Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:12][CH2:11]2)[C:5]([C:37]#[N:38])=[C:4]([S:39][CH2:40][C:41]2[N:42]=[C:43]([C:46]3[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=3)[S:44][CH:45]=2)[N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C@H:10]2[CH2:15][CH2:14][C@@H:13]([O:16][CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]2)[C:5]([C:37]#[N:38])=[C:4]([S:39][CH2:40][C:41]2[N:42]=[C:43]([C:46]3[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][CH:51]=3)[S:44][CH:45]=2)[N:3]=1
Reactant: CC(C)(C)[Si](OCCOC1CCC(c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1[C@H]1CC[C@@H](OCCO)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
43 mg (0.06 mmol) of the compound from Example 7A (cis isomer) are dissolved in 5 ml of dry THF, 22 mg (0.08 mmol) of tetra-n-butylammonium fluoride are added and the mixture is stirred at RT for 20 h. 15 ml of ethyl acetate are then added to the mixture. The mixture is washed twice with in each case 3 ml of saturated aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate. After removal of the solvent on a rotary evaporator the crude product is purified chromatographically initially by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5) and then once more on silica gel 60 (mobile phase: gradient dichloromethane/ethanol 200:1→10:1).
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[CH3:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].Cl>C(O)C.O.CCCCCC>[O:5]=[C:3]([CH2:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:2]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCCCC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CCCCCC
Solvent: O
Product: CCCCC(=O)CC(=O)C(=O)OCC
Reaction time: 45 h
Yield: 69.7 %

Procedure:
To a solution of sodium (9.3 g) in ethanol (200 ml) was added dropwise a mixture of diethyl oxalate (60 g) and 2-hexanone (40.9 g) with stirring. The reaction mixture was allowed to stand at room temperature for 45 hours. To a mixture of 1N-hydrochloric acid (500 ml) and hexane (500 ml) was added dropwise the reaction mixture with stirring vigorously. After the addition, water (500 ml) was added. The organic layer was washed with water (100 ml ×3), dried, and the solvent was removed by evaporation in vacuo. The residue was distilled under reduced pressure and the distillate at the boiling point of 110° to 111° C. (6 mmHg) was collected to give the desired product (57 g, 70%).
Reaction SMILES: [CH:1]([NH:3][NH2:4])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[C:21](=[NH:25])OCC)(=[O:14])=[O:13])=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O1CCOCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]2[C:21]2[N:25]=[CH:1][NH:3][N:4]=2)(=[O:13])=[O:14])=[CH:10][CH:11]=1
Reactant: CCOC(=N)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: NNC=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC[C@H]1c1nc[nH]n1
Yield: 32.6 %

Procedure:
Formylhydrazine (120 mg) was added to a solution of ethyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboximidate (295 mg) [see Preparation 41] in toluene (5 ml) and 1,4-dioxane (5 ml). The reaction mixture was stirred at reflux for 26 hours after which time the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 changing to 0:100 (in 10% increments), by volume, hexane:ethyl acetate to afford (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(1H-1,2,4-triazol-3-yl)piperidine (95 mg) as an off-white foam.
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:9][CH2:10]2)=[CH:6][C:5]=1[CH:19]=[O:20].O>C(O)C>[OH:20][CH2:19][C:5]1[CH:6]=[C:7]2[C:11]([CH2:10][CH2:9][CH:8]2[CH2:13][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)=[CH:12][C:4]=1[OH:3]
Reactant: O=Cc1cc2c(cc1O)CCC2Cc1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1cc2c(cc1O)CCC2Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (10 mg) is added into a solution of 6-hydroxy-3-(1H-imidazol-4-ylmethyl)-indan-5-carbaldehyde (58 mg) in ethanol (10 ml). The mixture is stirred at room temperature for one hour and then poured into water. Work-up of the mixture gives the crude product which is purified by flash chromatography and recrystallized from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>CCO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:36][C:34](=[O:35])[NH:33][CH:24]([C:23]2[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]([OH:29])=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccc(F)cc1F
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(F)cc3F)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 7.1 %

