Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][C:8]2[O:11][CH2:12][CH2:13][CH2:14][N:6]3[C:7]=2[C:2]=1[C@H:3]1[CH2:17][NH:16][CH2:15][C@H:4]1[CH2:5]3.[ClH:18].Cl.[CH:20]1C=CC2OCCCN3C=2C=1[C@H]1CNC[C@H]1C3.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCCl.C(O)C.CCOCC.C(O)(=O)C>[ClH:18].[ClH:18].[CH3:20][N:16]1[CH2:17][C@H:3]2[C@H:4]([CH2:5][N:6]3[CH2:14][CH2:13][CH2:12][O:11][C:8]4[CH:9]=[CH:10][CH:1]=[C:2]2[C:7]3=4)[CH2:15]1
Reactant: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CCCO2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCO
Product: CN1C[C@H]2CN3CCCOc4cccc(c43)[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-cis-6,7,9,9a,10,11,12,12a-octahydro-5H-[1,4]oxazepino[2,3,4-ij]pyrrolo[3,4-c]quinoline trifluroracetic acid salt from EXAMPLE 121 (100 mg, 0.29 mmol) in 10 mL of 1,2-dichloroethane was added 37% aqueous formaldehyde (0.05 mL, 0.58 mmol) and sodium triacetoxyborohydride (0.19 g, 0.87 mmol) and a couple drops of acetic acid. The resulting mixture was stirred at ambient temperature for 1 h and then the reaction was quenched with water. The mixture was partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. A portion of the residue (40 mg, 0.16 mmol) was dissolved in 1 mL ethanol and 5 mL of ether and then there was added 2M HCl in ether (0.25 mL, 0.5 mmol). A solid precipitated out of solution. The solvents were decanted and the solid was triturated twice with ether and dried in vacuo to afford the title compound of EXAMPLE 122 as an off white powder. 1H NMR (dmso-D6) δ: 11.20 (broad s, 1H), 6.85-6.77 (m, 1H), 6.75-6.70 (m, 2H), 4.27 (dt, 1H), 4.00-3.80 (m, 1H), 3.77-3.60 (m, 2H), 3.50-3.25 (m, 3H), 3.20-3.05 (m, 2H), 2.97-2.90 (m, 1H), 2.88-2.62 (m, 5H), 2.07-1.95 (m, 1H), 1.92-1.80 (m, 1H). LRMS (ES)+: 245.0 (M+H)+.
Reaction SMILES: Br.Br.[CH3:3][NH:4][CH:5]1[CH2:14][CH2:13][C:8]2[N:9]=[C:10](N)[S:11][C:7]=2[CH2:6]1.C(NC1CCC2N=CSC=2C1)CC>>[CH3:3][NH:4][CH:5]1[CH2:14][CH2:13][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1
Reactant: CNC1CCc2nc(N)sc2C1
Agent: Br
Agent: CCCNC1CCc2ncsc2C1
Product: CNC1CCc2ncsc2C1
Yield: 40 %

Procedure:
Methyl-(4,5,6,7-tetrahydro-benzothiazol-6-yl)-amine (3C) is prepared from 3B as described for 1C.
Reaction SMILES: C(OC(=O)[N:5]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)[CH2:6][CH2:7][CH3:8])C.[OH-].[Na+]>C(O)CO.O>[N:9]1([NH:5][CH2:6][CH2:7][CH3:8])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: CCCN(C(=O)OCC)n1ccc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCCNn1ccc2ccccc21
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a suspension of NaHCO3 (50 g) in 100 ml dichloromethane (DCM) was added a solution of 1H-indol-1-amine (36 g) in 200 ml DCM. After cooling to 0° C. with an ice bath, a solution of ethyl chloroformate (29 ml) in 50 ml DCM was added over a period of thirty minutes. After stirring at ambient temperature for three hours, the mixture was filtered, and the filtrate washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to an oil which was eluted on a silica gel column with DCM, via HPLC to give N-(1H-indol-1-yl) carbamic acid ethyl ester, 33.6 g (61%) as an oil. To a cold solution of N-(1H-indol-1-yl) carbamic acid ethyl ester (15 g) in 100 ml tetrahydrofuran, was added potassium t-butoxide (9 g) and the mixture stirred at 5° C. for one hour. To this was added 1-bromopropane (7.3 ml) and the mixture stirred at ambient temperature for five hours. The mixture was poured into 300 ml iced-water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated, NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester as an oil, 16.5 g (91%). To a solution of N-(1H-indol-1-yl)-N-propylcarbamic acid ethyl ester (16.5 g) in 35 ml ethylene glycol, was added a solution of NaOH (10 g) in 30 ml water. After stirring at 120° C. for four hours, the mixture was poured into 300 ml ice water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent was evaporated to give N-(1H-indol-1-yl)-N-propylamine, 9.0 g (78%) as an oil.
