Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:5][C:4]([C:20]2[C:25]([CH:26]=[O:27])=[C:24]([N:28]3[C:40](=[O:41])[C:32]4[CH:33]=[C:34]5[N:39]([C:31]=4[CH:30]=[N:29]3)[CH2:38][CH2:37][CH2:36][CH2:35]5)[N:23]=[CH:22][CH:21]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:27][CH2:26][C:25]1[C:24]([N:28]2[C:40](=[O:41])[C:32]3[CH:33]=[C:34]4[N:39]([C:31]=3[CH:30]=[N:29]2)[CH2:38][CH2:37][CH2:36][CH2:35]4)=[N:23][CH:22]=[CH:21][C:20]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6c(cc7n6CCCC7)c5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6c(cc7n6CCCC7)c5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a solution of 204a (160 mg, 0.29 mmol) in methanol (20 mL) was added NaBH4 (33.0 mg, 0.87 mmol). The mixture was stirred at 20° C. for 2 h and quenched with water. It was then evaporated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 204 (120 mg, 75%) as a white solid. MS-ESI: [M+H]+ 554.3. 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J=5.0 Hz, 1H), 8.46 (s, 1H), 8.23 (s, 1H), 8.09 (d, J=2.5 Hz, 1H), 7.49 (d, J=5.0 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 6.49 (s, 1H), 5.89 (s, 1H), 4.73 (bs, 1H), 4.30 (s, 2H), 4.27-4.25 (m, 2H), 3.93-3.91 (m, 2H), 3.58 (s, 3H), 3.49 (s, 2H), 2.95-2.93 (m, 2H), 2.78-2.76 (m, 2H), 2.34 (s, 3H), 2.04-1.99 (m, 2H), 1.88-1.83 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]1[C:15]([N:17]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH3:18])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[C:9]2[C:15](=[O:16])[N:17]([CH3:18])[CH:19]([C:20]([O:22][CH3:23])=[O:21])[C:13](=[NH:14])[C:10]=2[CH:11]=[CH:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN(C)C(=O)c1c(C#N)ccn1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1C(=N)c2ccn(Cc3ccccc3)c2C(=O)N1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
An ice cold solution of methyl 2-(1-benzyl-3-cyano-N-methyl-1H-pyrrole-2-carboxamido)acetate (9.2 g, 29.6 mmol) in Tetrahydrofuran (THF) (100 mL) was treated with NaH, 60% dispersion in mineral oil, (1.536 g, 38.4 mmol) and the mixture was stirred at 0° C. for 30 minutes, then allowed to warm to room temperature and stirred an additional 2 hours at ambient temperature. The mixture was quenched with saturated NH4Cl solution at 0° C. and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford methyl 1-benzyl-4-imino-6-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (9.0 g, 28.9 mmol, 98% yield) as a pale yellow solid which was used in the next step without any further purification. 1H NMR (400 MHz, DMSO-d6) ppm 7.42-7.51 (m, 1H) 7.18-7.36 (m, 5H) 6.78-6.89 (m, 1H) 6.39-6.54 (m, 2H) 5.77 (s, 2H) 3.78 (s, 3H) 3.38 (s, 3H); LCMS (m/z) ES+=312 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(F)cc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC(C)n1ncc2c(C(=O)O)cc(F)cc21

Procedure:
The title compound was prepared in the same manner as described for example 1 (step b) from methyl 6-fluoro-1-(1-methylethyl)-1H-indazole-4-carboxylate (0.31 g, 1.312 mmol) and NaOH (1.750 mL, 5.25 mmol) The product was collected as a yellow solid (0.27 g, 89%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48 (d, J=6.57 Hz, 6H), 5.03 (quin, J=6.63 Hz, 1H), 7.57 (dd, J=9.60, 2.27 Hz, 1H), 7.97 (dd, J=9.35, 1.26 Hz, 1H), 8.40 (s, 1H), 13.51 (br. s., 1H)
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:27])[C:17]2[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=2[CH3:26])=[CH:8][CH:7]=1)([O:3]CC)=[O:2].[OH-].[Na+]>>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:27])[C:17]2[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=2[CH3:26])=[CH:8][CH:7]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)c1ccc(CCNCC(O)c2sc(NC(C)=O)nc2C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1nc(C)c(C(O)CNCCc2ccc(C(=O)O)cc2)s1