Procedure:
A mixture of 1-(2,4-difluorophenyl)-2-phenylethanone (Intermediate 21) (250 mg, 1.1 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (189 mg, 0.90 mmol), urea (162 mg, 2.69 mmol), and concentrated HCl solution (0.075 mL, 0.90 mmol) in EtOH (10 mL) was refluxed overnight. The mixture was evaporated in vacuo, and the residue was purified by preparative HPLC to give Compound 49 (30.03 mg, yield 7%). 1H NMR (DMSO-d6 400 MHz): δ 10.32 (s, 1H), 8.91 (s, 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.43-7.37 (m, 1H), 7.29 (s, 1H), 7.11-6.89 (m, 5H), 6.88 (d, J=7.2 Hz, 2H), 5.27 (s, 1H), 4.08 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.2 Hz, 3H); MS (ESI): m/z 468.1 [M+1]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[O:8])[CH2:3][CH2:2]1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].O>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:10]1[N:11]=[C:12]([NH:14][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[O:22][C:21]([F:20])([F:32])[F:33])[S:13][C:9]=1[C:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8]
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccccc1OC(F)(F)F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Compound 454 (125 mg, 0.450 mmol) and DMAP (0.022 mmol) were suspended in pyridine (2 mL), and 2-(trifluoromethoxy)benzoyl chloride (202 mg, 0.900 mmol) was added thereto, followed by stirring at 80° C. for 6 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from ethanol to afford the entitled Compound 475 (111 mg, 53 as a pale yellow solid.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].BrC[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C)C=O>[CH:23]1([CH2:22][O:12][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:4]=2[O:3][CH:2]([F:13])[F:1])[CH:8]=[O:9])[CH2:25][CH2:24]1
Reactant: BrCCC1CC1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
To a mixture of 4-difluoromethoxy-3-hydroxy-benzaldehyde (5.0 g, 27 mmol) and potassium carbonate (5.5 g, 40 mmol) in dimethylformamide (30 ml) under inert atmosphere at 60° C. was added bromoethylcyclopropane (5 g, 37 mmol). The mixture was stirred and heated at 65° C. After 1.5 hour, the mixture was allowed to cool and was filtered. The filtrate was concentrated under reduced pressure. The mixture was extracted with ethyl acetate (2×25 ml) and water (25 ml). The organic layer was washed with water (25 ml), brine (25 ml) and dried over magnesium sulfate. The solvent was removed in vacuo to give 3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde as an oil (6.4 g, 100%). 1HNMR (CDCl3): δ 0.38–0.44 (m, 2H), 0.62–0.75 (m, 2H), 1.15–1.36 (m, 1H), 3.98 (d, J=4.5 Hz, 2H), 6.78 (t, JH-F=75 Hz, 1H), 7.30–7.50 (m, 3H), 9.96 (s, 1H).
Reaction SMILES: CO.[OH-].[Na+].[O:5]([C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[C:14]([NH:25][C:26](=[O:38])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N:33]3[CH:37]=[CH:36][CH:35]=[CH:34]3)[CH:28]=2)[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>C(OCC)(=O)C.O1CCOCC1>[O:5]([C:12]1[CH:24]=[CH:23][C:15]([C:16]([OH:18])=[O:17])=[C:14]([NH:25][C:26](=[O:38])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([N:33]3[CH:37]=[CH:36][CH:35]=[CH:34]3)[CH:28]=2)[CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cccc(-n2cccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1cc(Oc2ccccc2)ccc1C(=O)O)c1cccc(-n2cccc2)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
1.0 mL of methanol and 0.5 mL of 2.0 mol/L aqueous sodium hydroxide were added to 1.0 mL of dioxane solution containing 20 mg of tert-butyl 4-phenoxy-2-(3-(1H-pyrrol-1-yl)benzamido)benzoate at room temperature and stirred at 50° C. for 30 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. Diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 7.6 mg of 4-phenoxy-2-(3-(1H-pyrrol-1-yl)benzamido)benzoic acid as white solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14]O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>>[CH:1]1[C:13]2[CH:12]([CH2:14][Cl:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCC1c2ccccc2-c2ccccc21
Reactant: O=S(Cl)Cl
Product: ClCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 70 %

Procedure:
The precursor for Fm—S—Ph—CO2H, 9-fluorenylmethyl chloide (Fm—Cl) was synthesized as follows. A solution of 25.0 g of 9-fluorenmethanol (127 mmol, ALDRICH® Chemical Company was refluxed with 150 ml of thionyl chloride. for 30 minutes. The excess thionyl chloride was a removed by distillation and the residue distilled at reduced pressure, then crystallized from ethanol two times to afford 19.2 g of 9-fluorenylmethyl chloride (89.4 mmol, 70%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32]CC)=[O:31])=[CH:4][CH:3]=1.ClCC1C=CC2C(=CC=C([F:51])C=2)N=1>>[Br:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[C:23]([F:51])[CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:4][CH:3]=1
Reactant: Fc1ccc2nc(CCl)ccc2c1
Reactant: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Br)cc1
Product: CC(C)(Cc1nc2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(Br)cc1)C(=O)O