Reaction SMILES: [OH-:1].[K+].O.[CH2:4]([C:6]([C:25]1[CH:38]=[CH:37][C:28]([O:29][CH2:30][C@@H:31]2[O:35][C:34](=[O:36])[CH2:33][CH2:32]2)=[C:27]([CH3:39])[CH:26]=1)([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=2)=[C:11]([CH3:24])[CH:10]=1)[CH2:7][CH3:8])[CH3:5]>CO>[CH2:4]([C:6]([C:25]1[CH:38]=[CH:37][C:28]([O:29][CH2:30][C@H:31]([OH:35])[CH2:32][CH2:33][C:34]([OH:36])=[O:1])=[C:27]([CH3:39])[CH:26]=1)([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:18][CH:19]=2)=[C:11]([CH3:24])[CH:10]=1)[CH2:7][CH3:8])[CH3:5]
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2ccc(C(C)(C)O)o2)c(C)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC(CC)(c1ccc(OC[C@H](O)CCC(=O)O)c(C)c1)c1ccc(-c2ccc(C(C)(C)O)o2)c(C)c1
Reaction time: 1 h
Yield: 29.5 %

Procedure:
A 1 N potassium hydroxide aqueous solution (0.1 mL, 0.1 mmol) and water (0.1 mL) were added to a solution of 5(R)-[4-(1-ethyl-1-{4-[5-(1-hydroxy-1-methyl-ethyl)-furan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenoxymethyl]-dihydro-furan-2-one (Example 19-(3); 2.8 mg, 0.006 mmol) in methanol (1 mL) at room temperature, and the mixture was stirred at the same temperature for one hour. The reaction solution was directly purified by silica gel chromatography (dichloromethane/methanol=8/3, saturated with water) to give the title compound (0.9 mg, 31%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C@H:10]([C@H:28]([OH:33])[CH2:29][CH2:30][CH2:31][CH3:32])[C:11]([NH:13][C@H:14]([C:25]([OH:27])=[O:26])[CH2:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:12])=[CH:4][C:3]=2[O:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:40](I)[CH3:41]>CN(C)C=O.C(OCC)(=O)C>[CH2:40]([O:26][C:25](=[O:27])[C@H:14]([CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)[NH:13][C:11](=[O:12])[C@H:10]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[C@H:28]([OH:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH3:41]
Reactant: CCCC[C@@H](O)[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)c1ccc2c(c1)OCO2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC[C@@H](O)[C@H](C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
To a solution of Nα-[(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-tryptophan (300 mg) in N,N-dimethylformamide (10 ml) were added potassium carbonate (69 mg) and ethyl iodide (155 mg) and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with ethyl acetate (20 ml) and the solution was washed with 0.5N hydrochloric acid (20 ml×2), saturated sodium bicarbonate aqueous solution (20 ml×2) and brine (20 ml) successively and the organic layer was dried over magnesium sulfate. The solution was concentrated in vacuo and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give N [(2R,3R)-2-(3,4-methylenedioxyphenyl)-3-hydroxyheptanoyl]-L-tryptophan ethyl ester as an amorphous powder (260 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH2:28][CH2:29][NH:30][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Nc2ccccc2)cc1
Yield: 27.4 %

Procedure:
A solution of 4-(phenylamino)benzoic acid (0.048 g, 0.225 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.052 g; 0.225 mmol), HATU (0.094 g; 0.247 mmol) and N,N-diisopropylethylamine (0.097 mL; 0.563 mmol) in DMF (5 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.024 g (27%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]([NH:33]C(=O)OC(C)(C)C)[C:5](=[O:32])[NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][C:11]2[C:14]3[C:19]([NH:20][C:21]4[CH:30]=[CH:29][C:24]5[NH:25][C:26](=[O:28])[S:27][C:23]=5[CH:22]=4)=[N:18][CH:17]=[N:16][C:15]=3[S:31][C:10]=2[CH2:9]1.O1CCOCC1.Cl>C(N(CC)CC)C>[O:28]=[C:26]1[NH:25][C:24]2[CH:29]=[CH:30][C:21]([NH:20][C:19]3[C:14]4[C:11]5[CH2:12][CH2:13][CH:8]([CH2:7][NH:6][C:5](=[O:32])[C@H:4]([CH2:3][CH2:2][OH:1])[NH2:33])[CH2:9][C:10]=5[S:31][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:22][C:23]=2[S:27]1
