Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([F:12])[C:6]([S:10][CH3:11])=[C:7]([F:9])[CH:8]=1.[Br-:13].[Li+].CC(C)=O.[Br-].[Na+]>O>[Br:13][CH2:2][C:3]1[CH:4]=[C:5]([F:12])[C:6]([S:10][CH3:11])=[C:7]([F:9])[CH:8]=1
Reactant: CSc1c(F)cc(CCl)cc1F
Reactant: [Br-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CSc1c(F)cc(CBr)cc1F

Procedure:
A mixture of 5-(chloromethyl)-1,3-difluoro-2-(methylthio)benzene (21.3 g, 0.10 mol), lithium bromide (15 g, 0.17 mol), and acetone (200 mL) was heated and held at reflux for 18 hours. The cool mixture was poured into water and extracted with dichloromethane (1×200 mL, 2×50 mL). The combined extracts were dried using magnesium sulfate, and concentrated. The residue was dissolved in acetone (200 mL), lithium bromide (30 g, 0.34 mol) and sodium bromide (20 g, 0.19 mol) were added and the mixture heated and held at reflux for 42 hours. The mixture was cooled, added to water, and extracted with dichloromethane (1×150 mL, 1×50 mL). The combined extracts were washed with dilute sodium chloride, dried with magnesium sulfate, and concentrated. The 5-(bromomethyl)-1,3-difluoro-2-(methylthio)benzene was purified using silica gel chromatography using hexanes as a yellow solid (20.5 g, 80%). 1H NMR (CDCl3/400 MHz) 6.92-6.95 (m, 2H), 4.37 (s, 2H), 2.45 (s, 3H). HRMS m/z 251.9432 (M+, calcd 251.9420).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:8]1[C:9]([F:11])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccc(F)cc1F
Product: O=C(O)c1cc(S(=O)(=O)Cl)c(F)cc1F
Temperature: 155 °C
Yield: 94 %

Procedure:
A mixture of chlorosulfonic acid (200 mL) and 2,4-difluorobenzoic acid (40 g, 253 mmol, 1 equiv) was heated to 155° C. for 3 h. The reaction was cooled to RT and poured slowly over ice. The product was extracted into ether and the organics dried over MgSO4, filtered and concentrated to give 5-(chlorosulfonyl)-2,4-difluorobenzoic acid 6a as brown solid (61 g, 94% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[NH:6][CH2:5][CH:4]([CH2:7][S:8][CH2:9][CH3:10])[O:3]1.[CH2:12]([N:14]([CH2:17]C)CC)[CH3:13].C(C1C(Cl)=C(C([O-])=O)[S:24]C=1)C.CC1(C)N(C(=O)CCl)CC(CSCC)O1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[N:6]([C:17](=[S:24])[NH:14][CH2:12][CH3:13])[CH2:5][CH:4]([CH2:7][S:8][CH2:9][CH3:10])[O:3]1
Reactant: CCSCC1CNC(C)(C)O1
Reactant: CCc1csc(C(=O)[O-])c1Cl
Reactant: CCN(CC)CC
Agent: CCSCC1CN(C(=O)CCl)C(C)(C)O1
Solvent: c1ccccc1
Product: CCNC(=S)N1CC(CSCC)OC1(C)C

Procedure:
To 19.3 milliliters of 25 percent w/v, 2,2-dimethyl-5-ethylthiomethyl oxazolidine solution in 25 milliliters of benzene was added 2.9 grams of triethylamine and 3.4 grams of ethylchlorothiolformate as in the procedure for (a) supra. Work-up was similar to (a). There was obtained a yield of 7.1 grams of the title compound, nD30 1.4940. Infrared data supports the structure.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C@H:12]([CH2:15]OS(C3C=CC(C)=CC=3)(=O)=O)[O:11][C:10]=2[CH:27]=1)(=[O:5])=[O:4].[CH2:30]([NH2:33])[CH2:31][CH3:32].Cl>C(#N)C>[F:28][C:2]([F:29])([F:1])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C@H:12]([CH2:15][NH:33][CH2:30][CH2:31][CH3:32])[O:11][C:10]=2[CH:27]=1)(=[O:5])=[O:4]
Reactant: CCCN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(=O)(=O)C(F)(F)F)cc3O2)cc1
Agent: Cl
Solvent: CC#N
Product: CCCNC[C@H]1COc2ccc(S(=O)(=O)C(F)(F)F)cc2O1

