Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:35][O:36][C:37](Cl)=[O:38]>ClCCl>[CH3:35][O:36][C:37](=[O:38])[NH:2][C@H:3]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:10]([C:11]2[C:12]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=3)=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)=[O:27])[CH2:5][CH2:4]1
Reactant: COC(=O)Cl
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Oc2cccc(SC)c2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.6 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (150 mg, 0.364 mmol) was suspended in dichloromethane (2 ml) under nitrogen at room temperature and triethylamine (153 μl, 1.09 mmol) was added followed by methylchloroformate (31 μl, 0.4 mmol). The reaction was stirred at room temperature for 1.5 h and the mixture was quenched with sat. sodium bicarbonate solution (3 ml). The organic phase was separated and the aqueous phase was washed with dichloromethane (2×3 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) and the product was triturated with diethylether (3 ml) to give (cis-4-{[5-Fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexyl)-carbamic acid methyl ester (64 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([N:36]([CH2:38][CH2:39][CH2:40][CH3:41])[CH3:37])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:34]([N:36]([CH2:38][CH2:39][CH2:40][CH3:41])[CH3:37])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(=O)N(C)CCCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(C(=O)N(C)CCCC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-methyl-n-butylamino-carbonyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[N+:18]([O-])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.C(OCC)(=O)C>[C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[NH2:18])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a solution of 2-phenylsulfonylamino-5-chloro-1-nitrobenzene (172 mg; prepared in Reference Example 11.) in acetic acid (4 ml), reduced iron powder (154 mg) was added at room temperature under an atmosphere of argon. The suspension was stirred for 2 hours at 120° C. The reaction suspension was diluted with ethyl acetate and filtered. The filtrate was concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (AcOEt-hexane) to give the title compound (92 mg) having the following physical data.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([F:29])=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[CH:13]=[CH:14][C:15]=3[N+:16]([O-])=O)[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+].C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([F:29])=[C:12]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[CH:13]=[CH:14][C:15]=3[NH2:16])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](Nc1ccc(N)c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (S)-N3-(5-cyclopropyl-1H-pyrazol-3-yl)-2-fluoro-N1-[1-(4-fluorophenyl)ethyl]-4-nitrobenzene-1,3-diamine (Method 36; 0.40 g, 1.00 mmol) and zinc dust (0.327 g, 5.00 mmol) in MeOH:THF (1:1, 10 ml) was slowly added saturated ammonium chloride (4 ml). The mixture was stirred at 25° C. for 2 hours, to which was then added saturated ammonium acetate solution (5 ml). The resulting mixture was stirred for another 30 minutes. The Zn dust was removed by filtration and washed with EtOAc (15 ml). The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated. The title compound was used directly for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([NH2:19])=[O:18])[CH2:8][CH2:7]1)(=[O:4])[CH2:2][CH3:3].[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1CCCCC1.[OH:44][S:45]([OH:48])(=[O:47])=[O:46]>C(O)C.O>[OH2:4].[OH2:37].[S:45]([OH:48])([OH:47])(=[O:46])=[O:44].[C:1]([O:5][C:6]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][N:14]2[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17](=[O:18])[NH:19][CH:30]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:7]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OC1(c2ccccc2)CCN(CCNc2ccccc2C(N)=O)CC1
Reactant: O=Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCNCC1
Solvent: CCO
Solvent: O
Product: CCC(=O)OC1(c2ccccc2)CCN(CCN2c3ccccc3C(=O)NC2c2ccccc2)CC1
Reaction time: 1 h

Procedure:
A mixture of 2-[2-(4-propionoxy-4-phenylpiperidino)ethylamino]benzamide (12.55 g), benzaldehyde (3.55 g), piperidine (1.35 g), and absolute ethanol (80 ml) was refluxed for 30 hrs. The solvent was removed on a rotovap. The thick oily product was chromatographed using silica gel and 5% isopropanol in chloroform. The product was isolated and dissolved in 30 ml 95% ethanol The solution was made acid with 4N H2SO4 and then 90 ml H2O was added. After 1 hr, the product was isolated and recrystallized from 850 ml 95% ethanol; yield 8.7 g, m.p. 186°-189° (d).
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[CH:20](O)[CH:21]1[CH2:23][CH:22]1[C:24]#[N:25].[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[NH:33][CH:32]=[CH:31]2>ClCCCl>[F:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[CH:20]([C:31]1[C:30]2[C:34](=[C:35]([CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])[CH:36]=[C:28]([F:27])[CH:29]=2)[NH:33][CH:32]=1)[CH:21]1[CH2:23][CH:22]1[C:24]#[N:25]
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: Cc1ccc(C(O)C2CC2C#N)c(F)c1
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: Cc1ccc(C(c2c[nH]c3c(CS(C)(=O)=O)cc(F)cc23)C2CC2C#N)c(F)c1

