Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[C:17]([C:27]([O:29][CH3:30])=[O:28])=[C:16]([CH3:31])[N:15]=[C:14]2OC)=[O:12])=CC=1)([O-])=O.Cl.[CH2:35]([NH:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CCN(CC)CC>CC#N>[CH3:30][O:29][C:27]([C:17]1[CH:18]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=2)[N:13]2[C:11](=[O:12])[N:42]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:43]=[C:14]2[NH:15][C:16]=1[CH3:31])=[O:28]
Reactant: NNCc1ccccc1
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(C#N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C1=C(C)Nc2nn(Cc3ccccc3)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
Intermediate 5 (250 mg, 0.55 mmol) and benzyl hydrazine hydrochloride (120 mg, 0.61 mmol) were suspended in CH3CN (10 mL) at 0° C., and Et3N (85 μl, 0.61 mmol) was added. The reaction mixture was stirred at 0° C. for 30 mins and then allowed to reach RT and stirred for a further 1 hour. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-100% to yield the title compound as a yellow solid (100 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl.O>[Cl:21][CH2:22][C:23]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[C:2]([CH3:13])([CH3:1])[CH2:3]1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CC1(C)CNc2cc(C#N)ccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CN(C(=O)CCl)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of 3,3-dimethylindoline-6-carbonitrile (0.35 g, 2.0 mmol) and triethylamine (0.56 mL, 4.0 mmol) in DCM (10 mL) at 0° C. was added chloroacetyl chloride (0.16 mL, 2.0 mmol) dropwise. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was then diluted with water. The organic phase was then separated, dried over magnesium sulfate and concentrated to give the title compound (0.39 g). 1H NMR (CDCl3): 8.47 (s, 1H), 7.40 (d, 1H), 7.24 (d, 1H), 4.14 (s, 2H), 3.94 (s, 2H), 1.42 (s, 6H).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=1)[NH2:3].[CH3:14][C:15]1[N:19]([CH2:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[S:30][CH:31]=[C:32]([CH:34]=O)[N:33]=3)[CH2:25][CH2:24]2)=[O:22])[N:18]=[C:17]([C:36]([F:39])([F:38])[F:37])[CH:16]=1>C(O)C>[CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:11])[F:12])=[CH:6][N:5]=1)[N:3]=[CH:34][C:32]1[N:33]=[C:29]([CH:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[CH2:20][N:19]3[C:15]([CH3:14])=[CH:16][C:17]([C:36]([F:37])([F:39])[F:38])=[N:18]3)[CH2:28][CH2:27]2)[S:30][CH:31]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: CN(N)c1ccc(C(F)(F)F)cn1
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NN(C)c3ccc(C(F)(F)F)cn3)cs2)CC1
Reaction time: 24 h

Procedure:
At room temperature, 2-(1-methylhydrazinyl)-5-(trifluoromethyl)pyridine (58 mg) is added to a solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde (100 mg) in ethanol. The reaction mixture is stirred for 24 hours, and the solvent is then removed under reduced pressure. The residue is purified by column chromatography (silica gel, ethyl acetate:hexane 0%-100% elution gradient). This gives 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}) piperidin-4-yl)-1,3-thiazole-4-carbaldehyde methyl[5-(trifluoromethyl)pyridin-2-yl]hydrazone (79 mg, 56%), (log P (pH2.7)=4.23).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][NH2:33]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:33][CH2:32][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][NH:26]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCC1CCCCN1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3CCCCN3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(piperidin-2-yl)methanamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (d, J=7.6 Hz, 1 H), 7.93 (s, 1 H), 7.85 (d, J=7.6 Hz, 1 H), 7.73-7.70 (m, 2 H), 7.62-7.58 (m, 2 H), 6.02 (s, 1 H), 5.35 (s, 2 H), 4.51 (s, 2 H), 3.75-3.71 (m, 4 H), 3.51-3.40 (m, 2 H), 2.98-2.92 (m, 1 H), 2.46 (s, 3 H), 2.11-2.05 (m, 1 H), 1.96-1.90 (m, 2 H), 1.78-1.56 (m, 3 H).
