Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25]([CH2:27][C:28](Cl)=[O:29])#[N:26].O>C(#N)C>[C:25]([CH2:27][C:28]([NH:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][CH:3]=1)=[O:29])#[N:26]
Reactant: N#CCC(=O)Cl
Reactant: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: N#CCC(=O)Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 79.7 %

Procedure:
22.5 g (0.076 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole and 8 g (0.1 mol) of pyridine are taken in 200 ml of acetonitrile, and 13.2 g (0.128 mol) of cyanoacetyl chloride are added dropwise at 20°-25° C., while stirring and cooling. The reaction mixture is stirred at room temperature for a further two hours and then poured into water. After extraction with methylene chloride and drying of the organic phase over sodium sulphate, the solvent is distilled off in vacuo. The crystalline residue is stirred with a mixture of ligroin and diisopropyl ether and filtered off with suction. 22 g (80% of theory) of 5-cyanoacetylamino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-pyrazole of melting point 169°-175° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].Cl.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@H:26]2[C@@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][CH2:29][NH:28][CH2:27]2)=[CH:22][CH:21]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:28]2[CH2:29][CH2:30][C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:26]([C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH2:27]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ccc([C@@H]2CNCC[C@@H]2c2ccccc2)cc1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2)[C@H](c2ccc(Cl)cc2)C1

Procedure:
The title compound, MS: m/e=512.2 (M+), was prepared in accordance with the general method of example 1 from 3,5-bis(trifluoromethyl)benzoyl chloride and rac-cis-3-(4-chloro-phenyl)-4-phenyl-piperidine hydrochloride.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14]C)[N:11]=[C:10]([CH2:16][CH2:17][CH2:18]O)[CH:9]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][C:8]1[CH:9]=[C:10]2[N:11]([CH2:18][CH2:17][CH2:16]2)[C:12](=[O:14])[CH:13]=1)([CH3:4])[CH3:3]
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)cc(CCCO)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [I-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc2n(c(=O)c1)CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
A solution of 3-[4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-(methyloxy)-2-pyridinyl]-1-propanol (5.16 g, 16.59 mmol) in dichloromethane (250 ml) was treated with pyridine (2.94 ml, 36.47 mmol) and trifluoromethanesulfonic anhydride (3.1 ml, 19.88 mmol) and stirred at room temperature for 10 min before being treated with tetrabutylammonium iodide (30.61 g, 82.95 mmol) and stirred at room temperature for a further 4 h. Water was then added and the mixture was extracted three times with diethyl ether and the combined organic extracts washed again with water. The organic extracts were dried with magnesium sulphate and evaporated. The residue was chromatographed on silica eluting with 0-10% methanol in dichloromethane to give the desired product (3.93 g, 14.09 mmol)
Reaction SMILES: O=[C:2]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][C:12]2([CH3:22])[CH3:21])[CH:3]([CH3:8])[CH2:4][C:5](O)=[O:6].O.[NH2:24][NH2:25]>C(O)C>[CH3:8][CH:3]1[C:2]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][C:12]3([CH3:22])[CH3:21])=[N:25][NH:24][C:5](=[O:6])[CH2:4]1
Reactant: CC(CC(=O)O)C(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2C
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2c(c1)C(C)(C)CC(=O)N2C
Yield: 76.5 %

