Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:7][C:8]2[C:9]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.CC1C=CC(S(NN)(=O)=O)=CC=1.CC([O-])=O.[Na+]>C(COC)OC.O>[CH:1]1([O:7][C:8]2[C:9]([NH:14][C:15]3[S:16][CH:17]=[C:18]([CH3:20])[N:19]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1csc(Nc2ncccc2OC2C=CCCC2)n1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1csc(Nc2ncccc2OC2CCCCC2)n1
Yield: 55.3 %

Procedure:
3-(Cyclohex-2-enyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.115 g, 0.400 mmol) and 4-methylbenzenesulfonohydrazide (1.12 g, 6.00 mmol) were placed in dimethoxyethane (5 mL). NaOAc (0.492 g, 6.00 mmol) was dissolved in water (2 mL) and added to the above solution and refluxed. Additional 4-methylbenzenesulfonohydrazide (1.12 g, 6.00 mmol) was added and the reaction mixture was refluxed overnight. An aqueous work up was done and the crude material was purified by silica gel chromatography to provide 3-(cyclohexyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.064 g, 55.3%) after HCl salt formation. 1H NMR (d6-DMSO) δ 7.79 (d, 1H), 7.57 (d, 1H), 7.09 (m, 1H), 6.83 (s, 1H), 4.54 (m, 1H), 2.32 (s, 3H), 1.97 (m, 2H), 1.79, (m, 2H), 1.57 (m, 3H), 1.36 (m, 3H); Mass spectrum (apci) m/z=291.1 (M+H—HCl).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10]1)([OH:8])=[O:7].[CH3:19]O>>[CH3:19][O:7][C:6]([CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10]1)=[O:8]
Reactant: CO
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCc2ccccc2O1
Yield: 96 %

Procedure:
14.2 ml of sulphuric acid (100% strength) are added to a solution of 70.34 g (0.39 mol) of 2-carboxychroman in 1400 ml of methanol and the whole is boiled under reflux for 4 hours. After cooling, the reaction mixture is concentrated by evaporation in vacuo and the residue is dissolved in diethyl ether and washed with water, cold saturated sodium hydrogen carbonate solution and again with water. The ethereal phase is dried over sodium sulphate and concentrated by evaporation in vacuo. 72.8 g (96%) of 2-methoxycarbonylchroman are obtained in the form of a pale yellow oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1([C:14]2[CH:48]=[CH:47][CH:46]=[CH:45][C:15]=2[CH2:16][CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)=[CH:28][CH:27]=3)[N:19]=2)[CH2:13][CH2:12]1)(=[O:10])[NH2:9].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>C(Cl)Cl.O>[Cl:24][C:23]1[C:18]([CH2:17][CH2:16][C:15]2[CH:45]=[CH:46][CH:47]=[CH:48][C:14]=2[C:11]2([C:8]([NH2:9])=[O:10])[CH2:12][CH2:13]2)=[N:19][C:20]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
TFA (1.0 mL) was added to a solution of tert-butyl 4-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-chloropyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A15) (121 mg, 210 μmol) in DCM (5 mL) and the resulting mixture was stirred at room temperature for 16 hours. Saturated aqueous Na2CO3 was added until the solution was basic then EtOAc (50 mL) and water (50 mL) were added. The organic layer was separated, washed with brine (20 mL), dried over MgSO4 then the volatiles removed in vacuo. The resulting residue was adsorbed onto silica gel and the resulting material washed with MeOH (300 mL) then 1 M NH3 in MeOH/EtOH (1:1) (300 mL). The volatiles from the ammoniacal washing were removed in vacuo and the resultant gum sonicated in Et2O (20 mL) to give a precipitate that was collected by filtration. Air drying of the filter cake gave the product 7 as a white solid (55 mg, 55%); 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.52-7.46 (d, J=8.6 Hz, 2H), 7.46-7.41 (d, J=7.3 Hz, 1H), 7.37-7.32 (d, J=5.0 Hz, 2H), 7.31-7.25 (m, 2H, obscured), 7.23-7.18 (d, J=8.5 Hz, 2H), 7.15 (s, 1H), 5.33 (s, 2H), 3.34-3.12 (m, 6H), 2.84-2.71 (td, J=12.2, 2.3 Hz, 2H), 2.71-2.56 (tt, J=12.1, 3.7 Hz, 1H), 1.92-1.59 (m, 6H, obscured), 1.15 (s, 2H). LCMS-A: rt 4.527 min; m/z 477 [M+H]+.
Reaction SMILES: [BrH:1].[CH2:2]([O:4][C:5]([C:7]1[S:8][C:9](N)=[N:10][N:11]=1)=[O:6])[CH3:3].N([O-])=O.[Na+]>C(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>[CH2:2]([O:4][C:5]([C:7]1[S:8][C:9]([Br:1])=[N:10][N:11]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1nnc(N)s1
Reactant: Br
Agent: O=N[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1nnc(Br)s1
Temperature: 3 °C
Yield: 71 %

