Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[CH3:1][O:2][C:3](=[O:30])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:17]=2)[CH:12]=[C:13]([O:15][C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cccc(C(F)(F)F)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 60 %

Procedure:
The title compound was prepared in 60% yield from 2-(5-hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example C) and 3-trifluoromethylphenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1.[NH2:20][C:21]1[N:26]=[CH:25][C:24]2[CH2:27][C:28]3([CH2:38][C:23]=2[CH:22]=1)[C:36]1[C:31](=[N:32][CH:33]=[CH:34][CH:35]=1)[NH:30][C:29]3=[O:37].C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([NH:20][C:21]2[N:26]=[CH:25][C:24]3[CH2:27][C:28]4([CH2:38][C:23]=3[CH:22]=2)[C:36]2[C:31](=[N:32][CH:33]=[CH:34][CH:35]=2)[NH:30][C:29]4=[O:37])=[O:10])[C:5]2[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=2[N:3]1[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1
Reactant: O=C(O)Cn1c(=O)n(C2CCOC2)c2ccccc21
Reactant: Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cn1c(=O)n(C2CCOC2)c2ccccc21)Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (±)-(2-oxo-3-tetrahydrofuran-3-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (60 mg, 0.23 mmol, described in Intermediate 16), (±)-3-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 3), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:21])([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2)[C:6](OCC)=[O:7].NN>CC(O)(CC)C>[F:4][C:5]([F:21])([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2)[C:6]([NH:2][NH2:3])=[O:7]
Reactant: NN
Reactant: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Solvent: CCC(C)(C)O
Solvent: O
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Yield: 92.1 %

Procedure:
To a reactor under inert atmosphere was added 31.05 mL 2-methyl-2-butanol and 12.58 mL (0.259 mol) hydrazine hydrate. Then a solution of 26 g (0.103 mol) ethyl difluoro(quinolin-6-yl)acetate in 125 mL 2-methyl-2-butanol was dosed to the hydrazine solution at room temperature. The precipitate was filtered off from the reaction mixture and was washed with water and dried at 50° C. 22.51 g 2,2-difluoro-2-quinolin-6-ylacetohydrazide was obtained in 90% yield.
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=O.[CH2:12]([CH2:14][NH2:15])[OH:13]>CO>[SH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[CH2:6][CH2:7][C:8]([NH:15][CH2:14][CH2:12][OH:13])=[O:10]
Reactant: NCCO
Reactant: O=C(O)CCC(=O)NCCS
Solvent: CO
Product: O=C(CCC(=O)NCCS)NCCO

Procedure:
A solution of 4.4 g (23 mmol) of methyl ester of N-(2-mercaptoethyl)succinamic acid obtained in Example 1a) in 20 cm3 of methanol, and 1.68 g (27 mmol) of ethanolamine was stirred for 5 hours at 60° C. under argon atmosphere.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(Br)cccc1Br
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COc1c(Br)cccc1Br
Reaction time: 4 h
Yield: 58.9 %

Procedure:
A mixture of 2,6-dibromophenol (25 g, 0.099 mol), powder potassium carbonate (28 g, 0.2 mol, 2 equiv) and dimethyl sulfate (12.6 g, 0.099 mol) in acetonitrile (400 mL) was kept at reflux with good stirring for 4 hr. After cooling, the solids were removed by filtration and the solvent was removed in a rotary evaporator. The residue was taken in 2:1 heptane/ethyl acetate mixture (800 mL) and washed with water (2×400 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in a rotary evaporator, leaving almost pure 1 (15.5 g, 96%).
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH2:7][C:6]1=O)C.Cl.[NH2:21][C:22]([NH2:24])=[NH:23].C(=O)([O-])[O-].[Na+].[Na+].NC1N=CC2C(=O)CC(C3C=CC(Cl)=CC=3)CC=2N=1>>[NH2:23][C:22]1[N:24]=[CH:4][C:5]2[C:10](=[O:11])[CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH2:7][C:6]=2[N:21]=1
Reactant: Cc1ccc(C2CC(=O)C(=CN(C)C)C(=O)C2)cc1
Reactant: N=C(N)N
Agent: Cl
Agent: Nc1ncc2c(n1)CC(c1ccc(Cl)cc1)CC2=O
Agent: O=C([O-])[O-]
Product: Cc1ccc(C2CC(=O)c3cnc(N)nc3C2)cc1

Procedure:
The title compound was prepared from 2-dimethylaminomethylene-5-p-tolyl-cyclohexane-1,3-dione (484 mg, 1.77 mmol) from stage 1, guanidine hydrochloride (784 mg, 8.26 mmol) and sodium carbonate (1.31 g, 12.39 mmol), following the procedure described for the synthesis of 2-amino-7-(4-chloro-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/a stage 2) except that the mixture was heated at reflux for 24 h.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][Li].[Cl-].[NH4+]>>[CH3:14][CH:8]1[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1
Reactant: [Li]C
Reactant: O=C1C=CC(c2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Product: CC1CC(=O)CCC1c1ccccc1

