Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C@H:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[OH:9].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[OH-].[Na+]>CN(C=O)C.O>[C@H:3]1([O:10][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[O:9][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: O[C@H]1CCCC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(O[C@H]2CCCC[C@@H]2Oc2ccc(C#N)cc2)cc1
Reaction time: 8 h
Yield: 83.7 %

Procedure:
Sodium hydride (7.1 g, 0.3 mol) was dispersed in 200 ml DMF and added with (1S,2S)-cyclohexane-1,2-diol (11.42 g, 98.3 mmol) while cooling with ice. The mixture after being cooled with ice for another one hour was reacted at room temperature for 2 hours and cooled again, followed by addition of p-fluorobenzonitrile (25 g, 206 mmol). After the reaction was continued overnight, the mixture was added carefully with 5 ml water to inactivate excess sodium hydroxide, followed by distillation of DMF in pressure. The residue was added with 200 ml water and then extracted with ethyl acetate, followed by washing with a saturated solution of sodium chloride thereby obtaining a coarse crystalline product. The crystalline product was then recrystallized from 200 ml isopropanol thereby obtaining the intended product (26.2 g, 82.3 mmol, 84%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](B4OC(C)(C)C(C)(C)O4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:39][NH:40][C:41]([O:43][CH:44]([CH3:46])[CH3:45])=[O:42])([CH3:4])([CH3:3])[CH3:2].C(O)(=[O:50])C.OO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:47])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([OH:50])=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:39][NH:40][C:41]([O:43][CH:44]([CH3:45])[CH3:46])=[O:42])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)O
Reactant: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccc(O)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
According to the procedure in Organic Synthesis, vol. V, p. 918, a solution of 3-[2-(isopropoxycarbonylamino-methyl)-4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionic acid tert-butyl ester (1.4 g, 2.16 mmol, Example 368, Step A) in THF (8 mL) was treated with glacial acetic acid (194 mg, 3.24 mmol) at 0° C. A solution of 30% H2O2 in water (4.75 mL) was diluted with H2O (1 mL) and added to the reaction mixture. The mixture was warmed to room temperature and treated with 1M aqueous Na2S2O3 solution (50 mL). The THF was removed under vacuum and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with 1M Na2S2O3 (2×50 mL), dried (MgSO4), filtered, and concentrated to an oil containing (1.21 g). Purification using silica gel chromatography (1:1 ηεξανεσ:ετηψλ acetate) yielded the title compound as a white solid (1.10 g, 95%). 1H NMR (300 MHz CDCl3) δ 1.15 (d, 6H), 1.19 (s, 9H), 2.26 (s, 3H), 2.39 (t, 2H), 2.75 (t, 2H), 2.85 (t, 2H), 4.10 (t, 2H), 4.28 (d, 2H), 4.85 (m, 1H), 5.01 (br d, 1H), 6.63 (dd, 1H), 6.74 (m, 3H), 6.96 (d, 1 h), 7.70 (d, 2H); MS [EI+] m/z 539 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[F:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20]Br)=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][S:12][C:10]2[N:11]=[C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]3[N:9]=2)=[CH:16][CH:15]=1
Reactant: Fc1ccc(OCCBr)cc1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Product: Cc1cc(C)n2nc(SCCOc3ccc(F)cc3)nc2n1
Yield: 57 %

Procedure:
The title compound was prepared according to the experimentals described for Example 1 above from 5,7-dimethyl-[1,2,4]-triazolo[1,5-a]pyrimidine-2-thiol and 4-fluorophenoxy-ethylbromide in 57% yield; EM (calc.): 318.1; MS (ESI) m/e: 319.1 (M+H)+. NMR (DMSO-d6, 400 MHz) δ ppm: 7.11 (m, 3H), 7.00 (m, 2H), 4.31 (t, 2H), 3.59 (t, 2H), 2.67 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][CH2:13][O:14][CH3:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][O:25][CH3:26]>CN(C=O)C.CCOCC>[CH3:26][O:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][CH2:13][O:14][CH3:15])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCBr
Reactant: COCCc1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCOc1cc(CCOC)cc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-hydroxy-5-(2-methoxyethyl)benzoate (1 eq.) from the previous step in DMF (0.2 M) was added Cs2CO3 (2 eq.) and 1-bromo-2-methoxy-ethane (2 eq.). The reaction was heated to 80° C. and stirred for 18 h. After cooling to rt, the reaction was diluted with ether and washed extensively with water and brine. The organic extract was dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 25% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[O:9][CH:8](O)[CH2:7][C:6]=2[CH:11]=1>C(O)C.[Pt]=O>[Cl:1][C:2]1[C:3]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:11]=1
Reactant: OC1Cc2cc(Cl)c(N3CCCCC3)cc2O1
Agent: O=[Pt]
Solvent: CCO
Product: Clc1cc2c(cc1N1CCCCC1)OCC2

