Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]#[N:26])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.CO.C(Cl)Cl>[ClH:18].[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]#[N:26])[CH:20]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)C2CCNCC2)CC1
Reactant: N#Cc1cc(Cl)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)C2CCN(c3ccnc(C#N)c3)CC2)CC1
Reaction time: 2 h
Yield: 63.9 %

Procedure:
1-Isopropyl-4-(pipeddine-4-carbonyl)-piperazine (D1)(0.116 g), 4-chloro-2-cyanopyridine (T. Sakamoto, S-I. Kaneda, S. Nishimura and H. Yamanaka, Chem. Pharm. Bull., 1985, 33(2), 565-571)(0.2 g) and anhydrous potassium carbonate (0.347 g) were heated in dry DMSO at 150° C. with stirring, under argon, for 2 h. The cooled mixture was diluted with methanol and applied to an SCX resin column. The column was eluted initially with methanol and then with methanolic ammonia (2M). The ammoniacal eluates were concentrated and the resulting gum was further purified by silica gel chromatography eluting with 0-10% methanolic ammonia (2M) in DCM. The free-base thus obtained was dissolved in DCM (5 ml) and treated with ethereal HCl (1.0M, 5 ml). The resulting suspension was evaporated to dryness by blowing down with a gentle stream of argon, to give the title compound (E98) as an off-white solid (0.117 g). 1H NMR δ [DMSO-d6]: 1.29 (6H, d, J=7 Hz), 1.48-1.63 (2H, m), 1.75 (2H, m), 2.89 (1H, br. m), 3.02-3.14 (5H, m), 3.38 (2H, m), 3.47 (1H, m), 3.65 (1H, m), 4.11 (2H, br. m), 4.24 (1H, br. d, J≈14 Hz), 4.48 (1H, br. d, J≈14 Hz), 7.15 (1H, dd, J=7,3 Hz), 7.65(1H, d, J=3 Hz), 8.26 (1H, d, J=7 Hz), 11.10 (1H, br.); LCMS electrospray (+ve) 342 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]=[C:5]1[CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[C@H:8]([C:21]([O:23]CC2C=CC=CC=2)=[O:22])[C@@H:7]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:6]1.[H][H]>CO.[Pd]>[C:34]([O:33][C:31]([C@H:7]1[CH2:6][CH:5]([CH2:4][C:3]([O:2][CH3:1])=[O:38])[CH2:10][NH:9][C@@H:8]1[C:21]([OH:23])=[O:22])=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CN[C@H](C(=O)O)[C@@H](C(=O)OC(C)(C)C)C1
Yield: 88.6 %

Procedure:
A solution of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-(2-methoxy-2-oxoethylidene)piperidine-1,2,3-tricarboxylate (98 mg, 0.188) in methanol (5 mL) was hydrogenated in the presence of 10% palladium on carbon (100 mg, 0.094), under balloon pressure of hydrogen, overnight. The resulting reaction mixture was filtered through a pad of celite and the precipitate was washed with methanol (2×5 mL). The volatiles were removed in-vacuo to afford 50 mg (88%) of (2S,3S)-3-(tert-butoxycarbonyl)-5-(2-methoxy-2-oxoethyl)piperidine-2-carboxylic acid as a sticky amorphous solid, which was used directly in the following coupling without further purification. LCMS (ESI): 246 (M-t-Bu+H+), 302 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]=[C:6]3[C:11]4[C:16]([CH2:17][C:5]3([CH3:18])[C:4]=2[CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.[CH3:19][Li].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH3:19][C@@:6]12[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:17][C@:5]1([CH3:18])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=1[NH:7]2
Reactant: Cc1ccc2c(c1)C1(C)Cc3ccccc3C1=N2
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)[C@@]1(C)Cc3ccccc3[C@@]1(C)N2
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 9b,10-dihydro-8,9b-dimethylindeno[1,2-b]indole, (5.05 g, 0.022 mol) in dry tetrahydrofuran (100 cm3) at -78° C., under nitrogen, in a flame dried flask, was added dropwise methyllithium, (1.4M solution in diethyl ether, 23.2 cm3, 0.032 mol). The mixture was stirred at -78° C. for 2 hours and then at -15° C. for a further 1 hour. Saturated ammonium chloride solution (3 cm ) was then added and the mixture allowed to warm to room temperature. The reaction mixture was portioned between ether and saturated ammonium chloride solution and the layers separated. The aqueous phase was extracted with diethyl ether (2×25 cm3) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated to afford the title compound as an off white solid. This was purified by flash chromatography on silica gel eluting with 3-10% ethyl acetate/60°-80° petrol to yield a colourless solid. Yield: 2.73 g, 51% .M.p. 208°-212° C. 1H NMR (CDCl3) δ: 7.1-7.3 (4H, m), 6.94 (1H, m), 6.77 (1H, d, J=7.8 Hz), 6.46 (1H, d, J=7.8 Hz), 3.35 (1H, d, J=15.9 Hz), 3.06 (1H, d, J=15.9 Hz), 2.22 (3H, s), 1.46 (3H, s), 1.34 (3H, s).