Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=2)[O:3]1.[C:18]([O:22][C:23](=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([CH3:21])([CH3:20])[CH3:19].C(OCC)(=O)C>S(Cl)(Cl)=O.CCCCCC>[C:18]([O:22][C:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:15][C:14]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]3([CH3:12])[CH3:13])=[O:16])=[CH:29][CH:30]=1)=[O:32])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC1(C)CC(C)(C)c2cc(C(=O)O)ccc2O1
Reactant: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Cc1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A solution of 2,2,4,4-tetramethyl chroman-6-carboxylic acid (0.1 g, 0.43 mmol) in thionyl chloride (10 mL) was refluxed for 2 h. The thionyl chloride was evaporated under reduced pressure and the residue was dissolved in 5 mL of dichloromethane and treated with triethyl amine (5 mL) followed by tert-butyl-4-hydroxy phenyl acetate (Reagent E, 0.088 g, 0.427 mmol). After 0.5 h, the reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent to afford the title compound (0.1 g, 55%).
Reaction SMILES: [CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1Cl)[CH2:2][CH2:3][CH3:4].[CH2:16]([Mg]Br)[CH3:17]>[Cl-].[Mn+2].[Cl-]>[CH2:1](/[N:5]=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([F:14])[C:8]=1[CH2:16][CH3:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC/N=C/c1c(F)ccc(F)c1Cl
Reactant: CC[Mg]Br
Agent: [Mn+2]
Agent: [Cl-]
Product: CCCC/N=C/c1c(F)ccc(F)c1CC

Procedure:
Butyl-[1-(2-ethyl-3,6-difluoro-phenyl)-meth-(E)-ylidene]-amine was prepared from butyl-[1-(2-chloro-3,6-difluoro-phenyl)-meth-(E)-ylidene]-amine, ethylmagnesium bromide and manganese(II) chloride in analogy to Example 194a): brown oil; 1H-NMR (CDCl3): 0.97 (3H, t, CH3), 1.15 (3H, t, CH3), 1.43 (2H, sextet, CH2), 1.70 (2H, quintet, CH2), 2.98 (2H, qd, CH2), 3.66 (2H, t, CH2), 6.87 (1H, td, ArH), 6.99 (1H, td, ArH), 8.52 (1H, s, CH═N).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:22])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[F:23][C:24]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:25]=1[CH2:26][NH2:27].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:22])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:27][CH2:26][C:25]3[C:28]([F:33])=[CH:29][CH:30]=[C:31]([F:32])[C:24]=3[F:23])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: NCc1c(F)ccc(F)c1F
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Cl)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3c(F)ccc(F)c3F)cc2)c1
Yield: 94 %

Procedure:
4-[3-(3-Cyanophenyl)-ureido]-benzenesulfonyl chloride (1.0 g, 2.98 mmol) was dissolved in 20 ml THF, 2,3,6-trifluoro-benzylamine (0.48 g, 2.98 mmol) and DIEA (0.52 ml, 2.98 mmol) were added and the solution was refluxed for about 3 h. The solvent was removed in vacuo and the residue cristallized with ethanol/water. The solid was filtered and dried in vacuo. Yield 94% of 4-[3-(3-cyano-phenyl)-ureido]-N-(2,3,6-trifluorobenzyl)-benzenesulfonamide.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:13]([Cl:14])=[C:12]([Cl:15])[S:11][C:10]=1[Cl:16])[CH3:5].C(N(CC)CC)C.[CH3:24][N:25]1[CH:29]=[C:28]([C:30](Cl)=[O:31])[C:27]([C:33]([F:36])([F:35])[F:34])=[N:26]1>ClCCl.O>[CH3:1][O:2][N:3]([CH:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:13]([Cl:14])=[C:12]([Cl:15])[S:11][C:10]=1[Cl:16])[CH3:5])[C:30]([C:28]1[C:27]([C:33]([F:36])([F:35])[F:34])=[N:26][N:25]([CH3:24])[CH:29]=1)=[O:31]
Reactant: CONC(C)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)(F)F)C(C)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a stirred solution of trans O-methyl-N-{1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]ethyl}-hydroxylamine (0.25 g; 0.83 mmol) prepared as described in example P17 and triethylamine (0.16 ml; 1.08 mmol) in dichloromethane (5.0 ml) at ambient temperature was added dropwise 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.18 g; 0.83 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (3 ml) and extracted with dichloromethane (3×1 ml). Combined organic layers were washed with water (1 ml), brine and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 30:70) to afford 0.34 g (85% of theory) of trans 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid methoxy-{1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]-ethyl}-amide as a resin.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[C:9]1(=[O:18])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=1>C1COCC1>[O:18]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[CH2:2][C:25]1[CH:26]=[CH:27][C:22]([C:21]([O:20][CH3:19])=[O:29])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: O=C1CCc2ccccc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC2Cc3ccccc3C2=O)cc1
Temperature: 0 °C
Yield: 17 %