Procedure:
Preparation according to Example 2 using [(2R)-7-(trifluoromethylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.39 g, 0.98 mmol), propan-1-amine (1 ml) and ACN (2 ml). Yield: 0.150 g, 45%. The amine was converted to the hydrochloric acid salt and recrystallized from acetonitrile. M.p. 175° C. MS m/z (rel. intensity, 70 eV) 339 (M+, 2) 310 (10), 270 (6), 72 (bp), 70 (6). [α]=+50° (MeOH).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH2:6][C@@H:7]([CH3:17])[N:8]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:9][CH:10]=1)=O.[C:18](=[S:21])([S-:20])[NH2:19].[NH4+]>CO.C(N)(=S)C1C=CN=CC=1>[SH:21][C:18]1[S:20][CH:2]=[C:3]([C:5]2[CH2:6][C@@H:7]([CH3:17])[N:8]([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH2:9][CH:10]=2)[N:19]=1
Reactant: C=CCOC(=O)N1CC=C(C(=O)CCl)C[C@H]1C
Reactant: NC(=S)[S-]
Agent: NC(=S)c1ccncc1
Agent: [NH4+]
Solvent: CO
Product: C=CCOC(=O)N1CC=C(c2csc(S)n2)C[C@H]1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
To a solution of allyl (2R)-4-(chloroacetyl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (0.255 g, 1.0 mmol) in methanol (5 ml) were added at 0–5° C. thioisonicotinamide (5 mg) and ammonium dithiocarbamate (0.22 g, 2.0 mmol). The reaction mixture was raised to room temperature, stirred for 15 minutes and then stirred at 55–60° C. for 1.5 hour. The solvent was removed in vacuo and to the residue was added aqueous 1N NaOH solution to make the solution alkaline. To the solution were added ethyl acetate and hexane, and the mixture was separated with a separating funnel. The aqueous layer was acidified with 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo to give allyl (2R)-4-(2-mercapto-1,3-thiazol-4-yl)-2-methyl-3,6-dihydro-1(2 H)-pyridinecarboxylate (170 mg, 59%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CN(C=O)C.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>O>[O:20]=[C:18]1[N:17]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:16](=[O:21])[CH:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]3)=[CH:23][CH:22]=2)[S:19]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Sodium hydride (60% in mineral oil, 66 mg, 1.65 mmol) was added into a mixture of 5-[4-(4-oxo-1-piperidineyl)benzyl]-1,3-thiazolidine-2,4-dione (500 mg, 1.65 mmol) (which was obtained in Example 38), and DMF. The mixture was stirred for 1 hour at room temperature, and then tert-butyl bromoacetate (0.36 mL, 2.47 mmol) was added. The new mixture was stirred for 30 minutes, poured into water, and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate 3/1) gave a viscous oil (525 mg, 76% yield); 1H NMR (300 MHz, DMSO-d6) δ 1.40 (s, 9H), 2.40 (m, 4H), 2.9 (m, 1H), 3.45 (m, 1H), 3.56 (m, 4H), 4.20 (s, 2H), 5.05 (m, 1H), 6.97 (m, 2H), 7.18 (m, 2H); MS (ES) m/z: 419 (MH+); Anal. Calcd. for C15H16N2O3S : C, 60.27; H, 6.26; N, 6.69. Found: C, 60.21; H, 6.44; N, 6.52.
Reaction SMILES: [NH2:1][C:2]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1)=[S:3].[Cl:18][CH:19]([C:25](=O)[CH2:26][O:27][CH3:28])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[ClH:18].[NH2:10][CH:7]1[CH2:6][CH2:5][N:4]([C:2]2[S:3][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH2:26][O:27][CH3:28])[N:1]=2)[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(N)=S)CC1
Reactant: CCOC(=O)C(Cl)C(=O)COC
Product: CCOC(=O)c1sc(N2CCC(N)CC2)nc1COC
Product: Cl