Procedure:
Prepared analogously to Example 2 by reaction of N-[2-(4-carboethoxyphenyl)ethyl]-2-hydroxy-2-(2-acetylamino-4-methyl-thiazol-5-yl)ethanamine with 1N sodium hydroxide solution. After neutralisation with 1N hydrochloric acid, the mixture is evaporated to dryness, and the residue is recrystallised from 10 ml of water.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:16][CH:15]=1>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:19]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 11.7 %

Procedure:
In a manner similar to that described in Example 3, 4-nitro-benzoyl chloride (0.062 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.010 g of 4-[4-(4-nitro-benzoylamino)-phenyl]-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+343.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[N:12]=1.[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[N:12]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2[N+](=O)[O-])co1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)CCCCc1nc(-c2ccccc2N)co1

Procedure:
Combine 5-[4-(2-nitro-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (2.5 g, 8.2 mmol) with 5% Pd/C (300 mg) and Pd/black (50 mg) in THF and react with hydrogen (init. 39 psi) in a Parr® apparatus. When reduction is complete, filter the mixture through Celite® and concentrate the filtrate. Chromatograph the residue over silica gel (MeOH/CH2Cl2) to allow for recovery of 2.05 g (91%) of 5-[4-(2-amino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester. MS (ES): (M+1)+ 275.1, 276.2 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C@@H:17]3[C:12]([C:13]4[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:34][S:35]([CH2:38][CH2:39][NH2:40])(=[O:37])=[O:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C@@H:17]3[C:12]([C:13]4[CH:29]=[CH:28][C:27]([C:30]([NH:40][CH2:39][CH2:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:32])=[CH:26][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CC[C@@H]3[C@@H]2c2ccc(F)cc2)cc1Cl
Reactant: CS(=O)(=O)CCN
Agent: Cl
Product: CS(=O)(=O)CCNC(=O)c1ccc2c(c1)CC[C@H]1C2=NN(c2ccc(C#N)c(Cl)c2)[C@H]1c1ccc(F)cc1

Procedure:
The title compound was prepared from (3R,3aR)-2-(3-chloro-4-cyanophenyl)-3-(4-fluorophenyl)-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 3, and 2-(methylsulfonyl)ethanamine hydrochloride according to Method F. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.75-0.88 (m, 1H), 1.76-1.84 (m, 1H), 2.84-3.02 (m, 2H), 3.03 (s, 3H), 3.38 (t, J=6.85 Hz, 2H), 3.67 (q, J=6.62 Hz, 2H), 3.96 (ddd, J=13.43, 11.14, 4.97 Hz, 1H), 5.93 (d, J=11.01 Hz, 1H), 6.81-7.44 (m, 6H), 7.66 (d, J=8.86 Hz, 1H), 7.70 (s, 1H), 7.76 (dd, J=8.19, 1.48 Hz, 1H), 8.13 (d, J=8.32 Hz, 1H), 8.78 (t, J=5.64 Hz, 1H); HRMS m/z 551.1343 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH3:20][C:21]1([CH3:33])[C:30]2[C:25](=[CH:26][C:27]([Br:31])=[CH:28][CH:29]=2)[C:24](=O)[CH2:23][CH2:22]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=3)[C:21]([CH3:33])([CH3:20])[CH2:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Reactant: Cc1ccc(Br)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(Br)cc32)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of 6-methyl-3-bromopyridine (890 mg, 5.2 mmol) in THF (15 mL) was added n-BuLi in hexane (1.6M solution, 3.5 mL, 5.6 mmol) and stirred for 1 hour. This mixture was added to a flask containing 3,4-dihydro-4,4-dimethyl-7-bromo-1(2H)-naphthalenone (Compound A, 1.35 g, 5.4 mmol), in THF (5 mL) at −78° C. The reaction mixture was gradually warmed to ambient temperature and stirred for 16 hours. Thereafter it was diluted with ethyl acetate (100 mL), washed with water (10 mL), brine (10 mL) and dried with MgSO4. Solvent was removed by distillation, the crude material was dissolved in toluene (25 mL) and pTSA (530 mg, 2.8 mmol) was added. The mixture was heated at 90° C. for 36 hours. Thereafter it was diluted with ethyl acetate (100 mL), washed with 10% NaHCO3 (2×10 mL), brine (10 mL), dried with MgSO4 and the solvent was removed by evaporation. The title compound was obtained by recrystallization from ethyl acetate and hexane mixture (1:9).
Reaction SMILES: [NH:1]([C:22]([O:24]C(C)(C)C)=O)[CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[S:19])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH:29]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@@H:30](C(O)=O)[CH2:31][C:32](=[O:34])[NH2:33].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>FC(F)(F)C(O)=O.CN(C=O)C>[NH:29]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@@H:30]([C:22]([NH:1][CH2:2][C:3]([N:5]([CH3:21])[C@H:6]([C:14]([NH:16][NH:17][C:18]([NH2:20])=[S:19])=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4])=[O:24])[CH2:31][C:32](=[O:34])[NH2:33]
Reactant: CC(C)(C)OC(=O)N[C@H](CC(N)=O)C(=O)O
Reactant: CN(C(=O)CNC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CNC(=O)[C@@H](CC(N)=O)NC(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)NNC(N)=S
Reaction time: 0.17 h

