Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.Br[C:14]1[CH:23]=[N:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:20]2[CH:21]=[N:22][CH:23]=[CH:14][C:15]=2[C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccncc1Br
Reactant: NCc1ccc(C(F)(F)F)cc1
Product: COC(=O)c1ccncc1NCc1ccc(C(F)(F)F)cc1
Yield: 40 %

Procedure:
The title compound was prepared in 40% yield from 4-(trifluoromethyl)benzylamine and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (400 MHz, CDCl3): δ 8.12 (s, 1H), 7.95 (d, 1H, J=5.0 Hz), 7.93 (br s, 1H), 7.65 (d, 1H, J=5.0 Hz), 7.60 (d, 2H, J=8.1 Hz), 7.47 (d, 2H, J=8.1 Hz), 4.58 (d, 2H, J=5.9 Hz) 3.91 (s, 3H). [M+H] calc'd for C15H13F3N2O2, 311. found 311.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17]O)[N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:31]3[C:27](=[O:37])[C:28]4[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:30]3=[O:32])[N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:26])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CO)N(C(=O)OC(C)(C)C)C2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3ccccc3C1=O)N(C(=O)OC(C)(C)C)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
To a mixture of the above 2-amino-5-hydroxymethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (2.00 g, 5.20 mmol), phthalimide (0.92 g, 6.24 mmol) and triphenylphosphine (1.64 g, 6.24 mmol) in dry tetrahydrofuran (30 ml) cooled to 0° C. under a nitrogen atmosphere was added diethyl azodicarboxylate (DEAD) (0.98 ml, 6.24 mmol). The reaction mixture was allowed to stir overnight, slowly warming to room temperature. Next day the reaction mixture was again cooled to 0° C. and phthalimide (0.46 g, 3.12 mmol), triphenylphosphine (0.82 g, 3.12 mmol) and diethyl azodicarboxylate (DEAD) (0.49 ml, 3.12 mmol) was added in sequence and the reaction mixture was allowed to stir overnight, slowly warming to room temperature. The volatiles were evaporated in vacuo and the resultant solid dissolved in dichlorormethane (20 ml). The residue was subjected to flash column chromatography using a mixture of ethyl acetate/hexane (1:2) as eluant. Fractions were collected affording after evaporation in vacuo 1.0 g of the desired compound contaminated with phthalimide. Recrystallization from ethanol gave 0.23 g (9%) of pure 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:14]3[CH2:13][CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+]>>[C:23]1([S:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:15][C:14]4[CH2:13][CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2oc3ccc(Br)cc3c2C1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCCc2oc3ccc(S(=O)(=O)c4ccccc4)cc3c2C1
Yield: 22 %

Procedure:
The product of step E was coupled with sodium benzenesulfinate following the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 70:30 hexanes/ethyl acetate) provided tert-butyl 9-(phenylsulfonyl)-4,5-dihydro-1H-benzofuro[3,2-c]azepine-2(3H)-carboxylate (22 mg, 22%) as a light yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.09 (br s, 1H), 8.00-7.91 (m, 2H), 7.86-7.77 (m, 1H), 7.58-7.37 (m, 4H), 4.68-4.38 (m, 2H), 3.70 (br s, 2H), 3.01 (t, J=6.0 Hz, 2H), 2.09-1.92 (m, 2H), 1.53-1.20 (m, 9H).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:20]2[CH:21]=[C:16]([F:15])[CH:17]=[CH:18][C:19]=2[F:22])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Reactant: OB(O)c1cc(F)ccc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1c(-c2cc(F)ccc2F)nc2cc(F)ccc2c1Cl
Temperature: 100 °C