Procedure:
The title compound was prepared in a manner analogous to Intermediate 126 starting from tert-butyl [1-(aminocarbonothioyl)piperidin-4-yl]carbamate (Intermediate 125) and ethyl 2-chloro-4-methoxy-3-oxobutanoate (Intermediate 6).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH3:26])[NH:22][N:21]=2)[CH:16]=[C:15]([Cl:27])[N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:15]1[N:14]=[C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH3:26])[NH:22][N:21]=2)[CH:16]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: COc1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2cc(Cl)nc(N[C@@H](C)c3ncc(F)cn3)n2)n[nH]1
Temperature: 105 °C
Yield: 52.3 %

Procedure:
A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 512 mg), 2,6-dichloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 42, 682 mg) and DIPEA (1.16 ml) in n-BuOH (13 ml) was heated at 105° C. over night. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (500 mg). 1H NMR δ 8.92 (s, 2H) 5.95 (s, 1H) 5.18 (s, 1H) 3.77 (s, 3H) 1.49 (d, 3H); m/z 366.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:10]([O:13]C(=O)C)[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)C(C)C.[CH2:30]1[CH2:34]O[CH2:32][CH2:31]1>CCOCC.CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:10]([OH:13])[C@@H:11]([OH:12])[CH:30]([CH3:34])[CH2:31][CH3:32])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(=O)O[C@@H](C=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[Mg]Cl
Solvent: O
Solvent: CO
Solvent: CCOCC
Product: CCC(C)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 2 h

Procedure:
The title compound of Step 1 was dissolved under nitrogen in 100 mL of dry THF and cooled to -70° C. To this solution was added 13 mL (26 mmol) of a 2.0M solution of isobutylmagnesium chloride in ether and the stirred mixture was allowed to warm to room temperature and stir for 2 hrs. After decomposition with MeOH/H2O the mixture was diluted with ether, washed with saturated NH4Cl solution twice and dried with magnesium sulfate and the solvents evaporated under vacuum. The residue was allowed to stand overnight in 80% MeOH-H2O containing excess ammonium hydroxide. The MeOH was stripped off and the mixture was extracted with ether. These extracts were combined, washed with water, dilute KHSO4, then dried and evaporated to give 2.36 g of a yellow glass which crystallized from 50 mL of pentane on standing overnight. The yellow-white powder obtained was recrystallized from ether-hexane and furnished the title compound (0.41 g) as white, hairy needles, mp 134°-136° C., Rf (ether): single spot, 0.6. By chromatography of the mother liquors and crystallization of the appropriate fractions, an additional 0.22 g of product, mp 138°-139° C., was obtained. Anal: Calcd. for C19H31NO4 : C, 67.62; H, 9.26; N, 4.15. Found: C, 67.51; H, 9.43; N, 4.24.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:40])[CH:31]=[CH:32][C:33]=1[C:34]1[O:38][C:37]([CH3:39])=[N:36][CH:35]=1.[CH2:41]([C:48]1[CH:53]=[C:52]([CH3:54])[N:51]=[C:50](Cl)[N:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:41]([C:48]1[CH:53]=[C:52]([CH3:54])[N:51]=[C:50]([NH:40][C:30]2[CH:31]=[CH:32][C:33]([C:34]3[O:38][C:37]([CH3:39])=[N:36][CH:35]=3)=[C:28]([O:27][CH3:26])[CH:29]=2)[N:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COc1cc(N)ccc1-c1cnc(C)o1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-c1cnc(C)o1
Yield: 26.7 %

Procedure:
Palladium(II) acetate (5.4 mg, 0.024 mmol) and 2-(dicyclohexylphosphino)biphenyl (17 mg, 0.048 mmol) were stirred in dioxane (3 mL) for 20 minutes under an atmosphere of nitrogen. Sodium tert.-butylate (44 mg, 0.45 mmol), 3-methoxy-4-(2-methyl-oxazol-5-yl)-phenylamine (61 mg, 0.30 mmol, CAS 568556-28-5; E. J. Iwanowicz et. al. Bioorganic & Medicinal Chemistry Letters, 13(12), 2059-2063; 2003) and 4-benzyl-2-chloro-6-methyl-pyrimidine (72 mg, 0.33 mmol) were added. The reaction was heated for 30 minutes to 130° C. in a microwave oven. Water was added and the reaction was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane and then methylenechloride/methanol (19:1 v/v) as eluent to yield the title compound as a yellow solid (31 mg, 27%). MS ISP (m/e): 387.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.86 (s, 1H), 7.61 (d, 2H), 7.26-7.33 (m, 5H), 7.15 (br s, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 3.97 (s, 2H), 3.90 (s, 3H), 2.51 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH2:29]([O:39][C:40]([NH:42][C:43]1[N:51]=[CH:50][N:49]=[C:48]2[C:44]=1[N:45]=[CH:46][N:47]2[CH2:52][C:53](O)=[O:54])=[O:41])[C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:53](=[O:54])[CH2:52][N:47]1[CH:46]=[N:45][C:44]2[C:48]1=[N:49][CH:50]=[N:51][C:43]=2[NH:42][C:40]([O:39][CH2:29][C:30]1[CH:38]=[CH:37][C:36]2[O:35][CH2:34][O:33][C:32]=2[CH:31]=1)=[O:41])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccc4c(c3)OCO4)ncnc21
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1cnc2c(NC(=O)OCc3ccc4c(c3)OCO4)ncnc21