Procedure:
5 mg of platinum oxide are added to a solution of 250 mg (1.00 mmole) of crude 5-chloro-2-hydroxy-6-(piperidin-1-yl)-2,3-dihydrobenzofuran in 5 ml of absolute ethanol and the whole is hydrogenated at room temperature and 3 atmospheres. The catalyst is filtered off and the filtrate is concentrated in a vacuum rotary evaporator. The residue is chromatographed over silica gel using methylene chloride as eluant. Recrystallisation from petroleum ether yields 5-chloro-6-(piperidin-1-yl)-2,3-dihydrobenzofuran having a melting point of 38°-40°.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:32][CH:33]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Oc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(Oc2ccc(-c3nn4c(NC5CCCC5)cccc4c3-c3ccnc(NC4CCCC4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
To a solution of 4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (100 mg, 0.22 mmol) in dichloromethane (5 mL) was added copper (II) acetate (40 mg, 0.22 mmol), phenylboronic acid (80 mg, 0.66 mmol), triethylamine (92 μL, 0.66 mmol) and molecular sieves. The mixture was stirred at room temperature for 24 hours. Solids were removed by filtration and the filtrate was concentrated, followed by purification by flash chromatography (2:3 ethyl acetate:hexanes) to give N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (14 mg, 12%) as a yellow foam. 1H NMR (CDCl3): δ 8.05–6.85 (m, 12 H), 6.40 (d, 1H), 6.06 (m, 2H), 5.12 (d, 1H), 4.40 (m, 1H) 4.01 (m, 1H), 2.20–2.09 (m, 4H), 1.82–1.59 (m, 12H); MS m/z 531 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=O)=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36]>>[CH3:34][S:35]([NH:38][C:23]([C:18]1[C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][N:9]3[C:8]4[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=4[N:6]=[C:5]3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:16][CH:15]=2)=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:25])(=[O:37])=[O:36]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: CS(N)(=O)=O
Solvent: O=S(Cl)Cl
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)NS(C)(=O)=O)cc1

Procedure:
Prepared in analogous manner to Example 198 from 4'-[(2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid and thionyl chloride/methanesulphon-amide.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.Cl.[F:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[F:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:13]([C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[O:15])[CH2:26][CH2:25]2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 4-(4-Fluorobenzoyl)piperidine hydrochloride (31.4 mg, 0.151 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.7 mg, 0.197 mmol) and triethylamine (59.8 mg, 0.591 mmol) were mixed in dichloromethane (2 ml) and stirred at room temperature over night. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C23H21FN2O3: 392.1536, found 392.1542.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C@@H:19]([CH:35]([CH3:37])[CH3:36])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=1)[C@@H:10]([OH:17])[CH2:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:38](Cl)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].N1C=CN=C1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C@@H:19]([CH:35]([CH3:37])[CH3:36])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=1)[C@@H:10]([O:17][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)O)C(C)C)ccc1OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](C)C(=O)O)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Reaction time: 16 h

Procedure:
4.45 g of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid (crude) are stirred in 45 ml of dimethylformamide with 2.36 g of tert-butyldimethylsilyl chloride and 2.03 g of imidazole for 6 days at room temperature. The mixture is concentrated by evaporation and the residue is partitioned between 10% citric acid solution and ethyl acetate. The organic phase is concentrated and stirred in 20 ml of tetrahydrofuran, 8 ml of water and 20 ml of acetic acid at room temperature for 16 hours. After concentration by evaporation, ice/water is added to the residue and the mixture is then extracted with ethyl acetate. The title compound is obtained from the organic phase after FC (260 g of silica gel, ethyl acetate/hexane=1:1): Rf (ethyl acetate/hexane=1:1)=0.32.
Reaction SMILES: [Cl-].[NH4+:2].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1.CO>C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[C:8]([C:10](=[NH:2])[NH2:11])[CH:7]=[CH:6][N:5]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CO
Product: N=C(N)c1ccnc(Cl)c1
Temperature: 25 °C