Procedure:
347 mg (1.57 mmol) of indium(III) chloride and 0.18 ml (2.35 mmol) of trifluoroacetic acid were added to 268 mg (1.31 mmol) of the compound from Example 166A and 405 mg (1.57 mmol) of the compound from Example 87A with a purity of 88% under argon in 10 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 358 mg (66% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH3:1][CH:2]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:13](=O)[CH2:12][C:11]1([CH3:20])[CH3:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21]([NH2:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH3:1][CH:2]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([NH:33][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][C:11]1([CH3:20])[CH3:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(ON1C(C)(C)CC(=O)CC1(C)C)c1ccccc1
Reactant: CCCCCCCCCCCCN
Product: CCCCCCCCCCCCNC1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1

Procedure:
The title compound, a colorless oil, is prepared from 1-alpha-methylbenzyloxy-2,2,6,6-tetramethylpiperidin-4-one and dodecylamine according to the procedure given in Example 35.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:22][CH2:23][CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:22][CH2:23][CH3:24])[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(C)c21
Yield: 49.9 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.115 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.098 mL, 1.0 mmol) to give the title compound (0.070 g) as a white solid.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](=[O:14])[CH2:12][Cl:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[C:1]([NH:9][C@@H:10]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@@H:11]([OH:14])[CH2:12][Cl:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)c1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
(3S)-3-Benzoylamino-1-chloro-4-phenyl-2-butanone (301.8 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=1000) in ethyl acetate (0.5 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to afford a desired compound, (2R, 3S)-3-benzoylamino-1-chloro-2-hydroxy-4-phenylbutane (300.1 mg; yield: 98.8%). The production ratio of the desired (2R,3S)-form to the isomeric (2S,3S)-form, (2R,3S):(2S,3S), was 27.3:1. The results of elementary analysis were as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:13]=1)=[O:11].C(N(CC)CC)C.[C:35](Cl)(=[O:38])[O:36][CH3:37]>C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C@H:23]2[CH2:27][CH2:26][N:25]([C:35]([O:36][CH3:37])=[O:38])[CH2:24]2)[CH:13]=1)=[O:11]
Reactant: O=C(Nc1c(Cl)cccc1Cl)c1cn([C@H]2CCNC2)c2ncccc2c1=O
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CC[C@H](n2cc(C(=O)Nc3c(Cl)cccc3Cl)c(=O)c3cccnc32)C1
Reaction time: 0.67 h
Yield: 67 %

Procedure:
Then, to a 4 ml anhydrous methylene chloride solution of (S)-N-(2,6-dichlorophenyl)-1-(3-pyrrolidyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, 28 μl (0.20 mmol) of triethylamine and 12.4 μl (0.16 mmol) of methyl chlorocarbonate were added at room temperature and stirred for 40 minutes. The reaction solution was concentrated under vacuum and the residue was purified by a silica gel chromatography (hexane/ethyl acetate=1/2) to obtain 55 mg (67%) of the above-identified compound as a colorless oily substance.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]12[C:19]([CH3:21])([CH3:20])[CH:16]([CH2:17][CH2:18]1)[CH2:15][C:14](=[O:22])[O:13]2.O>C1(C)C=CC=CC=1>[CH3:11][C:12]12[C:19]([CH3:21])([CH3:20])[CH:16]([CH2:17][CH2:18]1)[CH2:15][CH:14]([OH:22])[O:13]2
Reactant: CC12CCC(CC(=O)O1)C2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC12CCC(CC(O)O1)C2(C)C
Temperature: -60 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
25 ml of a solution of 1.1M of diisobutylaluminum hydride in toluene was added at -60° C. over 90 minutes to a solution of 5 g of 1,8,8-trimethyl-2-oxa-bicyclo [3,2,1] octane-3-one [process of Ronald et al, J.A.C.S., Vol. 81 (1959), p. 925] in 20 ml of toluene and the mixture was stirred for 2 hours at -60° C. Water was added dropwise while the temperature was allowed to rise to 20° C. and the mixture was then stirred at 20° C. for 2 hours. The mixture was filtered to remove lithium salts and the filter was washed with methylene chloride. The decanted aqueous phase of the filtrate was extracted with methylene chloride. The organic phase was dried and evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 1--1 benzene-ethyl acetate mixture yielded 3.5 g of 1,8,8-trimethyl-2-oxa-bicyclo [3,2,1] octan-3-ol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:32][C:33]([NH2:41])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:34]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:30])[NH:41][C:33]([CH3:34])([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH3:32])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(N)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)NC(C)(C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-methyl-1-phenyl-ethylamine.
Reaction SMILES: [Br-].[Li+].[Br:3][CH2:4][CH2:5][CH2:6][CH2:7]Br.[CH3:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[Mg]Br>C1COCC1.[Cu]Br>[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][C:15]=1[O:17][CH3:18]
Reactant: COc1ccc([Mg]Br)c(OC)c1
Reactant: BrCCCCBr
Agent: [Cu]Br
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CCCCBr)c(OC)c1
Temperature: 40 °C
Yield: 73.2 %