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [6-N-(piperonyloxycarbonyl)-adenin-9-yl]-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 10.60 (s, 0.45H), 10.59 (s, 0.55H), 9.31 (brs, 0.55H), 9.11 (brs, 0.45H), 8.58 (s, 0.45H), 8.57 (s, 0.55H), 8.40 (d, 0.55H), 8.39 (d, 0.45H), 8.32 (s, 0.55H), 8.31 (s, 0.45H), 8.03–7.98 (m, 1H), 7.93 (d, 0.55H), 7.90 (d, 0.45H), 7.05 (s, 1H), 6.95 (d, 1H), 6.91 (d, 1H), 6.02 (s, 2H), 5.38 (s, 1.1H), 5.17 (s, 0.9H), 5.11 (s, 2H), 4.48 (s, 0.9H), 4.23 (q, 0.9H), 4.08 (s, 1.1H), 4.07 (q, 1.1H), 3.73 (t, 1.1H), 3.54 (t, 1.1H), 3.45 (t, 0.9H), 3.30 (t, 0.9H), 1.27 (t, 1.35H), 1.15 (t, 1.65H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:12][N:5]([CH2:4][CH2:3][CH2:2][O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(CCCBr)c1ccccc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCOc1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
To a solution of 23a (0.20 g, 0.88 mmol) and phenol (0.75 g, 0.79 mmol) in DMF (5.0 mL) was added K2CO3 (0.24 g, 1.75 mmol). The reaction was then stirred at 80° C. for 12 hours. The reaction mixture was concentrated and purified by column chromatography to isolate the compound 23 as a colorless oil (0.12 g, 0.49 mmol, 56.7% yield). MS (ESI, positive) m/z calcd. for C16H20NO [M+H]+: 242.15, found: 241.93. 1H NMR (CDCl3, 400 MHz) δ7.22-7.33 (m, 4H), 6.92-6.99 (m, 3H), 6.69-6.77 (m, 3H), 4.04 (t, J=6.0 Hz, 2H), 3.58 (t, J=6.8 Hz, 2H), 2.97 (s, 3H), 2.06-2.12 (m, 2H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1.[C:18](=[S:20])=[S:19].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CS(C)=O>[Br:3][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([Br:17])=[CH:11][CH:12]=3)[C:7](=[C:18]([S:20][CH2:15][CH2:16][CH2:4][CH2:5][CH2:6][CH3:14])[S:19][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]=2[CH:5]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: S=C=S
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCSC(SCCCCCC)=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 0 °C

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.26 g, 6.5 mmol) was added under nitrogen to 2,7-dibromofluorene (1.000 g, 3.09 mmol) in anhydrous dimethylsulfoxide (20 mL) at room temperature with stirring. The reaction mixture was stirred at room temperature for 10 minutes. Carbon disulfide (0.25 g, 0.2 mL, 3.3 mmol) was added via syringe and the reaction mixture was stirred at room temperature for 10 minutes. 1-Bromohexane (1.08 g, 6.5 mmol) was added and the reaction mixture was stirred at room temperature for 4 h. Ice-water (100 mL) was added and the resulting solid was filtered. The crude product was purified by recrystallization from iso-hexane to afford 1.225 g, (70%) as a bright yellow solid, purity 100% (GC): 1H and 13C NMR spectra as expected; M+=568 (t).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:18][NH2:19]>C(O)C>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N:18]1[C:5]([NH2:6])=[CH:4][C:3]([C:2]([F:9])([F:8])[F:1])=[N:19]1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: NNc1cccc(Cl)c1Cl
Solvent: CCO
Product: Nc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1Cl
Yield: 39.4 %