Procedure:
In 10 ml of trifluoroacetic acid is dissolved 0.80 g of BOC-Gly-MePhe-NHNHCSNH2 and the solution is shaken for 10 minutes, concentrated, treated with ether and filtered to obtain a powder. This powder is dissolved in 10 ml of DMF, and after ice-cooling, the solution is neutralized with 0.20 ml of TEA followed by addition of 0.47 g of BOC-(D)-Asn-OH, 0.40 g of HONB and 0.45 g of DCC. The mixture is stirred for 20 hours, the precipitated DCU filtered off, the solvent distilled off and the residue dissolved in n-butanol. The solution is washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order and dried over anhydrous sodium sulfate. The solvent is distilled off and the residue is treated with ether and filtered to obtain a powder, which is further reprecipitated from methanol-ether. Yield 0.69 g; m.p. 124°-127° C.; [α]D24 -42.5° (c=1.0, DMF); Rf1 0.16.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5](=O)[NH:4][C:3]1=[O:9].N1C=CN=C1.C(N(CC)CC)C.Cl[Si](C)(C)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)(Cl)Cl.O>[CH2:27]([NH:34][C:5]1[C:6](=[O:7])[N:2]([CH3:1])[C:3](=[O:9])[N:4]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CN1C(=O)NC(=O)C1=O
Reactant: NCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN1C(=O)N=C(NCc2ccccc2)C1=O
Reaction time: 2 h
Yield: 61.7 %

Procedure:
To a solution of 1-methyl-imidazolidine-2,4,5-trione (Example 1.3, Part A) (800 mg, 6.25 mmol), imidazole (467 mg, 6.87 mmol), N,N-dimethylaminopyridine (cat.) and triethylamine (1.82 mL, 13.1 mmol) in chloroform (13 mL) was added chlorotrimethylsilane (1.67 mL, 13.1 mmol) dropwise at room temperature under a nitrogen atmosphere, and the reaction mixture was stirred for 2 h. Benzylamine (0.75 mL, 6.87 mmol) was added and the reaction mixture was stirred for a further 22.5 h. The reaction mixture was diluted with chloroform and water and the chloroform extracts were dried and evaporated. The crude product was purified by column chromatography (PS with gradient elution to DCM:EtOAc 3:1) to give the product as a colourless solid (838 mg, 62%), mp 152-154° C. δH (300 MHz, CD3CN) 7.95 (v br s, 1H, NH), 7.41-7.27 (m, 5H, PhH), 4.64 (s, 2H, CH2), 2.95 (s, 3M, CH3). Mass spectrum (ESI) m/z 218 (M+H).
Reaction SMILES: [H-].[Na+].CS(O[CH2:8][CH2:9][N:10]1[CH2:14][C@@H:13]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12][C@H:11]1[C:25](=[O:28])[NH:26][CH3:27])(=O)=O.[Cl-].[Na+]>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][S:15][C@@H:13]2[CH2:14][N:10]3[C@H:11]([C:25](=[O:28])[N:26]([CH3:27])[CH2:8][CH2:9]3)[CH2:12]2)=[CH:18][CH:19]=1
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1CCOS(C)(=O)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2C[C@H]3C(=O)N(C)CCN3C2)cc1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
347 mg of sodium hydride (as a 55% w/w suspension in mineral oil) was added, whilst ice-cooling, to a solution of 2.64 g of (2S, 4S)-1-(2-methanesulfonyloxyethyl)-4-(4-methoxybenzylthio)-2-methylcarbamoylpyrrolidine dissolved in 30 ml of dry dimethylformamide, and the mixture was stirred at 0° to 5° C. for 30 minutes and then at 30° C. for 2 hours. The reaction mixture was then poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 5:1 by volume mixture of acetonitrile and methanol), to afford 1.75 g of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[CH:5][CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[Cl:19][C:20]1[C:29]([CH2:30]Br)=[C:28]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]>C(OCC)(=O)C>[Cl:19][C:20]1[C:29]([CH2:30][O:7][C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[C:28]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: Cn1nccc1O
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(C)(=O)=O)c(COc2ccnn2C)c1Cl
Temperature: 40 °C
Reaction time: 12 h

