Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:24][CH3:25])=[C:16]([O:26][CH3:27])[CH:15]=1)[CH2:9][CH2:10][CH3:11].[C:28](Cl)([CH3:30])=[O:29]>C(Cl)Cl>[C:28]([N:12]([CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:24][CH3:25])=[C:16]([O:26][CH3:27])[CH:15]=1)[CH2:8][CH2:9][CH2:10][CH3:11])(=[O:29])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCCCNCc1cc(OC)c(OC)c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(Cc1cc(OC)c(OC)c2ccccc12)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 111 %

Procedure:
Triethylamine (350 μL, 2.5 mmol) was added to a solution of aminonaphthalene 19 (250 mg, 0.9 mmol) and AcCl (90 μL, 1.27 mmol) in CH2Cl2 (5 mL) at 0° C. The cooling bath was removed after 10 min, the reaction mixture was stirred for 1 h at room temperature, diluted fivefold with CH2Cl2, washed with an aqueous solution of NaHCO3 followed by 3% HCl, brine and dried (MgSO4). The crude product (315 mg, 100%) obtained after evaporation of the solvent was used in the following step without further purification. 1H NMR (CDCl3) 8.19, 8.15 (2d, J=7.6, 8.4 Hz, 1H), 8.97, 7.80 (2d, J=7.9, 8.2 Hz, 1H), 7.35-7.58 (m, 2H), 7.16, 7.04 (2s, 1H), 5.05, 4.95 (2s, 2H), 4.01, 3.99 (2s, 3H), 3.99, 3.96 (2s, 3H), 3.47, 3.13 (2t, J=7.4, 7.8 Hz, 2H), 2.20, 2.09 (2s, 3H), 1.15-1.70 (m, 4H), 0.91, 0.87 (2t, J=7.2, 7.3 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([N+:15]([O-])=O)[CH:8]=2)[CH2:3][CH2:2]1.C(O)(=O)C>[Zn]>[NH2:15][C:9]1[CH:8]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: N#Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: N#Cc1ccc(N2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-morpholino-2-nitrobenzonitrile (388 mg, 1664 μmol) in acetic acid (6.00 mL, 104809 μmol) at rt was added all at once zinc powder (1632 mg, 24955 μmol). An exotherm developed. The reaction was stirred at ambient temperature for 2 h then filtered, and rinsed with EtOAc. The filtrate was concd under reduced pressure to afford a slightly yellow solid. Mass Spectrum (ESI) m/e=204.1 (M+1).
Reaction SMILES: [NH3:1].[CH3:2][C:3]1[CH:17]=[CH:16][C:6]([S:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.O>CO>[CH3:2][C:3]1[CH:17]=[CH:16][C:6]([S:7][C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:1])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(Sc2ccc(CBr)cc2)cc1
Reactant: N
Solvent: CO
Solvent: O
Product: Cc1ccc(Sc2ccc(CN)cc2)cc1
Reaction time: 96 h
Yield: 53 %

Procedure:
To a stirred mixture of 28% aq NH3 (40 ml) and methanol (200 ml) was added dropwise a solution (20 ml) of 4-(4-methylthiophenoxy)benzylbromide (5.00 g, 16.2 mM) in methanol at room temperature, and the mixture was stirred for 4 days at the same temperature. To the mixture was added water (100 ml), and the mixture was concentrated in vacuo. The residue was diluted with chloroform, and the mixture was washed with water and brine, dried with sodium sulfate, and concentrated in vacuo. The residue was chromatographed over alumina to give 4-(4-methylthiophenoxy)benzylamine (2.11 g, 53%) as colorless crystals, m.p. 61.8° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=O)[N:19]=[N:18]2)[CH:14]=[CH:15][CH:16]=1.FC1C=C(C=CC=1)N.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:55][CH2:56][C:57]([N:59]1[CH2:64][CH2:63][CH:62]([O:65][C:66]2[CH:71]=[C:70]([F:72])[CH:69]=[CH:68][C:67]=2[Cl:73])[CH2:61][CH2:60]1)=[O:58]>CN(C=O)C.O>[Cl:73][C:67]1[CH:68]=[CH:69][C:70]([F:72])=[CH:71][C:66]=1[O:65][CH:62]1[CH2:63][CH2:64][N:59]([C:57](=[O:58])[CH2:56][NH:55][C:22]([C:20]2[N:19]=[N:18][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=3)[CH:21]=2)=[O:24])[CH2:60][CH2:61]1
Reactant: O=C(O)c1cn(-c2cccc(F)c2)nn1
Reactant: NCC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccc(F)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1)c1cn(-c2cccc(F)c2)nn1
Reaction time: 0.03 h
Yield: 92.8 %