Procedure:
A 2M LDA solution in THF (4.16 ml, 8.32 mmol) was added to a solution of indanone (1.00 g, 7.57 mmol) in THF (10 ml) at −60° C. The solution was slowly warmed to 0° C. during a period of 15 min. and was agitated for 15 more min. The reaction was then cooled to −78° C. and a solution of methyl-4-bromobenzoate (1.73 g, 7.57 mmol) was slowly added. The solution was slowly warmed to −20° C. and stirred during 4 hours. The reaction mixture was quenched with HCL 1M and the solvent was evaporated. The residue was diluted in ethyl acetate, washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (5-20% AcOEt/HEx) to afford the title compound 271(245 mg, 17%) as a white solid. LRMS: 280.1 (Calc.). 281.1 (found).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:3].[CH3:14][O:15][CH2:16][CH2:17][Br:18]>CC(C)=O>[Br-:18].[CH3:14][O:15][CH2:16][CH2:17][N+:2]([CH3:1])([CH3:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCN(C)C
Reactant: COCCBr
Solvent: CC(C)=O
Product: CCCCCCCCCC[N+](C)(C)CCOC
Product: [Br-]

Procedure:
The reaction was performed in an inert atmosphere. N,N-dimethyldecylamine (16.21 mmol, 3.7 g) and 2-bromoethyl methyl ether (16.21 mmol, 2.25 g) were mixed together in a round bottom flask. Acetone (10 mL) was added to the reaction mixture. The reaction mixture was heated to reflux for 8 hours. The solvent was removed by a rotoevaporator and remaining viscous liquid was cooled and dried. A brownish white solid was obtained as N-(2-methoxyethyl)-N,N-dimethyldecan-1-aminium bromide. By using this method other surfactants were also synthesized. Other surfactants were also synthesized by heating in dioxane at 75° C. for 10 hours instead of using acetone.
Reaction SMILES: [CH:1](N(CC)C(C)C)(C)C.Cl.Cl.N1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[O:18]2)[CH2:14][CH2:13]1.Cl.[CH3:28][N:29]([CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:30](Cl)=[O:31]>C(Cl)(Cl)Cl>[CH3:28][N:29]([CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:30]([CH:1]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[O:18]2)[CH2:14][CH2:13]1)=[O:31]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(CCN1CCCCC1)C(=O)Cl
Reactant: O=C1OC2(CCNCC2)c2cccnc21
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CN(CCN1CCCCC1)C(=O)C1CCC2(CC1)OC(=O)c1ncccc12
Temperature: 70 °C
Reaction time: 11 h
Yield: 24 %

Procedure:
With cooling with ice, N,N-diisopropylethylamine (10.6 mL) and N-methyl-2-piperidin-1-ylethanamine (7.10 g) were added in that order to chloroform (140 mL) solution of triphosgene (8.15 g). The reaction liquid was stirred for 1 hour with cooling with ice, and then water (25 mL) was added thereto. The reaction liquid was azeotroped with toluene and then dried overnight under reduced pressure to obtain methyl(2-piperidin-1-ylethyl)carbamyl chloride monohydrochloride (20.0 g) as a pale yellow oily substance. Not further purified, the compound was used in the next reaction. Chloroform (2.0 mL), N,N-diisopropylethylamine (0.342 mL), 7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-7-one dihydrochloride (136 mg) were added to the obtained methyl(2-piperidin-1-ylethyl)carbamyl chloride monohydrochloride (100 mg), and stirred at 70° C. for 11 hours. The reaction liquid was concentrated under reduced pressure, and then purified through reversed-phase HPLC (0.1% TFA acetonitrile/H2O=5% to 50%, gradient) to obtain the entitled compound (57 mg, 24%) as a pale yellow oily substance.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[CH2:3]1.N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.C1COCC1>[O:1]([CH:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[CH2:3]1)[Si:14]([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CC(O)CCN1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CCNC(=O)C1)(c1ccccc1)c1ccccc1
Yield: 26.5 %

