Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.CCN(C(C)C)C(C)C.[NH:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH2:33]>ClCCl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:33][NH:32][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:11])[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(C(=O)O)n1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)NNC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 6-(methyloxy)-2-pyridinecarboxylic acid (1.00 g, 6.53 mmol) in dichloromethane (DCM) (13.52 ml) was stirred and cooled to 0° C. Oxalyl chloride (0.686 ml, 7.84 mmol) was added dropwise followed by DMF (5.06 μl, 0.065 mmol). The solution immediately turned yellow and the reaction was followed by LCMS. LCMS after circa 1 hour showed the methyl ester of the acid chloride to be present. The solvent was removed under reduced pressure and the residue was azeotroped with toluene. The residue was dissolved in dichloromethane (DCM) (27.0 ml) and cooled to 0° C. DIPEA (1.711 ml, 9.80 mmol) was added dropwise followed by 1,1-dimethylethyl hydrazinecarboxylate (0.949 g, 7.18 mmol) and the solution was left to stir at 20° C., under an argon atmosphere for 18 hours. A dark brown solution formed and LCMS showed the desired compound to be present. The solvent was removed under reduced pressure and the residue was diluted with dichloromethane and washed with saturated sodium bicarbonate, saturated ammonium chloride, water and brine. The organic extracts were dried over magnesium sulfate and the solvent was removed under vacuum to yield the desired product in 1.685 g.
Reaction SMILES: [CH:1]1([C:4]#[N:5])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([C:1]1([C:4]#[N:5])[CH2:3][CH2:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: N#CC1CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of cyclopropyl cyanide (3.0 mL, 40 mmol) in 20 mL THF was dropwise added to a stirred, freshly prepared, mixture of lithium diisopropylamide (40 mmol) in THF (100 mL) at −78° C. After 30 min, a solution of benzyl bromide 7.8 mL, 60 mmol) in THF (20 mL) was dropwise added. The resulting mixture was warmed slowly over several hrs and stirred at rt 48 h. The reaction was quenched (250 mL saturated NH4Cl), extracted with ether (3×100 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated to afford a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]=2[S:4](=[O:16])(=[O:15])[NH:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[Na].Cl[CH2:19][C:20](=[O:22])[CH3:21]>CO>[CH2:19]([N:3]1[C:2](=[O:1])[C:6]2[CH:7]=[CH:8][C:9]3[C:14]([C:5]=2[S:4]1(=[O:16])=[O:15])=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:20]([CH3:21])=[O:22]
Reactant: CC(=O)CCl
Reactant: O=C1NS(=O)(=O)c2c1ccc1ccccc21
Agent: [Na]
Solvent: CO
Product: CC(=O)CN1C(=O)c2ccc3ccccc3c2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
46.6 gm (0.2 mol) of 3-oxo-naphth[2,1-d]isothiazoline -1,1-dioxide were added to a solution of 5.3 gm (0.23 gm-atom) of sodium in 150 ml of methanol and the majority of the alcohol was distilled off. The residue was taken up in 50 ml of dry dimethyl sulfoxide. 23.2 gm (20 ml; 0.25 mol)of chloroacetone were added dropwise over a period of 10 minutes, and the resulting mixture was stirred at room temperature for 30 minutes and was then heated at 120° C for 2.5 hours. The dimethyl sulfoxide was then partly distilled off in vacuo, a solution of 25 gm of sodium acetate in 250 ml of water was added to the residue, accompanied by exterior cooling, and the resulting mixture was thoroughly stirred. The precipitatewhich had formed was suction-filtered off and washed first with water and then with a small quantity of ice-cold ethanol. The crude product (52.3 gm; 90% of theory) thus obtained, m.p. 163°-165° C, may be used as such in the next reaction step. Pure 2-acetonyl-3-oxo-naphth[2,1-d]isothiazoline-1,1-dioxide, recrystallized from ethanol, melted at 164°-165° C.