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)C(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N[C@@H](CCO)C(=O)NCC1CCc2c(sc3ncnc(Nc4ccc5[nH]c(=O)sc5c4)c23)C1
Yield: 23.2 %

Procedure:
A mixture comprising 32.5 mg (56 μmol) tert-butyl {(2R)-4-hydroxy-1-oxo-1-[({(7RS)-4-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methyl)amino]butan-2-yl}carbamate (prepared according to example 27), 1.0 mL 1,4-dioxane and 42.7 μL hydrochloric acid (4M in 1,4-dioxane) was stirred at 23° C. overnight. 1 mL N,N-diethylethanamine was added, the solvents removed and the residue purified by chromatography to give 6.3 mg (22%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:24])[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[C:16](=[O:22])[CH2:15][C:14]1=[O:23].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH:15]2[C:14](=[O:23])[C:13]([CH3:24])([CH3:12])[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[C:16]2=[O:22])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(=O)C(C(=O)Cc2ccc(Cl)cc2)C(=O)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chlorophenylacetic acid (1.7 g, 10 mmol) and oxalyl chloride (2 ml, 23 mmol) were stirred in 100 ml methylene chloride with two drops of dimethylformamide for two hours. The solvent and excess oxalyl chloride were removed under vacuum to give p-chlorophenylacetyl chloride. The 4-chlorophenylacetyl chloride and 4,4,6,6-tetramethyl-1,3,5-cyclohexanetrione (1.5 g, 8.2 mmol) were dissolved in methylene chloride. Triethylamine (3 ml) was added and the resulting solution stirred at room temperature for 30 minutes. The solution was washed with 1 normal hydrochloric acid (1N HCl), 5% potassium carbonate (5% K2CO3) and saturated sodium chloride (brine), dried over anhydrous magnesium sulfate (MgSO4) and concentrated under vacuum. The residue was dissolved in 15 ml acetonitrile. Triethylamine (3 ml) and acetone cyanohydrin (0.3 g) were added and the mixture stirred at room temperature for 4 hours. After dilution with ether, the solution was washed with 1N HCl and extracted with 5% K2CO3. The basic extract was acidified with hydrochloric acid and extracted with ether. The ether extract was washed with brine, dried (MgSO4) and concentrated under vacuum yielding 1.0 g of an oil that solidified on standing (m.p. 57°-61° C.). It was identified as such by nuclear magnetic resonance spectroscopy, infrared spectroscopy and mass spectroscopy.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Br:50][C:51]1[N:59]=[CH:58][CH:57]=[C:56]([CH3:60])[C:52]=1[C:53](O)=[O:54].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:50][C:51]1[N:59]=[CH:58][CH:57]=[C:56]([CH3:60])[C:52]=1[C:53]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:10][CH2:11]1)[CH3:5])=[O:54]
Reactant: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Reactant: Cc1ccnc(Br)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)ccnc3Br)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.3 %

Procedure:
(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine (0.070 g, 0.18 mmol), EDCI (0.039 g, 0.20 mmol) and HOBT (0.027 g, 0.20 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 2-bromo-4-methyl-nicotinic acid (0.043 g, 0.20 mmol) followed by DIPEA (38 μL, 0.22 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (Et2O:MeOH:NH4OH, 89:10:1, v/v/v) afforded 2-bromo-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide (0.040 g, 38%) as a white foam. 1H NMR (CDCl3) δ 0.98 (d+m, 4H,), 1.07 (m, 1H), 1.57 (m, 2H), 1.84 (m, 3H), 2.13 (br t, 1H), 2.36 (s, 6H), 2.53 (br t, 1H), 2.75-2.88 (m, 3H), 3.24-3.33 (m, 2H), 3.71 (s, 3H), 3.82 (m, 1H), 3.88 (m, 2H), 6.61 (d, 2H, J=9.0 Hz), 6.69 (d, 2H, J=9.0 Hz), 6.97 (d, 1H, J=6.0 Hz), 7.03 (d, 1H, J=6.0 Hz), 7.94 (d, 1H, J=6.0 Hz), 8.25 (s, 1H), 8.30 (d, 1H, J=6.0 Hz), 8.52 (br s, 1H). 