Procedure:
A solution of 2,4-dichloro-7-fluoro-3-methylquinoline (300 mg, 1.30 mmol) (in a mixture with the 5-F regioisomer; described herein), 2,5-difluorophenylboronic acid (268 mg, 1.70 mmol), tetrakis(triphenylphosphine)palladium(o) (151 mg, 0.130 mmol), and sodium carbonate (69 mg, 6.52 mmol) in acetonitrile (9.7 mL) and water (4.9 mL) was stirred and heated in a microwave at 100° C. for 120 min. The reaction mixture was then partitioned between EtOAc and water, and the organic layer was washed with brine, dried (MgSO4), and concentrated. Column chromatography of the crude product afforded 4-chloro-2-(2,5-difluorophenyl)-7-fluoro-3-methylquinoline) as a white solid. Mass Spectrum (ESI) m/e=308 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(N(CC)CC)C.[CH:20]1[C:25](O)=[CH:24][CH:23]=[C:22]([CH3:27])[CH:21]=1>S(Cl)(Cl)=O.ClCCl.CCCCCCC>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][C:25]1[CH:24]=[CH:23][C:22]([CH3:27])=[CH:21][CH:20]=1)=[O:8]
Reactant: Cc1ccc(O)cc1
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
5-chloro-2,4-difluorobenzoic acid (1.17 g, 0.00608 mol) was dissolved in thionyl dichloride (5.0 mL) and the reaction mixture was heated to 60° C. under nitrogen for 5 hours. The solvent was concentrated in vacuo and the residue was azeotroped twice with dichloromethane (10.0 mL) and once with toluene (10.0 mL). The crude was taken up in dichloromethane (15.0 mL) and cooled to 0° C. with an ice bath under nitrogen. Then N,N-diethylethanamine (1.05 mL, 0.00753 mol) and p-cresol (0.665 g, 0.00615 mol) dissolved in dichloromethane (10.0 mL) were added using a dropping funnel over 10 minutes. The resulting mixture was left to warm up to room temperature for 16 hours. The reaction was concentrated in vacuo and the crude was diluted in ethyl acetate (15.0 mL), washed twice with a saturated aqueous solution of sodium hydrogen carbonate (10.0 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Resulting crude was taken up in heptane (10.0 mL), put in a sonication bath for 5 minutes and the resulting solid was isolated by filtration. Title compound was obtained as white solid (1.20 g, 0.00425 mol, 70%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1)#[N:27]>>[NH2:19][C:13]1[O:14][CH2:15][C:16]([F:18])([F:17])[C@@:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[N:32][CH:33]=[C:28]([CH:29]=4)[C:26]#[N:27])[CH:3]=3)[O:8][CH:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10]2)[N:12]=1
Reactant: NC1=N[C@@]2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(F)(F)CO1
Reactant: N#Cc1cncc(B(O)O)c1
Product: N#Cc1cncc(-c2ccc3c(c2)[C@@]2(CC(c4ccccc4)O3)N=C(N)OCC2(F)F)c1
Yield: 16 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (2RS,4R)-6-bromo-5′,5′-difluoro-2-phenyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.3) with 5-cyanopyridin-3-ylboronic acid yielded the title compound (16% yield) as a white solid. MS (ISP): m/z=433.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][O:33][CH2:34][CH2:35]O.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C.O1CCCC1>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:35][CH2:34][O:33][CH3:32])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: COCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOc1ccc(C(=O)OC)c(O)c1
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a 50 ml tetrahydrofuran solution of 4.0 g (23.8 mmol) of methyl 2,4-dihydroxybenzoate, 7.49 g (28.5 mmol) of triphenylphosphine, 2.25 ml (28.5 mmol) of 2-methoxyethanol, and 4.5 ml (28.5 mmol) of diethyl azodicarboxylate were slowly added at 0° C. The mixture was brought to room temperature, and stirred for 1 hour. Then, the reaction mixture was diluted with ethyl acetate, and washed with water and a saturated aqueous solution of sodium chloride. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. To the residue, 100 ml of a solution of ethyl acetate/hexane (=1/4) was added, and insoluble solids were removed by filtration. Then, the mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to obtain 4.71 g (87%) of the captioned compound.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[NH:31]1[CH:35]=[C:34]([OH:36])[CH:33]=[N:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=CC=1C=NO>C(#N)C.[Cu-]=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([N:31]3[CH:35]=[C:34]([OH:36])[CH:33]=[N:32]3)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: Oc1cn[nH]c1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(-n3cc(O)cn3)c21
Temperature: 200 °C

Procedure:
Under an argon atmosphere, 150 mg (purity 62%, 0.18 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 2 ml of absolute acetonitrile, and 304 mg (3.62 mmol) of 1H-pyrazol-4-ol, 118 mg (0.36 mmol) of caesium carbonate, 5 mg (0.04 mmol) of copper(I) oxide and 20 mg (0.15 mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture was heated in the microwave for 1 h at 200° C. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 20 mg (24% of theor.) of the target compound was obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])#[N:6]>CN(C)C=O.ClCCl>[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([Cl:3])=[O:11])#[N:6]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)Cl)c1

