Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.C(N(CC)CC)C.[NH2:20][C:21]1[CH:42]=[CH:41][C:24]([C:25]([N:27]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH2:31][N:30]3[CH:38]=[CH:39][CH:40]=[C:29]3[CH2:28]2)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH:40]1[CH:39]=[CH:38][N:30]2[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:27]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=4[O:11][CH3:12])=[CH:42][CH:41]=3)=[O:26])[CH2:28][C:29]=12
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Cl)ccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 41.1 %

Procedure:
To a stirred solution of 0.406 g of 4-chloro-2-methoxybenzoyl chloride in 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours at room temperature. An additional 0.406 g of 4-chloro-2-methoxybenzoyl chloride and 0.346 g of triethylamine is added and stirring is continued for 2 hours. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a residue which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give a solid which is crystallized from ethyl acetate to give 0.320 g of the desired product as a white crystals, m.p. 222°-224° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C=CC(O)=CC=1)O.[Br:23][CH2:24][CH3:25]>CC(C)=O>[Br-:23].[C:1]([O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][N+:12]([CH3:14])([CH3:13])[CH2:24][CH3:25])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCOCCN(C)C
Reactant: CCBr
Agent: Oc1ccc(O)cc1
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCCOCC[N+](C)(C)CC
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(2-dimethylaminoethoxy)ethyl methacrylate (8 g) was dissolved in acetone (20 g) and small amounts of hydroquinone (approx. 0.1 g) was added followed by the addition of bromoethane (8 g). The mixture was stirred at room temperature for 24 hours and the solvent was removed under reduced pressure at 25° C. Product was obtained as an amorphous solid. Yield 12.2 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:11])([CH3:8])[CH2:6][CH3:7])[CH3:2].[BH-](O[C:42]([CH3:44])=O)(OC(C)=O)OC(C)=O.[Na+].[C:46](=O)([O-])O.[Na+]>ClCCl.CC(O)=O.CC(C)=O>[CH2:1]([O:3][C:4](=[O:31])[C:5]([NH:9][C:10]([C:12]1[CH:21]=[C:20]([Cl:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O:23][CH2:24][CH:25]1[CH2:26][CH2:27][N:28]([CH:42]([CH3:44])[CH3:46])[CH2:29][CH2:30]1)=[O:11])([CH3:8])[CH2:6][CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCNCC1
Reactant: O=C([O-])O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)C(C)(CC)NC(=O)c1cc(Cl)c2ccccc2c1OCC1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution containing 70 mg of 2-{[4-chloro-1-(piperidin-4-yl-methoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester (see example 160, step b)) and 9 mg of acetone in 6 mL dichloromethane was added 14 mg HOAc followed by addition of Na(OAc)3BH (46 mg). After 16 hours at room temperature, 9 mg of acetone, 14 mg of HOAc and 46 mg of Na(OAc)3BH were added. The reaction mixture was stirred at room temperature overnight. Aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with dichloromethane. The organic phase was washed with brine, dried over sodium sulphate and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, 7N NH3 in MeOH/dichloromethane) to give 46 mg of 2-{[4-chloro-1-(1-isopropyl-piperidin-4-ylmethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-butyric acid ethyl ester.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=2)[CH:29]=O)=[N:23][CH:22]=1>>[F:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][N:33]=[C:26]([C:24]3[S:25][C:21]([CH3:20])=[CH:22][N:23]=3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Reactant: Cc1cnc(-c2cc(C=O)ccn2)s1
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccnc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with 2-(5-methylthiazol-2-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 412.01 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][Cl:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCOc1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