Procedure:
To a suspension of ammonium chloride (10.7 g, 200 mmol) in 250 mL of dry toluene. was added a 2 M solution of Al(CH3) (100 mL, 200 mmol) in toluene dropwise under nitrogen at 0° C. The resulting reaction mixture was stirred at rt until no more evolution of gas was observed and then 2-chloropyridine -4-carbonitrile (13.86 g, 100 mmol) was added. The mixture was stirred at 90° C. overnight. It was then cooled down to 0° C. and 300 mL of methanol were added with subsequent stirring for 1 h at rt. After filtration, the solid was washed with methanol for several times, the solution was evaporated to dryness under vacuum. The residue was washed with methanol to give 2-chloropyridine-4-carboximidamide. (18.3 g, 95%). 1H NMR δ (400 MHz, d6-DMSO): 8.70 (dd, J=4.8, 0.4 Hz, 1H), 8.00 (dd, J=1.6, 0.4 Hz, 1H), 7.84 (dd, J=5.2, 1.6 Hz, 1H), 7.80 (m, 1H), 7.53 (t, J=8.1 Hz, 1H); MS (ESI) m/z (M+H)+ 156.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[C:10]([C:12]1[CH:41]=[CH:40][C:15]([O:16][CH2:17][C@@H:18](O)[CH2:19][N:20]2[CH2:27][CH:26]3[O:28][CH:22]([CH2:23][N:24]([CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:25]3)[CH2:21]2)=[CH:14][CH:13]=1)#[N:11]>ClCCl>[C:10]([C:12]1[CH:41]=[CH:40][C:15]([O:16][CH2:17][CH:18]([F:7])[CH2:19][N:20]2[CH2:27][CH:26]3[O:28][CH:22]([CH2:23][N:24]([CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:25]3)[CH2:21]2)=[CH:14][CH:13]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)NCCN1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)O2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN1CC2CN(CC(F)COc3ccc(C#N)cc3)CC(C1)O2
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of DAST (0.73 g, 0.0043 mol) in dichloromethane (10 mL) was added tert-butyl (2-{7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)carbamate (1.50 g, 0.0033 mol; see Preparation R above), in (10 mL) of dichloromethane, dropwise under a nitrogen atmosphere at −65° C. The reaction mixture was slowly brought to RT and stirred at this temperature for 2 h (monitored by HPLC). The reaction mixture was quenched with NaHCO3 (aq.) and extracted with dichloromethane. The organic layer was washed with water and brine and then dried over sodium sulfate. Solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel, using methanol-dichloromethane as the eluent, to yield 0.40 g of the title compound as a brownish, gummy solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([N:15]([C:22](=[O:24])[CH3:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]=1)C)(C)(C)C.C(OCC)(=O)C.Cl>C(OCC)(=O)C.C(O)C>[CH3:6][NH:7][CH2:9][C:10]1[CH:14]=[C:13]([N:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22](=[O:24])[CH3:23])[N:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]=1
Reactant: CC(=O)N(c1ccccc1)c1cc(CN(C)C(=O)OC(C)(C)C)nn1-c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(N(C(C)=O)c2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
tert-Butyl({5-[acetyl(phenyl)amino]-1-phenyl-1H-pyrazol-3-yl}methyl)methylcarbamate (83 mg) was dissolved in ethyl acetate (2 mL) and ethanol (1 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (3 mL), and the mixture was added to a solution of fumaric acid (23 mg) in ethanol (5 mL). The solvent was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and ethanol to give the title compound as colorless crystals (yield 32 mg, yield 43%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](=[S:21])[NH2:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22]([O:24][C:25](=[O:32])[C:26](=O)[CH:27](Cl)[CH2:28][CH3:29])[CH3:23]>CN(C)C=O>[CH2:22]([O:24][C:25]([C:26]1[N:20]=[C:19]([C:10]2[C:11]3[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)[S:21][C:27]=1[CH2:28][CH3:29])=[O:32])[CH3:23]
Reactant: CCOC(=O)C(=O)C(Cl)CC
Reactant: COc1cccc2c(C(N)=S)cn(CC3CCCCC3)c12
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)sc1CC
Yield: 152.3 %