Procedure:
To a stirred suspension of 4,4,4-trifluoro-3-oxobutanenitrile (20 g, 145.98 mmol, 1.0 eq.) in ethanol (200 mL) was added (2,3-dichlorophenyl)hydrazine (47.5 g, 145.98 mmol, 1.0 eq) and refluxed for 3 h. Ethanol was evaporated, the residue diluted with water and extracted with ethyl acetate (300 mL×2), dried (Na2SO4), and the solvent evaporated under vacuum. The crude product was purified by CC using EtOAc/PE (3:7) as eluent to get 1-(2,3-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (17.02 g, 39.65%, yellow solid; TLC system: EtOAc/PE (1:1) Rf: 0.6).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]2[C@H:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29]I>C1COCC1>[C:25]([O:24][C:22]([C:19]1([CH3:29])[N:16]2[C:17](=[O:18])[C:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[CH:13][N:14]=[C:15]2[CH2:21][CH2:20]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CI
Reactant: CC(C)(C)OC(=O)[C@@H]1CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Temperature: -30 °C
Reaction time: 0.08 h
Yield: 160.9 %

Procedure:
To a solution of intermediate 1g (200 mg, 0.519 mmol) in 5 mL THF at −78° C., was added a 1M solution of LIHMDS in THF (1.09 mL, 1.09 mmol). The mixture was stirred for 5 min, then MeI (162 mL, 2.60 mmol) was added. The mixture was stirred with warming to −30° C. over 1 h, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc and washed with H2O and brine, dried (Na2SO4), and concentrated. The resultant residue was combined with additional crude material from another batch for purification by flash chromatography (stepwise gradient, 40 to 45 to 50% EtOAc/hexanes) to afford 59 mg of intermediate 19a (18%, based on 0.835 mmol of starting material). LR MS.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>C(Cl)Cl>[O:19]([C:17]([NH:2][N:3]1[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]1)=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NN1CC=CCC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NN1CC=CCC1)Oc1ccccc1
Temperature: 5 °C
Reaction time: 4 h
Yield: 92.1 %

Procedure:
To a solution of N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylami-ne (2.024 g) in methylene chloride (60 ml) was added a solution of phenyl chloroformate (1.566 g) in methylene chloride (40 ml) and the mixture was stirred for 4 hours at 5° C. Evaporation of the solvent gave a residue, which was extracted with ethyl acetate (150 ml). The extract was washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo to give N-(phenoxy- carbonylamino)-1,2,3,6-tetrahydropyridine (2.01 g), which was recrystallized from diisopropyl ether to give the desired compound (0.732 g) as colorless needles. mp: 124°-125.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11]/[C:10](=[CH:26]\N(C(C)C)C(C)C)/[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C@@H:10]([CH3:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C@H:10]([CH3:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Product: C[C@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 20 °C
Reaction time: 120 h

Procedure:
1.3 g (R)-5-biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is dissolved in 40 ml of ethyl acetate. After addition of 0.3 g 10% Pd/C (Engelhard 4505) the system is flushed several times with hydrogen and subsequently stirred at 20° C. and 4 bar hydrogen for 5 days. The resulting reaction mixture is filtered through cellflock and concentrated to dryness yielding (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-a, R1=Boc) and (3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 33:67 (3-a, R1=Boc:3-b, R1=Boc) as determined by hplc.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)O)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([N:42]([CH3:50])[CH2:43][CH2:44][C:45]([O:47]CC)=[O:46])=[O:41])=[CH:36][CH:35]=1>>[CH2:1]([O:8][C:9]1[C:13]([CH:14]([NH:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]([N:42]([CH3:50])[CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[O:41])=[CH:38][CH:39]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:31])([F:32])[F:30])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: OC(c1cn(-c2ccc(OC(F)(F)F)cc2)nc1OCc1ccccc1)C1CCCCC1
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2cn(-c3ccc(OC(F)(F)F)cc3)nc2OCc2ccccc2)C2CCCCC2)cc1
Yield: 50.8 %

Procedure:
Using {3-(benzyloxy)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}(cyclohexyl)methanol (0.50 g) synthesized in Example 60(2) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.28 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.37 g, 52%) was obtained as a white solid.