Procedure:
DIPEA (168 mg, 1.3 mmol) was added to a stirred solution of 1-(3-fluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid (60 mg, 0.29 mmol) (prepared by the method used for the synthesis of Intermediate 64, starting from 3-fluoroaniline) in DMF (5 mL) followed by HOBt (43 mg, 0.32 mmol) and EDCI (139 mg, 0.72 mmol). After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (103 mg, 0.32 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Cold water was then added and the solid was collected to afford 128 mg (92.75% Yield) of 1-(3-fluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 476, 96.08%. 1H NMR (300 MHz, DMSO-d6): δ 9.4 (s, 1H), 8.54 (t, 1H), 8.0-7.96 (t, 2H), 7.72 (q, 1H), 7.54-7.34 (m, 2H), 7.34 (d, 1H), 6.9 (t, 1H), 4.9 (s, 1H), 4.3 (d, 2H), 3.8 (bs, 2H), 3.55 (bs, 2H), 2.05 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:14]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[C@@H:13]([CH3:20])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[NH:27][C:28]([C:30]2[C:39]([NH:40]C(=O)OCC3C=CC=CC=3)=[CH:38][C:37]3[C:32](=[CH:33][C:34]([CH:51]=[CH2:52])=[CH:35][CH:36]=3)[N:31]=2)=[O:29])[CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>CO.C1COCC1.[Pd]>[NH2:40][C:39]1[C:30]([C:28]([NH:27][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:21]=2[N:11]2[CH2:12][C@H:13]([CH3:20])[C@H:14]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[C@H:9]([NH2:8])[CH2:10]2)=[O:29])=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[C:34]([CH2:51][CH3:52])[CH:33]=2
Reactant: C=Cc1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3C[C@H](C)[C@H](n4ccnn4)[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc2cc(N)c(C(=O)Nc3cnccc3N3C[C@@H](N)[C@@H](n4ccnn4)[C@@H](C)C3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a solution of benzyl {2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-vinylquinolin-3-yl}carbamate (5.2 mg, 0.007 mmol) in MeOH (0.29 mL) and THF (0.29 mL) was added a mixture of palladium (2.9 mg) (10% Pd on carbon). The reaction mixture was deoxygenated under reduced pressure and hydrogen was introduced via a balloon. The reaction mixture was stirred at room temperature under hydrogen for 1 h. The mixture was filtered and concentrated under vacuum to give an intermediate. The intermediate was treated with 4.0 M HCl in dioxane (0.074 mL, 0.30 mmol) and stirred at room temperature for 30 min. The solution was then concentrated under reduced pressure. The residue was diluted with MeOH and NH4OH, filtered and purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the desired product as yellow powder (2.3 mg, 66%). LCMS calc. for C25H30N9O (M+H)+: m/z=472.3. Found: 472.3.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[S:14][C:13]2[CH:15]=[C:16]([O:19]C)[CH:17]=[CH:18][C:12]=2[C:11]=1[O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=1)([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[OH:19][C:16]1[CH:17]=[CH:18][C:12]2[C:11]([O:21][C:22]3[CH:23]=[CH:24][C:25](/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:1]([CH3:2])[CH3:3])[S:14][C:13]=2[CH:15]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(O)ccc23)cc1
Yield: 89.2 %

Procedure:
To a solution of (E)-methyl 3-(4-((2-(2-isopropylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30 mg, 0.065 mmol) in DCM (1.5 mL) at 0° C. was added BBr3 (1.0 M in heptane, 0.196 mL, 0.196 mmol) dropwise. After 1 h at 0° C. the reaction was quenched with sat. aq. NaHCO3 and extracted with EtOAc, the combined organic layers were passed through a phase separator and concentrated in vacuo to afford the crude product which was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (E)-methyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (25.8 mg, 0.058 mmol, 89% yield). 1H NMR (400 MHz, CDCl3) δ ppm=7.60 (d, J=15.9 Hz, 1H), 7.40-7.25 (m, 8H), 7.15 (ddd, J=8.1, 5.5, 3.0 Hz, 1H), 6.91-6.85 (m, 3H), 6.29 (d, J=16.0 Hz, 1H), 3.80 (s, 3H), 3.25 (p, J=6.8 Hz, 1H), 1.19 (d, J=6.8 Hz, 6H), LC/MS (m/z, M−H): 443.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:6](Br)=[CH:5][C:4]=1[CH:13]([CH3:15])[CH3:14].O.N.[CH3:18][N:19]1CCCC1=O>>[CH3:1][S:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:6]([C:18]#[N:19])=[CH:5][C:4]=1[CH:13]([CH3:15])[CH3:14]
Reactant: CSc1cc(C(C)C)c(Br)cc1C(C)C
Reactant: CN1CCCC1=O
Agent: N
Solvent: O
Product: CSc1cc(C(C)C)c(C#N)cc1C(C)C
Temperature: 25 °C