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:10]([NH:11][C:12](=[O:23])[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]2)=[C:9](Cl)[CH:8]=[C:7]([CH3:25])[N:6]=1.C1OCCOCCOCCOCCOCCOC1.C(Cl)(Cl)Cl.C[S:49]([CH3:51])=O>O>[OH:22][CH2:21][CH2:20][N:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:12]([NH:11][C:10]2[C:5]([S:49][CH3:51])=[N:6][C:7]([CH3:25])=[CH:8][C:9]=2[S:2][CH3:1])=[O:23])[CH2:15][CH2:16]1
Reactant: C[S-]
Reactant: Cc1cc(Cl)c(NC(=O)CN2CCN(CCO)CC2)c(Cl)n1
Reactant: CS(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 62.1 %

Procedure:
A 15% (w/v) aqueous solution (269 mL) of sodium thiomethoxide (576 mmol) was added to a solution of N-[2,4-dichloro-6-methylpyridin-3-yl]-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide (10.0 g, 29 mmol) and 18-crown-6 (1.52 g, 5.8 mmol) in dimethyl sulfoxide (200 mL). The resulting mixture was stirred for 5 hours at 100° C. and further stirred for 1 hour at 110° C. The reaction mixture was allowed to cool, and chloroform and water were added thereto. The organic layer was collected, and the aqueous layer was further extracted with chloroform. The combined organic layer was washed sequentially with water and saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was removed therefrom. The aqueous layer which had been employed for washing was extracted with chloroform, and the organic layer was washed sequentially with water and saturated brine. Subsequently, the solution was dried over sodium sulfate anhydrate, and the solvent was removed. The combined residue was purified through silica gel column chromatography (developer: chloroform/ammonia-saturated methanol=20/1), to thereby yield 6.63 g of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide as colorless crystals (yield: 62.1%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.C([O-])([O-])=[O:10].[K+].[K+].[Cl:15][C:16]1[S:17][C:18]([CH2:21]Cl)=[CH:19][N:20]=1>C(#N)C>[Cl:15][C:16]1[S:17][C:18]([CH2:21][N:2]2[CH2:7][CH2:6][C:5](=[O:10])[CH2:4][CH2:3]2)=[CH:19][N:20]=1
Reactant: O=C1CCCCN1
Reactant: O=C([O-])[O-]
Reactant: ClCc1cnc(Cl)s1
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: O=C1CCN(Cc2cnc(Cl)s2)CC1
Temperature: 60 °C

Procedure:
25 gm of piperidone hydrochloride was taken in 250 ml acetonitrile. 68.7 gm of K2CO3 was added under stirring at 60° C., followed by addition of 27.8 gm of 2-chloro-5-chloromethylthiazole and refluxed for 6 hours.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:19]4[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=4[N:13]([CH3:21])[CH:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH2:30][C:31]([N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:19]4[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=4[N:13]([CH3:21])[CH:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)=[O:32]
