Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:46][O:47][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:57]=1[CH2:56][CH:55]([NH:58][CH2:59][CH2:60][CH3:61])[CH2:54][CH2:53]2>CN(C=O)C>[CH3:46][O:47][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:57]=1[CH2:56][CH:55]([N:58]([CH2:59][CH2:60][CH3:61])[C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:54][CH2:53]2
Reactant: CCCNC1CCc2cccc(OC)c2C1
Reactant: Cc1ccc(C)c(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(C(=O)Cc1cc(C)ccc1C)C1CCc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 340 mg (2.1 mmol) 2,5-dimethylphenylacetic acid (A3-4: W=OH, Cy=2,5-dimethylphenyl) and 0.70 mL diisopropylethylamine (DIPEA) (4.24 mmol) in 10 mL of dry DMF was cooled in an ice-bath. After addition of 950 mg (2.5 mmol) O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) in 5.0 mL dry DMF a solution of 640 mg (2.9 mmol) of the free base of N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1) in 8.0 mL dry DMF was added dropwise, the ice-bath was removed and the reaction mixture was stirred for 3 hrs at room temperature. The mixture was washed with a saturated solution of aqueous NaHCO3 for several times and the resulting aqueous layer was extracted with CH2Cl2. The organic layers were dried over MgSO4 and the solvent was evaporated in vacuo. Flash chromatography of the residue on silica gel with a mixture of hexane/ethyl acetate 60/10 gave the product N-(8-methoxytetralin-2-yl)-N-propyl-2-(2,5-dimethylphenyl)acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[F:27])=[C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=3[F:27])=[C:15]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=2)[CH:7]=1
Reactant: Oc1cncc(Br)c1
Reactant: COc1ccc(F)c(-c2ccc(CCl)cc2C(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(COc3cncc(Br)c3)cc2C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
A dry round bottom flask containing 3-bromo-5-hydroxypyridine (0.1304 g, 0.749 mmol) (commercially available from Aldrich) in dry DMF (2 mL) was cooled in an ice bath. After 10 minutes, sodium hydride (0.0361 g, 0.903 mmol) (60% wt in oil) was added carefully, and the mixture was stirred at 0° C. After 10 minutes, 8.10 (0.2301 g, 0.750 mmol) was added. The reaction was allowed to stir overnight at room temperature. After 18 hours, the reaction was diluted with water and then extracted five times with EtOAc. The combined organic layers wee then washed one time with brine and dried over anhydrous magnesium sulfate. The solid was filtered off, and the solvent was concentrated. The residue was purified by silica gel flash chromatography (0-25% EtOAc/hexane) to afford 96.A (203.4 mg, 61% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.36 (2H, dd, J=13.1, 2.2 Hz), 7.62 (1H, d, J=1.6 Hz), 7.57 (1H, m), 7.29 (1H, dd, J=7.6, 1.8 Hz), 7.10 (1H, d, J=7.4 Hz), 7.02 (1H, t, J=8.8 Hz), 6.95 (2H, m), 5.14 (2H, s), 3.80 (3H, s), 1.27 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][C@H:19](O)[CH2:18][C@H:17]1[C:22]([N:24]1[CH2:30][CH2:29][CH2:28][N:27]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[CH2:26][CH2:25]1)=[O:23])=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH:19]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:18][C@H:17]1[C:22]([N:24]1[CH2:30][CH2:29][CH2:28][N:27]([CH:31]2[CH2:32][CH2:33][CH2:34]2)[CH2:26][CH2:25]1)=[O:23])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Reactant: Oc1cccc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Oc2cccc(F)c2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1

Procedure:
Reaction of 3-fluorophenol and (2S,4R)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester was performed as described in Example 11, using resin bound triphenylphosphine and CH2Cl2 to give the title compound as a mixture of diastereomers (89:11), as determined by chiral SFC. MS (ESI): mass calcd. for C25H36FN3O4, 461.27; m/z found, 462.3 [M+H]+. 1H NMR (CDCl3): 7.25-7.16 (m, 1H), 6.69-6.53 (m, 3H), 5.01-4.69 (m, 2H), 3.89-3.42 (m, 6H), 2.92-2.79 (m, 1H), 2.69-2.20 (m, 6H), 2.06-1.72 (m, 6H), 1.71-1.53 (m, 2H), 1.44-1.39 (m, 9H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH2:9][F:10].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])#[N:12].O>CN(C=O)C>[F:10][CH2:9][CH2:8][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]#[N:12]
Reactant: FCCBr
Reactant: N#Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1OCCF
Temperature: 70 °C
Yield: 84.7 %