Procedure:
Commercially available copper(I)bromide (7.17 g, 50 mmol) and anhydrous lithium bromide (8.68 g, 100 mmol) were added to anhydrous THF (100 mL). Vigorous shaking gave a dark greenish solution. 11.5 mL (5.75 mmol) of this solution was added to a mixture of 1,4-dibromobutane (74.8 g, 346 mmol) in THF (90 mL). The mixture was warmed to 40°C, after which a solution of 2,4-dimethoxyphenylmagnesium bromide (115 mmol) in THF (100 mL), prepared by standard methods, was added over 45 min. The temperature was never more than 50° C. After the addition, the mixture was stirred for an additional 1 h at 50° C. The reaction mixture was allowed to reach 30° C. after which it was poured into ice water (200 mL). Effective stirring for 10 min gave a deep blue color. The mixture was extracted with diethyl ether (2×250 mL), dried (MgSO4) and evaporated. The excess of 1,4-dibromobutane was distilled off, and the residue was filtered through a short column of silica gel (hexane-EtOAC, 95:5). Evaporation gave the title compound as a colorless liquid (23.0 g): 1H NMR (CDCl3 -d) 7.00 (d, J=8.0 Hz, 1 H), 6.44-6.39 (m, 2 H), 3.79 (s, 6 H), 3.42 (t, J=6.9 Hz, 2 H), 2.56 (t, J=7.5 Hz, 2 H), 1.90-1.83 (m, 2 H), 1.73-1.62 (m, 2 H); 13C NMR (CDCl3 -d) 159.13, 158.24, 129.90, 122.56, 103.74, 98.44, 55.30, 55.22, 33.87, 32.47, 28.56 (two overlapping carbon); MS (EI, 70 eV): m/z (rel.int.) 274/272 (M+, 100/96), 151 (54), 121 (43), 91 (14).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=NN=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1>C1COCC1>[C:13]1([C:10]2[C:26]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][N:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(-c2nnc(-c3ccccc3)nn2)cc1
Reactant: C1=CCCCCCC1
Agent: C1=C/CCCCCC/1
Solvent: C1CCOC1
Product: c1ccc(-c2nnc(-c3ccccc3)c3c2CCCCCC3)cc1
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A dry round-bottomed flask was charged with 3,6-diphenyl-1,2,4,5-tetrazine (0.030 g, 0.13 mmol) and the flask was evacuated and filled with nitrogen. Anhydrous THF (1.3 mL) and trans-cyclooctene (0.014 g, 0.21 mmol) were added to the reaction mixture. After approximately 20 minutes the purple solution turned yellow, indicating that the reaction had gone to completion. The reaction mixture was concentrated under reduced pressure. The crude yellow residue was chromatographed on silica gel using a gradient (0-50%) of EtOAc in hexanes as the eluent to give 38 mg (95%) of the title compound as a pale yellow solid, mp 163-165° C. The adduction product had aromatized upon workup and chromatography to provide the titled compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][NH2:24])=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]([F:38])([F:37])[C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[CH2:1]([NH:8][C:9]([C:11]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][NH:24][S:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:37])[F:38])[CH:28]=2)(=[O:35])=[O:34])=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCc1ccccc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: O=C(NCc1ccccc1)c1ccccc1-c1ccccc1CNS(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
From 0.28 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid benzylamide (precursor 5 b) and 3-trifluoromethylphenylsulfonyl chloride, according to the general working procedure 131 mg of 21-(3-trifluoromethylphenyl-sulfonylaminomethyl)biphenyl-2-carboxylic acid benzylamide were obtained; m.p. 126° C. MS (ES+): m/e=525 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[C:4]([F:10])[CH:3]=1.[CH:11]12[O:17][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]2.[Cl-].[NH4+]>C(OCC)C>[F:10][C:4]1[CH:3]=[C:2]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[OH:17])[CH:7]=[C:6]([F:8])[C:5]=1[F:9]
Reactant: C1CCC2OC2C1
Reactant: Fc1cc(Br)cc(F)c1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: OC1CCCCC1c1cc(F)c(F)c(F)c1
Temperature: -58 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a solution of 1-bromo-3,4,5-trifluorobenzene (480 mg, 2.2 mmol) in diethyl ether (4.5 mL) was added drop wise at −76° C. under nitrogen butyl lithium (1.6 M in hexane, 1.31 mL, 2.1 mmol) keeping the temperature below −69° C. After 5 minutes cyclohexene oxide (216 uL, 2.1 mmol) was added dropwise keeping the temperature below −73° C. and then boron trifluoro etheroate (268 uL, 1.0 mmol) keeping the temperature below −66° C. The reaction was stirred for 30 minutes at −58° C. and then for 30 minutes at room temperature. Saturated aqueous ammonium chloride solution was added and the reaction was extracted twice with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified on silica gel using heptane/ethyl acetate (7:3 v/v) as eluent to yield the title compound (221 mg, 43%) as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm)=6.83-6.91 (m, 2H), 3.57 (m, 1H), 2.37 (m, 1H), 2.10 (m, 1H), 1.75-1.86 (m, 3H), 1.26-1.56 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:10]3[CH:19]=[C:20]([S:23][CH3:24])[CH:21]=[CH:22][C:9]=3[S:8][C:7]=2[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][C:38]1=[O:42]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([N:13]3[CH2:14][CH2:15][N:16]([CH2:35][CH2:36][N:37]4[CH2:41][CH2:40][CH2:39][C:38]4=[O:42])[CH2:17][CH2:18]3)[C:10]3[CH:19]=[C:20]([S:23][CH3:24])[CH:21]=[CH:22][C:9]=3[S:8][C:7]=2[CH:25]=1
Reactant: COc1ccc2c(c1)Sc1ccc(SC)cc1C(N1CCNCC1)C2
Reactant: O=C1CCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)Sc1ccc(SC)cc1C(N1CCN(CCN3CCCC3=O)CC1)C2