Procedure:
The title compound was prepared with similar methods to those for ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate using 2-(chloromethyl)-6-fluoroquinoline and similar methods described in Example 26. MS (ESI): mass calcd. for C29H25BrFN3O3, 561.11; m/z found, 562.0 [M+H]+. (500 MHz, CD3OD) δ 8.35 (d, J=8.6, 1H), 8.13-8.04 (m, 1H), 7.74 (d, J=8.6, 1H), 7.67-7.57 (m, 2H), 7.55-7.43 (m, 3H), 7.35 (d, J=2.2, 1H), 7.26 (dd, J=9.1, 2.4, 1H), 7.12 (d, J=8.5, 2H), 5.73 (s, 2H), 5.45 (s, 2H), 3.42 (s, 2H), 1.38 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([O:21][Si](C(C)(C)C)(C)C)[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH2:11][C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([OH:21])[CH:15]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CNC(=O)OCc3ccccc3)[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NCc1cc2ccc(O)cc2[nH]1)OCc1ccccc1
Temperature: -78 °C

Procedure:
[6-(tert-Butyl-dimethyl-silanyloxy)-1H-indol-2-ylmethyl]-carbamic acid benzyl ester (0.80 g, 1.95 mmol) is dissolved in THF (2 ml). Cooled to −78° C. 1 M TBAF solution in THF (3.90 ml) is added. The reaction mixture is concentrated and the residue is purified by column chromatography (30% ethyl acetate in hexanes) to obtain (6-Hydroxy-1H-indol-2-ylmethyl)-carbamic acid benzyl ester.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:14]=1>>[CH3:29][C:27]1[NH:26][N:25]=[C:24]([NH:23][C:15]2[N:14]=[C:13]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[C:22]3[C:17]([CH:16]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:28]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Oc1cccc(C(F)(F)F)c1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3cccc(C(F)(F)F)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 3-trifluoromethyl-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-[1-(3-trifluoromethyl-phenoxy)-isoquinolin-3-yl]-amine. LC-MS m/e 385(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([Cl:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.Cl[C:25]1C=C(Cl)C=CC=1CNC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH2:13][CH3:25])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([Cl:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: CNCc1ccc(Cl)cc1Cl
Product: CCN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1

Procedure:
Using procedures outlined in Example 1 to prepare intermediate 1.6, substituting N-(2,4-dichlorobenzyl)ethanamine for 1-(2,4-dichlorophenyl)-N-methylmethanamine, the title compound was prepared as a hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([O:34][C:35](=[O:46])[NH:36][C:37]1([CH2:43][CH2:44]O)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:46])[NH:36][C:37]1([CH2:43][CH2:44][N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)[S:21][C:20]2=[O:22])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC1(CCO)CCOCC1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)NC1(CCN2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CCOCC1

Procedure:
[4-(2-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}ethyl)tetrahydro-2H-pyran-4-yl]carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione (from Example 1) and ([4-(2-hydroxyethyl)-tetrahydro-2H-pyran-4-yl]-carbamic acid tert-butyl ester following General Procedure J.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)[CH:2]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1cnc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cnc(-c2cccnc2)cn1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
Pyridin-3-ylboronic acid (307 mg, 2.50 mmol), 5-bromopyrazin-2-amine (391 mg, 2.25 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (88 mg, 0.13 mmol) were added to degassed dioxane (12 mL) and the mixture was stirred for 30 min. Then sodium carbonate (795 mg, 7.50 mmol) and degassed water (8 mL) were added and the reaction was heated in a closed reaction vial at 100° C. for 8 h. The reaction was allowed to stand at ambient temperature over the weekend. It was diluted into ethyl acetate (100 mL) and extracted with brine (3×25 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (0 to 5% methanol/ethyl acetate) to afford 5-(pyridin-3-yl)pyrazin-2-amine (235 mg, 1.37 mmol, 54.6% yield). 1H NMR (400 MHz, Acetone) δ ppm 9.13 (1H, d, J=1.51 Hz), 8.54 (1H, d, J=1.26 Hz), 8.50 (1H, dd, J=4.78, 1.51 Hz), 8.22-8.28 (1H, m), 8.07 (1H, d, J=1.26 Hz), 7.39 (1H, ddd, J=7.87, 4.72, 0.76 Hz), 6.05 (2H, br. s.). MS (LC/MS) R.T.=0.58; [M+H]+=173.20.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:12]=2)[N:7]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][C:6]1[N:15]([CH3:24])[C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:12]=2)[N:7]=1
Reactant: COC(=O)c1ccc2c(=O)[nH]c(Cc3cccc(Cl)c3)nc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1ccc2c(=O)n(C)c(Cc3cccc(Cl)c3)nc2c1
Yield: 80.6 %