Procedure:
A mixture of 20 g of 4-oxo-4-(1,4,4-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-methylbutanoic acid, 10 g of hydrazine hydrate and 200 ml of ethanol was heated under reflux for one hour. After cooling, the precipitated crystals were filtered off and recrystallized from ethanol to give 15.1 g of 6-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-2-one, melting at 238°-241° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][NH:35][CH:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:41]1[N:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[C:44]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:43][N:42]=1.CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][NH:35][CH:36]([CH:37]([CH3:39])[CH3:38])[C:24]3=[CH:23][C:22]=2[CH:21]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:18][CH2:19][C:20]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][C:26]2[N:25]3[CH2:33][CH2:34][N:35]([C:41]4[N:46]=[C:45]([C:47]([F:49])([F:50])[F:48])[C:44]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:43][N:42]=4)[CH:36]([CH:37]([CH3:38])[CH3:39])[C:24]3=[CH:23][C:22]=2[CH:21]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Agent: CC(C)C1NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(N2CCn3c(cc4cc(CO)c(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The intermediate 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole was prepared following a procedure analogous to that described in Preparation 4. The mixture of compound 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (0.19 mmol), ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (97 mg, 0.38 mmol) and DIEA (100 μL, 0.57 mmol) in i-PrOH/CH2Cl2 (1 mL/0.5 mL) was stirred at 50° C. for 8 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with EtOAc/hexanes (1/1) to give racemic ethyl 2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate. LC-MS m/z 563 [M+Na]+. 1H NMR (400 MHz, CD3OD): δ 9.31 (s, 1H), 8.11 (s, 1H), 7.80 (s, 1H), 6.55 (s, 1H), 6.02-5.92 (m, 1H), 5.23-5.17 (m, 1H), 5.07 (s, 2H), 4.52-4.47 (m, 1H), 4.34 (q, J=7.2 Hz, 2H), 4.19-4.06 (m, 1H), 4.00-3.93 (m, 1H), 3.27 (s, 3H), 2.42-2.32 (m, 1H), 1.36 (t, J=7.2 Hz, 3H), 1.18 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.CO.[C:18](#[N:21])[CH:19]=[CH2:20]>N1C=CC=CC=1>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:11]([NH:15][CH2:20][CH2:19][C:18]#[N:21])=[N:12][O:13][N:14]=1
Reactant: C=CC#N
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Solvent: CO
Solvent: c1ccncc1
Product: N#CCCNc1nonc1-c1nc2ccccc2[nH]1

Procedure:
To a solution of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.10 g, 0.497 mmol) in pyridine (5 ml) sodium in methanol (0.02 g, 0.86 mmol in 1 ml) and acrylonitrile (0.03 g, 0.39 mmol) are added sequentially at 0° C. The mixture is stirred over night. Evaporation of the solvent under reduced pressure and partitioning of the resulting residue between water and ethyl acetate followed by drying of the organic solution over sodium sulphate gives the title compound in pure form. 1H-NMR (400 MHz, d6-DMSO): 13.7 (s, 1H); 7.82 (d, 1H); 7.60 (d, 1H); 7.36 (m, 2H); 7.20 (t, 1H); 3.67 (q, 2H); 2.94 (t, 2H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:6][O:7]CC1C=CC=CC=1)=[N+]=[N-].[H][H].[C:26](Cl)([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].CCN(C(C)C)C(C)C>CO.[Pd]>[CH2:29]([O:28][C:26](=[O:27])[NH:1][CH2:4][C@H:5]([N:15]([C:16]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:22])[CH3:23])[CH2:6][OH:7])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CN=[N+]=[N-])COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)[C@H](CO)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 132.7 %

Procedure:
To a solution of the crude (S)-tert-butyl 1-azido-3-(benzyloxy)propan-2-yl(methyl)carbamate (1.8 g, ˜4.90 mmol) in MeOH (20 mL) was added Pd/C (300 mg). The mixture was transferred to an autoclave reactor, charged with hydrogen (45 psi), and stirred at RT overnight. The solid was filtered off. To the filtrate were added CbzCl (0.83 mL, 5.88 mmol) and DIEA (1.22 mL, 7.35 mmol) and the resulting mixture was stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure and dissolved in EtOAc. The organic mixture was washed with NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give [(S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-hydroxy-propyl]carbamic acid benzyl ester (2.2 g of crude), which was used without purification (2.2 g, crude). LRMS (M+H+-Boc) m/z 239.1.
Reaction SMILES: [CH2:1]([C@H:8]([N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])[C@@H:9](OS(C)(=O)=O)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl>O1CCCC1.ClCCl.O>[C:2]1([CH2:1][C@@H:8]([C@H:9]2[CH2:10][O:11]2)[N:17]2[C:18](=[O:27])[C:19]3=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]3[C:21]2=[O:22])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@@H](CO)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 20 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
2.16 g of N-[1(S)-benzyl-3-hydroxy-2(R)-(methylsulphonyloxy)propyl]phthalimide were added to a stirred suspension of 200 mg of sodium hydride (80% dispersion in mineral oil) in 50 ml of dry tetrahydrofuran and the mixture was stirred at 20° C. for 2 hours. A further 100 mg of sodium hydride were added and the stirring was continued for 3.5 hours. The mixture was diluted with dichloromethane and water and the pH of the aqueous layer was adjusted to 7 by adding 2M hydrochloric acid. The organic layer was separated, washed with saturated sodium chloride solution and evaporated. The residue was chromatographed on silica gel using ethyl acetate/n-hexane (1:2) for the elution to give 0.67 g of 2(S)-[2-phenyl-1(S)-phthalimidoethyl]oxirane as a white solid, MS: m/e 294 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]C)=[CH:8][CH:7]=1.B(O[O-])=[O:15].[Na+]>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](=[S:12]=[O:15])[CH2:8][CH:7]=1
Reactant: O=BO[O-]
Reactant: CSc1ccc(OCCCCl)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S=C1C=CC(OCCCCl)=CC1