Procedure:
(±) 4-hydroxypiperidin-2-one (0.80 g, 6.94 mmol) was dissolved in DMF. DMAP (0.085 g, 0.694 mmol) and imidazole (0.92 g, 13.88 mmol) were added. After the resulting mixture was stirred evenly, the solution of TBDPS-Cl (2.3 g, 8.33 mmol) in THF was added and stirred at room temperature overnight. After the reaction completed, the reaction mixture was dried by spinning. Column chromatography afforded colorless oily liquid 0.65 g, yield 60%.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:9][C:8]=1[NH:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([O:40][CH3:41])=[CH:35][CH:34]=2)=[O:30])(=O)C.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[CH2:21]([O:20][C:18]([NH:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH2:6][CH2:5][OH:4])=[C:8]([NH:28][C:29]([C:31]2[NH:32][C:33]3[C:38]([CH:39]=2)=[CH:37][C:36]([O:40][CH3:41])=[CH:35][CH:34]=3)=[O:30])[CH:9]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc2[nH]c(C(=O)Nc3cc(NC(=O)OCc4ccccc4)c4ccccc4c3CCOC(C)=O)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C(=O)Nc3cc(NC(=O)OCc4ccccc4)c4ccccc4c3CCO)cc2c1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of 2-[4-(N-benzyloxycarbonylamino)-2-(5-methoxyindole-2-carboxamido)naphthalen-1-yl]ethyl acetate (0.5 g, 0.91 mmol) in methanol: tetrahydrofuran=1:1 (10 mL) was added potassium carbonate (0.13 g, 0.91 mmol) at room temperature and stirred overnight. The reaction mixture was diluted with AcOEt (100 mL) and washed with H2O (20 mL), saturated aqueous NaCl (20 mL), and then the organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield as a brown foam 2-[4-(N-benzyloxycarbonylamino)-2-(5-methoxyindole-2-carboxamido)naphthalen-1-yl]ethanol (0.42 g, 94%): mp 198° C. (decomp.); 1H NMR (DMSO-d6, 500 MHz) δ 10.18 (s, 1H), 8.26 (d, 8.5, 1H), 7.97 (d, 8.5, 1H), 7.51 (t, 7.0, 1H), 7.43 (d, 8.5, 1H), 7.39 (d, 7.5, 2H), 7.33 (s, 1H), 7.31 (s, 1H), 7.28 (t, 7.5, 2H), 7.18 (t, 7.5, 1H), 7.11 (brs, 1H), 7.08 (d, 2.5, 1H), 6.91 (t, 6.0, 1H), 6.86 (dd, 9.0, 2.5, 1H), 6.81 (s, 1H), 5.35 (t, 4.5, 1H), 4.47 (d, 5.5, 2H), 3.76 (s, 3H), 3.69 (m, 2H), 3.11 (t, 6.0, 2H);); FABMS (NBA) m/z 465 (M−CO2+), IR (neat) νmax 3272, 2945, 2874, 1646, 1594, 1528, 1479, 1453, 1422, 1404, 1261, 1213, 1162, 1030, 841, 805, 758, 734, 699 cm−1.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][N:17]=[N:16][N:15]=2)=[CH:10][CH:9]=1)([O-:7])=[O:6]>CN(C=O)C>[CH3:3][N:16]1[N:17]=[N:18][C:14]([C:11]2[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=2)=[N:15]1.[CH3:3][N:15]1[C:14]([C:11]2[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=2)=[N:18][N:17]=[N:16]1
Reactant: O=[N+]([O-])c1ccc(-c2nnn[nH]2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccc([N+](=O)[O-])cc2)n1
Product: Cn1nnnc1-c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 7 %
Yield: 49 %

Procedure:
To a stirred solution of 60% NaH (0.116 g, 2.89 mmol) and MeI (0.196 mL, 3.15 mmol) in DMF (2 mL) (cooled to 0° C., under N2) is added dropwise, a solution of 5-(4-nitrophenyl)-1H-tetrazole (0.502, 2.63 mmol) in DMF (7 mL). The reaction mixture is stirred under N2 for 1 hour and 30 min at 5° C. and then quenched with water and extracted with EtOAc. The organic layers are combined and washed with sat. NaCl, dried over MgSO4, filtered and evaporated to give a residue purified by silica gel column chromatography. Elution with 80:20 followed by 60:40 petroleum ether-EtOAc affords 2-methyl-5-(4-nitro-phenyl)-2H-tetrazole (0.265 g, 49%) as a white solid and 1-methyl-5-(4-nitro-phenyl)-1H-tetrazole (37.7 mg, 7%) as a yellow solid. The isomers are identified by NOE experiments.
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26]>>[CH2:18]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: NC(CO)CO
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC(CO)CO)cn1
Yield: 30 %