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].C([Li])CCC.[N:10]1([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[O:17])[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)(O)[O-].[Na+]>O1CCCC1.CCCCCC.C(O)(=O)C>[C:1]([CH:2]([CH3:3])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])([OH:17])[CH2:15][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)#[N:4]
Reactant: CCC#N
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(C#N)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Propionitrile (1.21 g) in dry tetrahydrofuran (50 ml) was cooled to -72° C. A solution of n-butyllithium in n-hexane (14.2 ml, 1.55 molar) was then slowly added while maintaining the temperature of the reaction mixture at -45° C. or below. After stirring for about 30 minutes, 2-(1H-1,2,4-triazol-1-yl)-2',4'-dichloroacetophenone (2.56 g) in dry tetrahydrofuran (THF) (50 ml) was added slowly with stirring over a 20 minute period, the temperature of the mixture being maintained at -70° C. Stirring was continued at this temperature for one hour and then at -10° for a half hour, then glacial acetic acid (10 ml) in dry THF (15 ml) was added. The reaction mixture was allowed to warm to room temperature (20° C.), adjusted to pH 8 with solid sodium bicarbonate, and extracted with ethyl acetate (3×75 ml). The combined organic extracts were washed three times with water, dried (MgSO4), evaporated and ethyl ether (30 ml) was added to the residue, yielding a white crystalline solid and a yellow solution. The solid was filtered off, dissolved in a small volume of methylene chloride, and loaded onto an 18 g flash chromatography column of Merck's "Kieselgel 60" (Trade Mark) 230-400 mesh silica in ether (11×2 cm. diameter). Elution was carried out using 5% (by volume) acetone in ether at one p.s.i. (0.07 kg/m2) "Diastereoisomer 1" of the title compound was eluted first, 0.79 g, m.p. 178°-180° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16](=[O:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[H-].[Na+].[CH2:21](I)[CH2:22][CH3:23]>CN(C=O)C>[CH3:13][C:9]1([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]2[CH:4]=[C:3]([C:16](=[O:18])[CH3:17])[C:2]([O:1][CH2:21][CH2:22][CH3:23])=[CH:11][C:10]1=2
Reactant: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1cc2c(cc1C(C)=O)C(C)(C)CCC2(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (Intermediate 4, 6.4 g, 26 mmol) in DMF (100 mL) at 0° C. was added NaH (1.2 g, 60%, 31 mmol). After stirring for 30 min, PrI (3.0 mL, 31 mmol) was added. The reaction was stirred at 0° C. for 4 h, was quenched with aqueous NH4Cl and extracted with Et2O (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.C([O-])(O)=O.[Na+].[N:25]1[C:32]([Cl:33])=[N:31][C:29](Cl)=[N:28][C:26]=1[Cl:27]>C1COCC1>[CH2:13]([O:12][C:4]1[CH:3]=[C:2]([NH:1][C:29]2[N:31]=[C:32]([Cl:33])[N:25]=[C:26]([Cl:27])[N:28]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:11])[CH3:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(=O)Nc1ccc(N)cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
N-(4-Amino-2-benzyloxy-phenyl)-acetamide (399) (0.65 g, 2.54 mmol) and NaHCO3 (1.28 g, 15.24 mmol) were suspended in THF (100 mL) and chilled on a dry-ice/acetone bath. The cyanuric chloride (5) (0.465 g, 2.54 mmol) was dissolved in THF (4 mL) and added to the chilled solution. The ice-bath was removed and the mixture was stirred while warming to room temperature over a period of 45 minutes. TLC (Rf: 0.6 compared to Rf: 0.1 for compound 399 and Rf: 0.95 for compound 400 in 1:1 hexane/EtOAc, single spot) indicated complete reaction at this point. This reaction mixture was used directly in the next step without further purification or characterization.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[CH2:52]([N:54]=[C:55]=[O:56])[CH3:53]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:55]([NH:54][CH2:52][CH3:53])=[O:56])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Reactant: CCN=C=O