Procedure:
4.3 g (44 mmol) of 1-methyl-5-hydroxypyrazol, 9.1 g of potassium carbonate and 100 ml of tetrahydrofurane are heated at 65° C. for 1 h. 15 g (44 mmol) of methyl 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate and 150 ml of tetrahydrofurane are added to this mixture and heated at 40° C. for 4 h. This mixture is stirred for 12 h, freed from the solvent under reduced pressure, taken up in ethyl acetate, washed with sodium bicarbonate solution and water, dried and freed form the solvent. The crude product is purified over silica gel (eluent: cyclohexane/ethyl acetate=1/1). Yield: 7.6 g; m.p. 70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][C:13]=1[C:22]([F:25])([F:24])[F:23]>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:7][C:6]2[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:10])(=[O:19])=[O:20])=[CH:14][C:13]=1[C:22]([F:25])([F:23])[F:24]
Reactant: CSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Following General Procedure B, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:46]=[C:45]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][C:54]5[CH2:59][CH2:58][C:57]([CH3:61])([CH3:60])[CH2:56][C:55]=5[C:62]5[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=5)[CH2:49][CH2:48]4)[CH:44]=[CH:43][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:32][O:31][CH2:30][CH2:29][N:28]4C(OC(C)(C)C)=O)=[C:21]([N+:40]([O-:42])=[O:41])[CH:20]=3)(=[O:18])=[O:17])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1>FC(F)(F)C(O)=O.ClCCl>[Cl:68][C:65]1[CH:66]=[CH:67][C:62]([C:55]2[CH2:56][C:57]([CH3:60])([CH3:61])[CH2:58][CH2:59][C:54]=2[CH2:53][N:50]2[CH2:51][CH2:52][N:47]([C:45]3[CH:44]=[CH:43][C:12]([C:13]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]5[CH2:32][O:31][CH2:30][CH2:29][NH:28]5)=[C:21]([N+:40]([O-:42])=[O:41])[CH:20]=4)(=[O:18])=[O:17])=[O:14])=[C:11]([O:10][C:8]4[CH:9]=[C:4]5[CH:3]=[CH:2][NH:1][C:5]5=[N:6][CH:7]=4)[CH:46]=3)[CH2:48][CH2:49]2)=[CH:63][CH:64]=1
Reactant: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5COCCN5C(=O)OC(C)(C)C)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5COCCN5)c([N+](=O)[O-])c4)c(Oc4cnc5[nH]ccc5c4)c3)CC2)=C(c2ccc(Cl)cc2)C1

Procedure:
A solution of EXAMPLE 66B in 50% trifluoroacetic acid and dichloromethane mixture was stirred at ambient temperature for 2 hours. The solvents were evaporated and the residue was purified on a reverse phase HPLC using a gradient of 20-80% acetonitrile in water containing 10 mM ammonium acetate. 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 11.61 (s, 1H), 8.52 (bs, 1H), 8.49 (d, 1H), 7.98 (d, 1H), 7.78 (d, 1H), 7.54 (d, 1H), 7.46 (s, 1H), 7.42 (s, 1H), 7.34 (d, 2H), 7.04 (m, 3H), 6.65 (dd, 1H), 6.34 (s, 1H), 6.21 (d, 1H), 3.89 (d, 1H), 3.76 (d, 1H), 3.55-3.46 (m, 2H), 3.40-3.35 (m, 4H), 3.04 (m, 4H), 2.91 (t, 1H), 2.73 (s, 2H), 2.20-2.12 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21])=[O:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:21])([F:22])[F:23])[C:2]([O:4][CH2:5][CH3:6])=[O:3])=[O:11]
Reactant: CCOC(=O)Cl
Reactant: O=C(NNc1ccccc1C(F)(F)F)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)N(NC(=O)c1ccccc1Cl)c1ccccc1C(F)(F)F