Procedure:
A mixture of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (0.227 g, 0.754 mmol) and crude 3-chloro-2-oxo-pentanoic acid ethyl ester (1.34 g, 7.52 mmol) in dimethylformamide (4 ml) was subjected to microwave irradiation for 25 min at 140° C. The reaction mixture was concentrated in vacuo and the obtained reside was purified by silica gel column chromatography eluting with 25% acetone in heptane to afford crude 2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-5-ethyl-thiazole-4-carboxylic acid ethyl ester (0.490 g). This material was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br:18][C:19]1[C:27]2[N:26]=[C:25](Cl)[NH:24][C:23]=2[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1>>[Br:18][C:19]1[C:27]2[N:26]=[C:25]([N:15]3[CH2:16][CH2:17][N:12]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=4)[CH2:13][CH2:14]3)[NH:24][C:23]=2[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(Cl)c1
Product: FC(F)(F)c1cnc(N2CCN(c3nc4c(Br)cc(C(F)(F)F)cc4[nH]3)CC2)c(Cl)c1

Procedure:
The reaction of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine (212 mg, 0.8 mmol, ABCR) and 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (210 mg, 0.7 mmol, Example 6b) under the conditions of Example 3c afforded the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 530 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.O>COCCOC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH:10]([CH2:25][C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1F
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a solution of ethyl 3-(2,4-difluorophenyl)-3-oxopropionate (9 g, 39.4 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.58 g, 39.4 mmol) under ice-cooling and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (9.43 g, 39.4 mmol) in 1,2-dimethoxyethane (50 ml) and the reaction solution was stirred at room temperature for 3 hrs. The reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced-pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1-toluene) and recrystallized from diisopropyl ether-hexane to give ethyl 3-(2,4-difluorophenyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (11.6 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)[CH2:11][C:10]([NH2:21])=[N:9]2)=[CH:4][CH:3]=1>ClCCl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([NH2:21])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(C2CC(N)=NN2c2ccc(F)cc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CSc1ccc(-c2cc(N)nn2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A mixture of 4,5-dihydro-1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazol-3-amine (1 g) and manganese (IV) oxide (1.16 g) in dichloromethane (100 ml) was stirred at ambient temperature for 2 hours. The insoluble was filtered and the filtrate was concentrated to dryness. The residue (1 g) was purified by column chromatography on silica gel (16 g) eluting with a mixture of chloroform and ethyl acetate (5:1 to give a pale brown powder of 1-(4-fluorophenyl)-5-[4-(methylthio)phenyl]pyrazol-3-amine (0.64 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: CO
Reactant: Cc1cc(C(=O)O)ccc1N
Product: COC(=O)c1ccc(N)c(C)c1

Procedure:
In a 300 mL three-necked, round-bottomed flask were dissolved 5.2 g (34.4 mmole) of 4-amino-3-methylbenzoic acid in 75 ml of anhydrous methanol. Anhydrous hydrogen chloride was bubbled into the flask for 3 to 5 minutes and the resulting solution was refluxed for 2 hours. The solvent was removed using a rotary evaporator, the resulting residue was introduced into a mixture of 200 ml of water and 100 ml of methylene chloride and the mixture was then separated into two phases. The aqueous layer was made basic with 10% aqueous sodium hydroxide and extracted with methylene chloride (3×100 ml). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent removed using a rotary evaporator yielding 5.68 g methyl 4-amino-3-methylbenzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[NH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=[O:23].OS(O)(=O)=O.O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:21]2[CH:20]=[CH:19][C:18](=[O:23])[NH:17][CH:22]=2)=[CH:4][CH:3]=1
Reactant: O=c1cccc[nH]1
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(c2ccc(C)cc2)c2ccc(=O)[nH]c2)cc1
Temperature: 180 °C
Yield: 13.8 %

Procedure:
A mixture of bis(4-methylphenyl)methanol (5 g), and pyridin-2(1H)-one (6.72 g) was stirred at 180° C. To the solution was added concentrated H2SO4 (0.07 mL), and the mixture was stirred at 250° C. for 2 hours. Water (15 mL) and DCM (15 mL) were poured into the reaction mixture. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc). The desired fractions were collected and evaporated in vacuo, and the residue was washed with MeCN and dried in vacuo to give 5-[bis(4-methylphenyl)methyl]pyridin-2(1H)-one (0.94 g) as white crystals.