A mixture of 4-chlorophenol (100 g), 1-bromo-2-chloroethane (335 g), potassium carbonate (129 g) and acetone (2 l) was boiled under reflux with stirring for 18 hours. The mixture was evaporated to dryness under reduced pressure and then dichloromethane was added to the cool residue. The mixture was filtered and the filtrate washed with 5M sodium hydroxide solution, water, dried, filtered and evaporated to give 2-chloroethyl 4-chlorophenyl ether as an oil.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][NH2:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1([CH3:30])[C:24](Cl)=[CH:25][CH:26]=[CH:27][CH:28]=1.C(N(CC)CC)C.CN([CH:41]=[O:42])C>>[CH:1]1([NH:7][S:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:21][NH:22][C:41](=[O:42])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH3:30])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccccc1Cl
Reactant: CN(C)C=O
Reactant: NCc1ccc(S(=O)(=O)NC2CCCCC2)c2ccccc12
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)NCc1ccc(S(=O)(=O)NC2CCCCC2)c2ccccc12

Procedure:
To a solution of naphthalenyl methylamine 42 (100 mg, 0.32 mmol) in DMF (2 mL) was added o-tolylchloride (49 μL, 0.38 mmol) and triethylamine (88 μL, 0.63 mmol). The resultant solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified using HPLC to give the title compound (G-5) (30 mg) as pale yellow solid. 1H NMR (300 MHz, MeOD) δ 8.78 (d, 1H), 8.34 (d, 1H), 8.20 (d, 1H), 7.72 (m, 2H), 7.63 (d, 1H), 7.35 (d, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 5.07 (s, 2H), 2.95 (s, 1H), 2.34 (s, 3H), 1.55 (m, 5H), 1.05 (m, 5H); LC/MS m/z 437 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH3:11][S:12]([O-:14])=[O:13].[Na+].CNCCNC.C(OCC)(=O)C>CS(C)=O.O>[CH3:11][S:12]([C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1)(=[O:14])=[O:13]
Reactant: CS(=O)[O-]
Reactant: COc1cc(Br)ccc1O
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(S(C)(=O)=O)ccc1O
Temperature: 130 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
A mixture of 4-bromo-2-methoxyphenol (500 mg, 2.46 mmol), sodium methanesulfinate (1 g, 9.84 mmol), copper(I) trifluoromethanesulfonate benzene complex (124 mg, 0.25 mmol) and N,N′-dimethylethylenediamine (53 μL, 0.49 mmol) in dimethyl sulfoxide (3 mL) was stirred overnight at 130° C. The mixture was allowed to cool to room temperature followed by the addition of ethyl acetate (8 mL) and water (8 mL). The resulting mixture was filtered through Celite pad and to the filtrate was added 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→1/1) to give the title compound as a white crystal (258 mg, yield 52%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:12])[C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH3:12][N:4]1[C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=[C:3]1[CH2:2][O:1][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: Cn1c(CO)nc2cncnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cncnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.37 g of 2-hydroxymethyl-3-methylimidazo[5,4-d]pyrimidine (prepared as described in Preparation 50), 2.51 g of 5-(4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4 dione, 1.34 ml of tributylphosphine, 1.36 g of 1,1'-(azodicarbonyl) dipiperidine and 50 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in a ratio of 2:1 by volume, and then in ratios ranging from 1:1 to 1:2 by volume, and subsequently a 6:1 by volume mixture of ethyl acetate and ethanol as the eluent. The desired fractions were collected and concentrated by evaporation under reduced pressure. The concentrate was further purified by preparative reverse-phase high speed liquid chromatography through YMC-Pack ODS-A (a product of YMC Inc.) using a 100:100:1:1 by volume mixture of acetonitrile, water, acetic acid and triethylamine as the eluent, to give 0.24 g of the title compound, melting at 55-65° C. (softening).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[O:8][CH2:7][C@@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@H:21]([OH:23])[CH3:22])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CO>[OH:23][C@@H:21]([C:10]1[N:9]([C@@H:6]2[CH2:7][O:8][C@@H:3]([CH2:2][NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:4][CH2:5]2)[C:13]2=[C:14]3[S:20][CH:19]=[CH:18][C:15]3=[N:16][CH:17]=[C:12]2[N:11]=1)[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)OC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CNS(C)(=O)=O)OC1