Agent: O=C([O-])C(F)(F)F
Product: CCNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and ethyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 1.03 (t, 7 Hz, 3H), 1.39 (s, 6H), 1.82 (m, 1H), 2.18-2.58 (m, 3H), 3.07 (q, 2H), 4.12 (s, 2H), 4.32 (m, 1H), 4.87 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.31 (d, 15 Hz, 1H), 7.08-7.40 (m, 17H). FAB-MS: calculated for C39H43N5 O5 661; found 662 (M+H, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=2)[O:3]1.[CH3:17][C:18]([NH2:22])([CH3:21])[C:19]#[CH:20]>CN(C=O)C.CCN(CC)CC.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>[CH3:17][C:18]([NH2:22])([CH3:21])[C:19]#[C:20][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5]2)=[CH:10][CH:11]=1
Reactant: C#CC(C)(C)N
Reactant: CC1(C)OB(c2ccc(Br)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(N)C#Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)bromobenzene (J. Organomet. Chem. 2006, 691 (26), 5725) (200 mg; 0.71 mmol) 1,1-dimethyl-prop-2-ynylamine (350 mg; 4.25 mmol) Pd(PPh3)2Cl2 (99 mg; 0.14 mmol) and Cul (27 mg; 0.14 mmol) are dissolved in DMF/NEt3 (3.5 ml/1.5 ml) and microwaved at 100° C. for 20 minutes. The reaction mixture is evaporated and purified via chromatography (SiO2; TBME/MeOH/M/NH3conc 95:5:0.8) to yield the title compound as yellowish crystals. H-NMR (400 Hz; DMSO-d6): 7.64 (d, 2H); 7.38 (d, 2H); 2.08 (bs, 2H); 1.39 (s, 6H); 1.31 (s, 12H). MS (m/z) ES+: 285 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)[C:35]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][N:51]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc([N+](=O)[O-])cn1)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
A solution of triphenylphosphine (393 mg, 1.5 mmol) in methylene chloride (10.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (303 mg, 1.7 mmol). After stirring at 0° C. for 10 min, the reaction mixture was treated with 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 87, 304 mg, 1.0 mmol). The reaction mixture was stirred at 0° C. for 20 min and at 25° C. for 30 min. At this time, the reaction mixture was treated with 2-amino-5-nitropyridine (290 mg, 1.5 mmol) and pyridine (0.14 mL, 1.8 mmol). The resulting reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 200–400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide (425 mg, 60%) as a white solid: mp 121–122° C.; EI-HRMS m/e calcd for C20H19F4N3O3 (M+) 425.1363, found 425.1363.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-])=O)=[CH:6][C:5]=1[F:14])[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4]1[C:5]([F:14])=[CH:6][C:7]([NH2:11])=[C:8]([F:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(F)c([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc(F)c(N)cc1F
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of 1-ethoxy-2,5-difluoro-4-nitro-benzene (1.00 g, 4.92 mmol) and palladium on carbon (10%, 50% water, 307 mg) in ethanol (20 mL) were shaken in a hydrogenator under H2 atmosphere at 45 psi. After 30 minutes, solids were filtered off, washed with ethanol, and filtrate was concentrated to give 4-ethoxy-2,5-difluoro-phenylamine as a red solid (835 mg, 98%). 1HNMR (CDCl3, 400 MHz) δ 6.72-6.67 (m, 1H), 6.58-6.53 (m, 1H), 4.03-3.97 (q, J=7.0 Hz, 2H), 3.50 (s br, 2H), 1.41-1.37 (t, J=7.0 Hz, 3H). Exact mass calculated for C8H9F2NO 173.07 found 174.2 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH3:11])[N:4]=1.N12CCN(CC1)CC2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[S:28]([N:31]=[C:32]=[O:33])(=[O:30])=[O:29]>C(#N)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH3:11])[N:4]=[C:3]([N:2]([CH3:1])[C:32]([NH:31][S:28]([C:22]2[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=2[Cl:20])(=[O:29])=[O:30])=[O:33])[N:8]=1