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine HCl (200 mg, 0.663 mmol), (2,5-difluorophenyl)acetic acid (120 mg, 0.696 mmol), HATU (265 mg, 0.696 mmol) in DMF (5 mL) was added Hunig's base (0.463 mL, 2.65 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, white solid formed. The solid was filtered and dried to afford 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a white solid. NMR showed there is 1 eq. of DMF in the compound. LCMS (ES) m/z=420 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d ppm 3.27 (t, J=8.46 Hz, 2H), 3.74 (s, 3H), 3.95 (s, 2H), 4.29 (t, J=8.46 Hz, 2H), 6.05 (br. s., 2H), 7.21-7.27 (m, 5H), 7.34 (s, 1H), 8.09 (d, J=8.34 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7](C(OC(C)(C)C)=O)[CH2:8][C@@H:9]([NH:23]C(=O)OC(C)(C)C)[C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH2:11][OH:12])=[N:4][CH:3]=1.[CH3:38]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.BrC1SC(N(C(OC(C)(C)C)=O)C[C@@H](NC(=O)OC(C)(C)C)[C@H](C2C=CC(C(F)(F)F)=CC=2)C=O)=NC=1.C[Mg]Br.BrC1SC(N(C(OC(C)(C)C)=O)C[C@@H](NC(=O)OC(C)(C)C)[C@H](C2C=CC(C(F)(F)F)=CC=2)[C@@H](O)C)=NC=1.CC1(C)C(C)(C)OB([C:146]2[CH:147]=[C:148]3[C:152](=[CH:153][CH:154]=2)[NH:151][C:150](=[O:155])[CH2:149]3)O1>>[NH2:23][C@@H:9]([C@H:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=1)[CH:11]([OH:12])[CH3:38])[CH2:8][NH:7][C:5]1[S:6][C:2]([C:146]2[CH:147]=[C:148]3[C:152](=[CH:153][CH:154]=2)[NH:151][C:150](=[O:155])[CH2:149]3)=[CH:3][N:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CN(C(=O)OC(C)(C)C)c1ncc(Br)s1)[C@@H](CO)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC1(C)OB(c2ccc3c(c2)CC(=O)N3)OC1(C)C
Agent: CC(C)(C)OC(=O)N[C@H](CN(C(=O)OC(C)(C)C)c1ncc(Br)s1)[C@@H](C=O)c1ccc(C(F)(F)F)cc1
Agent: C[C@H](O)[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CN(C(=O)OC(C)(C)C)c1ncc(Br)s1)NC(=O)OC(C)(C)C
Agent: C[Mg]Br
Product: CC(O)[C@@H](c1ccc(C(F)(F)F)cc1)[C@H](N)CNc1ncc(-c2ccc3c(c2)CC(=O)N3)s1

Procedure:
The title compound was synthesized in a manner similar to Example 158 starting with tert-butyl (2S,3S)-1-(5-bromothiazol-2-yl-(Boc)-amino)-4-hydroxy-3-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate as shown in Scheme 36. After an oxidation with Dess-Martin periodinane, tert-butyl (2S,3S)-1-(5-bromothiazol-2-yl-(Boc)-amino)-4-hydroxy-3-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate was converted to tert-butyl (2S,3S)-1-(5-bromothiazol-2-yl-(Boc)-amino)-4-oxo-3-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate. The aldehyde tert-butyl (2S,3S)-1-(5-bromothiazol-2-yl-(Boc)-amino)-4-oxo-3-(4-(trifluoromethyl)-phenyl)butan-2-ylcarbamate reacted with methylmagnesium bromide to generate tert-butyl (2S,3S,4S)-1-(5-bromothiazol-2-yl-(Boc)-amino)-4-hydroxy-3-(4-(trifluoromethyl)phenyl)pentan-2-ylcarbamate as the intermediate for the Suzuki reaction with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one leading to the final product. MS m/z: 477 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 7.68 (d, J=8.22 Hz, 2H) 7.54 (d, J=8.22 Hz, 2H) 7.34 (d, J=1.56 Hz, 1H) 7.26 (dd, J=8.12, 1.86 Hz, 1H) 6.87 (d, J=8.22 Hz, 1H) 4.39 (dd, J=9.00, 6.06 Hz, 1H) 3.77-3.82 (m, 1H) 3.41 (dd, J=13.69, 5.28 Hz, 1H) 3.37 (s, 3H) 3.20 (dd, J=13.50, 8.02 Hz, 1H) 2.92 (dd, J=9.00, 3.52 Hz, 1H) 1.08 (d, J=6.26 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2[CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:4]=2[NH:3]1.[Cl:19][S:20](Cl)(=[O:22])=[O:21]>>[Cl:19][S:20]([C:15]1[CH:16]=[CH:17][C:18]2[C:4]3[NH:3][C:2](=[O:1])[C:11]4[C:6]([C:5]=3[CH2:12][C:13]=2[CH:14]=1)=[CH:7][CH:8]=[CH:9][CH:10]=4)(=[O:22])=[O:21]
Reactant: O=c1[nH]c2c(c3ccccc13)Cc1ccccc1-2
Reactant: O=S(=O)(Cl)Cl
Product: O=c1[nH]c2c(c3ccccc13)Cc1cc(S(=O)(=O)Cl)ccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
Compound 6 (40 g, 0.17 mol) was added in small portions to chlorosulfonyl chloride (112 mL, 1.71 mol) at 0°C. and the reaction mixture was allowed to warm to room temperature and stir for 2 h. The reaction mixture was slowly poured on ice and the resulting yellow solid was filtered, washed thoroughly with water and EtOAc and dried in vacuo to provide the above-titled product 7 (52 g, 92%). 1H NMR (DMSO-D6): δ 3.91 (s, 2H), 7.43-7.48 (m, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.74-7.76 (m, 2H), 7.79 (s, 1H), 7.90 (d, J=7.5 Hz, 1H), 8.23 (d, J=7.8 Hz, 1H), Anal. Calcd for C16H12ClNO4S: C, 54.94; H, 3.46; N, 4.00. Found C, 55.28; H, 3.43, N, 3.68, Karl-Fisher, 2.95.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]=[C:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])[CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH:23]=[C:24]2[S:28][C:27](=[O:29])[N:26]([CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]3[N:12]4[CH:13]=[CH:14][N:15]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[C:25]2=[O:30])[CH2:19][CH2:18]1
