CO)C3)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(CO)C3)nc2c1C#N
Temperature: 150 °C
Reaction time: 19 h
Yield: 130.3 %

Procedure:
7-Fluoro-2-[3-(hydroxymethyl)azetidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-192) (220 mg, 0.37 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (166 μl, 1.19 mmol) and (3S)-3-(dimethylamino)pyrrolidine (159 μl, 1.25 mmol) were added, followed by stirring in a sealed tube at 150° C. for 19 hours. After cooling, concentration under reduced pressure, dilution with methylene chloride and washing with water, the organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (208 mg, 74%) as a white amorphous substance.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH:22]2[CH:20]([O:21]2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Cl>CN(C=O)C.[K]>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH:22]([O:1][C:2]2[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=2[CH:4]=[O:5])[CH:20]([OH:21])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC2OC2C1
Reactant: O=Cc1cc(I)ccc1O
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(I)cc2C=O)C(O)C1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 2-hydroxy-5-iodo-benzaldehyde (Aldrich, 4.96 g, 20 mmol) in DMF (80 mL), potassium carbobate (10 g, 60 mmol) and 7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (8 g, 40 mmol) were added and the mixture was stirred at 70° C. for three days and 80° C. for two days. The mixture was poured into 1N HCl and the mixture was extracted with EtOAc (3×50 mL). The extracts were combined and dried over sodium sulfate and concentrated to give an oil, which was chromatographied on an ISCO machine (10-30% EtOAc/Hexanes) to yield an oil, 3.4 g. MS (H+), 348.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][N:28]=1.C([Mg]Cl)(C)C>C1COCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][N:8]1[C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4](=[O:5])[C:6]([C:15]([C:30]2[CH:29]=[N:28][C:27]([Cl:26])=[CH:32][CH:31]=2)=[O:16])=[CH:7]1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Reactant: Clc1ccc(I)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 600 mg (1.68 mmol) of 1-(3-chloro-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 4 mL THF and 887 mg (3.70 mmol) of 2-chloro-5-iodo-pyridine in 4 mL THF with 1.93 mL 2M isopropylmagnesium chloride. Yield: 418 mg of a white powder. LC-MSD, m/z for C22H14Cl2N2O2 [M+H]+=409.0, 411.0; HPLC retention time: 3.3 min.
Reaction SMILES: [CH2:1]([C:7]12[S:14][CH2:13][C:10]([CH2:15][CH2:16][CH3:17])([CH2:11][S:12]1)[CH2:9][S:8]2=[O:18])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].S([O-])([O-])(=O)=[O:20].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[CH2:1]([C:7]12[S:12][CH2:11][C:10]([CH2:15][CH2:16][CH3:17])([CH2:13][S:14]1)[CH2:9][S:8]2(=[O:20])=[O:18])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCCC12SCC(CCC)(CS1)CS2=O
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: C#CCCCCC12SCC(CCC)(CS1)CS2(=O)=O
Reaction time: 72 h

Procedure:
To a stirred solution of 1-(hex-5-ynyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane-2-oxide (0.302 g.) in dry acetone (120 ml) containing anhydrous magnesium sulphate (0.75 g) at -20° C. was added a solution of potassium permanganate (0.24 g) in dry acetone (25 ml). The mixture was allowed to warm to 20° and stirred for 72 hours. The colourless mixture was filtered through kieselguhr and the solid residue was washed with acetone. The filtrates were evaporated in vacuo and a colourless solid residue was obtained. The residue was purified by chromatography on silica eluting with dichloromethane. 1-(Hex-5-ynyl)-4-n-propyl-2,6,7-trithiabicyclo[2.2.2]octane-2,2-dioxide was obtained as a colourless solid (100 mg).
Reaction SMILES: C[NH:2][NH:3][CH3:4].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][C:15]([C:17](Cl)=[O:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH:20]1C=CC=CC=1>>[CH3:20][N:3]([CH3:4])[NH:2][C:17]([C:15]1[O:16][C:12]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1)=[O:18]
Reactant: c1ccccc1
Reactant: O=C(Cl)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: CNNC
Product: CN(C)NC(=O)c1ccc(-c2ccc(Cl)cc2)o1

Procedure:
To a solution of 36 g (0.60 mole) of dimethylhydrazine and 150 ml of benzene was added portionwise 60 g (0.25 mole) of 5-(p-chlorophenyl)-2-furoyl chloride with the temperature being controlled below 50° by means of an ice bath. The reaction mixture was refluxed for 2 hours with dissolution, cooled and the resulting precipitate filtered, washed with water and dried at 60° to yield 48 g (73%). An analytical sample was prepared by recrystallizing a sample from ethyl acetate/Darco and drying in the vacuum pistol at room temperature, m.p. 150°-152°.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]3[N:46]=[CH:47][N:48]=[C:22]23)=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4[NH:3][C:4](=[O:7])[O:5][N:42]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]3[N:46]=[CH:47][N:48]=[C:22]23)=[CH:19][CH:20]=1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC)cc2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OC)cc2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogen carbonate (2.3 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(4-methoxyphenyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.64 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.45 g, 63%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(C(C)C)C(C)C.Cl.[NH2:21][OH:22]>CCO>[OH:22][NH:21][C:4](=[NH:5])[C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1]
Reactant: NO
Reactant: N#Cc1ccc(F)cc1F
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NO)c1ccc(F)cc1F
Temperature: 70 °C