Procedure:
As described for example 9, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (150 mg, 0.49 mmol) was converted, using 2-amino-1,3-propanediol instead of rac-2-amino-1-propanol, to the title compound (53 mg, 30%) which was obtained as a white solid after purification by chromatography (silica, 0 to 8% methanol in dichloromethane). MS: m/e=364.3 [M+H]+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[C:7]=1O)[OH:6].[CH2:14]([O:21][CH2:22][C:23](Cl)=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.CC[O:29]CC>ClCCl>[CH2:14]([O:21][CH2:22][C:23]([C:13]1[C:12]([OH:29])=[CH:11][C:9]([OH:10])=[CH:7][C:5]=1[OH:6])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOCC
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Oc1cccc(O)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(COCc1ccccc1)c1c(O)cc(O)cc1O
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 32.2 %

Procedure:
Anhydrous aluminum trichloride (27.5 g, 206 mmol) was dissolved into 200 mL dichloromethane and cooled to −10° C. A solution of pyrogallol (20 g, 159 mmol) in ether was slowly added dropwise to the reaction mixture. After stirring 10 min at −10° C., a solution of benzyloxy acetyl chloride (26.4 g, 143 mmol) in dichloromethane (30 ml) was added dropwise. The reaction mixture was heated to 50° C. for 24 hours, and then cooled to room temperature. 1N HCl solution was carefully added to the mixture. The organic phase was separated and extracted with dichloromethane twice. The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Yellow oil product was obtained after filtering and concentration, and further purified by silica gel column chromatography (eluent:methanol/dichloromethane, 1:200) to give the desired white compound (14 g, yield 32.2%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[O:9]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:23]([O:25][CH:26]([O:29][CH2:30][CH3:31])[CH2:27]Br)[CH3:24]>CN(C)C=O>[CH2:23]([O:25][CH:26]([O:29][CH2:30][CH3:31])[CH2:27][O:22][C:19]1[CH:18]=[CH:17][C:16]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:21][CH:20]=1)[CH3:24]
Reactant: CCOC(CBr)OCC
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(Oc2ccccc2)cc1)OCC
Temperature: 150 °C

Procedure:
150 g of potassium carbonate and 4 g of finely powdered potassium iodide are added to a solution of 112 g (0.6 mole) of 4-phenoxyphenol and 157.6 g (0.8 mole) of bromoacetaldehyde diethyl acetal in 480 ml of dimethylformamide, and the batch is heated, under nitrogen, for 14 hours at 150° C. The salts are then removed by filtration from the reaction solution, and most of the dimethylformamide is distilled off in a water jet vacuum. The residue is dissolved in ether and the resultant solution is washed twice with water, three times with 20% potassium hydroxide solution and again with water. The ethereal solution is then dried over sodium sulfate and the ether is distilled off entirely. The resultant 4-phenoxyphenoxyacetaldehyde diethyl acetal is used without further purification for the preparation of the free aldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[N:3]=1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1>O.C(OCC)(=O)C>[ClH:1].[ClH:1].[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=3)[N:3]=2)[CH2:31][CH2:30]1
Reactant: CCC(CC)n1cnc2c(Nc3ccc(OC(F)(F)F)cc3)nc(Cl)nc21
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(CC)n1cnc2c(Nc3ccc(OC(F)(F)F)cc3)nc(N[C@H]3CC[C@H](N)CC3)nc21
Product: Cl
Reaction time: 4 h

Procedure:
The operation is carried out as in Stage 3 of Example 3 starting from 160 mg of the product obtained in Stage 1 above and 456 mg of trans-1,4-diaminocyclohexane and the reaction medium is taken to a temperature of 140 to 150° C. for 4 hours then cooled down to 70–80° C. and diluted with 20 ml of water/ethyl acetate in a proportion of 50/50 and left to settle, followed by washing with 10 ml of water and 5 ml of an aqueous solution of sodium chloride, drying and evaporating to dryness. After purification on silica eluting with methanol/ammonium hydroxide (NH4OH) in a proportion of 98/2 and salification with 1.4 N hydrochloric acid in ethanol, 149 mg of expected product is obtained in the form of crystals.
Reaction SMILES: [N:1]#[C:2]Br.C(=O)([O-])[O-].[K+].[K+].[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:15]=[C:14]2[CH:26]1[CH2:31][CH2:30][N:29](C)[CH2:28][CH2:27]1.O>CS(C)=O>[F:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[N:15]=[C:14]2[CH:26]1[CH2:31][CH2:30][N:29]([C:2]#[N:1])[CH2:28][CH2:27]1
Reactant: N#CBr
Reactant: CN1CCC(c2nn(-c3ccccc3)c3ccc(F)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCC(c2nn(-c3ccccc3)c3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 28 h
Yield: 93.6 %