Reactant: ClCCCCSc1cccc2nccn12
Reactant: CN1CCN(C=C2SC(=O)NC2=O)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(C=C2SC(=O)N(CCCCSc3cccc4nccn34)C2=O)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 241 mg (1.0 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 227 mg (1.0 mmol) of 5-(1-methylpiperazin-4-yl)methylene-thiazolidine-2,4-dione in 10 ml of N,N-dimethylformamide, 0.15 ml (1.0 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by stirring at 80° C. for 3 hours. After the reaction mixture was cooled, water was added; the mixture was extracted with ethyl acetate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/ethanol=50/1) to yield 330 mg (76.0%, light yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH2:26]([CH2:28][NH2:29])[OH:27]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]([NH:29][CH2:28][CH2:26][OH:27])=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: NCCO
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)NCCO)cc2)=C(C)C1=O
Yield: 6.9 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (200 mg, 0.58 mmol) obtained in Example 2 and ethanolamine (46 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (14 mg, 0.04 mmol, yield 6%).
Reaction SMILES: [S:1]([Cl:3])Cl.N1C=CC=[CH:6][CH:5]=1.[NH:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][C:12]([O-:14])=[O:13]>C(Cl)(Cl)(Cl)Cl>[CH2:19]([O:18][C:16]([CH2:15][N:10]([CH2:11][C:12]([O:14][CH2:5][CH3:6])=[O:13])[S:1][Cl:3])=[O:17])[CH3:20]
Reactant: ClSCl
Reactant: CCOC(=O)CNCC(=O)[O-]
Reactant: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CN(CC(=O)OCC)SCl
Reaction time: 1 h

Procedure:
2.1 g (0.02 mole) of sulfur dichloride was dissolved in 35 ml of carbon tetrachloride, and 1.6 g (0.02 mole) of pyridine was dropwise added to the resulting solution at 0° to 5° C. After completion of the dropwise addition, 3.8 g (0.02 mole) of ethyl iminodiacetate was further dropwise added thereto at 10° to 20° C., and the resulting mixture was stirred for one hour at the same temperature. After completion of the reaction, crystals were filtered off, and the mother liquor was concentrated under reduced pressure to obtain an oily product. Yield: 5.0 g (98%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[C:15]([F:14])=[CH:20][CH:19]=[CH:18][C:17]=2[N:21]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(F)c1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(F)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
A mixture of (S)-2-tertbutoxycarbonylaminopropionic acid (480 mg, 2.53 mmol), 3-fluoro-N2-phenylbenzene-1,2-diamine (466 mg, 2.30 mmol), HOAt (345 mg, 2.53 mmol), 4-methylmorpholine (560 μL, 5.07 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (486 mg, 2.53 mmol) in DCM (15 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between additional DCM and an aqueous solution of NaHCO3. The organic layer was dried and concentrated in vacuo and the resulting residue (1.0 g) was dissolved in AcOH (20 mL) and stirred for 18 h at 70° C. After cooling to RT, volatiles were evaporated under reduced pressure and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The organic layer was washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in DCM) affording [(S)-1-(7-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester as a yellow/orange oil (631 mg, 77%). LCMS: RT 3.64 min [M+H]+ 356.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[S:42](Cl)(=[O:44])=[O:43]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[S:42]([C:38]2[S:37][CH:41]=[CH:40][CH:39]=2)(=[O:44])=[O:43])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.7 %