Reaction SMILES: CI.[Mg].Br[CH2:5][C@@H:6]([CH3:16])[CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1.[CH3:17][CH:18]([CH3:22])[CH2:19][CH2:20]O.C1(C)C=CC(S([O-])(=O)=O)=CC=1>O1CCCC1>[CH3:16][C@H:6]([CH2:5][CH2:20][CH2:19][CH:18]([CH3:22])[CH3:17])[CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1
Reactant: C[C@H](CBr)CCOC1CCCCO1
Reactant: CC(C)CCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)CCOC1CCCCO1
Reaction time: 0.08 h

Procedure:
4.7 g (0.202 mol) of magnesium shavings in a 3-necked flask under an argon atmosphere and provided with a calcium chloride tube are activated by addition of 2.0 ml of methyl iodide. After 5 minutes, the methyl iodide is removed and the magnesium washed several times with absolute tetrahydrofuran. To the activated magnesium is added dropwise a solution of 44 g (0.175 mol) of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran in 50 ml of absolute tetrahydrofuran at such a rate that the solvent just boils. Where the Grignard reaction does not start itself, it is warmed to 85° with the oil bath. After completed addition of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran, the mixture is stirred at 85° for so long (0-15 min.) until only traces of 2-[(S)-4-bromo-3-methylbutoxy]-tetrahydro-2H-pyran are still present in accordance with gas-chromatographical analysis. The solution obtained is cooled to -78° and treated dropwise with 21.2 g (0.0875 mol) of 3-methyl-1-butanol-p-toluenesulphonate followed by 3.6 ml of a 0.1 molar solution of Li2CuCl4 in absolute tetrahydrofuran. This reaction mixture is stirred at -78° during 10 min. then at 0° for 2 hours and subsequently at room temperature for a further 14 hours. For the working up of the 2-[(R)-3,7-dimethyloctanoxy]-tetrahydro-2H-pyran obtained the mixture is poured on to ice and brought to pH 5-6 with 2-N sulphuric acid. By three-fold extraction with ether and removal of the solvent on the rotary evaporator there is obtained a mixture of (R)-3,7-dimethyl-1-octanol and 2-[(R)-3,7-dimethyloctanoxy]-tetrahydro-2H-pyran. This mixture is treated portionwise in 100 ml of methanol at 0° with a total of 100 ml of 7-N aqueous hydrochloric acid. After 2-hours stirring at room temperature, the mixture is neutralised with dilute aqueous caustic soda and extracted with ether. After chromatography on silicagel, deactivated with 0.5% ammonia, with pentane/ether (4:1), there are obtained 10.6 g (76% based on 3-methyl-1-butanol-p-toluenesulphonate employed) of pure (R)-3,7-dimethyl-1-octanol. B.p. 58°-59°/0.05 Torr; [α]D20 = +4.0 (c = 1.03, CHCl3).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[OH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=2[O:31][CH2:32][CH:33]2[CH2:35][O:34]2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1>CO.O1CCCC1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=2[O:31][CH2:32][CH:33]([OH:34])[CH2:35][N:12]2[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: OC1CCNCC1
Reactant: COc1cc(CCCCc2ccccc2OCC2CO2)cc(OC)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CCCCc2ccccc2OCC(O)CN2CCC(O)CC2)cc(OC)c1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