Procedure:
The title compound is prepared by treating 1-(3-chloropropoxy)-4-methylthiobenzene with sodium perborate in glacial acetic acid.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C1COCC1>[S:19]1[CH2:20][CH2:21][N:17]([C:15]([C@H:9]2[NH:8][CH2:12][C@@H:11]([CH2:13][NH:14][S:32]([C:35]3[CH:36]=[CH:37][C:38]([C:39]([OH:41])=[O:40])=[CH:42][CH:43]=3)(=[O:34])=[O:33])[CH2:10]2)=[O:16])[CH2:18]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(S(=O)(=O)NC[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 17D (32 mg, 0.1 mmol) in anhydrous THF (5 mL) was added N,N-diisopropylethylamine (0.035 mL, 0.2 mmol) followed by 4-chlorosulfonyl-benzoic acid (20.92 mg, 0.12 mmol). The mixture was stirred for 8 hours at room temperature and concentrated under reduced pressure. The residue was taken up in anhydrous dichloromethane (3 mL) and trifluoroacetic acid (0.075 mL) in dichloromethane (0.075 mL) was added and the mixture was allowed to stir for 5 hours at room temperature. The mixture was concentrated under reduced pressure and purified using RP-HPLC to provide the titled compound. MS (ESI) m/e 400 (M+H)+, 398 (M−H)−; 1H NMR (500 MHz, CD3OD) δ ppm 1.78 (m, 1 H) 2.65 (m, 1 H) 3.00 (m, 2 H) 3.08 (m, 1 H) 3.14 (m, 1 H) 3.20 (m, 1 H) 3.49 (m, 1 H) 3.60 (m, 1 H) 3.73 (m, 1H) 3.88 (m, 1 H) 4.50 (m, 1 H) 4.66 (m, 2 H) 7.95 (d, 2 H) 8.19 (d, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[S:4]([O-:7])(=[O:6])=[O:5].[CH3:13][C:14]([O:16]C(C)=O)=[O:15].CCN(CC)CC>C(Cl)Cl>[C:14]([O:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[S:4]([O-:7])(=[O:5])=[O:6])(=[O:15])[CH3:13].[C:14]([O-:16])(=[O:15])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cc(C)ccc1S(=O)(=O)[O-]
Product: CC(=O)[O-]

Procedure:
The racemic acetate substrate was prepared by one of two methods. The diol route began with racemic 1,2-dihydroxy-3-butene which could be prepared by reacting EpB with water under neutral conditions or with acid catalysis. The diol was treated with p-toluenesulfonyl chloride (p-TsCl) in pyridine at 4° C. to afford the desired monotosylate contaminated with about 10% of the corresponding ditosylate. The monotosylate could be selectively crystallized to afford pure monotosylate in 61% yield. Hydroxytosylate was acetylated under normal conditions (Ac2O, Et3N, CH2Cl2) to provide the acetoxy-tosylate (the desired racemic acetate) in 93% yield. The diol route is illustrated as follows: ##STR3##
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:16].[C:17](OC(=O)C)(=[O:19])[CH3:18].S(OCC)(O[CH2:28][CH3:29])(=O)=O.C(Cl)C>C(O)(=O)C.[OH-].[Na+]>[NH:1]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:16][CH2:28][CH3:29])[C:17]([CH3:18])=[O:19]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(O)ccc2cc(S(=O)(=O)O)ccc12
Agent: CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOc1ccc2cc(S(=O)(=O)O)ccc2c1NC(C)=O