Procedure:
The intermediate 3-methyl-4-phenylcyclohexanone is prepared, first by the reaction of 4-phenylcyclohexanone with phenylselenenyl chloride and aqueous 30% hydrogen peroxide, yielding 4-phenyl-2-cyclohexenone, and then the reaction of the cyclohexenone with 1.4M methyllithium and aqueous ammonium chloride, affording 3-methyl-4-phenylcyclohexanone. The cyclohexanone is then reacted with cyanoguanidine as previously described. Example 15 provides a detailed description of how this reaction is conducted.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][CH2:19][NH2:20].[OH-].[NH4+]>O>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:20][CH2:19][CH2:18][C:14]1[S:13][CH:17]=[CH:16][CH:15]=1
Reactant: NCCc1cccs1
Reactant: Fc1cccc2c(Cl)ccnc12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc2c(NCCc3cccs3)ccnc12
Yield: 33.3 %

Procedure:
A mixture of 2.0 g of 4-chloro-8-fluoroquinoline and 2.8 g of 2-(2-thienyl)ethyl amine was heated under nitrogen to 160°-165° C. for two hours, then cooled and combined with 200 mL of a 50:50 mixture of ammonium hydroxide and water. The product was extracted into CH2Cl2, which was then concentrated to dryness. The residue was recrystallized from pentane/CH2Cl2 to give 1.0 g of the title product. Yield 34.5%. M.P. 157°-158° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][C:24]=4[F:25])[NH:21][CH:20]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:30]([O:37]CCC=O)[C:31]1C=CC=C[CH:32]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][C:24]=4[F:25])[N:21]([CH2:32][CH2:31][CH2:30][OH:37])[C:20]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=CCCOCc1ccccc1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2n1CCCO
Reaction time: 0.17 h
Yield: 8 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoroindolin-5-yl)cyclopropanecarboxamide (160 mg, 0.50 mmol) in anhydrous dichloromethane (3.4 mL) was added 3-(benzyloxy)propanal (160 mg, 0.98 mmol) at room temperature. After 10 min of stirring, NaBH(OAc)3 (140 mg, 0.65 mmol) was added in one portion and the reaction mixture was stirred for 4 h at room temperature. The solvent was removed under reduced pressure and the residue was taken-up in a mixture of 50/50 CH3CN—H2O containing 0.05% TFA. The mixture was concentrated to dryness and the residue was dissolved in CDCl3 (5 mL) and briefly exposed to daylight. The purple solution was stirred open to the atmosphere at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was treated with Pd—C (10 mg) in MeOH (2 mL) under 1 atm of H2 for 2 h. The catalyst was filtered through Celite and the solvent was removed under reduced pressure. The residue was purified by preparative TLC 30% ethyl acetate/hexanes to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-1-(3-hydroxypropyl)-1H-indol-5-yl)cyclopropanecarboxamide (18 mg, 8% from 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoroindolin-5-yl)cyclopropane-carboxamide). 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J=7.8 Hz, 1H), 7.31 (d, J=2.2 Hz, 1H), 6.94 (dd, J=7.9, 1.7 Hz, 1H), 6.91 (d, J=1.6 Hz, 1H), 6.85 (d, J=11.7 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.10 (s, 1H), 5.94 (s, 2H), 4.25-4.21 (m, 2H), 3.70 (dd, J=5.7, 5.7 Hz, 2H), 1.93-1.86 (m, 2H), 1.61 (dd, J=6.8, 3.7 Hz, 2H), 1.35 (s, 9H), 1.04 (dd, J=6.8, 3.7 Hz, 2H). MS (ESI) m/e (M+H+) 453.0.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]1([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1)[O:8][CH2:7]2.C1C(=O)N(Cl)C(=O)C1.[Cl:31][C:32]1[CH:33]=[C:34]([C:40](=[O:45])[C:41]([F:44])([F:43])[F:42])[CH:35]=[C:36]([Cl:39])[C:37]=1[F:38].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:31][C:32]1[CH:33]=[C:34]([C:40]2([C:41]([F:43])([F:44])[F:42])[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[C:9]3([CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]3)[O:8][CH2:7]4)[O:45]2)[CH:35]=[C:36]([Cl:39])[C:37]=1[F:38]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=NO)ccc12
Reactant: O=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)O3)ccc12
Temperature: 55 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a stirred solution of tert-butyl 5′-((hydroxyimino)methyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 43) (0.5 g, 1.645 mmol, 1 eq) in DMF (6.5 mL) was added NCS (0.218 g, 1.645 mmol, 1 eq). Reaction mixture was stirred at 55° C. for 1 hour under nitrogen atmosphere. After 1 hour (chloro intermediate formation), 1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (0.437 g, 1.678 mmol, 1.02 eq) was added followed by addition of sodium bicarbonate (0.140 g, 1.678 mmol, 1.02 eq) at room temperature. Resulting reaction mixture was stirred at 55° C. for 3 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched by water (10 mL) and extracted with ethyl acetate (3×50 mL). Combined organic phase was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown thick oil (0.6 g, crude). Crude compound was purified by Combiflash using 40 g Redisep column. Desired compound was eluted in 25% ethyl acetate in hexane to afford title compound as colorless thick oil (0.33 g, impure). 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 9H), 4.11 (d, J=10.04 Hz, 2H), 4.32 (d, J=9.92 Hz, 2H), 5.15 (s, 2H), 7.56-7.58 (m, 1H), 7.64-7.68 (m, 3H), 7.86 (d, J=8.04 Hz, 1H), 8.02-8.04 (dd, J1=6.12 Hz, J2=0.64 Hz, 1H). LC-MS (m/z): No ionization.
Reaction SMILES: [F:1][C:2]([F:39])([C:8]1([O:29][C@H:28]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:10]1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:9])[C:3]([O:5]CC)=[O:4].[OH-].[Na+].C(=O)=O>C(O)C>[F:39][C:2]([F:1])([C:8]1([O:29][C@H:28]([CH2:30][O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:10]1[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:9])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(F)(F)C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(F)(F)C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 4.07 g of 2-deoxy-2,2-difluoro-4,5,7-tris-O-(phenylmethyl)-D-arabino-3-heptulofuranosonic acid, ethyl ester in 75 ml of ethanol was added 15 ml of 1N sodium hydroxide. After 60 minutes at 25° C., the mixture was acidified with carbon dioxide and concentrated. The residue was stirred with ether and water and acidified with hydrochloric acid. The ether layer was washed with water and brine, dried, and concentrated to give a colorless oil, IR 1770 cm-1 (CF2COOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:44]1[C:56]2[NH:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]=2[C:47]([O:57][CH2:58][CH:59]([OH:63])[CH2:60][NH:61][CH3:62])=[CH:46][CH:45]=1>CN(C=O)C.C(Cl)Cl>[CH:44]1[C:56]2[NH:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]=2[C:47]([O:57][CH2:58][CH:59]([OH:63])[CH2:60][N:61]([CH3:62])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:46][CH:45]=1
Reactant: CNCC(O)COc1cccc2[nH]c3ccccc3c12
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N(C)CC(O)COc2cccc3[nH]c4ccccc4c23)cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.3 %