Procedure:
K2CO3 (1.74 g, 12.5 mmol) and 1-bromo-2-fluoro ethane (0.78 mL, 10.47 mmol) were added to a solution of 2-cyanophenol 134 (0.5 g, 4.19 mmol) in anhydrous DMF (10 mL), and heated at 70° C. for 45 min. After completion, the reaction mixture was cooled to room temperature and water (10 mL) was added and the mixture extracted with diethyl ether. The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified on flash silica gel column chromatography (hexane:ethyl acetate=2:1) to give the compound 135 (0.586 g, 84%) as a white solid. 1H NMR (CDCl3, 300 MHz) d 7.51-7.58 (m, 2H), 6.98-7.07 (m, 2H), 4.89 (t, J=3.9 Hz, 1H), 4.73 (t, J=4.2 Hz, 1H), 4.40 (t, J=3.9 Hz, 1H), 4.31 (t, J=3.9 Hz, 1H). HRMS calculated for C8H7NOF (M+H)+: 152.0513. found 152.0539.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1.[CH:23]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH2:24].C(N(CC)CC)C.Cl>CN(C)C=O.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>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:24]=[CH:23][S:25]([NH2:28])(=[O:27])=[O:26])[CH:16]=1
Reactant: C=CS(N)(=O)=O
Reactant: Nc1c(C(=O)c2cccc(Br)c2)cnn1-c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1c(C(=O)c2cccc(C=CS(N)(=O)=O)c2)cnn1-c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (1.5 g, 4.14 mmol) [prepared as described in Example 1 above], vinylsulfonamide (1.33 g, 12.4 mmol), bis(triphenylphosphine)palladium chloride (0.3 g, 0.42 mmol) and triethylamine (6 ml, 43 mmol) in dimethylformamide (18 ml) was heated at 100° C. under argon. After 16 h, the reaction mixture was cooled to room temperature and poured into 1 N hydrochloric acid. The product was extracted into ethyl acetate, washed with brine, dried over sodium sulfate and filtered. The organic layer was removed in vacuo and the residue was purified by flash chromatography (elution gradient: 40-80% ethyl acetate/hexane) to give 5-amino-4-[3-(2-aminosulfonylethenyl)benzoyl]-1-(4-fluorophenyl)pyrazole which was recrystallized from a mixture of methanol/ethyl acetate/hexane to give 0.78 g of the desired product.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[CH2:13][O:12][CH2:11][O:10][C:8]3=[CH:9][C:4]=2[N:3]=[C:2]1[SH:14].[OH-].[Na+].[ClH:17].[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][Cl:26])=[N:23][CH:24]=1>O>[ClH:26].[ClH:17].[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][S:14][C:2]2[NH:1][C:5]3[CH:6]=[C:7]4[CH2:13][O:12][CH2:11][O:10][C:8]4=[CH:9][C:4]=3[N:3]=2)=[N:23][CH:24]=1
Reactant: Sc1nc2cc3c(cc2[nH]1)COCO3
Reactant: Cc1ccc(CCl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(CSc2nc3cc4c(cc3[nH]2)COCO4)nc1
Reaction time: 0.5 h

Procedure:
To 3.7 g of 1,8-dihydro-m-dioxino(4,5-f)benzimidazole-2-thiol, suspended in 60 ml of alcohol, were added dropwise while stirring 1.5 g of sodium hydroxide in 30 ml of water and, after 30 minutes, there were added 3.4 g of 5-methyl-2-chloromethylpyridine hydrochloride. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in methylene chloride. This mixture was washed first with 3 N sodium hydroxide, then neutral with water, dried over sodium sulfate and evaporated in vacuo. The crude product was dissolved while heating in a small amount of methanol and treated with 25 ml of 5 N hydrochloric acid in ethylacetate. There was obtained 1,8-dihydro-2-[[(5-methyl-2-pyridyl)methyl]thio]-m-dioxino(4,5-f)benzimidazole dihydrochloride of melting point 153°-155° C.
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([OH:22])[CH:20]=[CH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(OCC)(=O)C>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]2=[N:10][C:9]=1[CH:19]([OH:22])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C=CC(O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.8 %