Procedure:
4-Cyano-2,5-diisopropylphenyl methyl sulfide was prepared as follows: A mixture of 20.4 g of 4-bromo-2,5-diisopropylphenyl methyl sulfide prepared as in Example 1C and 8.9 g of cuprous cyanide was heated at reflux in 100 ml of N-methylpyrrolidone under nitrogen for 2 hours. After cooling to ambient temperature, the reaction mixture was poured into a mixture of 200 ml of water and 100 ml of concentrated aqueous ammonia. The product was filtered and extracted into ether. The extract was washed with 5% HCl followed by a saturated solution of sodium chloride. The organic layer was dried over sodium sulfate and the solvent removed to give 15.5 g of 4-cyano-2,5-diisopropyl methyl sulfide which was recrystallized from n-hexane giving pure product having a melting point of 72°-75°C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1C(O)=O.B.[CH3:14][OH:15]>O1CCCC1>[O:1]1[C:5]2[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)C1Cc2ccccc2O1
Agent: B
Solvent: C1CCOC1
Product: OCc1cccc2c1OCC2
Temperature: 25 °C

Procedure:
2,3-Dihydrobenzofuran carboxylic acid (5.047 g) in tetrahydrofuran at −10° C. was treated dropwise with a solution of 1.0 M borane.tetrahydrofuran (20 mL). The temperature was allowed to warm to room temperature overnight, treated with additional 1.0 M borane.tetrahydrofuran (10 mL), and stirred at room temperature for 2 hours. The mixture was cooled to 5° C., slowly treated with methanol (20 mL), and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate (2×), saturated sodium chloride, dried (sodium sulfate), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (hexanes:ethyl acetate, 3:2) to provide the title compound. MS (DCI/NH3) m/z 168 (M+NH4)+; 1H NMR (CDCl3) δ 3.21 (t, 2H), 4.60 (t, 2H), 4.68 (s, 2H), 6.83 (t, 1H), 7.08 (dd, 1H), 7.14 (dd, 1H).
Reaction SMILES: [C:1]([CH:9]([CH2:15][C:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[CH:24]=2)[CH:19]=1)=[O:17])C(OCC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCCC1>[CH3:29][O:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([C:16](=[O:17])[CH2:15][CH2:9][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH:27]=[CH:26]2
Reactant: CCOC(=O)C(CC(=O)c1ccc2cc(OC)ccc2c1)C(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)CCC(=O)c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.2 %

Procedure:
Ethyl 2-benzoyl-4-(6-methoxy-2-naphthyl)-4-oxobutanoate (5.00 g, 12.8 mmol), prepared in the previous step, was dissolved in 300 mL of tetrahydrofuran. After complete dissolution of the ester, 1N NaOH solution (28.2 mL, 28.2 mmol) was added to the THF solution. The mixture was heated to gentle reflux for 24 hours, then allowed to cool back to ambient temperature. The mixture was acidified with 1N hydrochloric acid (105 mL) and allowed to stir for 15 minutes. The THF was then removed under reduced pressure and the residue was partitioned between methylene chloride and 1N HCl. The layers were separated, and the aqueous layer was extracted two times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure. Purification on silica gel (300 g, 200–300 mesh) using methylene chloride as the eluent gave 1-(6-methoxy-2-naphthyl)-4-phenylbutane-1,4-dione as a white solid (1.64 g, 40%), mp 163.5–164.5° C. Elemental Analysis for C21H18O3 Calc'd: C, 79.23; H, 5.70; N, 0.00. Found: C, 79.25; H, 5.70; N, 0.00.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3=[O:21])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3=[O:21])[CH2:13][CH2:14]2)[S:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=2)(=[O:32])=[O:31])=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCCCC1N1CCC(Nc2ccc(F)cc2)CC1
Product: COc1ccc(S(=O)(=O)N(c2ccc(F)cc2)C2CCN(C3CCCCC3=O)CC2)cc1