Procedure:
To a mixture of 2,4-difluorobenzonitrile (1.39 g, 10 mmol) and DIEA (5.13 ml, 30 mmol) in EtOH (15 ml) was added 2.12 g of hydroxylamine hydrochloride (30 mmol) and the reaction was heated at 70° C. for 48 h. Half of the solvent was removed under reduced pressure. The mixture was poured in DCM (100 ml) and water (30 ml). 2.5 ml of NaOH 1N was added until pH=9-10. The organic layer was separated and the aqueous phase was extracted with DCM. The organic layers were combined, washed with water, dried over MgSO4, filtered and evaporated under reduced pressure to afford N-hydroxy-2,4-difluoro-benzamidine which was used without further purification for the next step.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][OH:8].[CH3:11][C:12](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:13].[C:35](OCC)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:12]([O:10][CH2:1][CH2:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][O:8][C:35](=[O:37])[CH3:36])(=[O:13])[CH3:11]
Reactant: OCCCC(O)CCCO
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCC(O)CCCOC(C)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of heptane-1,4,7-triol (162 mg, 1.09 mmol) in pyridine (4 ml) was added acetic anhydrous (216 mg, 2.28 mmol) at 0° C. The resulting mixture was allowed to stir for 4 hours at 0° C. and then diluted with ethyl acetate (100 ml). The organic solution was washed with sat. NaHCO3, brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by column chromatography on silica gel, using 30% ethyl acetate in hexanes, gave the title compound (120 mg, 50%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([F:13])[CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[N:3]=1.[Cl:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:23][C:24]1[S:28][C:27]([S:29]([NH:1][C:2]2[C:10]3[C:5](=[C:6]([F:13])[CH:7]=[CH:8][C:9]=3[O:11][CH3:12])[N:4]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[C:17]([C:18]#[N:19])[CH:16]=3)[N:3]=2)(=[O:31])=[O:30])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: COc1ccc(F)c2c1c(N)nn2Cc1cccc(C#N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(F)c2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of 3-{[3-amino-7-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrile (for a preparation see Intermediate 44) (665 mg, 2.24 mmol) in dry DCM (10 mL) was added 5-chloro-2-thiophenesulfonyl chloride (0.300 mL, 2.24 mmol), followed with pyridine (2 mL). The resultant dark yellow solution was stirred at room temperature overnight. More 5-chloro-2-thiophenesulfonyl chloride was added (0.100 mL) and the reaction stirred for a further 1 h. The reaction mixture was partitioned between ethyl acetate and 2N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (×2). The combined organic solutions were washed with water and brine, dried (Na2SO4) and concentrated in vacuo to leave a deep red oil. This residue was loaded in dichloromethane to a silica 100 g cartridge and purified by chromatography on Flashmaster eluting with a 0-100% ethyl acetate-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (323 mg, 30%) as a pale yellow powder. LCMS (System A) RT=1.2 min, ES+ve m/z 476/478 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[C:13]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=3[Cl:19])[N:7]=[CH:6][C:5]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:3][CH2:2]1.[CH3:25][NH:26][CH3:27]>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[C:13]([S:15]([N:26]([CH3:27])[CH3:25])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=3[Cl:19])[N:7]=[CH:6][C:5]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnn(-c2cc(S(=O)(=O)Cl)ccc2Cl)c1C1CC1
Reactant: CNC
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cc(S(=O)(=O)N(C)C)ccc2Cl)c1C1CC1
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
A solution of ethyl 5-cyclopropyl-1-(2-chloro-5-{chlorosulfonyl}phenyl)-1H-pyrazole-4-carboxylate (0.315 g, 0.812 mmol) in CH2Cl2 (3 mL) was treated at 23° C. with dimethylamine (2 M in THF, 3 mL, 6 mmol). The resulting mixture was stirred for 15 min and concentrated in vacuo. The residue was partitioned between EtOAc and HCl (0.1 M aq). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by Flash 40S™ chromatography (65:35 hexanes-EtOAc) to afford 0.276 g (86% yield) of desired product as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])#[N:18]>>[C:17]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:23])#[N:18]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(C#N)c3)c2)CC1
Yield: 26.6 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 3-cyanobenzoyl chloride (114 mg, 0.687 mmol), 21.2 mg (27%) of the title compound were recovered.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:3].C(OCC)(=O)C.Cl>[Pd].C(OCC)C>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:3]
Reactant: CN(C)CCC=Cc1ccccc1-c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN(C)CCCCc1ccccc1-c1ccccc1

Procedure:
A solution of 3.0 g. of N,N-dimethyl-4-(1,1'-biphenyl-2-yl)-3-butenylamine in 200 ml. of ethyl acetate containing 2.0 g. of five percent palladium oncarbon was stirred for one hour at 25° C. under hydrogen at 40 psi. The reaction mixture then was filtered and the solvent was removed from the filtrate by evaporation to provide an oil. The oil was dissolved in 100 ml. of diethyl ether and stirred while excess hydrogen chloride was added to the solution. The precipitate which formed was collection by filtration and was recrystallized from ethanol and diethyl ether to provide 2.1 g. of N,N-dimethyl-4-(1,1'-biphenyl-2-yl)butylaminum chloride.M.P. 114°-116° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Reactant: Nc1ccccc1
Product: N#Cc1ccc(N(CC(=O)Nc2ccccc2)CC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)glycine and aniline: MS (APCI) m/z 374 (M+1).