Procedure:
According to Examples 2 and 3 of German Democratic Republic Pat. No. 9,728, 1-amino-2-ethoxy-naphthalene-6-sulphonic acid, is obtained by a procedure in which, in a first stage, 1-acetamino-2-hydroxy-naphthalene-6-sulphonic acid is prepared from 1-amino-2-hydroxy-naphthalene-6-sulphonic acid by reaction with acetic anhydride in dilute acetic acid, this intermediate product is etherified, in a second stage, with diethyl sulphate or with ethyl chloride in aqueous-alcoholic sodium hydroxide solution to give 1-acetamino-2-ethoxy-naphthalene-6-sulphonic acid, and, finally, this intermediate product is deacetylated, without intermediate isolation, by heating with aqueous sodium hydroxide solution to give 1-amino-2-ethoxy-naphthalene-6-sulphonic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[N:3]=1.Cl[CH2:14][CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18]>>[O:18]=[S:17]1(=[O:19])[CH2:16][CH2:15][CH2:14][N:1]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[N:3]=1
Reactant: COC(=O)c1ccc(N)nc1C
Reactant: O=S(=O)(Cl)CCCCl
Product: COC(=O)c1ccc(N2CCCS2(=O)=O)nc1C

Procedure:
Using methyl 6-amino-2-methylnicotinate (170 mg) described in Preparation Example 36 and 3-chloropropane-1-sulfonyl chloride (0.25 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (220 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[CH3:18][C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:24][C:21]1[S:22][CH:23]=[C:19]([CH3:18])[N:20]=1)=[O:8]
Reactant: CN(c1cncnc1)c1cccc(C(=O)O)c1
Reactant: Cc1csc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2cccc(N(C)c3cncnc3)c2)n1
Yield: 16.1 %

Procedure:
Compound 17 (0.1 g, 0.4 mmol, 1 eq), 4-methylthiazol-2-amine (60 mg, 0.53 mmol, 1.2 eq), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (348 mg, 0.915 mmol, 2.10 eq), and DIEA (160 μL, 0.915 mmol, 2.10 eq) were dissolved in CH2Cl2 (5 mL) and DMF (1 mL) and stirred rt for 48 h. The reaction was diluted with CH2Cl2 and washed with water (1×). The organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 21 mg (15%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 8.68 (s, 2H), 7.58 (m, 1H), 7.45 (m, 1H), 7.18 (m, 1H), 6.81 (s, 1H), 3.39 (s, 3H), 2.28 (s, 3H); [M+1]+: 326.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([CH2:9][C@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11]([O:13][CH3:14])=[O:12])[C:5](OC)=[O:6].CCN(CC)CC.O>C1COCC1>[C:19]([O:18][C:16]([NH:15][C@@H:10]([CH2:9][CH:4]1[CH2:3][CH2:2][NH:1][C:5]1=[O:6])[C:11]([O:13][CH3:14])=[O:12])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)C(CCN)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@H](CC1CCNC1=O)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of (4S)-dimethyl 2-(2-aminoethyl)-4-((tert-butoxycarbonyl)amino)pentanedioate (crude) in THF (20 mL) was added Et3N (20 mL). The reaction mixture was stirred at 60° C. overnight and then cooled to ambient temperature. Water (50 mL) was added and the resulting mixture was extracted with methylene chloride (100 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (heptanes/EtOAc=1:1) to afford (2S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2-oxopyrrolidin-3-yl)propanoate (5.5 g, 60% yield over two steps) as a light brown oil.
Reaction SMILES: [OH:1][C:2](/[C:5](=[CH:8]/[I:9])/[CH2:6][OH:7])([CH3:4])[CH3:3].C(Cl)Cl.CO>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[OH:1][C:2](/[C:5](=[CH:8]/[I:9])/[CH:6]=[O:7])([CH3:4])[CH3:3]
Reactant: CC(C)(O)/C(=C/I)CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(O)/C(C=O)=C/I
Yield: 95 %