13C NMR (CDCl3) δ. ES-MS m/z 582 (M+H), 604 (M+Na). Anal. Calcd. for C30H38N5O2Br.0.25 CH2Cl2: C, 60.37; H, 6.45; N, 11.64. Found: C, 60.34; H, 6.47; N, 11.52.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]([CH:18]=[CH2:19])[C:5]([N:7]1[C@H:11]([CH:12]([CH3:14])[CH3:13])[C:10]([CH3:16])([CH3:15])[O:9][C:8]1=[O:17])=[O:6])[CH3:3].N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C)C=O>[C:28]([Si:25]([CH3:27])([CH3:26])[O:1][C@@H:2]([C@@H:4]([CH:18]=[CH2:19])[C:5]([N:7]1[C@H:11]([CH:12]([CH3:13])[CH3:14])[C:10]([CH3:16])([CH3:15])[O:9][C:8]1=[O:17])=[O:6])[CH3:3])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=C[C@@H](C(=O)N1C(=O)OC(C)(C)[C@H]1C(C)C)[C@@H](C)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=C[C@@H](C(=O)N1C(=O)OC(C)(C)[C@H]1C(C)C)[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
A cooled (0° C.) solution of (R)-3-[(R)-2-((R)-1-hydroxy-ethyl)-but-3-enoyl]-4-isopropyl-5,5-dimethyl-oxazolidin-2-one (654 mg, 2.43 mmol, prepared as described in Tetrahedron 2009, 65, 7837-7851) and imidazole (727 mg, 10.68 mmol) in N,N-dimethylformamide (5 mL) was treated with tert-butyldimethylsilyl chloride (474 mg, 3.16 mmol). After stirring for 5 h at room temperature, the reaction was quenched with saturated ammonium chloride. The aqueous layer was extracted with diethyl ether (2×20 mL). The organics were combined and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Biotage cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (800 mg, 86%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 3H), 0.09 (s, 3H), 0.84 (s, 9H), 0.92 (d, J=6.7 Hz, 3H), 1.01 (d, J=7.1 Hz, 3H), 1.16 (d, J=6.2 Hz, 3H), 1.40 (s, 3H), 1.50 (s, 3H), 2.05-2.20 (m, 1H), 4.17 (d, J=3.3 Hz, 1H), 4.25-4.40 (m, 1H), 4.67 (t, J=9.1 Hz, 1H), 5.25 (dd, J=10.3, 1.6 Hz, 1H), 5.46 (dd, J=17.2, 1.3 Hz, 1H), 5.65-5.79 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7]O)[CH2:4][O:3]1.CCN(CC)CC.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:9][C:2]1([CH3:1])[O:6][CH:5]([CH2:7][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:4][O:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)CC2COC(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
To a solution of solketal (2.00 mL, 16.0 mmol) in CH2Cl2 (50 mL) was added Et3N (4.50 mL, 32 mmol). A solution of p-toluensulfonyl chloride (4.30 g, 22 mmol) in CH2Cl2 (30 mL) was then added dropwise at 0° C. The resulting solution was stirred at 25° C. for 6 h, then was diluted with CH2Cl2 (50 mL). This solution was washed with HCl (5w, 100 mL) and brine (100 mL), dried and concentrated in Vacuo to afford the crude product. This was purified by flash-chromatography on silica gel using EtOAc/n-hexane as eluant to give the title compound as a colorless oil (2.03 g, 45%): 1H NMR (CDCl3) δ1.31 (s, 3H), 1.34 (s, 3H), 2.45 (s, 3H), 3.77 (q, J=5.1 and 8.7 Hz, 1H), 3.90-4.10 (m, 3H), 4.28 (p, J=5.7 Hz, 1H), 7.35 (d, J=8.1 Hz, 2H), 7.80 (d, J=8.1 Hz, 2H);
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13](C2C=C([N+]([O-])=O)C=CC=2C([O-])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:28].[Na+]>CO>[OH:28][C@@H:13]1[CH2:14][CH2:15][C@H:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](c2cc([N+](=O)[O-])ccc2C(=O)[O-])CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](O)CC1
Reaction time: 20 h

Procedure:
cis-4-[(tert-Butoxycarbonyl)aminomethyl]cyclohexyl-4-nitrobenzoate (4.81 g, 12.7 mmol) was dissolved in methanol (345 mL) and sodium hydroxide (10.17 g, 254.2 mmol) was added. After 20 hours at room temperature, methanol was removed under vacuum. The residue was taken up in water and extracted with ethyl acetate. After drying the organic phase over sodium sulphate, and removing the drying agent and solvent residues under vacuum, the product was obtained at 88% yield (2.57 g), and was used without purification in the next reaction.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][NH2:11])=[O:4].C(N(CC)CC)C.C[O:20][C:21](=O)[N:22]=[C:23](SC)[C:24]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=1)=[N:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:47][O:46][C:40]1[CH:39]=[C:38]([CH:24]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([CH3:37])[O:34][N:33]=3)=[CH:28][CH:27]=2)[C:23]2[NH:22][C:21](=[O:20])[N:10]([C:9]3[CH:8]=[CH:7][S:6][C:5]=3[C:3]([OH:2])=[O:4])[N:11]=2)[CH:43]=[CH:42][C:41]=1[O:44][CH3:45]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OC)c(OC)c1
Reactant: COC(=O)c1sccc1NN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 85 °C
Reaction time: 18 h
Yield: 75.2 %

Procedure:
After adding 30 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 25 μl of triethylamine to a solution of 80 mg of {2-(3,4-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (36d)) in 3 ml of DMF, the mixture was stirred at 85° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 2 ml of methanol and 2 ml of THF. After adding 35 μl of acetic acid and 56 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 15 hours. Next, 2 ml of an aqueous 1N sodium hydroxide solution was added to the reaction mixture, and stirring was continued at room temperature for 2 hours. After adding 2 ml of 1N hydrochloric acid to the reaction mixture, extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 70 mg of 3-(3-{(3,4-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH:14]([C:21]2[N:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[N:23]=[C:24]3[C:29]=2[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:22]2[C:21]([CH:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:13][S:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=3)(=[O:12])=[O:11])=[C:29]3[C:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)=[N:23]2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)CC(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.9 %

Procedure:
To a stirred solution of [rac]-4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-ethanesulfonyl}-benzoic acid methyl ester (40 mg, 0.076 mmol) in MeOH (5 ml) was added NaOH (5.18 mg, 0.129 mmol) in water (2 ml) dropwise at 0° C. The reaction mixture was then stirred at 25° C. for 14 h. After the completion of the reaction (monitored through TLC), MeOH was concentrated in vacuo, diluted with H2O (5 ml) and the aqueous layer was acidified (pH ˜2-3) with 2 N HCl, and then extracted with EtOAc (3×5 ml). Combined organic layers were washed with brine (10 ml) and finally dried over Na2SO4. Organic layer was distilled under reduced pressure to get crude title compound (32 mg). Purification was done by column chromatography over silica gel (230-400 mesh; 2% MeOH/DCM) to give the title compound (18 mg, 47.1%) as an off white solid. MS: m/e=527.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:19]=[C:18]([NH2:28])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:7]=1.[O:29]=[C:30]1[NH:34][CH2:33][C@@H:32]([C:35](O)=[O:36])[CH2:31]1.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:19]=[C:18]([NH:28][C:35]([C@H:32]3[CH2:31][C:30](=[O:29])[NH:34][CH2:33]3)=[O:36])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: C[C@@H](OCc1cc(Cl)cc(-c2cc(N)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: C[C@@H](OCc1cc(Cl)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a solution of 5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-(4-fluorophenyl)-1H-pyrazol-3-ylamine (79 mg) in chloroform (0.4 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (26 mg) prepared according to the same procedures as Preparation 14 and WSC.HCl (47 mg) at room temperature, and the mixture was stirred for 2 hours. This reaction mixture was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration and was dried under reduced pressure to give the titled compound (43 mg).