Procedure:
1.8 ml (19 mmol) of ethyl chloroformate are added dropwise while cooling to a mixture of 4.28 g (14 mmol) of 2-chloro-N'-(α,α,α-trifluoro-o-tolyl)-benzhydrazide and 2.7 ml (19 mmol) of triethylamine in 30 ml of toluene. The reaction mixture is heated at the reflux temperature for a further 4 hours and then extracted with diethyl ether against water and sodium bicarbonate solution. The organic phase is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residual oil is then purified by chromatography using ethyl acetate/n-hexane (1:4) as the eluent. In this manner there is obtained ethyl 3-(2-chlorobenzoyl)-2-(α,α,α-trifluoro-o-tolyl)-carbazate as an almost colourless oil, IR spectrum (CHCl3): 3405, 1735, 1710 cm-1 ; 1H-NMR (CDCl3): 4.28 (q,OCH2CH3).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH:5]([C:8]2[O:9][C:10]3[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH2:4]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>O1CCCC1>[C:21]([Si:18]([CH3:20])([CH3:19])[O:17][C:16]1[C:10]2[O:9][C:8]([CH:5]3[CH2:6][CH2:7][O:3][CH2:4]3)=[CH:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2cc(C3CCOC3)oc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc2cc(C3CCOC3)oc12
Reaction time: 1.5 h
Yield: 101.7 %

Procedure:
Sodium hydride (80 mg, 60% dispersion in mineral oil) was added to a stirred solution of 2-(tetrahydrofuran-3-yl)-benzofuran-7-ol (0.37 g) in dry tetrahydrofuran (10 ml) at room temperature under a dry nitrogen atmosphere. After stirring for 10 minutes tert-butyldimethylsilyl chloride (0.27 g) was added and the reaction stirred for 90 minutes. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (2×25 ml). The combined aqueous washings were extracted with ethyl acetate (30 ml). The organic extracts were combined, dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow oil (0.58 g).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH2:9]([O:16][C:5]([CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[O:6])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCC(=O)O1
Reactant: OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)CCCC(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
A mixture of glutaric anhydride (11.4 g, 0.1 mol) and benzyl alcohol (11.4 mL, 1.1 equiv.) in toluene (200 mL) was heated at 70° C. for 2 days. Solvent was evaporated at reduced pressure to give the product which was dried under high vacuum and was pure enough to use in the next step. 1H NMR (CDCl3): δ1.96 (t, J=7.2 Hz, 2H), 2.44 (q, J=7.0 Hz, 4H), 5.13 (s, 2H), 7.33 (s, 5H).
Reaction SMILES: [CH3:1]I.[CH3:3][O:4][CH:5]([O:10][CH3:11])[CH2:6][C:7](=[O:9])[CH3:8]>CCOCC>[CH3:3][O:4][CH:5]([O:10][CH3:11])[CH2:6][C:7]([OH:9])([CH3:1])[CH3:8]
Reactant: COC(CC(C)=O)OC
Reactant: CI
Solvent: CCOCC
Product: COC(CC(C)(C)O)OC
Temperature: 25 °C

Procedure:
CH3I (18.5 mL, 297 mmol) in 50 mL of ether was added slowly, to maintain reflux, to a suspension of Mg (6.0 g, 250 mmol) in 50 mL of ether. The solution was vigorously stirred during the addition. After the magnesium was consumed, the solution was chilled with an ice bath to ≃5° C. Acetylacetaldehyde dimethyl acetal (16.5 mL, 124 mmol) in 50 mL of ether was added very slowly, over a period of 2 h. After the addition was complete, the reaction was stirred for an additional hour while warming to room temperature. The reaction was quenched with 1 mL of saturated (NH4)2SO4 (aq) and filtered. The residue was washed with ether (2×50 mL). The combined filtrates were dried over Na2SO4, and the solvent was removed under water aspirator vacuum. Distillation of the residue yielded 9.9 g of 3-hydroxy-3-methylbutanal dimethyl acetal, bp4.2 53°-56° C. (67 mmol bp10 60°-65° C., bp14 72°-79° C. in agreement with Malik, O. P.; Kapil, R. S., Anand, N., Ind. J. Chem. 14B (1976) 449); 1H-NMR (200 MHz, CDCl3) δ 1.24 (s, 6H, CH3), 1.80 (d, J=5.9 Hz, 2 H, CH2), 3.36 (s, 6H, CH3O), 3.41 (s, 1 H, OH), 4.66 (t, J=5.9 Hz, 1 H, CH), 13C-NMR (50 MHz, CDCl3) δ 29.46 (CH3), 43.85 (CH2), 52.61 (CH3O), 68.63 (COH), 102.51 (CH).