Procedure:
A mixture of 0.097 g (0.33 mmol) of the product from Step 7 (23) and 0.02 g of Palladium on activated carbon was stirred in 5 mL of ethyl acetate. The flask was equipped with a balloon containing hydrogen gas and the reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was then filtered through celite and washed with ethyl acetate. The resulting organic mixture was concentrated yielding 0.084 g (0.28 mmol, 85%) of 3-benzyl-2-(1-hydroxypropyl)-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (24) as a clear oil.
Reaction SMILES: Br[N:2]1[C:6]2[N:7]=[CH:8][CH2:9][NH:10][C:5]=2[CH:4]=[CH:3]1.[C:11]([C:13]1[CH:14]=[C:15]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[C:26]([C:38]([F:41])([F:40])[F:39])[CH:25]=2)=[O:22])[CH:16]=[CH:17][C:18]=1[CH3:19])#[CH:12]>>[NH:10]1[CH2:9][CH:8]=[N:7][C:6]2[N:2]([C:12]#[C:11][C:13]3[CH:14]=[C:15]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[C:26]([C:38]([F:41])([F:39])[F:40])[CH:25]=4)=[O:22])[CH:16]=[CH:17][C:18]=3[CH3:19])[CH:3]=[CH:4][C:5]1=2
Reactant: Brn1ccc2c1N=CCN2
Reactant: C#Cc1cc(NC(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Product: Cc1ccc(NC(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cn1ccc2c1N=CCN2

Procedure:
The title compound was prepared using 5-bromo-1H-pyrrolo[2,3-b]pyrazine and N-(3-ethynyl-4-methylphenyl)-N′-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]urea as raw materials, according to the method described in Step 4 of Example 1.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[N:4]=1.C(N1C=CN=C1)([N:25]1[CH:29]=[CH:28]N=C1)=O.C(N)C>ClCCl.O1CCCC1>[CH2:29]([NH:25][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:22])[F:21])=[N:4]2)=[CH:13][CH:14]=1)[CH3:28]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: CCN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A suspension of 4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]benzoic acid (310 mg, 1.0 mmol) in dichloromethane (5 ml) was treated with 1,1′-carbonyldiimidazole (162 mg, 1.0 mmol) at room temperature under argon. This mix was stirred for 30 minutes and then treated with a 2M solution of ethylamine in tetrahydrofuran (0.5 ml). The whole mix was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate. The organic layer was separated, dried over sodium sulphate and reduced to minimum volume by rotary evaporation to give a beige solid (250 mg) which was purified by column chromatography on a 5 g pre-packed silica column, eluting from 0-50% ethyl acetate in petroleum ether to give the title compound as a colourless solid (128 mg, 38%).
Reaction SMILES: Cl.[CH2:2]([NH:10][NH2:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([NH2:17])(=[O:16])[C:13]([CH3:15])=O.O.O.O.C([O-])(=O)C.[Na+]>O>[CH2:2]([NH:10][N:11]=[C:13]([CH3:15])[C:12]([NH2:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)C(N)=O
Reactant: NNCCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=NNCCc1ccccc1)C(N)=O