Reactant: CNc1nc(C)cc(OC)n1
Reactant: O=C=NS(=O)(=O)c1cc(Cl)ccc1Cl
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1cc(C)nc(N(C)C(=O)NS(=O)(=O)c2cc(Cl)ccc2Cl)n1
Reaction time: 16 h
Yield: 57.4 %

Procedure:
To a stirred mixture of 0.8 g of 2-methylamino-4-methoxy-6-methylpyrimidine in 25 ml of acetonitrile containing a few crystals of 1,4-diazabicyclo[2.2.2]octane was added dropwise 1.3 g of 2,5-dichlorobenzenesulfonyl isocyanate. The mixture was stirred for 16 hours and the resultant solid was filtered to afford 1.2 g of N-[N-(4-methoxy-6-methylpyrimidine-2-yl)-N-methylaminocarbonyl]-2,5-dichlorobenzenesulfonamide melting at 182°-185°. Infrared absorption spectrum showed peaks at 1690 cm-1, 1590 cm-1, and 1550 cm-1 which are typical for this type of compound.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[CH3:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[C:31]1([CH2:5][CH2:7][CH2:8][CH:9]=[CH:9][CH2:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:30]=[CH:29][CH:34]=[CH:33][CH:32]=1
Reactant: CCCCCC
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCC=CCCCc1ccccc1

Procedure:
First, 207 mg of metalic sodium was dissolved in 4 ml of absolute ethanol, and the ethanol was evaporated off to obtain sodium ethoxide powder, to which was then added at once a solution of 4.75 g ethoxycarbonylpropyltriphenylphosphonium bromide in 15 ml of absolute dimethylformamide with stirring. The mixture was stirred for 1.5 hours, and after adding dropwise a solution of 1.04 g 4-phenylbutylaldehyde in 5 ml of absolute dimethylformamide at 5° C. over 5 minutes, stirred overnight at a room temperature. To the reaction mixture were added 100 ml of n-hexane and 30 ml of water and the resulting layers were separated, and the aqueous solution was extracted with 20 ml of n-hexane. The n-hexane layers were combined, washed with water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated under a reduced pressure to obtain an oily residue. The residue was applied to a silica gel column and eluted with n-hexane/ethyl acetate (50:1) to obtain 831 mg of the title compound as a colorless liquid.
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:2]([C:7]([N:9]2[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:10]2[CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.NN>CO>[NH2:16][CH2:15][C@@H:10]1[CH2:11][C@@H:12]([OH:14])[CH2:13][N:9]1[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:8]
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1-c1ccccc1
Agent: NN
Solvent: CO
Solvent: O
Product: NC[C@@H]1C[C@@H](O)CN1C(=O)c1ccccc1-c1ccccc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A mixture of the above mentioned 2-(((2S,4R)-1-(biphenylcarbonyl)-4-hydroxypyrrolidin-2-yl)methyl)isoindoline-1,3-dione (˜5.6 mmol) and hydrazine monohydrate (0.65 mL, 10 mmol) in MeOH was stirred at 70° C. for 4 h. The resulting white suspension was cooled to rt, filtered and the filtrate was concentrated in vacuo to a white solid, which was purified by column chromatography on silica gel (100% MeOH) to provide ((2S,4R)-2-(aminomethyl)-4-hydroxypyrrolidin-1-yl)(biphenyl-2-yl)methanone as a white solid (1.1 g, 66% yield over two steps. MS (ESI) 297.05 (M+H).