Procedure:
To a solution of {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (78.9 mg, 0.200 mmol), prepared in Step A of Example 13a, triethylamine (44.6 mg, 0.221 mmol) and dichloroethane (10 mL) was added thiophene-2-sulfonyl chloride (40.3 mg, 0.221 mmol). The reaction was stirred for 24 h and additional triethylamine (0.221 mmol) and thiophene-2-sulfonyl chloride (40.3 mg, 0.221 mmol) were added. After stirring for 24 h at room temperature the reaction was heated at reflux for 24 h and was cooled to room temperature. The organic solution was washed sequentially with 5.5% HCl, water, saturation sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CH3:MeOH 99.1) provided the title compound of Step A (58 mg). MS 539 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]2[C:28]3[CH2:27][CH2:26][N:25]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:24][C:23]=3[C:22]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)=[N:21]2)[CH2:13][CH2:12]1.C(O)(=O)C>CCO.[Zn]>[Cl:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]3[C:28]4[CH2:27][CH2:26][N:25]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:24][C:23]=4[C:22]([C:33]4[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:38]=4)=[N:21]3)[CH2:13][CH2:12]2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(Cl)cccc3[N+](=O)[O-])CC2)C1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(c3c(N)cccc3Cl)CC2)C1
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
To a stirred solution of 1-{3-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-propyl}-5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (0.153 g, 0.244 mmol) in EtOH (2.44 mL) was added zinc dust (0.80 mg, 1.22 mmol) and slow addition of acetic acid (0.70 mL). After 15 min the yellow solution became colorless and the access zinc dust was filtered through a plug of celite. The filtrate was concentrated and the residue was purified by column chromatography (silica, 0-10% MeOH/CH2Cl2) to afford 3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperazin-1-yl)-phenylamine (0.146 g, 100%). MS (electrospray): exact mass calculated for C27H32ClF3N6O2S, 596.2; m/z found, 597.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.73 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 6.88 (t, J=8.2 Hz, 1H), 6.63 (t, J=7.6 Hz, 2H), 4.55 (s, 2H), 4.36 (s, 2H), 4.15 (t, J=6.5 Hz, 2H), 3.60-3.70 (m, 4H), 2.97 (t, J=5.3 Hz, 2H), 2.90 (s, 3H), 2.83 (d, J=10.8 Hz, 2H), 2.74 (d, J=11.5 Hz, 2H), 2.37 (t, J=6.6 Hz, 2H), 2.11-2.20 (m, 4H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][N:9]=[C:10]=[O:11].[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14]C=1>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>[C:1]1([O:7][C:10](=[O:11])[NH:9][CH3:8])[C:6]2[CH:16]3[CH2:15][CH:14]([CH:12]=[CH:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Reactant: Oc1ccccc1
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: CNC(=O)Oc1cccc2c1C1C=CC2C1
Temperature: 100 °C

Procedure:
##STR7## The phenol, II (1.2 g.) was dissolved in benzene (50 ml.) and placed in a pressure bottle. Methyl isocyanate (0.43 g.) was added followed by two drops of dibutyltin diacetate. The solution was then heated at 100° C. overnight. Removal of the solvent gave a light yellow solid (1.5 g.), which recrystallized from methyl ethyl ketone to give the carbamate V, (0.9 g.) m.p., 158°-162° C. The structure was confirmed by the infrared spectrum, (C=O at 5.8μ as expected from the product).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([C:44]([NH2:46])=[O:45])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:43][CH2:42][CH:41]([C:44]([NH2:46])=[O:45])[CH2:40][CH2:39]3)=[O:36])[C:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NC(=O)C1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperidine-4-carboxylic acid amide (isonipecotamide, Aldrich) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C34H41N6O3Cl2 [(M+H)+] 651.2612, observed 651.2613.