561 mg of potassium t-butoxide were added, whilst ice-cooling, to a solution of 688 mg of 4-hydroxypiperidine hydrochloride in methanol, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, the residue was mixed with tetrahydrofuran, and insoluble materials were filtered off. The filtrate was concentrated by evaporation under reduced pressure, to give a colorless oil, which was dissolved in 20 ml of tetrahydrofuran. 1.02 g of 2-{2-[4-(3,5-dimethoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in Example 11(a)] were added to the resulting solution, and the mixture was stirred at 60° C. for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of methylene chloride and methanol as the eluent, to give 1.26 g (yield 95%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1.[C:54]([O:57][BH-](OC(=O)C)OC(=O)C)(=[O:56])C.[Na+].O>C(Cl)Cl>[CH:54]([OH:57])=[O:56].[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:48])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:49]3[CH2:53][CH2:52][CH2:51][CH2:50]3)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C=O)cc4)c4ccccc43)cn12
Reactant: C1CCNC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CN5CCCC5)cc4)c4ccccc43)cn12
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Intermediate 176b (0.188 mmol) and pyrrolidine (31.1 μL, 0.38 mmol) in DCM (3 mL), sodium triacetoxyborohydride (59.8 mg, 0.28 mmol) was added. The mixture was stirred at RT for 1 h. Water was added and the mixture extracted with DCM. The combined organics were passed through a phase separator and concentrated to dryness. The resulting residue was purified by RP-HPLC (C18, 18 mL/min, 20-85% MeCN in H2O+0.1% HCO2H) and the relevant fractions combined and concentrated to dryness. The title product was isolated as a light orange solid (49.5 mg). LCMS (Method 5): Rt 3.66 min, m/z 702.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.27 (9H, s), 1.50 (2H, m), 1.69 (6H, m), 1.75-1.95 (4H, m), 1.98-2.17 (2H, m), 2.47 (4H, m, obscured by solvent), 2.90 (1H, m), 3.15 (1H, m, obscured by solvent), 3.63 (2H, s, obscured by solvent), 4.81 (1H, m), 5.51 (1H, t, J=4.3 Hz), 6.33 (1H, s), 7.09 (1H, d, J=8.9 Hz), 7.19 (1H, dd, J=9.6, 2.2 Hz), 7.24-7.38 (4H, m), 7.43 (4H, m), 7.64 (1H, d, J=9.6 Hz), 7.69 (1H, d, J=1.3 Hz), 8.09 (1H, s), 8.16 (1.4H, s).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]([N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]>O1CCCC1>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][N:7]([C:5]([O:2][CH3:1])=[O:6])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccccc1CN(C(=O)Cl)c1ccccc1Oc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(Cc1ccccc1OC)c1ccccc1Oc1ccccc1
Yield: 97.9 %

Procedure:
To a solution of 226 mg of sodium methoxide in 5 ml of tetrahydrofuran was added dropwise a solution of 1.22 g of N-chlorocarbonyl-N-(2-methoxybenzyl)-2-phenoxyaniline in 5 ml of tetrahydrofuran under ice-cooling with stirring, followed by stirring at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, poured into water and extracted with ethyl acetate, and the extract was washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:6) and recrystallized from ethyl acetate to give 1.18 g of N-(2-methoxybenzyl)-N-methoxycarbonyl-2-phenoxyaniline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Mg]Br.O.[Cl-].[NH4+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([OH:14])([CH3:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.05 mmol) in diethyl ether (20 mL) at −25 to −30° C. was added methyl magnesium bromide (3M in diethyl ether, 3.35 mL, 10.05 mmol) dropwise under argon. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Water (20 mL) was then added dropwise, followed by saturated ammonium chloride (20 mL) and the ether layer was separated. The aqueous phase was further extracted with ether (50 mL) and the combined organic layer was dried over sodium sulfate, filtered and evaporated to afford the title compound (2.09 g, 97%). 