Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:37])=[C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:26][C:27]([C:29]5[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=5)=O)[CH2:22][CH2:21]4)[CH:18]=3)[C:13](=[O:38])[C:12]([C:39]([OH:41])=[O:40])=[CH:11]2)=[C:6]([F:42])[CH:5]=1)([O-:3])=[O:2].Cl.[NH2:44][OH:45].C(=O)(O)[O-].[Na+].C(Cl)Cl.CO>C(O)C.O.C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:37])=[C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:26][C:27](=[N:44][OH:45])[C:29]5[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=5)[CH2:24][CH2:25]4)[CH:18]=3)[C:13](=[O:38])[C:12]([C:39]([OH:41])=[O:40])=[CH:11]2)=[C:6]([F:42])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)CN2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc([N+](=O)[O-])cc3F)CC2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCO
Product: COc1ccc(C(CN2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc([N+](=O)[O-])cc3F)CC2)=NO)cc1
Yield: 77.5 %

Procedure:
To a solution of the 1-(4-nitro-2-fluorophenyl)-6-fluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.58 g, 1 mmol) in absolute ethanol (20 ml) were added hydroxylamine hydrochloride (0.14 g, 2 mmol) and sodium bicarbonate (0.17 g, 2 mmol) dissolved in distilled water (2 ml). The reaction mixture was refluxed for 20 hr, then diluted with CH2Cl2 (50 ml). The organic phase was washed successively with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a pale yellow solid which was purified by flash column chromatography (silica gel, with CH2Cl2/methanol (10:1) as the eluant) and crystillization from CH2Cl2/methanol 5:1 to give 1-(4-nitro-2-fluorophenyl)-6-fluoro-7-{4-[2-hydroxyimino-2-(4-methoxy-phenyl)ethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.46 g, 80% yield). Mp: 216° C. (dec). 1H NMR (DMSO-d6) δ 2.54 and 3.02 (two n, 8H), 3.63 (s, 2H), 3.76 (s, 3H), 6.36 (d, 1H, J=6.8), 6.89 (d, 2H, J=8.8), 7.67 (d, 2H, J=8.8), 7.98 (d, 1H, J=13.2), 8.12-8.53 (m, 3H) 8.91 (s, 1H), 11.22 (s, 1H), 14.85 (br s, 1H) . Anal. Calcd. for C29H,5F2N5O7•2.5 H2O: C, 54.55; H, 4.74; N, 10.97. Found: C, 54.19; H, 4.36; N, 10.66.
Reaction SMILES: [OH:1][C@:2]12[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]3[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]3=[O:14])[C@@:6]1([O:21][CH3:22])[O:5][CH2:4][CH2:3]2.[CH3:23][O:24][C:25]1[CH:46]=[CH:45][C:28]([C:29](Cl)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:27][CH:26]=1.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.ClCCl>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]([O:11][CH2:10][C@H:9]2[O:8][C@@H:7]([N:12]3[CH:20]=[C:18]([CH3:19])[C:16](=[O:17])[NH:15][C:13]3=[O:14])[C@:6]3([O:21][CH3:22])[C@@:2]2([OH:1])[CH2:3][CH2:4][O:5]3)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:28]2[CH:45]=[CH:46][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CO[C@]12OCC[C@@]1(O)[C@@H](CO)O[C@H]2n1cc(C)c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@@]3(OC)OCC[C@@]23O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
A mixture of compound 17 (0.95 g, 3.03 mmol) and 4,4′-dimethoxytrityl chloride (1.54 g, 4.77 mmol) was dissolved in anhydrous pyridine (20 cm3) and stirred for 4 h at room temperature. The reaction mixture was evaporated to give an oily residue which was co-evaporated with toluene (2×20 cm3). Dichloromethane (50 cm3) and a saturated aqueous solution of sodium hydrogencarbonate (50 cm3) were added, the organic phase was separated and evaporated, and the residue purified by silica gel HPLC (the residue was dissolved in the minimum amount of dichloromethane containing 0.5% triethylamine (v/v) and applied to the column equilibrated by the same solvent. The column was washed (ethylacetate:petroleum ether:triethylamine; 15:84.5:0.5 (v/v/v, 1000 cm3) and the product was eluted in a gradient of methanol (C-2%) in dichloromethane containing 0.5% of triethylamine (v/v/v) to give compound 18 (1.71 g, 92.8%) as white solid material. δH (CDCl3) 7.51-7.17 (10H, m, DMT, 6-H), 6.79-6.85 (4H, m, DMT), 6.04 (1H, s, 1′-H), 4.12-3.98 (3H, m, 5-Ha, 5′-Hb, 4′-H), 3.77 (6H, s, CH3-DMT), 3.49 (3H, s, CH3—O), 3.45-3.32 (2H, m, 2″-Ha, 2″-Hb), 2.11-2.01 (1H, m, 1″-Ha), 1.94-1.87 (1H, m, 1″-Hb), 1.93 (3H, s, CH3). δC (CDCl3) 164.2 (C-4), 158.6, 144.7, 135.7, 130.1, 128.2, 127.9, 126.8, 113.2 (DMT), 150.7 (C-2), 137.7 (C-6), 109.8, 109.7 (C-5, C-2′), 86.5, 85.3, 85.0, 81.4 (DMT, C-1′, C-3′, C-4′), 69.2, 62.4 (C-5′, C-2″), 55.2 (CH3-DMT), 51.7 (CH3—O), 35.5 (C-1″), 12.7 (CH3). FAB-MS m/z 617.26 [M+H]+, 639.23 [M+Na]+ (Found: C, 66.4; H, 6.1; N, 4.2; C34H36O9N2 requires C, 66.2; H, 5.9; N, 4.5%).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[S:30][CH:31]=[C:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[N:28]=3)[CH2:33][CH2:34]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccc(F)cc4)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 12 h
Yield: 32.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (273 mg, 0.835 mmol), 1-[4-(4-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (110 mg, 32.9%) as a solid.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[C:25]4[C:24]5[C@@H:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21][C:20]=5[S:19][C:18]=4[N:17]=[CH:16][N:15]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[CH3:29][S:30]([O:28][CH2:27][CH2:26][C@H:23]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:13][CH:10]4[CH2:9][CH2:8][CH:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[CH2:12][CH2:11]4)[C:25]=3[C:24]1=2)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: OCC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)OCC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol (202 mg, 0.50 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) was added MsCl (86 mg, 0.75 mmol, 1.50 equiv) and triethylamine (153 mg, 1.51 mmol, 3.00 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and diluted with DCM (80 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the desired 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethyl methanesulfonate (230 mg, 95%) as a white solid. MS (ES): m/z 482 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH2:13][C:14]([N:16]2[CH2:22][CH2:21][CH2:20][C@H:17]2[CH2:18][OH:19])=[O:15])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.O>CS(C)=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([CH2:12][CH2:13][C:14]([N:16]2[CH2:22][CH2:21][CH2:20][C@H:17]2[CH:18]=[O:19])=[O:15])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCC(=O)N1CCC[C@H]1CO)NCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: O=C[C@@H]1CCCN1C(=O)CCC(=O)NCCc1ccccc1
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
N-[3-[N-(2-phenylethyl)carbamoyl]propanoyl]-L-prolinol (490 mg; prepared in reference example 1) was dissolved in dry DMSO (5 ml). Triethylamine (0.79 ml) was added to the solution. A solution of sulfur trioxide-pyridine complex (450 mg) in DMSO (2 ml) was dropped to the solution. After 10 mins' stirring, the solution was poured into water. The mixture was extracted with ethyl acetate. The oily layer was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrocarbonate and a saturated brine, successively, dried and then evaporated. The residue was purified by column chromatography on silica gel to give the title compound (371 mg) having the following physical data:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([O-:3])=[O:2].[C:17](#[N:20])[CH:18]=[CH2:19]>C1C=CC=CC=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[C:17]([CH2:18][CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)#[N:20]
Reactant: C=CC#N
Reactant: O=[N+]([O-])c1ccc2[nH]c3ccccc3c2c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccccc1
Product: N#CCCn1c2ccccc2c2cc([N+](=O)[O-])ccc21
Temperature: 50 °C

Procedure:
21.2 g (0.1 mol) 3-nitrocarbazole were suspended in 250 ml benzene in a three-necked flask equipped with stirrer, condenser and thermometer and present in an oil-bath, then mixed with 50 ml acrylonitrile, heated to 50°C and, after the addition of two drops of benzyl trimethyl ammonium hydroxide, reacted for two hours at 70°C, while stirring. After evaporation of the reaction mixture and recrystallization of the residue from aqueous acetone, there were obtained 22 g 9-(β-cyanoethyl)-3-nitrocarbazole, which was further worked up directly.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]3[CH2:31][C:32]([OH:34])=O)=O)C3C(=CC=CC=3)C=2C=CC=1.C(Cl)(=O)C(Cl)=O.[Br:41][C:42]1[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][C:43]=1[NH2:44].C(N(C(C)C)CC)(C)C.N1CCNCC1>ClCCl.CN(C)C=O.O1CCCC1>[Br:41][C:42]1[C:48]([CH3:49])=[CH:47][CH:46]=[CH:45][C:43]=1[NH:44][C:32](=[O:34])[CH2:31][CH:19]1[NH:18][CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20]1
Reactant: Cc1cccc(N)c1Br
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)C(CC(=O)O)C1
Agent: C1CNCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(NC(=O)CC2CN(C(=O)OC(C)(C)C)CCN2)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazin-2-yl)acetic acid (3.00 g, 6.43 mmol) in dichloromethane (50 mL) with N,N-dimethylformamide (2 drops) was added oxalyl chloride (1.13 mL, 12.9 mmol) drop wise. The reaction mixture was stirred at room temperature for 1 hour, and then it was concentrated. The concentrate is taken up in tetrahydrofuran (50 mL) and 2-bromo-3-methyl aniline (1.33 g, 7.07 mmol) was added in tetrahydrofuran (5 mL) and diisopropylethylamine (5.62 mL, 36.2 mmol). The solution is heated to 70° C. for 2 hours. The mixture was then cooled to 50° C. and piperazine (1.66 g, 19.3 mmol) was added. The reaction mixture stirred for 16 hours before concentration onto silica gel. Purification via flash chromatography (0-20% methanol/dichloromethane) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.54-7.71 (m, 1H), 7.06-7.31 (m, 2H), 3.62-3.98 (m, 2H), 2.26-3.45 (m, 10H), 0.87-1.05 (m, 9H); MS (APCI+) m/z 412, 414 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[C@@H:3]([NH:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9])[CH3:4].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CN(C)C=O>[CH3:15][N:16]([CH:18]=[C:7]([C:8](=[O:10])[CH3:9])[C:6]([NH:5][C@H:3]([CH:2]([CH3:12])[CH3:1])[CH3:4])=[O:11])[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CC(=O)N[C@@H](C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)C(=CN(C)C)C(=O)N[C@@H](C)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of N-((2S)-3-methylbutan-2-yl)-3-oxobutanamide obtained in Step A (56.6 g) in N,N-dimethylformamide (220 mL) was added dropwise 1,1-dimethoxy-N,N-dimethylmethanamine (88 mL) over 15 min under ice bath, and the mixture was stirred at room temperature for 20 hr. The solvent was evaporated under reduced pressure to give the title compound (62.7 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([F:10])=[CH:4][N:3]=1.[C:11](OCC)(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].N1CCCCC1>C(O)C>[F:10][C:5]1[CH:6]=[C:7]2[C:2](=[N:3][CH:4]=1)[NH:1][C:11](=[O:18])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8]2
Reactant: Nc1ncc(F)cc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cc(F)cnc2[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-amino-5-fluoropyridine-3-carboxaldehyde (2.80 g), diethyl malonate (6.40 g) and piperidine (0.85 g) in ethanol (50 ml) were heated to reflux with stirring for 18 hours, allowed to cool to ambient temperature then evaporated under reduced pressure. The residual solid obtained was washed with diethyl ether then filtered from solution, and sucked to dryness to give the required product as a pale brown solid, 3.97 g. 1H NMR (CDCl3) δ: ca 11.0 (1H, bs), 9.33 (1H, m), 8.66 (1H, d), 8.42 (1H, s), 7.74 (1H, m), 4.45 (2H, q), 1.44 (3H, t).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[N:9]1([C:14](N2C=CN=C2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1>C(Cl)Cl>[N:9]1([C:14]([O:8][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: OCC1CCCCO1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(OCC1CCCCO1)n1ccnc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a mixture of (tetrahydro-2H-pyran-2-yl)methanol (369 mg, 3.17 mmol) and di(1H-imidazol-1-yl)methanone (1.03 g, 6.35 mmol) was added 10.5 mL of CH2Cl2. The reaction was stirred at 50° C. for 3 hours. The reaction mixture was used without further purification. LC/MS: m/z 211.1 (M+H)+ at 0.94 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[C:31]1([CH2:37][CH2:38][NH2:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[C:8]([O:12][C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([NH:39][CH2:38][CH2:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCCc1ccccc1
Temperature: 0 °C

Procedure:
Triethylamine (2.8 ml.) was added with stirring to a solution of N-(tert-butyloxycarbonyl)-L-proline (4.3 g.) in tetrahydrofuran (50 ml.) maintained at 0° C. The temperature was lowered to -20° C., isobutyl chloroformate (2.7 ml.) was added, and stirring was continued for15 minutes. 2-Phenylethylamine (2.5 ml.) was then added with continued stirring, and the mixture was allowed to warm to room temperature and filtered. Concentration of the filtrate afforded a solid. Crystallization of the solid from ethyl acetate gave the product in two parts by filtration and in a third part from the filtrate, which was washed with water, aqueous citric acid (5%), saturated aqueous sodium chloride and saturated aqueous sodium bicarbonate, then dried and concentrated. High pressure liquid chromatography of the three parts on silica gel (350 g.) using hexane-ethyl acetate (7:3) as the eluant (200 ml./min.) afforded in fractions 7-8 1-(tert-butyloxycarbonyl)-N-(2-phenylethyl)-L-prolinamide (3.2 g., m.r. 153°-154° C.)
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1.Cl>ClCCl.CO.O1CCOCC1>[F:1][CH:2]([F:17])[CH2:3][N:4]1[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(CC(F)F)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@@H]1CCN(CC(F)F)C1
Reaction time: 1.5 h

Procedure:
To a solution of EXAMPLE 180A (525 mg) in a mixture of dichloromethane (3 mL) and methanol (4.0 mL) was added hydrogen chloride, 4M in dioxane (5.24 mL) and the reaction was stirred for 1.5 hours. The reaction was concentrated and the crude material was taken up in dichloromethane and the solvent evaporated, then taken up in ether and the solvent evaporated, and then dried on high vacuum.
Reaction SMILES: [CH:1]([C:3]1[CH2:4][CH:5]([CH2:9][C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)[CH2:6][CH2:7][CH:8]=1)=[CH2:2].NN.[OH2:17].OO>C(O)C>[CH2:1]([C:3]1[CH2:4][CH:5]([CH2:9][C:10]2[NH:11][C:12](=[O:17])[NH:13][CH:14]=2)[CH2:6][CH2:7][CH:8]=1)[CH3:2]
Reactant: C=CC1=CCCC(Cc2c[nH]cn2)C1
Reactant: O
Agent: NN
Agent: OO
Solvent: CCO
Product: CCC1=CCCC(Cc2c[nH]c(=O)[nH]2)C1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A mixture of NiCl2 (0.364 g, 2.81 mmol) in EtOH (20 mL) was reacted with NaBH4 (0.053 mg, 1.40 mmol) at rt for 15 m after saturation of the solution with hydrogen gas. Ethylene diamine (0.17 g, 2.81 mmol) was added followed by the alkynyl imidazol (Intermediate R15, 0.26 g, 1.40 mmol) at rt for 45 m under an atmosphere of hydrogen gas. The mixture was filtered, diluted with chloroform and subjected to an aqueous work-up. The residue was purified by chromatography on SiO2 to give 4-(3-vinyl-cyclohex-3-enylmethyl)-1H-imidazole (72%). To 4-(3-vinyl-cyclohex-3-enylmethyl)-1H-imidazole (0.09 g, 0.47 mmol) in ethanol (3 mL) at 0° C. was added H2NNH2.H2O (0.93 mL, 19.1 mmol) followed by H2O2 (30%) (0.488 g, 14.4 mmol) and the mixture was stirred for 45 m at 0° C. and an additional 6 h at rt. The reaction was quenched and the material was purified by an aqueous work-up. The imidazole compound was purified further by isolation of the fumaric acid salt. The fumarate was converted to the compound 4-(3-ethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound 59) by the applicable step of Method P.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[O:32]1[CH2:36][CH2:35][CH:34]([CH2:37][OH:38])[CH2:33]1.C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>>[C:23]1([C:20]2[CH:21]=[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=2)[NH:16][CH:15]=[C:14]3[CH:11]2[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][O:38][CH2:37][CH:34]3[CH2:35][CH2:36][O:32][CH2:33]3)(=[O:7])=[O:6])[CH2:9][CH2:10]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCC1CCOC1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCOCC4CCOC4)CC3)c[nH]c12
Yield: 15.3 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol), tetrahydro-3-furanylmethanol (102 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg) were reacted to give the title compound (7.0 mg, 15.3%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14](Br)[S:15][C:16]=1[Br:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)[S:15][C:16]=1[Br:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Br)sc(Br)c1NC(=O)OCc1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(-c2ccc(Cl)cc2)sc(Br)c1NC(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
Palladium tetrakis-triphenylphosphine (19.3 mg, 17 μmol) was added to a degassed solution of dibromide 4 (150 mg, 334 μmol) and 4-chlorophenylboronic acid 5 (54.8 mg, 350 μmol) in ethanol: water:toluene (2:1:1, 1.67 mL) and sodium carbonate (177 mg, 1.6 mmol). The resulting mixture was heated under N2 and stirred for 1 h at 80° C. The mixture was then cooled filtered through a 0.45 μm syringe filter and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-50% ethyl acetate in hexane) provided 6 (76.8 mg, 48%) as a solid: LRESIMS m/z 479.8 [M+H]+, calcd. for C20H16Br1Cl1N1O4S1 480.0.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:28]([OH:30])=[O:29])[CH2:20][NH:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.[Cl:37][C:38]1[CH:46]=[C:45]([C:47]([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([OH:57])[CH:52]=2)=[O:48])[CH:44]=[CH:43][C:39]=1[C:40]([OH:42])=O.C1C=NC2N(O)N=NC=2C=1>CN1CCCC1=O>[Cl:37][C:38]1[CH:46]=[C:45]([C:47]([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([OH:57])[CH:52]=2)=[O:48])[CH:44]=[CH:43][C:39]=1[C:40]([NH:18][C@H:19]([C:28]([OH:30])=[O:29])[CH2:20][NH:21][C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[O:42]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Reactant: C=CCOC(=O)NC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Solvent: C1CCNCC1
Product: C=CCOC(=O)NC[C@H](NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 150 mL cylindrical glass vessel equipped with a coarse glass frit was charged with N-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-[(2-propenyloxy)carbonyl]amino-L-alanine resin (Example 64; 5 g) and 25% piperidine in N-methylpyrrolidinone (50 mL). The mixture was agitated at room temperature for 30 min. The resin was filtered and treated again with fresh 25% piperidine in N-methylpyrrolidinone (50 mL) at room temperature for 30 min. After filtration, the resin was washed with dichloromethane and methanol. To the resin was added a solution prepared from 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoic acid (Example 26; 2.5 g, 8.2 mmol), HOAT (3.7 g, 27.2 mmol) and DICI (4.3 mL, 27.5 mmol) in N-methylpyrrolidinone (50 mL). The reaction mixture was agitated at room temperature for 1 h, and then filtered. The resin was washed with dichloromethane and methanol, and dried under vacuum to afford resin-bound N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(2-propenyloxy)carbonyl]amino-L-alanine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9](Cl)(Cl)Cl)=[CH:4][CH:3]=1.Br[C:14]1[CH:19]=[CH:18][CH:17]=C[N:15]=1>C(N)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:18][CH:19]=[CH:14][N:15]=2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Sc1ccc(Br)cc1
Reactant: Brc1ccccn1
Solvent: O
Solvent: NC=O
Product: Brc1ccc(Sc2ccccn2)cc1
Temperature: 75 °C
Yield: 64.5 %

Procedure:
A solution of (4-bromophenyl)(trichloromethyl)sulfane (0.25 g, 0.816 mmol) in 12 mL of formamide was degassed with nitrogen and treated with 2-bromopyridine (0.078 ml, 0.816 mmol). The reaction solution was heated at 75° C. overnight. Then it was cooled to room temperature and diluted with water, extracted with DCM, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel, eluted with 1-5% of EtOAc in 20% DCM/heptanes (v/v), affording 0.14 g (65% yield) of 2-((4-bromophenyl)thio)pyridine.