Procedure:
A 500 mL (three neck) round-bottom flask with a stir bar, needle inlet, and a gas outlet to a trap containing a 10% solution of Na2S2O3 was charged with CuBr (1.24 g, 8.67 mmol, 0.1 equiv.) and HBr (48% aqueous solution, 108 mL). The purple solution was cooled to 3° C. (internal, ice bath), to which was added portion-wise a solid mixture of 5-amino-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (15.0 g, 86.6 mmol) and sodium nitrite (27.0 g, 391.3 mmol, 4.5 equiv.) over the course of 30 min. The reaction mixture was allowed to warm to room temperature for 2 h 15 min. The reaction mixture was diluted with CH2Cl2 and 10% aqueous Na2S2O3 and the layers were separated. The aqueous layer was extracted 3 times with CH2Cl2. The combined organic layers were washed with Brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (ISCO XL, 330 g SiO2 column, 20-25% EtOAc/Hexanes) to provide an off-white solid that was triturated with 5% EtOAc/Hexanes. Filtration provided 5-bromo-[1,3,4]thiadiazole-2-carboxylic acid ethyl ester (14.5 g, 71%) as white needles. Concentration and trituration of the mother liquor provided an additional product (2.3 g, 11%).
Reaction SMILES: [CH3:1][C:2]1([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[C:20]1(=O)N(C2CCCNC2=O)C(=O)C2=CC=CC=C12>>[CH3:20][O:8][C:3]1[C:2]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])([CH3:1])[CH2:7][CH2:6][CH2:5][N:4]=1
Reactant: O=C1NCCCC1N1C(=O)c2ccccc2C1=O
Reactant: CC1(N2C(=O)c3ccccc3C2=O)CCCNC1=O
Product: COC1=NCCCC1(C)N1C(=O)c2ccccc2C1=O

Procedure:
By analogy with the method described in example 1 (step 1.1), using 2-(3-methyl-2-oxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione (prepared by analogy to the method described in Liebigs Annalen der Chemie (1987), (7), 647-8. Archiv der Pharmazie (Weinheim, Germany) (1989), 322(8), 499-505, (Heterocycles (1996), 42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5), 417-20)) in place of 3-phtalimidopiperidin-2-one, the compound was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[Br:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:17][CH2:16][Br:15])=[CH:11][CH:12]=1
Reactant: COC(=O)CCCc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccc(OCCBr)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 16.8 %

Procedure:
4-(4-hydroxyphenyl)butanoic acid methyl ester (2) (2.6 g) from the previous step was dissolved in N,N′-dimethylformamide (30 mL), 1,2-dibromoethane (12.6 g) and potassium carbonate (3.7 g) were added, and stirred at 80° C. for two days. The reaction solution was poured into water, and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated sodium chloride solution (50 mL). After drying on anhydrous sodium sulfate, filtration and vacuum concentration, the residue was purified by silica gel flash column chromatography (developing solvent: n-hexane:ethyl acetate=8:1) to give the above-identified compound (676 mg, yield 17%).
Reaction SMILES: [CH3:1][C:2]([O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([N+:30]([O-])=O)=[CH:22][CH:21]=1)([CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=1.[H][H]>CO.CC(O)=O.[Pt]>[NH2:30][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([O:19][C:2]([CH3:18])([CH3:1])[CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:5]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CC(C)(C)Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(CC(C)(C)Oc2ccc(N)c3ccccc23)ccn1
Yield: 98.6 %