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a solution of (1R)-1-{1-[(3S,6R)-6-(aminomethyl)tetrahydro-2H-pyran-3-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol (11 mg, 0.033 mmol) in methanol (0.5 mL) was added N,N-diisopropylethylamine (17 μL, 0.099 mmol) and methanesulfonyl chloride (2.8 μL, 0.036 mmol). After stirring for 0.5 h, another equivalent of methanesulfonyl chloride was added. After stirring for 20 min, The reaction solution was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (5 mg, 37%). LCMS calculated for C17H23N4O4S2 (M+H)+: m/z=411.1. Found: 411.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[N:11][NH:12][N:13]=1.[CH3:14][C:15](O)([CH3:17])[CH3:16].S(=O)(=O)(O)O.[OH-].[K+]>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[CH3:14][C:15]([N:13]1[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[N:10][NH:11][NH:12]1)([CH3:17])[CH3:16]
Reactant: COc1ccccc1-c1nn[nH]n1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1=NNNN1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
A mixture of 5-(2-methoxyphenyl)-2H-tetrazole (0.83 g, 4.71 mmol), 2-methyl-2-propanol (0.7 g, 9.4 mmol), and sulfuric acid (0.24 g, 2.4 mmol) in 4.6 mL of TFA was stirred under nitrogen at room temperature for 16 hours. The reaction mixture then was diluted with ethyl acetate, poured into 2 M potassium hydroxide, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated. Purification of the residue by column chromatography on silica gel (elution: 10% ethyl acetate/hexane) gave 1-(1,1-dimethylethyl)-5-(2-methoxyphenyl)-2H-tetrazole (0.5102 g, 1.67 mmol), as an oil.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=O)[CH3:2].[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[CH2:18])=[CH:13][CH:12]=1)[CH3:9].[Cl:28][C:29]1[C:30]([Cl:42])=[C:31]([Cl:41])[C:32]([Cl:40])=[C:33]2[C:38](=O)[O:37][C:35](=[O:36])[C:34]=12.[OH-].[Na+]>O.ClC1C=CC=CC=1Cl>[CH3:27][N:25]([CH3:26])[C:22]1[CH:21]=[CH:20][C:19]([C:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:8][CH3:9])=[CH:12][CH:13]=2)=[CH:18][C:38]2([CH:18]=[C:17]([C:14]3[CH:13]=[CH:12][C:1]([O:4][CH2:5][CH3:6])=[CH:2][CH:15]=3)[C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[C:33]3[C:34](=[C:29]([Cl:28])[C:30]([Cl:42])=[C:31]([Cl:41])[C:32]=3[Cl:40])[C:35](=[O:36])[O:37]2)=[CH:24][CH:23]=1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: CC(=O)OC(C)=O
Reactant: C=C(c1ccc(OCC)cc1)c1ccc(N(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CCOc1ccc(C(=CC2(C=C(c3ccc(OCC)cc3)c3ccc(N(C)C)cc3)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccc(N(C)C)cc2)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
Into a mixture of 25 ml of acetic anhydride and 75 ml of o-dichlorobenzene, 13.4 g of 1-(p-ethoxyphenyl)-1-(p-dimethylaminophenyl)ethylene (melting at 110°-111° C.) and 21.5 g of tetrachlorophthalic anhydride were added and the mixture was stirred for 6 hours at 120° C. After adding the reaction mixture into 200 ml of water and making the mixture alkaline by sodium hydroxide, the alkaline mixture was extracted with 70 ml of toluene. The solid matter obtained by distilling off toluene from the extract was recrystallized from acetone while purifying with activated carbon to obtain 16.2 g of pale yellow crystals in a yield of 80.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:27])([F:26])[F:25])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[C:16]([CH:18]=2)[NH2:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28]I>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:26])([F:25])[F:27])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[C:16]([CH:18]=2)[NH:17][CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CI
Reactant: Nc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Solvent: ClCCl
Product: CNc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)aniline (0.3 g, 0.7 mmol) in CH2Cl2 (10 mL) was added TEA (0.155 mL, 1.09 mmol) and methyl iodide (0.124 g, 0.873 mmol). The reaction was stirred at ambient temperature for 18 h. The CH2Cl2 layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc/Pet ether) to afford the title compound as a yellow semi-solid (0.07 g, 70%).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:18]=1[NH:26][S:27]([CH2:30][C:31]1[N:32]=[N:33][NH:34][N:35]=1)(=[O:29])=[O:28])[CH3:16].CCN(CC)CC>CC#N>[CH3:16][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:24])[CH3:25])[C:18]=1[NH:26][S:27]([CH2:30][C:31]1[N:32]=[N:33][N:34]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:35]=1)(=[O:29])=[O:28])[CH3:14].[CH3:16][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:24])[CH3:25])[C:18]=1[NH:26][S:27]([CH2:30][C:31]1[N:35]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:34]=[N:33][N:32]=1)(=[O:29])=[O:28])[CH3:14]