Procedure:
Thionyl chloride (10 ml) and dimethylformamide (1 drop) were added to a solution of 3-cyanobenzoic acid (10 ml) in dichloromethane (100 ml), and the mixture was refluxed for 3 hours. After the reaction, the solvent was evaporated under reduced pressure to give 3-cyanobenzoyl chloride. Then, the oil was dissolved in dichloromethane (25 ml), and the solution was dropwise added to a solution of 4-aminopyridine (5 g) and diisopropylethylamine (8.9 g) in dichloromethane (50 ml), which was followed by stirring at room temperature for 1 hour. The precipitated crystals were collected by filtration, and recrystallized from chloroform-methanol,ether to give 5.3 g of N-(4-pyridyl)-3-cyanobenzamide.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[H-].[Na+].[CH3:39]I.Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25][N:26]([CH3:39])[S:27]([CH3:30])(=[O:29])=[O:28])[C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C(O)c2ccccc21
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1csc2c1S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)(C)C)C1=O)N2)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of Example 187 (124 mg, 0.22 mmol) in 2 mL of N,N-dimethyl formamide was cooled to 0° C., treated with sodium hydride (24 mg, 60% in oil, 0.5 mmol), stirred at 0° C. for 1 h, stirred at room temp for 30 min, treated with methyl iodide (9 μL, 0.14 mmol), stirred for 2 h, treated with methyl iodide (7 μL, 0.11 mmol), and stirred at room temp over night. The mixture was diluted with water and ethyl acetate, treated with 1N HCl, and extracted with ethyl acetate. The organic phase was washed with 2×10 mL of H2O and concentrated in vacuo. The crude material was chromatographed on silica gel with a gradient of methanol in dichloromethane (0-5%) to afford the title compound (48 mg, 39% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.40 (td, J=12.8, 3.7 Hz, 1 H), 0.72 (s, 9 H), 0.81 (td, J=12.9, 4.4 Hz, 1 H), 1.56 (s, 3 H), 2.01 (m, 1 H), 2.21 (td, J=12.8, 4.6 Hz, 1 H), 2.85 (s, 3 H), 3.02 (s, 3 H), 4.39 (s, 2 H), 7.32 (s, 1 H), 7.50 (m, 1 H), 7.71 (m, 2 H), 8.12 (d, J=7.8 Hz, 1 H), 14.21 (s, 1 H); MS (APCI−) m/z 564 (M−H)−.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH:15]=3)=[N:12][CH:13]=2)=[N:4]1>O1CCOCC1.C(Cl)Cl>[ClH:1].[ClH:1].[CH3:2][N:3]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH:15]=3)=[N:12][CH:13]=2)=[N:4]1
Reactant: Cn1cnc(-c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1cnc(-c2ccc(C3=CCNCC3)nc2)n1
Reaction time: 3 h

Procedure:
4M HCl in dioxane (20 ml) was added to a solution of Tert-butyl 4-(5-(1-methyl-1H-1,2,4-triazol-3-yl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (4BX) (4 g, 11.67 mmol) in CH2Cl2 (50 ml) at room temperature. The mixture was stirred for 3 hours then solvent was evaporated yielding title product as a white solid (3.8 g).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][NH2:16])=[N:13][CH:14]=1>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][NH:16][C:5](=[O:7])[CH3:6])=[N:13][CH:14]=1
Reactant: NNc1ccc(Br)cn1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NNc1ccc(Br)cn1
Reaction time: 16 h
Yield: 80.8 %

Procedure:
Acetic anhydride (1.13 mL, 12.0 mmol) was added to a solution of 5-bromo-2-hydrazinylpyridine (1.90 g, 10.0 mmol) and TEA (2.09 mL, 15.0 mmol) in DCM (200 mL). After 16 hours, the reaction mixture was concentrated by rotoevaporation and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with water and brine, dried with Na2SO4, and the solvent was removed under vacuum. The resulting residue was triturated with DCM to afford the title compound as a white solid (1.86 g).
Reaction SMILES: C([O:9][CH2:10][C:11]1[CH:16]=[C:15]([C@H:17]2[C@H:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:21]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:20]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:19]([CH2:47][O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[O:18]2)[CH:14]=[CH:13][C:12]=1[Cl:56])(=O)C1C=CC=CC=1>C1COCC1.CO.O>[Cl:56][C:12]1[CH:13]=[CH:14][C:15]([C@H:17]2[C@H:22]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@@H:21]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@H:20]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@@H:19]([CH2:47][O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[O:18]2)=[CH:16][C:11]=1[CH2:10][OH:9]
Reactant: O=C(OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl)c1ccccc1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.5 %