Reaction SMILES: Br[CH:2]([CH3:18])[C:3]([C:5]1[CH:6]=[C:7]([CH2:13][C:14]([O:16]C)=[O:15])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)=[O:4].CC(C)=O.[ClH:23].O>C(Cl)Cl>[Cl:23][CH:2]([CH3:18])[C:3]([C:5]1[CH:6]=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: Cl
Reactant: COC(=O)Cc1cc(C(=O)C(C)Br)ccc1OC
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)C(C)Cl)cc1CC(=O)O
Yield: 64 %

Procedure:
To a 250 mL round bottom flask containing 11.4 grams (36.3 mmole) of methyl ester 8 was added 70 mL of acetone and the mixture sonicated until solution was complete. To the solution was then added 15 mL of concentrated HCl, 20 mL of H2O and the resulting solution refluxed for 6 hours. At the end of 6 hours the volatile components of the reaction mixture were removed under reduced pressure to give an oil/water mixture which was then dissolved in 100 mL of CH2Cl2. The organic/aqueous mixture was then extracted with 150 mL of saturated NaHCO3. The aqueous layer was then removed and acidified with concentrated hydrochloric acid to a pH equal to 1. The aqueous mixture was then quickly extracted with 100 mL of CH2Cl2. The organic layer was then dried over MgSO4, filtered and the volatile components removed under reduced pressure to give an oil which crystallized to give 6.0 grams (64% yield) of 9 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:21]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23]([N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:36]=3[N:35]=[C:34]2[CH:44]([F:46])[F:45])[N:22]=1>C1COCC1.C(O)(=O)C.O>[F:46][CH:44]([F:45])[C:34]1[N:33]([C:23]2[N:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:26]=[C:21]([NH:1][C:2]3[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=3)[N:22]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:36]=2[N:35]=1
Reactant: COc1cc(N)ncn1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Nc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)ncn1
Reaction time: 0.17 h
Yield: 28.3 %

Procedure:
To 0.282 g (2.25 mmol) of 4-amino-6-methoxypyrimidine in THF (4 mL) was added 1.30 mL of NaHMDS (2 M solution in THF) and the mixture was stirred for 10 min. A solution of 0.297 g (0.75 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) in THF (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hr. After neutralization with acetic acid, the mixture was diluted with water, and extracted with EtOAc. The organic layer was washed successively with water and aqueous NH3, and dried. Removal of the solvent, followed by chromatography on silica eluting with CH2Cl2/EtOAc (1:1) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.103 g (30% yield) of 4-(2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl)-N-(6-methoxypyrimidin-4-yl)-6-morpholino-1,3,5-triazin-2-amine: mp 256-259° C.; 1H NMR (CDCl3) δ8.52 (s, 1H), 7.96-7.94 (m, 2H), 7.59 (s, 1H), 7.49 (t, JHF=53.5 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 3.99-3.96 (m, 4H), 3.84 (s, 4H); HRMS (FAB MH+) Calcd for C21H22F2N9O3: m/z 486.1808. Found: m/z 486.1808.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl.FC(F)(F)S(O[C:29]1[C:41]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][C:33]=2[CH:32]=[CH:31][CH:30]=1)(=O)=O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[CH:5][C:6]([C:29]2[C:41]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[NH:34][C:33]=3[CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:8]=1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: O=S(=O)(Oc1cccc2[nH]c3ccccc3c12)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2cccc3[nH]c4ccccc4c23)cn1
Yield: 49.6 %

Procedure:
0.96 g of [2-trifluoromethylpyridin-5-yl]boronic acid, 4.55 g of caesium carbonate and 0.13 g of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride as a complex with dichloromethane (1/1) [PdCl2(dppf).CH2Cl2] are successively added, under argon, to a solution of 1.1 g of 4-trifluoromethanesulphonyloxycarbazole, obtained in stage 1 of Example 1, in a mixture of 50 ml of dioxane and 17 ml of water. The reaction mixture is refluxed for 5 hours, filtered through celite and concentrated under reduced pressure. The residue is subsequently purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (85/15 by volume) so as to give 0.54 g of 4-[6-(trifluoromethyl)pyridin-3-yl]-9H-carbazole in the form of a pale yellow oil, the characteristics of which are the following: