Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[NH:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:26][O:27][C:28](OC)(OC)OC.C(O)(=O)CC>>[NH:21]1[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=[C:17]1[C:15]([N:12]1[CH2:13][CH2:14][CH:9]([N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=[C:26]2[O:27][CH3:28])[CH2:10][CH2:11]1)=[O:16]
Reactant: Nc1cccnc1NC1CCN(C(=O)c2nc3ccccc3[nH]2)CC1
Reactant: COC(OC)(OC)OC
Solvent: CCC(=O)O
Product: COc1nc2cccnc2n1C1CCN(C(=O)c2nc3ccccc3[nH]2)CC1
Temperature: 90 °C
Yield: 9.8 %

Procedure:
(4-((3-Amino-pyridin-2-yl)amino)piperidin-1-yl)(1H-benzo[d]imidazol-2-yl)methanone (520 mg, 1.55 mmol) was combined with tetramethylorthocarbonate (2 mL) and propionic acid (8 mg) and heated at 90° C. for 2 hours. After that, the reaction solution was concentrated under reduced pressure and the residue was purified by silica chromatography to give (1H-benzo[d]imidazol-2-yl)(4-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)piperidin-1-yl)methanone (57 mg, 0.15 mmol, 9.8% yield). M+1: 377.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10](=[O:17])[NH:11]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:35](OC(=O)C)([F:37])[F:36]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([O:17][CH:35]([F:37])[F:36])=[N:11]2
Reactant: COC(=O)COc1ccc(F)c2[nH]c(=O)c(Cc3ccc(Cl)cc3)c(C)c12
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of [3-(4-chlorobenzyl)-8-fluoro-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester (1.0 g), N7N-dimethylformamide (15 mL), potassium carbonate (0.89 g) and acetic acid chlorodifluoromethyl ester (1.1 mL) was stirred at 70° C. for 18 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (4:1 by volume) gave title compound as a white solid, 0.49 g.
Reaction SMILES: [H-].[Na+].C([O:5][C:6]([C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:27][N:26]=[C:25]([CH3:28])[C:24]=4[CH2:29]Br)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)=[O:7])C.[CH2:31]([OH:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH3:28][C:25]1[C:24]([CH2:29][O:39][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:23]([C:20]2[CH:19]=[CH:18][C:17]([C:14]3[CH:13]=[CH:12][C:11]([C:8]4([C:6]([OH:5])=[O:7])[CH2:10][CH2:9]4)=[CH:16][CH:15]=3)=[CH:22][CH:21]=2)[O:27][N:26]=1
Reactant: OCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COCCc1ccccc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60% in mineral oil, 0.027 g, 0.68 mmol) was added to a solution of 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.200 g, 0.45 mmol) and phenethyl alcohol (0.06 mL, 0.45 mmol) in DMF (5 mL). The reaction was stirred at 55° C. overnight, then partitioned between EtOAc and H2O and acidified with 1 N aqueous HCl. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:13]O)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][N:38]2[C:37](=[O:39])[C:36]3=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]3[C:34]2=[O:44])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
To a solution of 3,5-dinitrobenzylic alcohol 6 (1.38 g, 6.94 mmol), triphenylphosphine (2.19 g, 8.33 mmol) and phthalimide (1.23 g, 8.33 mmol) in dry THF (40 mL) was added DIAD (1.64 mL, 8.33 mmol) under an N2 atmosphere. The resulting mixture was stirred at 25° C. for 48 hours after which solvents were evaporated under reduced pressure. The crude product mixture was triturated in EtOAc and filtered under reduced pressure to give the title compound 7 as a beige solid (1.33 g, 4.05 mmol, 58%). 1H NMR (400 MHz, CDCl3) δ 8.98 (t, J=2.0 Hz, 1H), 8.61 (d, J=2.0 Hz, 2H), 7.93-7.89 (m, 2H), 7.81-7.77 (m, 2H), 5.05 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 168.5, 168.4, 149.6, 141.3, 135.5, 132.5, 129.6, 124.7, 119.3, 41.2; HRMS (ESI) Calculated for C15H10N3O6 [M+H]+: 328.0564. Found: 328.0568. m.p.: 171° C.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.O>COC(C)(C)C>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:9]
Reactant: C1CCNC1
Reactant: Cc1ccccc1OCc1ccccc1C(=O)Cl
Solvent: O
Solvent: COC(C)(C)C
Product: Cc1ccccc1OCc1ccccc1C(=O)N1CCCC1
Yield: 84.6 %

Procedure:
At 20 to 30° C., 15.6 g (0.06 mol) of 2-(2-methylphenoxymethyl)benzoyl chloride (EP-A 493 711, page 22) are added dropwise to a solution of 8.53 g (0.12 mol) of pyrrolidine in 40 ml of t-butyl methyl ether. The mixture is admixed with water and the organic phase is separated off, dried over sodium sulphate and concentrated under reduced pressure. The residue crystallizes when stirred with diisopropyl ether. 15 g (84.6% of theory) of N-[2-(2-methylphenoxymethyl)-benzoyl]-pyrrolidine are obtained.
Reaction SMILES: CC1C(N=C=O)=CC([N:8]=C=O)=CC=1.[C:14]([O:19][CH2:20][CH2:21]O)(=[O:18])[C:15](C)=[CH2:16]>C1(C)C=CC=CC=1>[C:14]([OH:19])(=[O:18])[CH:15]=[CH2:16].[NH2:8][C:14]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: C=C(C)C(=O)OCCO
Solvent: Cc1ccccc1
Product: C=CC(=O)O
Product: CCOC(N)=O
Reaction time: 4 h

Procedure:
To toluene solution of tolylene diisocyanate was dropwise added 2-hydroxyethyl methacrylate so as to have a ratio of the number of moles of NCO groups to the number of moles of OA group of 1:0.5 to advance a reaction. Thus, a compound having isocyanate groups and acryloyl groups was obtained. Then, to the solution was added toluene solution of hydrogenated bisphenol A (manufactured and sold by Kyoeisha Chemical Co., Ltd., Japan) and the reaction was conducted at 70° C. for 4 hours. Then, to the resultant solution was added dibutyltindilaurate and the reaction was conducted for 3 hours, to thereby obtain an urethane acrylate (hereinafter, referred to as UA-1) of hydrogenated bisphenol A.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([CH:11]=[O:12])[CH2:9][C@H:8]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:6]12[CH3:7])[C:21]1[CH:20]=[CH:19][C:18]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:17][C:16]=1[CH2:15][CH2:14]3)(=[O:3])[CH3:2].CC(C)=[O:35].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CO.O>[CH2:26]([O:25][C:18]1[CH:19]=[CH:20][C:21]2[C@@H:22]3[C@H:13]([C@H:8]4[C@@:6]([CH2:24][CH2:23]3)([CH3:7])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:10]([C:11]([OH:35])=[O:12])[CH2:9]4)[CH2:14][CH2:15][C:16]=2[CH:17]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(=O)O[C@H]1[C@H](C=O)C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@@]21C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CC(=O)O[C@H]1[C@H](C(=O)O)C[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@@]21C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of 824 mg (1.90 mmol) of 5 in 120 mL of acetone was cooled to 0° C. and 710 μL of Jones reagent solution (8 M solution of CrO3 in aqueous H2SO4)37 was added. The reaction mixture was stirred at 0° C. for 30 min, diluted with MeOH (20 mL) and H2O (20 mL), concentrated to about 30 mL, and extracted with CH2Cl2 (3×, 70 mL). Combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on a 2×17 cm column of silica gel using EtOH/CH2Cl2 (5:95) gave 784.4 mg (92%) of 6 as a white foam. Data for 6: TLC, T-4, Rf0.78. 1H NMR (500 MHz, CDCl3) δ 0.87 (s, 3H, H-18), 2.10 (s, 3H, OAc), 5.02 (d, 1H, J=7.1 Hz, H-17α), 5.04(s, 2H, benzylic), 6.72 (d, 1H, J=2.8 Hz, H-4), 6.79 (dd, 1H, J=8.5, 2.8 Hz, H-2), 7.20 (d, 1H, J=8.5 Hz, H-1), 7.31-7.44 (m, 5H, Ar—H); HRMS (ES) calcd for C28H32O5Na (M+Na+) m/e 471.2147, found m/e 471.2146.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:21](=[O:24])(O)[O-].[Na+].C(Cl)(Cl)=O.[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH3:41])=[C:38]([CH:40]=1)[NH2:39])([CH3:33])([CH3:32])[CH3:31]>ClCCl>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH3:41])=[C:38]([NH:39][C:21]([NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)=[O:24])[CH:40]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1ccc(C(C)(C)C)cc1N
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: O=C([O-])O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(C)(C)C)cc1NC(=O)Nc1ccc(OCCN2CCOCC2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-[2-(Morpholin-4-yl)ethoxy]napth-1-yl-amine (280 mg, 1.0 mmol) was dissolved in dichloromethane (15 mL). An equal volume of sat. aqueous sodium bicarbonate was added, and the biphasic solution was cooled to 0° C. During the addition of phosgene (1.93 M in toluene, 1.0 mL), stirring was stopped. Immediately afterward, stirring was resumed for 15 min with the reaction mixture at 0° C. The layers were separated, the organics were dried over solid magnesium sulfate and concentrated to approximately 5 mL of solution. 5-tert-Butyl-2-methylaniline (150 mg, 0.9 mmol) in dichloromethane (5 mL) was added, and the reaction mixture was stirred for 17 h at ambient temperature. The desired compound was obtained after treatment of the reaction mixture with petroleum ether and filtering to collect the precipitate (180 mg, 42%).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:18])([CH3:17])[C:8]1[CH2:9][CH:10]([CH2:14][CH:15]=O)[CH2:11][CH2:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].S([CH2:29][N+:30]#[C-:31])(C1C=CC(C)=CC=1)(=O)=O.[C-]#[N:33].[Na+]>C(O)C.N>[C:1]([SiH2:5][O:6][C:7]([CH3:18])([CH3:17])[C:8]1[CH2:9][CH:10]([CH2:14][C:15]2[N:33]=[CH:29][NH:30][CH:31]=2)[CH2:11][CH2:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1=CCCC(CC=O)C1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[SiH2]OC(C)(C)C1=CCCC(Cc2c[nH]cn2)C1
Temperature: 100 °C
Yield: 746.1 %

Procedure:
The aldehyde (Intermediate A5) (10 g, 37.2 mmol) in anhydrous ethanol (70 mL) was treated with tosylmethyl isocyanide (7.2 g, 3.7 mmol) (available from Aldrich) followed by addition of a catalytic amount of NaCN (150 mg) at rt for 15 m. The mixture was reduced in volume to about 20 mL under reduced pressure. The residue was dissolved in NH3 (7M in MeOH) and placed into re-sealable tubes and heated to 100° C. for 18 h. The mixture was cooled and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel with 5% MeOH:EtOAc to remove TsOH and the product was eluted with 5% NH3-MeOH in CH2Cl2 to yield 7 g (60%) of 4-[3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohex-3-enylmethyl]-1H-imidazole (Intermediate A6).
Reaction SMILES: [CH:1]([C@@H:4]1[NH:28][C:27]2[O:29][C:24](=[N:25][N:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]2[CH:30]=[C:31]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13][N:12]=[C:11]3[O:10][C@H:9]2[CH2:32][N:6]([C@H:7]([C:33]([O:35][CH3:36])=[O:34])[CH2:8]2)[C:5]1=[O:37])([CH3:3])[CH3:2].OS(C(F)(F)F)(=O)=O.[I:46]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[I:46][C:14]1[C:15]2[C:31]3=[CH:30][C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]4[O:29][C:27]([NH:28][C@@H:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:37])[N:6]5[CH2:32][C@H:9]([O:10][C:11]3=[N:12][CH:13]=1)[CH2:8][C@H:7]5[C:33]([O:35][CH3:36])=[O:34])=[N:26][N:25]=4)=[CH:17][CH:16]=2
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)C)Nc1nnc(o1)CCCCCc1ccc3ccnc(c3c1)O2
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)C)Nc1nnc(o1)CCCCCc1ccc3c(I)cnc(c3c1)O2
Reaction time: 16 h

Procedure:
To a 0.3 M solution of methyl (3R,5S,8S)-8-isopropyl-7-oxo-2,28-dioxa-6,9,11,12,25-pentaazapentacyclo[17.6.2.13,6.110,13.022,26]noncosa-1(25),10,12,19,21,23,26-heptaene-5-carboxylate (from Step 1) in dry DCM was added triflic acid (2 eq) and N-iodosuccinimide (2 eq) and the mixture was stirred under N2 for 16 h. An additional portion of N-iodosuccinimide (2 eq) was added and the reaction was stirred for additional 24 h. The reaction mixture was poured into saturated NaHCO3 and extracted with DCM (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting crude compound was purified on silica gel (20% to 40% EtOAc in PE) to yield the compound as a yellow solid. MS (ES+) C27H32IN5O5 requires: 633. Found: 634 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[K+].NC1C=CC([S-])=CC=1.[K+].Cl[C:21]1[CH:30]=[N:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:31])[CH:27]=2)[N:22]=1>CS(C)=O.O>[Cl:31][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)[CH:30]=[N:29]2
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: Nc1ccc(S)cc1
Agent: Nc1ccc([S-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Sc2cnc3cc(Cl)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.7 %

Procedure:
5.7 g (0.045 mol) of p-aminothiophenol together with 3 g (0.045 mol) of 86% potassium hydroxide and 2 ml of water in 80 ml of dimethylsulfoxide was heated under stirring at 80°-90° C. for 5 hours to make the potassium p-aminothiophenolate. The water generated was removed off by azeotropic distillation under reduced pressure. To this solution which was allowed to be cooled to room temperature was added a solution of 9 g (0.045 mol) of 2,6-dichloroquinoxaline dissolved in 100 ml of dimethylsulfoxide. The mixture was subjected to the reaction, while stirring, at 80°-90° C. for 8 hours. After the reaction mixture was cooled to the room temperature, it was poured into a great deal of water and stirred. The precipitating solid was filtered off, washed with 5% aqueous solution of sodium hydroxide and then washed with water, followed by drying. The crude crystals thus obtained were recrystallized from a mixed solution of ethanol-benzene to produce 6.7 g (yield 52%) of the intended compound (Compound No. 10) as light-yellow crystals, m.p. 144°-147° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C@@H:20]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1cccc2ccccc12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-3-(1-naphthyl)propionate hydrochloride (Bachem), the title compound was prepared as a solid (mp=103-130° C.). The reaction was monitored by tlc (Rf=0.8 in 5% MeOH/methylene chloride) and the product was purified by flash column chromatography using 6% MeOH/methylene chloride as the eluent.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([CH3:17])[CH:9]=1.CN(C=O)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>ClCCl>[Br:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:14])=[C:10]([CH3:17])[CH:9]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(Br)ccc1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 10.6 ml (47 mmol) oxalyl chloride in 30 ml dichloromethane is added dropwise to a iced-cooled solution of 5.21 g (23.5 mmol) 4-bromo-2-methyl-benzoic acid and 0.0087 ml DMF in 100 ml CH2Cl2. After complete addition, the cooling bath is removed and stirring maintained for 2 h at RT. The solvent is evaporated to dryness and the residue is dried in vacuo and dissolved in 100 ml dichloromethane and 8.21 ml N-ethyl-diisopropylamine is added. To this solution 2.5 ml (28 mmol) morpholine is added slowly. Stirring is continued for 0.5 h, then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo to afford the title compound which is used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].[CH3:15][C:16]([C:25]([F:28])([F:27])[F:26])([CH:23]=[CH2:24])[CH2:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>C(Cl)Cl.O>[CH3:8][N:9]([CH3:14])[S:10]([N:21]1[CH:22]=[C:18]([CH2:17][C:16]([CH3:15])([C:25]([F:26])([F:27])[F:28])[CH:23]=[CH2:24])[N:19]=[CH:20]1)(=[O:12])=[O:11]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: C=CC(C)(Cc1c[nH]cn1)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(C)(Cc1cn(S(=O)(=O)N(C)C)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (3 mL, 14.02 mmol) followed by dimethylsulfamoyl chloride (1.5 mL, 14.02 mmol) were added to an ambient temperature solution of 4-[2-methyl-2-(trifluoromethyl)but-3-en-1-yl]-1H-imidazole (1.43 g, 7.01 mmol) in methylene chloride (20 mL). After stirring at ambient temperature overnight, the reaction mixture was diluted with water and extracted with ethyl acetate and methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[S:8])[NH2:7].C(N(C(C)C)C(C)C)C.Br.[C:19]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH:24](Br)[CH2:23]1)(=[O:21])[CH3:20]>C(#N)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:8][C:24]2[CH2:23][N:22]([C:19](=[O:21])[CH3:20])[CH2:27][CH2:26][C:25]=2[N:7]=1
Reactant: NC(=S)c1cccs1
Reactant: CC(=O)N1CCC(=O)C(Br)C1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)N1CCc2nc(-c3cccs3)sc2C1
Temperature: 50 °C

Procedure:
2.8 mmol of thiophene-2-thiocarboxamide was dissolved in 10 ml acetonitrile. 5.6 mmol of N-ethyl-diisopropylamine was added, followed by 3.4 mmol 1-acetyl-3-bromo-piperidin-4-one hydrobromide (prepared according to patent U.S. Pat No. 4,122,083). The reaction mixture was heated to 50° C. for 4 hours, cooled and concentrated. Chromatography of the residue (SiO2; ethyl acetate) yields the title compound as a yellowish gum. MS (m/e): 265.0 (M+H+).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:10]([C:12]1([NH:15][C:16]([C@H:18]2[CH2:22][C@H:21]([S:23]([C:26]3[CH:31]=[CH:30][C:29](Br)=[CH:28][C:27]=3[C:33]([F:36])([F:35])[F:34])(=[O:25])=[O:24])[CH2:20][C@@H:19]2[O:37][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:17])[CH2:14][CH2:13]1)#[N:11].C(C1(NC([C@H]2C[C@H](S(C3C=CC(Br)=CC=3C(F)(F)F)(=O)=O)C[C@@H]2OC)=O)CC1)#N>>[C:10]([C:12]1([NH:15][C:16]([C@H:18]2[CH2:22][C@H:21]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[CH:28][C:27]=3[C:33]([F:36])([F:35])[F:34])(=[O:25])=[O:24])[CH2:20][C@@H:19]2[O:37][CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:17])[CH2:14][CH2:13]1)#[N:11]
Reactant: CC(C)N1CCNCC1
Reactant: N#CC1(NC(=O)[C@H]2C[C@H](S(=O)(=O)c3ccc(Br)cc3C(F)(F)F)C[C@@H]2OC2CCCC2)CC1
Agent: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Product: CC(C)N1CCN(c2ccc(S(=O)(=O)[C@@H]3C[C@H](OC4CCCC4)[C@@H](C(=O)NC4(C#N)CC4)C3)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in analogy to example 176 using 1-isopropyl-piperazine instead of morpholine and (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-cyclopentyloxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 195) instead of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide. White solid. MS (EI): 595.4 (M−H)−.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([OH:15])[C:13]#[CH:14])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](O)=[CH:19][CH:18]=1.[C:28]1(C)C=CC=CC=1>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:20](=[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=13)[O:15][C:12]([CH3:28])([C:9]1[CH:10]=[CH:11][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:7][CH:8]=1)[CH:13]=[CH:14]2
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: C#CC(O)c1ccc(N2CCCC2)cc1
Reactant: Cc1ccccc1
Product: CC1(c2ccc(N3CCCC3)cc2)C=Cc2cc(Cl)c3ccccc3c2O1

Procedure:
A solution of p-pyrrolidinophenylpropargyl alcohol (2C) (5 g) and 4-chloro-1-naphthol (5 g) in toluene (75 cm3) was passed down a column of acidic alumina (100 g), using toluene as eluant. The colourless but heliochromic fraction (which turned blue on exposure to light from a flashgun) was evaporated and the residual solid recrystallised from acetone. The first crop of pure near colourless crystals was the benzochromene (4D; R=Cl).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Br)=O.O.O.O.O.O.O.O.O.O.[S-2:23].[Na+].[Na+].O.Cl>CCO>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[S:23][CH:1]=[N:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: [S-2]
Reactant: O=CNc1cc([N+](=O)[O-])ccc1Br
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2scnc2c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
A solution of formamide from Step 1 (5.83 g, 23.8 mmol) and sodium sulfide nonahydrate (8.60 g, 35.8 mmol) in EtOH (120 ml) was heated to reflux for 2 h under nitrogen. After this time the reaction was cooled to RT then poured into cold water (600 ml). The resulting solution was cooled in an ice bath and acidified to pH 1 with 37% HCl. The solution was cooled in an ice bath for a further 1 h, during which time an orange precipitate formed. This solid was isolated by filtration and dried under vacuum to afford 5-nitrobenzothiazole as an orange solid (2.28 g). The above filtrate was extracted with EtOAc (3×200 ml), and the combined organic extracts dried over Na2SO4, filtered and concentrated under vacuum to afford additional 5-nitrobenzothiazole (0.89 g) as an orange solid. NMR and TLC analysis indicated that both crops of product were identical; the combined yield was 3.17 g. 1H NMR (CDCl3) δ 9.19 (s, 1H), 9.02 (d, 1H), 8.35 (dd, 1H), 8.12 (d, 1H); 13C NMR (CDCl3) δ 157.3, 153.1, 147.0, 140.2, 122.5, 120.1, 119.3. MS (ESI+) for m/z 181 [M+H]+.