Procedure:
To a solution of benzoate 104 (6.13 g, 7.97 mmol) in THF/MeOH/H2O (150 mL/5 mL/5 mL) was added LiOH monohydrate (1.0 g, 23.9 mmol) at room temperature. The mixture was stirred at room temperature for 15 hours. The mixture was extracted with EtOAc/aq. saturated NH4Cl solution (100 mL/100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield the title compound 105 (5.33 g, 10%), which was carried on to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([NH2:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:25][C@H:26]1[C:30](=[O:31])[NH:29][CH2:28][C@@H:27]1[C:32](O)=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:23])[F:21])[CH:14]=3)=[CH:11][C:10]([NH:24][C:32]([C@@H:27]3[C@@H:26]([CH3:25])[C:30](=[O:31])[NH:29][CH2:28]3)=[O:33])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1C(=O)NC[C@@H]1C(=O)O
Reactant: Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1C(=O)NC[C@@H]1C(=O)Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(F)c2)n1
Yield: 35.4 %

Procedure:
To a solution of 1-(3-fluorophenyl)-5-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-3-ylamine (68 mg) in N,N-dimethylformamide (0.7 ml) were sequentially added (3R,4R)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (38 mg) prepared in Preparation 1, HOBt.H2O (46 mg) and WSC.HCl (58 mg), and the mixture was stirred at room temperature for 2 hours. To this reaction solution were added water and a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (33 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[C:8]1[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]=1.[K+].[C:20]([C:22]1[N:23]=[C:24]([C:35]([O-])=[O:36])[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=1)#[N:21]>CCOC(C)=O.CCCCCC>[C:16]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][CH:9]=2)=[C:2]([NH:1][C:35]([C:24]2[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=[C:22]([C:20]#[N:21])[N:23]=2)=[O:36])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(N)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c1
Yield: 84 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (f) using 1-[3-amino-4-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethanone (as prepared in the previous step, 243 mg, 1.00 mmol) and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 321 mg, 1.05 mmol). Silica gel chromatography (5-15% EtOAc/hexane) afforded the title compound (415 mg, 84%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C27H36N4O3Si, 493.3 (M+H), found 493.0.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C:7](=[O:9])[CH3:8])(=O)[CH3:4].OC1C=[CH:15][C:14]([C:17]2[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>C1COCC1>[C:7]([O:6][C:3]1[CH:12]=[CH:13][C:14]([C:17]2[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:18]=2)=[CH:15][CH:4]=1)(=[O:9])[CH3:8]
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)s1
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC(C)=O)cc2)s1
Temperature: 25 °C

Procedure:
Sodium hydride and acetic anhydride were added to a THF solution of methyl 5-(4-hydroxyphenyl)thiophene-2-carboxylate and the whole was stirred at room temperature to obtain methyl 5-[4-(acetyloxy)phenyl]thiophene-2-carboxylate. ES: 277.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[C:21](Cl)(=[O:23])[CH3:22]>ClCCl>[C:21]([O:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:23])[CH3:22]
Reactant: OCCc1cccc2ccccc12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.3 %

Procedure:
Triethylamine (691 mL, 4.96 mol) was added to an ice cold solution of 1-(2-hydroxy-ethyl)-naphthalene (569 g, 3.30 mol) in dichloromethane (2.2 L). Acetyl chloride (282 mL, 3.97 mol) was added dropwise over 90 minutes. After the addition was complete, the reaction mixture was stirred for an additional 30 minutes with ice-bath cooling. The reaction mixture was washed sequentially with water (2×1 L), 1N HCl (1 L, 500 mL), water (1 L), 5% aqueous NaHCO3 (500 mL), water (1 L), and brine (500 mL), then dried over magnesium sulfate, filtered, and evaporated to afford 1-(2-acetoxy-ethyl)-naphthalene (723.2 g) as a yellow oil that slowly crystallized.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:8]1(O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)([CH3:7])[CH3:6])[CH3:2].CN(C)C=O.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[C:5]([C:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)C1(O)CCN(Cc2ccccc2)CC1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)(C)C1=CCN(Cc2ccccc2)CC1
Yield: 38.4 %

Procedure:
2-(1-benzyl-4-hydroxy-piperidin-4-yl)-2-methyl-propionic acid ethyl ester (3.24 g, 10.6 mmol) from above was dissolved in chloroform (13 mL) containing N,N-dimethylformamide (34 □L). To this solution was added thionyl chloride (1.56 mL). The mixture was refluxed overnight. Solvents were evaporated and the residue was extracted with ethyl acetate and sodium hydroxide (1N) solution. The organic layer was washed with brine and dried over sodium sulfate. After evaporation of solvents, the residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give 2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-propionic acid ethyl ester (1.17 g) as an oily material. The NMR spectrum obtained on the sample is compatible with its structure. LC-MS calcd for C18H25NO2 (m/e) 287.4, obsd 288.2 (M+H).