Procedure:
The title compound, MS (ISP): m/e=539.4 (M+H+), was prepared as for example 99, steps (A) to (F). Step (B) was performed using 4-fluoro-aniline, and yielded (+/−)-trans-2-[4-(4-fluoro-phenylamino)-piperidin-1-yl]-cyclohexanol, which was oxidized to (+/−)-2-[4-(4-fluoro-phenylamino)-piperidin-1-yl]-cyclohexanone in step (C). This was then reacted with 4-methoxy-benzensulfonyl chloride in step (D), yielding (+/−)-N-(4-fluoro-phenyl)-4-methoxy-N-[1-(2-oxo-cyclohexyl)-piperidin-4-yl]-benzenesulfonamide. The final step (F) was performed with bromobenzene.
Reaction SMILES: C1([SiH3])C=CC=CC=1.[Cl:8][C:9]1[C:14]([F:15])=[C:13]([CH:16]=[CH2:17])[N:12]=[CH:11][N:10]=1.[Cl:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])=[O:21].C(C1N=CC=CN=1)=C>O1CCCC1.CN([C@@H]([C]1[C](P(C2C=CC=CC=2)C2C=CC=CC=2)[CH][CH][CH]1)C1C=CC=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C.[CH]1[CH][CH][CH][CH]1.[Fe]>[Cl:18][CH2:19][C@@:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])([OH:21])[C@H:16]([C:13]1[C:14]([F:15])=[C:9]([Cl:8])[N:10]=[CH:11][N:12]=1)[CH3:17]
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: C=Cc1ncnc(Cl)c1F
Agent: [Fe]
Agent: C=Cc1ncccn1
Agent: CN(C)[C@@H]([C]1[CH][CH][CH][C]1P(c1ccccc1)c1ccccc1)c1cccc(P(c2ccccc2)c2ccccc2)c1
Solvent: C1CCOC1
Product: C[C@@H](c1ncnc(Cl)c1F)[C@](O)(CCl)c1ccc(F)cc1F
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 148 %

Procedure:
To CuF(PPh3)3 methanol solvate (0.0094 g) and (RP)-1-[(R)-α-(dimethylamino)-2-(diphenylphosphino)benzyl]-2-diphenylphosphinoferrocene (0.0068 g) under argon was added tetrahydrofuran (1 mL). The mixture was stirred at 20° C. (under argon) for 30 minutes until all solids were dissolved. The solution was then cooled to −20° C. and phenyl silane (0.027 g) was added. After 10 minutes, a solution of 4-chloro-5-fluoro-6-vinylpyrimidine (0.180 g) and 2-chloro-1-(2,4-difluorophenyl)ethanone (0.095 g) in tetrahydrofuran (1.5 mL) was added over approximately 5 minutes. The reaction mixture was stirred for 1 hour at −20° C. until complete consumption of the vinyl pyrimidine was observed by HPLC analysis. The reaction was quenched by addition of aqueous ammonium chloride (1 M, 3 mL), followed by methyl tert-butyl ether (5 mL). The organic layer was dried to a residue which was then subjected to purification by column chromatography (eluting with 0-20% ethyl acetate in cyclohexane) to give (2R,3S)-1-chloro-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)butan-2-ol (0.259 g, 65% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:29][CH2:28][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:30]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:27][O:26][C:23]1[N:22]=[CH:21][C:20]([CH2:19][NH:18][C:17]2[C:12]3[CH2:11][N:10]([C:5]4[CH:4]=[CH:3][C:2]([CH3:30])=[CH:9][C:6]=4[C:7]#[N:8])[CH2:29][CH2:28][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:25][CH:24]=1
Reactant: CB(O)O
Reactant: COc1ccc(CNc2ncnc3c2CN(c2ccc(Br)cc2C#N)CC3)cn1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CNc2ncnc3c2CN(c2ccc(C)cc2C#N)CC3)cn1
Temperature: 100 °C