Reactant: CC(C)c1cccc(C(C)C)c1NS(=O)(=O)Cc1nn[nH]n1
Reactant: CCCCCCCCCCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCn1nnc(CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CCCCCCCCCCCCn1nnnc1CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
Dodecyl bromide (0.386 g, 1.55 mM) was added dropwise to a solution of N-[2,6-bis(1-methylethyl) phenyl]-2H-tetrazole-5-methanesulfonamide (0.5 g, 1.55 mM), Et3N (0.157 g, 1.55 mM) in CH3CN (50 mL), and heated for 20 hours. The residue from solvent removal was redissolved in 20 mL EtOAc, washed with 0.1 N HCl, brine, and evaporated. N-[2,6-Bis(1-methylethyl) phenyl]-2-dodecyl-2H-tetrazole-5-methanesulfonamide was isolated by chromatography (0.13 g, 22%), mp 85°-86° C., along with trace amounts of N-[2,6-bis(1-methylethyl)phenyl]-1-dodecyl-1H-tetrazole-5-methanesulfonamide.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.C([Sn](CCCC)(CCCC)[C:21]#[C:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)CCC.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:23]1([C:22]#[C:21][N:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]([C:9]=34)=[CH:2]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Agent: [Pd]
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCc2cn(C#Cc3ccccc3)c3cccc1c23
Temperature: 60 °C
Yield: 55.2 %

Procedure:
Tricyclic bromide 11 (58.6 mg, 0.22 mmol) in DMF (1 mL) was degassed and treated with tributyl(phenylethynyl)tin (95.2 mg, 0.24 mmol) and tetrakis(triphenylphosphine) palladium(0) (13 mg, 2 mol %). One crystal of 2,6-di-t-butyl-4-methyl phenol was added, and the solution was heated at 60° C. for 10 h. Starting material was still present, so the solution was heated at 100° C. for an additional 2 h. The reaction mixture was cooled to ambient temperature and diluted with water (2 mL) and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by radial chromatography (2 mm SiO2; 3% MeOH in CH2Cl2) to yield 17 as a white solid (34.8 mg, 55%). mp 255-256° C. (dec); 1H NMR (DMSO-d6) δ 11.86 (s, 1H), 8.17 (m, 1H), 7.75 (d, 1H, J=7.6 Hz), 7.63 (m, 3H), 7.51 (m, 3H), 7.33 (t, 1H, J=7.6 Hz), 3.50 (m, 2H), 3.09 (m, 2H); HRMS (FAB, M+H) Calcd for C19H14N2O+H: 287.1184, Found: 287.1192; Anal. (C19H14N2O.0.6 H2O) C, H, N.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[N:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[N:33][CH:32]=[CH:31][N:30]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2cc(C(F)(F)F)c(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M101) (0.28 g, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (50 mg, 23%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]=[C:4]([O:11][CH3:12])[N:3]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22]>C(#N)C>[F:9][CH:8]([F:10])[C:6]1[N:5]=[C:4]([O:11][CH3:12])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([F:28])([F:13])[F:27])(=[O:22])=[O:23])=[O:26])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: COc1nc(N)nc(C(F)F)n1
Solvent: CC#N
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(F)(F)F)nc(C(F)F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2.65 g of 2-amino-4-difluoromethyl-6-methoxy-1,3,5-triazine (15 mmol) in 20 ml of acetonitrile was treated at 25° C. with 3.7 g of 2-trifluoromethylbenzenesulfonyl isocyanate (15 mmol). The mixture was subsequently stirred at 25° C. for 16 h, the solvent was removed in a water-jet vacuum at 40° C. and the solid residue was stirred vigorously with 100 ml of diethyl ether. The product was filtered off with suction, washed with a little ether and dried. 4.3 g (10 mmol, 67% of theory) of the title compound of m.p. 143-145° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:6][CH:7]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCI
Reactant: CCCCCC1CCC(c2ccc(O)cc2)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(C2CCC(CCCCC)CO2)cc1
Reaction time: 16 h

Procedure:
A mixture of 24.8 g of 2-p-hydroxyphenyl-5-pentyltetrahydropyran (obtainable by diazotization of 2-p-aminophenyl-5-pentyltetrahydropyran and hydrolysis), 6.9 g of K2CO3, 25 g of hexyl iodide and 250 ml of DMF is heated, with stirring, at 80° for 16 hours, then cooled and worked up as usual. 2-p-Hexoxyphenyl-5-pentyltetrahydropyran is obtained.