Procedure:
tert-Butyl 4-(2-methyl-2-(4-nitronaphthalen-1-yloxy)propyl)pyridin-2-ylcarbamate (27) (100 mg, 0.229 mmol) in MeOH (30 mL) and AcOH (8.0 mL) was passed through a Thales H-cube (1.0 mL·min−1, 30° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode). The volatiles were removed under reduced pressure to give tert-butyl 4-(2-(4-aminonaphthalen-1-yloxy)-2-methylpropyl)pyridin-2-ylcarbamate (28) (92 mg, 99%) as a purple oil: m/z 408 (M+H)+ (ES+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10]([OH:12])=[O:11].[C:16](O)([CH3:19])([CH3:18])[CH3:17].N1C=CC=CC=1.Cl>C(Cl)Cl>[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10]([O:12][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11]
Reactant: CC(C)(C)O
Reactant: C=C(C(=O)O)C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C(=O)OC(C)(C)C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Oxalyl chloride (87.3 g, 0.68 mol) was added to a solution of TFMAA (15.0 g, 0.11 mol) in methylene chloride (90 mL) in a dropwise manner at room temperature under a nitrogen atmosphere. The solution was heated to reflux for 5 hours, and the solvent and excess reagent were removed on a rotary evaporator. The resulting acid chloride was added to a stirred solution consisting of t-butanol (44 g, 0.59 mmol) and pyridine (33.6 g, 0.42 mol) in dichloromethane at 0° C. over a 10 min period. After stirring overnight at room temperature, the solution was neutralized with diluted aqueous HCl and washed with saturated aqueous sodium bicarbonate. The organic phase was removed, and the aqueous phase was extracted with pentane. The combined organic solvents were reduced to a small volume by distillation and then the residue was chromatographed on a column of silica gel. The product was re-purified by distillation to give 14.0 g of TBTFMA as a colorless liquid (70%).
Reaction SMILES: [OH-].[Na+].[C:3]1([CH:9]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:31]=[CH:30][C:20]4[N:21]([CH3:29])[C:22]([NH:24]C(=O)OC)=[N:23][C:19]=4[CH:18]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O>[C:32]1([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:31]=[CH:30][C:20]4[N:21]([CH3:29])[C:22]([NH2:24])=[N:23][C:19]=4[CH:18]=3)[CH2:12][CH2:11]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)Nc1nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(N)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Reaction time: 8 h

Procedure:
To a stirred solution of 4 parts of sodium hydroxide in 50 parts of water are added 4.7 parts of methyl {5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazol-2-yl}carbamate. The whole is stirred and refluxed for 3.50 hours. The reaction mixture is cooled and allowed to stand overnight. It is acidified with a hydrochloric acid solution 10 N. The precipitated product is filtered off, washed with water and boiled in ethanol. After cooling, the product is filtered off, washed with ethanol and with 2,2'-oxybispropane and dried, yielding 2.5 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazol-2-amine; mp. 267.5° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>ClCCl>[CH3:9][C:6]1([CH3:10])[O:5][C@@H:4]([CH2:3][CH2:2][O:1][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:8][O:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OC[C@H](CCO)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OC[C@H](CCOS(C)(=O)=O)O1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 101 %

Procedure:
To a solution of (4S)-(+)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (Aldrich) (21.1 g, 0.14 mol) and triethylamine (40 mL, 0.28 mol) in dichloromethane (250 mL) at 0° C. was added methanesulfonyl chloride (13.4 mL, 0.17 mol) dropwise. The reaction mixture was stirred at 0° C. for 1.5 h, then water was added. The organic layer was separated, washed with water, brine, dried over MgSO4, concentrated to give methanesulfonic acid 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl ester as a yellow oil (31.7 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>ClCCl>[C:21]1([O:20][C:18](=[O:19])[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccncc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Amino pyridine (500 mg, 5.3 mmol) and N,N-diisopropylethylamine (685 mg, 5.3 mmol) are dissolved in dichloromethane (5 ml). Phenyl chloroformate (830 mg, 5.3 mmol) is added to the reaction mixture. The reaction mixture is stirred at room temperature for 72 hours. The reaction mixture is partitioned between dichloromethane and saturated NaHCO3 (aq). The aqueous is washed with dichloromethane (×2). The organics are combined, dried (MgSO4), filtered and reduced in vacuo to give the title compound.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH:24]([CH3:26])[CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH:24]([CH3:26])[CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: CC(C)c1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 14.6 %