Procedure:
To a mixture of 5-bromo-2-(4-((6-methoxypyridin-3-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (55 mg, 0.12 mmol), methylboronic acid (18 mg, 0.30 mmol), potassium phosphate (90.6 mg, 0.427 mmol), tricyclohexylphosphine (6.8 mg, 0.024 mmol), toluene (3 mL), and water (0.2 mL) under argon was added palladium acetate (2.7 mg, 0.012 mmol). The mixture was heated at 100° C. for 3 h and then cooled to rt. The mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by preparative HPLC to yield an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)#[CH:13].N>>[F:20][C:18]1[CH:19]=[C:14]([C:12]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:13]=2)[CH:15]=[C:16]([F:21])[CH:17]=1
Reactant: C#Cc1cc(F)cc(F)c1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3cc(F)cc(F)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-ethynyl-3,5-difluorobenzene (Apollo, 69 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) 87.16 (tt, J=9.1, 2.2 Hz, 1H), 7.53 (s, 1H), 7.54-7.63 (m, 2H), 8.17 (ddd, J=9.1, 2.8, 1.6 Hz, 1H), 8.62 (d, J=2.8 Hz, 1H), 8.97 (t, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 277 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28]Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[N:31]1[C:39]2[CH2:38][CH2:37][NH:36][CH2:35][C:34]=2[S:33][CH:32]=1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:36]5[CH2:37][CH2:38][C:39]6=[N:31][CH2:32][S:33][C:34]6=[CH:35]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: c1nc2c(s1)CNCC2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3C=C4SCN=C4CC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine following a procedure analogous to that described for Intermediate 42. LC (method 1): tR=1.16 min; Mass spectrum (ESI+): m/z=545 [M+H]+.
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C@H:12]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:23][C:15]2[C:16]3[CH:17]=[N:18][NH:19][C:20]=3[CH:21]=[CH:22][C:14]=2[CH2:13]1.[CH3:32][N:33]1[C:37]2([CH2:46][CH2:45][C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:47](O)=[O:48])[CH:43]=3)[CH2:38]2)[C:36](=[O:50])[NH:35][C:34]1=[O:51].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:29][C:28]([CH3:31])([CH3:30])[CH2:27][N:24]1[C:25](=[O:26])[C@H:12]([NH:11][C:47]([C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[CH2:38][C:37]2([C:36](=[O:50])[NH:35][C:34](=[O:51])[N:33]2[CH3:32])[CH2:46][CH2:45]3)=[O:48])[CH2:13][C:14]2[CH:22]=[CH:21][C:20]3[NH:19][N:18]=[CH:17][C:16]=3[C:15]=2[CH2:23]1
Reactant: CN1C(=O)NC(=O)C12CCc1cc(C(=O)O)ccc1C2
Reactant: CC(C)(C)CN1Cc2c(ccc3[nH]ncc23)C[C@@H](N)C1=O
Agent: CS(=O)(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1C(=O)NC(=O)C12CCc1cc(C(=O)N[C@@H]3Cc4ccc5[nH]ncc5c4CN(CC(C)(C)C)C3=O)ccc1C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 7-(R)-amino-9-(2,2-dimethylpropyl)-6,7,9,10-tetrahydro-3H-2,3,9-triazacyclohepta[e]inden-8-one bis-methanesulfonate (110 mg, 0.23 mmol) [Chaturvedula et al. WO 2006/052378], (±)-3-methyl-2,5-dioxo-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-6′-carboxylic acid (77 mg, 0.28 mmol) [Bell et al. WO 2004/082605], HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (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 (2×20 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: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CC(N(C)C)=O>[N+:11]([C:5]1[CH:4]=[CH:3][C:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([O-:13])=[O:12]
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A mixture of 5-chloro-2-nitrobenzoic acid (13.7 g), piperidine (27 ml) and DMA (100 ml) was stirred and heated to 120° C. for 18 hours. The mixture was evaporated. The residue was dissolved in water and the solution was basified to pH10 by the addition of 2N aqueous sodium hydroxide solution. The solution was extracted with ethyl acetate. The aqueous layer was acidified to pH2 by the addition of concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated to give 2-nitro-5-piperidinobenzoic acid (16.25 g), m.p. 130°-140° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[CH2:22][C@H:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:29][CH:28]=2)=[O:26])[CH2:20][CH2:19]3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[CH2:22][C@H:21]([NH:24][C:25](=[O:26])[C:27]2[CH:32]=[CH:31][C:30]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[CH:29][CH:28]=2)[CH2:20][CH2:19]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCOCC4)cc2)CC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CCc2cccc(N3CCNCC3)c2C1)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 69 %

Procedure:
To an ice-cooled solution of (R)-N-[8-(4-tert-butyloxycarbonylpiperazin-1-yl)-1,2,3,4 tetrahydro-2-naphthyl]-4-morpholinophenylcarboxamide (1.0 g, 2 mmol) in methylene chloride (100 mL) was added trifluoroacetic acid (3 mL). The reaction was stirred at ambient temperature for 7 h. The solvent was evaporated in vacuo and the residue was dissolved in water (20 mL), alkalized with a 2 M aqueous sodium hydroxide solution and extracted, twice, with methylene chloride. The phases were separated, the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. Purification on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent gave 580 mg (70% yield) of the title compound as white crystals: mp 202-203° C.;