Procedure:
3.4 g. Phenethylhydrazine hydrochloride are dissolved in 10 ml. water and mixed with 1.7 g. pyruvamide dissolved in 50 ml. water. 2.1 g. sodium acetate trihydrate are added thereto and the reaction mixture well shaken up. 2-(Phenethylhydrazono)-propionamide crystallizes out. It is filtered off and recrystallized from a mixture of cyclohexane and toluene. The yield is 2.0 g. (50% of theory); m.p. 78° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7]O)[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:34]I>C1(C)C=CC=CC=1>[I:34][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1
Reactant: CC1(C)OCC(CO)O1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OCC(CI)O1
Temperature: 90 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (10 g, 75.67 mmol) in dry toluene (200 mL) was added triphenylphospine (23.82 g, 90.81 mmol), imidazole (15.45 g, 227 mmol), and iodine (24.97 g, 98.36 mmol). The mixture was stirred at 90° C. for 3 h. The solvent was then removed in vacuo and the residue was dissolved in DCM (200 mL) and washed with saturated Na2S2O3 solution water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude compound was purified on column of silica gel (DCM) to give the subject compound (15.79 g, yield 86%). Intermediate 12 was characterized by the following spectroscopic data: 1H NMR (CDCl3-d1, 300 MHz) δ (ppm) 4.33 (m, 1H), 4.19 (m, 1H), 3.82 (m, 1H), 3.32 (m, 1H), 3.27 (m, 1H), 1.49 (s, 3H), 1.38 (s, 3H).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)=O.Cl.[CH2:28](O)C>>[NH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([O:23][CH2:24][CH3:28])=[O:22])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CCO
Reactant: COC(=O)c1ccc(-c2ccc(CCCNC(=O)C(F)(F)F)cc2)cc1
Agent: Cl
Product: CCOC(=O)c1ccc(-c2ccc(CCCN)cc2)cc1

Procedure:
A mixture of methyl 4′-[3-[(trifluoroacetyl)amino]-propyl]-1,1′-biphenyl-4-carboxylate (920 mg), 4N hydrochloride in ethanol (2 ml) and ethanol (2 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo. The residue was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (chloroform:methanol=100:1) to give ethyl 4′-(3-aminopropyl)-1,1′-biphenyl-4-carboxylate (200 mg) as a colorless foam.
Reaction SMILES: C[CH2:2][S:3]([N:6]([C:10]1[CH:15]=[C:14]([CH2:16]O)[CH:13]=[C:12]([CH2:18][O:19][CH2:20][C:21]([NH2:30])([CH3:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=1)[CH2:7][CH2:8][CH3:9])(=[O:5])=[O:4].C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[NH2:30][C:21]([CH3:29])([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][O:19][CH2:18][C:12]1[CH:11]=[C:10]([N:6]([CH2:7][CH2:8][CH3:9])[S:3]([CH3:2])(=[O:5])=[O:4])[CH:15]=[C:14]([CH2:16][Br:32])[CH:13]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCN(c1cc(CO)cc(COCC(C)(N)Cc2ccccc2)c1)S(=O)(=O)CC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCN(c1cc(CBr)cc(COCC(C)(N)Cc2ccccc2)c1)S(C)(=O)=O
Reaction time: 15 h

Procedure:
To a solution of methyl N-[3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-(hydroxymethyl)phenyl]-N-propylmethanesulfonamide (140 mg, 0.269 mmol) in dichloromethane (2.5 mL) were added carbon tetrabromide (116 mg, 0.350 mmol) and triphenylphosphine (85.0 mg, 0.323 mmol). After 15 h, the reaction mixture was concentrated in vacuo and purified by flash chromatography (silica, 0-35% EtOAc/hexanes) to provide N-[3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-(bromomethyl)phenyl]-N-propylmethanesulfonamide as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.31 (s, 1H),), 7.30-7.20 (m, 4H), 7.18-7.14 (m, 2H), 4.60-4.50 (m, 3H), 4.49 (s, 2H), 3.64 (t, J=7.2 Hz, 2H), 3.55 (A of AB, d, J=8.7 Hz, 1H), 3.45 (B of AB, d, J=8.7 Hz, 1H), 3.14 (A of AB, d, J=13.3 Hz, 1H), 2.94 (B of AB, d, J=13.3 Hz, 1H), 2.88 (s, 3H), 1.56-1.47 (m, 2H), 1.46 (s, 9H), 1.27 (s, 3H), 0.91 (t, J=7.4 Hz, 3H).
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][NH2:11])=O)(C)(C)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>>[CH3:6][NH:8][CH2:9][CH2:10][NH:11][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Product: CNCCNS(C)(=O)=O