Procedure:
To a solution of 3,4-Dimethoxybenzoic acid (0.2 g, 1.11 mmol) in DMF (5 mL) was added DIPEA (0.48 mL, 2.8 mmol), EDCI (0.355 g, 1.85 mmol), HOBt (0.05 g, 0.37 mmol) followed by 1-(9H-carbazol-4-yloxy)-3-(methylamino)propan-2-ol (0.25 g, 0.925 mmol) prepared following the procedure described above in step I, example 72. The reaction was stirred at room temperature for 12 hours and was diluted with DCM (50 mL), washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4, concentrated. The crude compound was purified by dissolution in dichloromethane (3 mL) and precipitation by adding diisopropyl ether (5 mL) and hexane (10 mL). The resulting white solid was filtered, and dried to afford the desired compound (0.15 g, 38%) with m.p.: 77-80° C. 1H NMR (400 MHz, CDCl3) δ (ppm): 3.10-3.40 (m, 3H), 3.70-4.10 (m, 7H), 4.07 (s, 1H), 4.20-4.25 (m, 1H), 4.38 (s, 1H), 4.56 (s, 1H), 4.76 (s, 1H), 6.74 (s, 1H), 6.87 (s, 1H), 6.90-7.15 (m, 4H), 7.20-7.49 (m, 3H), 8.17 (s, 1H), 8.30 (s, 1H). MS m/z: 435.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:5]=[CH:6][C:7]([O:9][CH2:24][CH3:25])=[O:8]
Reactant: CCO
Reactant: O=C(O)C=Cc1ccc(C2CCCCC2)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C=Cc1ccc(C2CCCCC2)c(Cl)c1

Procedure:
3-Chloro-4-cyclohexylcinnamic acid (20.0 g.; 0.075 moles) is allowed to reflux with 8-10 pieces of Orierite in absolute ethanol (20 ml) containing concentrated sulfuric acid (5 ml) for 21 hours. The cooled reaction mixture is diluted with chloroform and filtered hot. The filtrate is washed 3 times with water, once with 10% sodium bicarbonate and twice more with water. After drying over sodium sulfate, the solvent is removed to give ethyl 3-chloro-4-cyclohexylcinnamate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[N:4][C:5]([F:11])=[C:6]([Cl:10])[C:7]=1[CH:8]=[O:9].[BH4-].[Na+].Cl>C(O)C>[Cl:10][C:6]1[C:5]([F:11])=[N:4][C:3]([F:12])=[C:2]([Cl:1])[C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1c(Cl)c(F)nc(F)c1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1c(Cl)c(F)nc(F)c1Cl
Temperature: 0 °C
Yield: 58.4 %

Procedure:
To a mixture of 5.0 g (0.024 mole) of 3,5-dichloro-2,6-difluoropyridine-4-carboxaldehyde (from Step B) in 100 ml of ethanol that had been cooled to 0° C. was added slowly 1.4 g (0.037 mole) of sodium borohydride. After complete addition the reaction mixture was allowed to warm to room temperature and was stirred for approxmately seventeen hours. The reaction mixture was quenched with a stoichiometric amount of glacial acetic acid, and the ethanol was evaporated under reduced pressure, leaving a residue. This residue was mixed with dilute hydrochloric acid, and this mixture was extracted with diethyl ether. The combined extracts were washed repeatedly with a 5% aqueous solution of sodium bicarbonate. The extract was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, leaving 3.0 g of 3,5-dichloro-2,6-difluoro4-hydroxymethylpyridine as a residue.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40]>CN(C=O)C.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.[Cu](I)I>[CH3:11][C:5]1[CH:4]=[CH:3][C:2]([C:43]#[C:42][Si:39]([CH3:41])([CH3:40])[CH3:38])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(Br)cc1C(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C#C[Si](C)(C)C)cc1C(N)=O
Temperature: 120 °C

Procedure:
To a mixture of 5-bromo-2-methylbenzamide (I69) (0.292 g, 1.36 mmol), PdCl2(PPh3)2 (0.049 g, 0.070 mmol), triphenylphosphine (0.054 g, 0.21 mmol) and copper iodide (0.036 g, 0.19 mmol) in DMF (3 mL) was added triethylamine (0.570 mL, 4.09 mmol) and trimethylsilylacetylene (0.210 mL, 1.49 mmol) and the resulting mixture heated under microwave irradiation at 120° C. for 25 minutes. The resulting mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-20% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I70) (0.190 g, 60%); 1H NMR (400 MHz, d6-DMSO) δ 7.80 (s, 1H), 7.40 (m, 3H), 7.24 (d, J=7.9 Hz, 1H), 2.36 (s, 3H), 0.22 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[N:10]=[CH:9][C:8]=2[OH:19])[CH:4]=[N:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:26]([C:28]1[CH:29]=[C:30]([S:35]([NH:38][C:39]2[S:40][CH:41]=[CH:42][N:43]=2)(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1F)#[N:27]>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[N:10]=[CH:9][C:8]=2[O:19][C:33]2[CH:32]=[CH:31][C:30]([S:35]([NH:38][C:39]3[S:40][CH:41]=[CH:42][N:43]=3)(=[O:36])=[O:37])=[CH:29][C:28]=2[C:26]#[N:27])[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc(-c3cnn(C)c3)c(O)cn2)cn1
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(-c3cnn(C)c3)c(Oc3ccc(S(=O)(=O)Nc4nccs4)cc3C#N)cn2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.1 %

Procedure:
10 mg (0.04 mmol) of 4,6-bis(1-methyl-1H-pyrazol-4-yl)pyridin-3-ol was dissolved in 3 mL of N,N-dimethylformamide, and 32 mg (0.1 mmol) of Cs2CO3 was added thereto, followed by stirring at room temperature for 10 minutes. Then, 11 mg (0.04 mmol) of 3-cyano-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide was added thereto, and the solution was stirred at room temperature for 3 hours. After completion of the reaction as checked by TLC, the solvent was removed, and the remaining material was diluted with ethyl acetate and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 16.0 mg (80% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCCCOC(=O)c1ccccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCCCOC(=O)c1ccccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), butyl salicylate (388 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight and at 140° C. for 3 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (106 mg, yield 57%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]\[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[OH:30]>[Pd]>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=2)[CH2:10][CH:9]1[OH:30])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CO
Reactant: CCOC(=O)/C=C(/C)c1ccc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Product: CCOC(=O)CC(C)c1ccc(C2CCN(C(=O)OC(C)(C)C)C(O)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 12-1 (400 mg, 1.0 mmoles), 10% Pd/C (160 mg), and CH3OH (5 mL) was stirred at ambient temperature under a hydrogen atmosphere for 3.0 hours. The reaction mixture was filtered through a celite pad and the filtrate concentrated to give 12-2 as a yellow oil. Rf 0.33 (silica, 30% EtOAc/hexanes).