1H NMR (CDCl3, 300 MHz): 3.76-3.62 (m, 2H), 3.30-3.13 (m, 2H), 2.48-2.39 (m, 1H), 1.57-1.51 (m, 4H), 1.46 (s, 9H), 1.27 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:16][C:11]=3[C:12]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([O:23][CH:24]([CH3:25])[CH3:26])=[CH:16][C:11]=3[C:12]=2[C:13]([NH:27][CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)Oc1cc2c(C(=O)O)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)Oc1cc2c(C(=O)NCCNC(=O)OC(C)(C)C)c(-c3ccc(F)cc3)oc2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(4-fluorophenyl)-5-isopropoxy-6-nitrobenzofuran-3-carboxylic acid (1.3 g, 3.62 mmol), tert-butyl (2-aminoethyl)carbamate (0.696 g, 4.34 mmol) in DMF (50 mL) at room temperature was added N,N-diisopropylethylamine (DIPEA) (2.53 mL, 14.47 mmol). The mixture was cooled to 0° C., added with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (2.40 g, 5.43 mmol), and then stirred at room temperature (rt) overnight. The reaction mixture was diluted with water, stirred for 5 min. The solid was filtered and dried under suction to obtain the title compound as a yellow solid. Yield: 1.6 g, (88%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.61 (t, J=5.65 Hz, 1H) 8.32 (s, 1H) 7.90-8.09 (m, 2H) 7.50 (s, 1H) 7.28-7.46 (m, 2H) 6.91 (t, J=5.65 Hz, 1H) 4.87 (dt, J=12.17, 5.96 Hz, 1H) 3.35-3.49 (m, 2H) 3.06-3.23 (m, 2H) 1.09-1.47 (m, 15H). LCMS: (ES+) m/z=502.34 (M+H)+; Column—ACQUITY UPLC BEH C8 (50×2.1 mm; 1.7 nm); M phase A: 5 mM Ammonium Acetate: MeCN (95:5); M phase B: 5 mM Ammonium Acetate:MeCN (5:95)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl>N1C=CC=CC=1>[S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH3:16])=[CH:7][CH:8]=1)([O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:14])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCO
Agent: Cl
Solvent: c1ccncc1
Product: COCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 86.1 %

Procedure:
To a solution of 38 g of 2-methoxyethanol in 12 ml of pyridine was added portionwise, over two hours, 95.3 g of p-toluenesulfonyl chloride at 0° C. The reaction mixture was stirred for 20 hours, poured into 200 ml of concentrated hydrochloric acid and 1 liter of ice cubes, extracted with methylene chloride and washed successively with methylene chloride, water and a saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and stripped to yield 99 g of 2-methoxyethyl tosylate as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.CC1(C)[C@]2(CS(O)(=O)=O)[C:23](C[C@H]1CC2)=[O:24].[CH:32](OC)(OC)OC.C(=O)([O-])O.[Na+]>CO.O.CC(=O)OCC>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:5]=[C:4]([C:14]([O:24][CH3:23])([O:16][CH3:32])[CH3:15])[CH:3]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Reactant: CC(=O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(C)(OC)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[3-Bromo-5-(pentafluorosulfanyl)phenyl]ethanone (835 mg, example 26c) was dissolved in methanol (50 ml), and admixed at RT with DL-10-camphorsulfonic acid (0.9 mg) and with trimethyl orthoformate (0.85 ml). The reaction mixture was stirred at RT for 2 h and then stood overnight. Then the mixture was stirred at RT for a further 5 h. Subsequently, saturated sodium hydrogencarbonate solution was used to adjust the pH to 9, and a large amount of EA and water were added. The organic phase was removed and the aqueous phase was extracted five times with EA. The combined EA phases were dried over magnesium sulfate, filtered and concentrated. 900 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[OH-].[Na+]>O>[CH2:20]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