Procedure:
By using N-t-butoxycarbonyl-N-methylethylenediamine (500 mg) and methanesulfonyl chloride (289 μl) as starting materials, the title compound (260 mg) was obtained in the same manner as that of Reference Example 58.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:14]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].C=O.[C:31](O)(=O)C.[Na]>C1COCC1>[CH3:1][C:2]([CH3:28])([CH3:27])[C@H:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:14]2[CH2:20][CH2:19][CH2:18][N:17]([CH3:31])[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CC(=O)O
Reactant: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CNCCC2)C(C)(C)C
Agent: C=O
Agent: [Na]
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C)CCC2)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Compound 314 (0.38 g), 30% aqueous paraformaldehyde (0.8 mL) and acetic acid (60 μL) in THF was added sodium triacetoxyboronhydride (0.42 g). After stirring at room temperature for two hours, the THF was removed by evaporation under reduced pressure. The residue was partitoned between saturated aqueous NaHCO3 and EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography with 10% to 60% MeOH in DCM. The combined pure fractions were evaporated to give a white solid, which was triturated in EtOAc/DCM (2:1) and filtered. The filtrate was evaporated to dryness under reduced pressure. The resulting residue was extracted between water and DCM. The organic phase was dried over anhydrous Na2SO4 and evaporated to give Compound 317 (0.31 g). 1H-NMR (400 MHz, CDCl3) δ: 1.27 (s, 9H), 1.90 (br, 2H), 2.47 (s, 3H), 2.79 (d, J=4.8 Hz, 3H), 3.04 (br, 2H), 4.16 (br, 2H), 4.29 (d, J=9.5 Hz, 1H), 4.32 (br, 2H), 5.95 (br, 1H), 7.20-7.23 (dd, J=2.0, 9.6 Hz, 1H), 7.47-7.53 (m, 5H), 7.82 (d, J=9.5 Hz, 1H). LCMS (+ESI) m/z 398.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](O)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:42])=O>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([Cl:42])=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Reaction time: 2 h

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid (0.29 g) in dry dichloromethane (9 mL) was treated with oxalyl chloride (0.21 g) for 30 minutes. One drop of N,N-dimethylformamide was added and the reaction mixture stirred for a further 2 hours. The reaction mixture was concentrated under reduced pressure and the product used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.C(O)C.[Pd]>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COc1ccc(F)c2c1C=CN(C(=O)C(F)(F)F)CC2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(F)c2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 91.1 %

Procedure:
Dissolve 9-fluoro-6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-benzo[d]azepine (9.4 g, 32.4 mmol) with 10% Pd/C (dry basis, Degussa type, 1.4 g, 0.65 mmol) in EtOAc/ethanol (1:1, 200 mL) and stir at ambient temperature under a balloon of hydrogen for 4.5 h. Filter the mixture through a pad of silica gel and evaporate the filtrate to obtain the desired intermediate (8.6 g, 91%). MS (ES+) m/z: 292 (M+H)+.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([O:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([C@H:30]3[CH2:32][C@H:31]3[CH2:33][CH2:34][OH:35])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)[CH3:16].[Br:36][C:37]1[C:42]([F:43])=[CH:41][C:40](O)=[CH:39][C:38]=1[F:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:36][C:37]1[C:42]([F:43])=[CH:41][C:40]([O:35][CH2:34][CH2:33][C@@H:31]2[CH2:32][C@@H:30]2[CH:27]2[CH2:26][CH2:25][N:24]([C:21]3[N:22]=[CH:23][C:18]([O:17][CH2:15][CH3:16])=[CH:19][N:20]=3)[CH2:29][CH2:28]2)=[CH:39][C:38]=1[F:45]
Reactant: Oc1cc(F)c(Br)c(F)c1
Reactant: CCOc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(Br)c(F)c3)CC2)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
DIAD (2.45 mL, 12.6 mmol) was slowly added to a solution of 2-((1S,2R)-2-(1-(5-ethoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethanol (2.45 g, 8.41 mmol), 4-bromo-3,5-difluorophenol (1.93 g, 9.25 mmol), and triphenylphosphine (3.31 g, 12.6 mmol) in DCM (30 mL) that had been cooled to 0° C. The ice bath was removed and the resulting mixture was stirred at rt for 3 hrs. The reaction mixture was diluted with DCM (20 mL) and washed with a 2 N NaOH solution (30 mL×1). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (KP-Sil 100 g SNAP column, Biotage system) eluting with 5-40% EtOAc:hexanes over 12 CV to afford the title compound. LC/MS (m/z): 482 (M+H)+.