Procedure:
To a stirred mixture of cyanogen bromide (4.05 g, 0.038 moles) and potassium carbonate (6.2 g, 0.045 moles) in dimethylsulfoxide (75 ml) was added dropwise a solution of 5-fluoro-1-phenyl-3-(1-methyl-4-piperidinyl)-1H-indazole (11.0 g, 0.036 moles) free base of Example 111(b) in hot dimethylsulfoxide (75 ml). The reaction was stirred at ambient temperature for 28 hours and then poured into water. The product was extracted (dichloromethane), dried (MgSO4) and concentrated to yield 10.8 g of an oil which crystallized upon standing. The product was recrystallized twice from isopropyl alcohol-ether and once from isopropyl alcohol which yielded 3.8 g (33%) of the 4-(5-fluoro-1-phenyl-1H-indazol-3-yl)piperidine-1-carbonitrile, m.p. 137°-139°.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:21](Cl)(=[O:23])[CH3:22]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]([C:9]#[C:10][Si:11]([CH3:13])([CH3:12])[CH3:14])[C:5]([NH:8][C:21](=[O:23])[CH3:22])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc(Br)nc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.3 %

Procedure:
To a solution of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (5.0 g, 19 mmol) and pyridine (3.8 mL, 46 mmol) in anhydrous THF (75 mL) was added acetyl chloride (1.6 mL, 23 mmol) in a drop-wise manner. After stirring for 48 hr at rt, additional acetyl chloride (0.4 mL, 6 mmol) was added and the mixture was stirred for an additional 48 hr at rt. The solvent was removed in vacuo, and the residue was diluted with 30% EtOAc in hexanes. The mixture was filtered, and the filtrate was purified via silica gel chromatography eluting with 30% EtOAc in hexanes to give a yellow-brown solid (1.8 g, 31%). 1H NMR (CDCl3, 300 MHz): δ 8.34 (s, 1H), 8.08 (s, 1H), 2.46 (s, 3H), 0.32 (s, 9H). HPLC retention time: 2.29 minutes. MS ESI (m/z): 312.2, 314.2 (M+H)+, calc. 311.
Reaction SMILES: C12(COC3C(C4CC4)=[CH:20][C:16](C(O)=O)=[CH:15][N:14]=3)CC3CC(CC(C3)C1)C2.[C:25]12([CH2:35][O:36][C:37]3[C:45]([CH:46]4[CH2:48][C:47]4([F:50])[F:49])=[CH:44][C:40]([C:41]([OH:43])=O)=[C:39]([F:51])[CH:38]=3)[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.COCC[S:56]([NH2:59])(=[O:58])=[O:57]>>[C:25]12([CH2:35][O:36][C:37]3[C:45]([CH:46]4[CH2:48][C:47]4([F:50])[F:49])=[CH:44][C:40]([C:41]([NH:59][S:56]([N:14]4[CH2:15][CH2:16][CH2:20]4)(=[O:58])=[O:57])=[O:43])=[C:39]([F:51])[CH:38]=3)[CH2:32][CH:31]3[CH2:33][CH:27]([CH2:28][CH:29]([CH2:30]3)[CH2:34]1)[CH2:26]2
Reactant: O=C(O)c1cc(C2CC2(F)F)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: COCCS(N)(=O)=O
Reactant: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2(F)F)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Yield: 31 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-(adamantan-1-ylmethoxy)-5-(2,2-difluorocyclopropyl)-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with azetidine 1-sulfamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.040 g, 31%): 1H NMR (300 MHz, DMSO-d6) δ 11.65 (br s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.00 (d, J=12.9 Hz, 1H), 4.01 (t, J=7.7 Hz, 4H), 3.68-3.57 (m, 2H), 2.84-2.71 (m, 1H), 2.20-2.06 (m, 2H), 2.06-1.88 (m, 5H), 1.75-1.54 (m, 12H); MS (ES+) m/z 499.2 (M+1).