Procedure:
11 G. of 1-(10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin-10-yl)-piperazine are heated together with 15 g. of potassium carbonate, 0.5 g. of sodium iodide, 11 g. of N-( β-chloroethyl)-2-pyrrolidinone and 100 ml. of toluene under reflux conditions for 17 hours. Then, the mixture is evaporated under reduced pressure. The residue is partitioned between water and ether, and the ethereal phase dried over sodium sulfate and evaporated. The residue obtained is chromatographed with chloroform over aluminum oxide. The 1-{2-[4-(10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-pyrrolidinone thus obtained is converted into the corresponding dihydrochloride by reaction with hydrogen chloride. The resulting dihydrochloride melts at 202° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:57][C:58]1[O:59][C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=1.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[O:59]1[C:60]2[CH:66]=[CH:65][CH:64]=[CH:63][C:61]=2[N:62]=[C:58]1[NH:57][C:14](=[O:15])[CH:13]([C:5]1[CH:6]=[CH:7][C:8]([S:9]([CH3:12])(=[O:10])=[O:11])=[C:3]([C:1]#[N:2])[CH:4]=1)[CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1nc2ccccc2o1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3o2)cc1C#N
Yield: 55.1 %

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 26, 100 mg, 0.311 mmol), triethylamine (0.13 mL, 0.933 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (206 mg, 0.467 mmol), and 2-aminobenzoxazole (63 mg, 0.467 mmol) in methylene chloride (3 mL) was stirred at 25° C. for 3 h. The reaction mixture was then diluted with water (40 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (40 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded N-benzooxazol-2-yl-2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (75 mg, 55%) as a yellow foam: mp 108-112° C.; EI-HRMS m/e calcd for C23H23N3O4S (M+) 437.1409, found 437.1409.