To a 250 mL flask, ethyl 4-(dibenzylamino)cyclohexanecarboxylate (7.2 g, 20.5 mmol) and a solution of conc. H2SO4 (7.64 mL, 143 mmol) in water (80 mL) were added. The reaction mixture was stirred at about 90° C. for about 18 h, cooled to about 5° C. and the pH was adjusted to about 7 with the addition of 50% aqueous NaOH. The aqueous solution was extracted with ether (300 mL). The organic layer was dried over anhydrous Na2SO4, filtered and washed with ether. The filtrate was concd under reduced pressure to give 4-(dibenzylamino)cyclohexanecarboxylic acid (5.6 g, 85%) as a solid: LC/MS (Table 1, Method b) Rt=1.65 min; MS m/z: 324 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[NH:19][CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].CN(C)[C:38](Cl)=[O:39].N>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([O:39][CH2:38][C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)=[CH:23][CH:24]=5)[N:19]([C:27]([O:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[O:28])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1
Reactant: O=C(c1ccn2c1CSC2c1cccnc1)c1c[nH]c2ccccc12
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)C(=O)Cl
Agent: N
Product: O=C(c1ccn2c1CSC2c1cccnc1)c1cn(C(=O)Oc2ccccc2)c2cc(OCc3ccccc3)ccc12

Procedure:
The desired compound was prepared according to the method of Example 2, except substituting 3-(pyridin-3-yl)-7-(6-phenylmethoxyindol-3-)carbonyl-1H,3H-pyrrolo[1,2-c]thiazole, prepared as in Example 4 for 3-(pyridin-3-yl)-7-(indol-3-yl)carbonyl-1H,3H-pyrrolo[1,2-c]thiazole and substituting phenyl chloroformate for N,N-dimethylcarbamoyl chloride. 1H NMR (DMSO-d6, 300 MHz) δ4.45 (d, 1H, J=15 Hz), 4.62 (dd, 1H, J=15 Hz, 2 Hz), 5.16 (s, 2H), 6.69 (d, 1H, J=3 Hz), 6.76 (s, 1H), 6.85 (d, 1H, J=3 Hz), 7.12 (dd, 1H, J=9 Hz, 3 Hz), 7.26-7.52 (m, 11H), 7.60-7.68 (m, 1H), 7.77 (d, 1H, J=3 Hz), 8.08 (d, 1H, J=9 Hz), 8.30 (s, 1H), 8.51-8.54 (m, 2H), MS (DCI/NH3) m/e 572 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCCCC1.ClC(OCC)=O.Cl.[CH3:31][NH:32][O:33][CH3:34]>ClCCl>[CH3:34][O:33][N:32]([CH3:31])[C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:12]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCCCC1
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Temperature: -40 °C
Reaction time: 2.5 h
Yield: 106.3 %

Procedure:
To a stirred solution of (2S)-2-[(tert-butoxycarbonyl)amino]hexanoic acid (27.8 g, 120.0 mmol) in dichloromethane (150 mL) at −40° C. was added a solution of 1-methylpiperidine (18.4 mL, 151.5 mmol) in dichloromethane (40 mL) over 20 min. Ethyl chloroformate (13.9 mL, 145.4 mmol) in dichloromethane (40 mL) was then added over 30 min and the reaction mixture was stirred at −40° C. for 2.5 h. A solution of N,O-dimethylhydroxylamine hydrochloride (14.2 g, 145.4 mmol) and 1-methylpiperidine (18.4 mL, 151.5 mmol) in dichloromethane (90 mL) was added over 45 min, and the reaction mixture was allowed to slowly warm to ambient temperature. It was stirred for 18 h, and then washed with water (100 mL), 1% hydrochloric acid (2×100 mL), and saturated aqueous sodium bicarbonate (100 mL). The organic layer was then dried with magnesium sulfate and concentrated in vacuo to afford the desired title compound (35.0 g, 106%) as a thick oil. 1H NMR (400 MHz, DMSO-d6): δ 6.94 (d, J=8 Hz, 1H), 4.35-4.25 (m, 1H), 3.68 (s, 3H), 3.05 (s, 3H), 1.52-1.36 (m, 2H), 1.32 (s, 9H), 1.30-1.14 (m, 4H), 0.80 (t, J=6 Hz, 3H).