Procedure:
Using cyclohexyl{3-(1-methylethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.50 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.32 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.11 g, 14%) was obtained as a pale-yellow solid.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C@H:25]3[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]3)[C:16]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]3)=[O:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[C:9]([N:15]([C@H:25]3[CH2:26][CH2:27][C@H:28]([OH:31])[CH2:29][CH2:30]3)[C:16]([C@H:18]3[CH2:23][CH2:22][C@H:21]([CH3:24])[CH2:20][CH2:19]3)=[O:17])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3CCCCC3)sc2C(=O)O)[C@H]2CC[C@H](O)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (22 mg, 0.05 mmol) in dry MeOH (1 ml) was added 10% palladium on charcoal (3 mg). The resulting reaction mixture was placed under H2 atmosphere, stirred at room temperature for 16 h, and then filtered on celite and evaporated to dryness. The crude product was purified by flash chromatography using CH2Cl2: MeOH hexanes as eluent to to give 5-cyclohexyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (7 mg, 32%).
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:25]O)[C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:13][C:12]=2[CH:24]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:25]=[CH2:1])[C:11]2[O:15][C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[CH:13][C:12]=2[CH:24]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(-c2cc3cc(OC)cc(CO)c3o2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(OC)cc2cc(-c3ccc(OC)cc3)oc12
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
Methyl triphenylphosphonium bromide (0.122 g, 0.334 mmole) was dissolved in 5 mL THF and placed in an acetone/dry ice bath at −78° C. n-Butyl lithium (0.131 mL, 0.328 mmole) was added and the mixture was allowed to stir for 30 minutes. To this solution was added aldehyde 3 (0.078 g, 0.278 mmole) in 3 mL THF. After stirring at room temperature for 4 hours, the reaction mixture was placed in an oil bath and allowed to stir overnight at 65° C. The solvent was evaporated and the residue was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 95:5) to afford 0.055 g (71%) of 28 as a white solid: Mp=182-184° C.; 1H NMR (DMSO-d6) δ 7.87 (d, 2 H, J=8.4 Hz), 7.22 (s, 1 H), 7.08 (m, 3 H), 6.98 (m, 1 H), 6.96 (d, 1 H, J=2.3 Hz), 6.30 (d, 1 H, J=17.8 Hz), 5.59 (d, 1 H, J=11.4 Hz), 3.82 (s, 3 H), 3.80 (s, 3 H); MS 281 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5]([Cl:7])[N:4]([CH2:8][C:9]([OH:11])=O)[N:3]=1.Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[CH:21]1[O:25][N:24]=[C:23]([C:26]2[N:27]=[C:28]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:29][CH:30]=2)[CH2:22]1.C(N(CC)CC)C>S(Cl)(Cl)=O.ClCCl>[Cl:1][C:2]1[N:6]=[C:5]([Cl:7])[N:4]([CH2:8][C:9]([N:34]2[CH2:35][CH2:36][CH:31]([C:28]3[S:29][CH:30]=[C:26]([C:23]4[CH2:22][CH:21]([C:15]5[C:14]([F:13])=[CH:19][CH:18]=[CH:17][C:16]=5[F:20])[O:25][N:24]=4)[N:27]=3)[CH2:32][CH2:33]2)=[O:11])[N:3]=1
Reactant: O=C(O)Cn1nc(Cl)nc1Cl
Reactant: Fc1cccc(F)c1C1CC(c2csc(C3CCNCC3)n2)=NO1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(Cn1nc(Cl)nc1Cl)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3,5-dichloro-1H-1,2,4-triazole-1-acetic acid (i.e. the product of Example 16, Step B), (114 mg, 0.58 mmol) in thionyl chloride (5 mL) was heated at reflux for 1 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The resulting crude acid chloride was dissolved in dichloromethane (5 mL) and added to a solution of 4-[4-[4,5-dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl]-2-thiazolyl]piperidine hydrochloride (196 mg, 0.51 mmol) and triethylamine (0.5 mL) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 3 h, diluted with dichloromethane, washed with 1 N hydrochloric acid, aqueous sodium chloride, and dried (MgSO4). The reaction mixture was concentrated under reduced pressure and further purified by medium-pressure liquid chromatography to give 80 mg of the title product as a white solid melting at 147-150° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([NH:15][C:16]([C:18]2[C:19]([CH3:30])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:22][CH:23]=2)=[O:17])[CH:6]=1)=[O:4].[OH-].[K+]>CO.O.CCOC(C)=O>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:15][C:16]([C:18]1[C:19]([CH3:30])=[N:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:22][CH:23]=1)=[O:17])[CH:6]=[C:5]2[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cn(NC(=O)c2cnc(-c3ccccn3)nc2C)c2ccc(F)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1cc(C(=O)O)c2cc(F)ccc21
Yield: 19.2 %