Procedure:
A mixture of 160 mg of methyl 2-(3-chlorobenzyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate which was synthesized in Production Example 1, 65 mg of potassium carbonate, 20 mL of acetonitrile and 67 mg of methyl iodide was heated for 2 hours under reflux. Further 20 mg of methyl iodide was added, followed by another hour's heating under reflux. The reaction mixture was allowed to cool off, and then concentrated under reduced pressure, 10 mL of water was added thereto, and extracted with 60 mL of ethyl acetate. The organic layer was washed with 10 mL of saturated saline solution, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified on silica gel chromatography (hexane:ethyl acetate=2:1) to provide 130 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[S:11][CH2:12]C(O)=O.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(OC(=O)C)(=[O:23])C>>[C:16]([N:8]1[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[S:11][C:12]1=[O:23])(=[O:18])[CH3:17]
Reactant: O=C(O)CSc1c(Cl)cccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)n1c(=O)sc2c(Cl)cccc21
Temperature: 100 °C

Procedure:
A mixture of 79.0 gm (0.32 mol) of [(2-chloro-6-nitro-phenyl)-thio]acetic acid, 150.0 gm (1.83 mol) of anhydrous sodium acetate and 600 ml of acetic acid anhydride was heated for 30 minutes at 100° C. The acetic acid anhydride was distilled off in an aspirator vacuum, the residue was stirred with 1 liter of water, and the precipitate was collected by suction filtration. After purification by chromatography on silica gel, using dichloromethane/ethyl acetate (volume ratio 1:1) for elution, the product was recrystallized from ethanol. 19.2 gm (26% of theory) of colorless crystals with a melting point of 74° C. were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O-:7])=[O:6].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[CH2:20](N(CC)CC)C>C(Cl)Cl>[CH3:16][C:15]([Si:12]([CH3:14])([CH3:13])[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:20])=[O:6])([CH3:18])[CH3:17]
Reactant: Cc1ccc(C(=O)[O-])cc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-hydroxy-4-methylbenzoate (5.55 g, 33 mmol) from Preparation 12, tert-butyldimethylsilyl chloride (7.6 g, 50 mmol), and triethylamine (14 mL, 100 mmol) in 50 mL CH2Cl2 is stirred at room temperature for 24 hours. An additional 25 mL of CH2Cl2 is added and washed with water. The organic layer is dried (MgSO4) and concentrated. The product is isolated by silica gel chromatography (100% CH2Cl2). An oil of methyl 3- [[(1,1-dimethylethyl)-dimethylsilyl]oxy]-4-methylbenzoate is obtained (9.05 g, 97%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[C:21]([N+:27]([O-])=O)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O.[Pt]>[NH2:27][C:21]1[CH:20]=[C:19]([C:17]2[S:18][C:14]3[C:13]([C:33]4[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=4)=[C:12]([C@H:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:31]([CH3:32])=[CH:30][C:15]=3[N:16]=2)[CH:24]=[CH:23][C:22]=1[NH:25][CH3:26]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc(NC)c([N+](=O)[O-])c3)sc2c1-c1ccc(Cl)cc1
Agent: [Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc(NC)c(N)c3)sc2c1-c1ccc(Cl)cc1

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-(methylamino)-3-nitrophenyl)benzo[d]thiazol-6-yl)acetate (510 mg) in EtOH (4 mL) and EtOAc (2 mL) was added 5% Pt/C (150 mg). The reaction mixture was flushed with hydrogen gas and stirred under hydrogen atmosphere (using a balloon) for 1.5 h. The mixture was filtered through celite and concentrated in vacuo and (S)-ethyl 2-(2-(3-amino-4-(methylamino)phenyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate was used without further purification. LCMS-ESI+: calc'd for C29H33ClN3O3S: 538.2 (M+H+); Found: 538.2 (M+H+).