Procedure:
To a solution of E-2-(1-hydroxy-1-methylethyl)-3-iodoprop-2-en-1-ol (III) (5.7 mmol, 1.4 g) in dry methylene chloride (25 ml), manganese dioxide (10 eq., 57 mmol, 5 g) is added in portions, at room temperature (rt), under an inert atmosphere. The progress of the reaction is monitored by analytical chromatography on a silica gel plate (eluent CH2Cl2/MeOH 97/3). After the disappearance of the starting material, the mixture is filtered on Celite®. The filtrate, evaporated under reduced pressure, gives Z-2-(1-hydroxy-1-methylethyl)-3-iodopropenal (IV) (1.3 g, 94%) in the form of a slightly yellow oil.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1.[CH2:26]([N:28](CC)[CH2:29]C)C.CS([Cl:37])(=O)=O.CNC>C(Cl)Cl.C(#N)C.C1COCC1>[ClH:37].[CH3:26][N:28]([CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1)[CH3:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: Cc1c(-c2ccc(C(=O)N3CCCC(CO)C3)s2)noc1C(F)(F)F
Agent: CNC
Solvent: CC#N
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CCCC(CN(C)C)C3)s2)noc1C(F)(F)F
Product: Cl
Temperature: 45 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
A solution of (3-Hydroxymethyl-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone (Example 46, 170 mg, 0.454 mmol) and triethylamine (111 μL, 0.795 mmol) in CH2Cl2 (4 mL) at −10 to −5° C., was treated with methanesulfonyl chloride (53 μL, 0.681 mmol) and allowed to stir for 1 hr. The reaction mixture was then quenched with CH2Cl2 (4 mL) and water (4 mL), and the organic portion further washed with a 1 N aqueous hydrochloric acid solution (2×3 mL) followed by a saturated aqueous NaHCO3 solution (2×3 mL) and brine (3 mL). The organic layer was then dried over MgSO4, filtered, and evaporated to the Methanesulfonic acid 1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-ylmethyl ester intermediate as an oil (180 mg, 88%). A solution of the intermediate sulfonate (60 mg, 0.1326 mmol) in acetonitrile (2 mL) was treated with a 2 N THF solution of dimethylamine (265 μL, 0.5304 mmol) and heated at 45° C. in a sealed tube for 2 weeks. The reaction was then evaporated and the resulting oil triturated with water (3×2 mL) then dissolved in EtOAc (2 mL), dried over MgSO4, filtered, and evaporated. The crude oil product was then dissolved in diethyl ether (2 mL) and treated with a 4 N solution of hydrogen chloride in 1,4-dioxane to precipitate product as a colorless solid. The solid was filtered with the aid of diethyl ether and air dried to afford product as a colorless solid (30 mg, 52%). 1H NMR (CDCl3) 1.12-1.29 (m, 1 H), 1.44-1.58 (m, 1 H), 1.67-1.79 (m, 2 H), 1.80-1.90 (m, 1 H), 2.05-2.15 (m, 8 H), 2.29 (d, J=1.3, 3 H), 2.70 (br s, 1 H), 3.00 (br s, 1 H), 4.10-4.40 (br m, 2 H), 7.28 (d, J=3.5, 1 H), 7.38 (d, J=3.5, 1 H). 13C NMR 7.9, 25.2, 29.7, 34.9, 46.1, 63.3, 114.7, 118.8 (q, J=271), 128.0, 129.1, 131.0, 140.8, 155.1 (q, J=40), 158.0, 162.8. 19F NMR −63.1. LC/MS 4.52 min, [M+1]+ 402.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:9]2[CH:10]=[C:11]([S:13]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])=[O:14])[S:12][C:8]=2[S:7](=[O:22])(=[O:21])[NH:6][CH2:5]1.Br[CH2:24][CH:25]=[CH:26][CH2:27]Br.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C>[OH:3][CH:4]1[C:9]2[CH:10]=[C:11]([S:13]([NH:16][C:17]([CH3:18])([CH3:19])[CH3:20])(=[O:14])=[O:15])[S:12][C:8]=2[S:7](=[O:22])(=[O:21])[N:6]([CH2:24][CH:25]=[CH:26][CH2:27][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH2:5]1
Reactant: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NCC2O
Reactant: C1COCCN1
Reactant: BrCC=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1cc2c(s1)S(=O)(=O)N(CC=CCN1CCOCC1)CC2O
Reaction time: 0.33 h
Yield: 58 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.113 g, 2.82 mmol) was added to a solution of the product from Example 1, Step F (0.80 g, 2.35 mmol) in anhydrous DMF (50 mL) under nitrogen. After 20 min, the reaction mixture was cooled (ice bath), 1,4-dibromo-2-butene (0.754 g, 3.53 mmol) was added and the mixture stirred for 2 h. Morpholine (5 mL) was added and the reaction mixture was stirred at ambient temperature for 18 h. DMF was evaporated under reduced pressure and the residue was mixed with a saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4), filtered and evaporated to dryness. Chromatography on silica (ethyl acetate) gave the desired product as a viscous oil (0.65 g, 58%).