Procedure:
A solution of 5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-indole-3-carboxylic acid methyl ester (2.6 mmol) in MeOH (10 mL) is treated with an aqueous solution of KOH (500 mg, 8.9 mmol) in H2O (200 mL) and heated at reflux for 2 h. The mixture is diluted with EtOAc (50 mL) and extracted with 1% aqueous KOH (3×50 mL). The combined aqueous layer is neutralized with HCl (conc.), and the precipitate is collected by filtration and dried in vacuo to afford 5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-indole-3-carboxylic acid (195 mg, 19%, 3 steps). MS: 392 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 12.44 (s, OH, 1H), 12.31 (s, NH, 1H), 9.31 (s, 1H), 8.81 (d, 1H), 8.48 (d, 1H), 8.35 (s, 1H), 8.03 (m, 1H), 7.77 (m, 1H), 7.62 (m, 2H), 7.19 (m, 1H), 2.79 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[C:4](F)=[C:5]2[O:9][C:8]([CH:10]3[CH2:12][CH2:11]3)=[N:7][C:6]2=[C:13]([C:16]#[N:17])[C:14]=1[CH3:15].C(N(CC)CC)C.[CH3:27][N:28]([CH3:34])[C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>CSC>[CH:10]1([C:8]2[O:9][C:5]3[C:6](=[C:13]([C:16]#[N:17])[C:14]([CH3:15])=[C:3]([N:2]([CH3:19])[CH3:1])[C:4]=3[N:31]3[CH2:32][CH2:33][C@H:29]([N:28]([CH3:34])[CH3:27])[CH2:30]3)[N:7]=2)[CH2:12][CH2:11]1
Reactant: Cc1c(N(C)C)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CSC
Product: Cc1c(N(C)C)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 100 °C
Reaction time: 24 h
Yield: 56.6 %

Procedure:
6-Dimethylamino-2-Cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-321) (34 mg, 0.10 mmol) was dissolved in dimethyl sulfide (4 ml), then triethylamine (29 μl, 0.20 mmol) and (3S)-3-(dimethylamino)pyrrolidine (27 μl, 0.21 mmol) were added, followed by stirring under nitrogen atmosphere at 100° C. for 24 hours. After cooled, this was concentrated under reduced pressure, diluted with chloroform, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (20 mg, 64%) as a white crystal.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Na+]>CO>[C:1]([CH:3]1[CH2:4][CH2:5][CH:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: COC(=O)C1CCC(C#N)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC1CCC(C(=O)O)CC1
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To the solution of methyl 4-cyanocyclohexylcarboxylate (470 mg, 2.81 mole) prepared according to the method described in J. Am. Chem. Soc., 82, 2547 (1960) in methanol (5 ml) was added 1N sodium hydroxide (2.8 ml) under ice-cooling, and the mixture was stirred overnight during which the temperature of the mixture was left rising up to room temperature. After the reaction mixture was concentrated, water was added. The resulting mixture was washed with ether and acidified with 5N hydrochloric acid. After extracted thrice with chloroform, the mixture was dried with anhydrous magnesium sulfate. After the inorganic salt was removed by filtration, the filtrate was concentrated under reduced pressure to give 362 mg of the title compound as a colorless crystal (yield, 84%).