Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10])[CH:4]=[CH2:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1.[O-][Mo]([O-])(=O)=O>[CH2:3]([O:6][CH2:7][CH:8]([O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][O:10][CH2:15][CH:14]=[CH2:13])[CH2:4][CH2:5][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: C=CCOCC(O)CO
Reactant: CCCCCCCCCCCCCCBr
Agent: O=[Mo](=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=CCOCC(COCCCCCCCCCCCCCC)OCCCCCCCCCCCCCC
Temperature: 25 °C
Yield: 57.2 %

Procedure:
Benzene (250 ml) was added to 95% sodium hydride (11.4 g, 450.0 mmol), and the flask was flushed with nitrogen and sealed. A solution of 3-allyloxy-1,2-propanediol (6.6 g, 50.0 mmol) in benzene (75 ml) was added to the flask. Using a syringe, 97% 1-bromotetradecane (36.7 ml, 120.0 mmol) was added to the flask and the reaction was left to reflux overnight under a constant stream of nitrogen. Once cooled to room temperature, the excess sodium hydride was slowly quenched with ethanol until no further effervescence was observed. The solution was transferred to a reparatory funnel with benzene (250 ml) and washed with distilled water (3×200 ml). The organic layer was dried with magnesium sulfate and the solvent removed on the rotary evaporator to yield a colourless oil. TLC (5% ether-hexane, developed in Molybdate) indicated that most of the starting material had reacted to form product. This resulting product was further purified by flash column chromatography (1-5% ether-hexane) to yield 15.0 g (57.3%) of 1,2-dimyristyloxy-3-allyloxypropane 1.
Reaction SMILES: C([O:5][CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C(C)=C)C=CC.[C:16]1([C:18](=[CH:20][C:21](=[CH:23][CH:24]=1)C)C)[CH3:17]>>[CH2:15]([CH:10]([CH2:11][C:12]([CH3:13])=[CH:17][C:16]1[CH:24]=[CH:23][CH:21]=[CH:20][CH:18]=1)[CH:6]=[O:5])[CH3:14]
Reactant: Cc1ccc(C)c(C)c1
Reactant: C=C(C)C(OCC=CC)c1ccccc1
Product: CCC(C=O)CC(C)=Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
The [1-(2-butenyloxy)-2-methyl-2-propenyl]benzene (26.9 g, 0.126 mol), [RuCl2(PPh3)3] (280 mg), BHT (100 mg) and pseudo-cumene (25 ml) were heated together in an autoclave placed in an oil bath at 180° C. for 4 hours. After cooling to room temperature, the pseudo-cumene was distilled off (40° C./5 mbar) and the residue purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 50:1 to 10:1) followed by bulb-to-bulb distillation (87° C./0.008 mbar). 13.0 g of the desired product were obtained (yield=51%) as a 9:1 mixture of E/Z isomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][C:25]([NH:27][CH3:28])=[O:26].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.[I-].[K+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][C:25]([NH:27][CH3:28])=[O:26])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CNC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)CN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 94.8 %

Procedure:
A mixture of 12.1 g (0.040 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 5.2 g (0.048 mole) of 2-chloro-N-methylacetamide, 17.0 g (0.160 mole) of anhydrous sodium carbonate and 0.4 g (0.002 mole) of potassium iodide in 100 mL of N,N-dimethylformamide was heated on a steam bath for 16 h. The mixture was poured into 1.5 L of water and extracted twice with 500 mL portions of ethyl acetate. The ethyl acetate layers were combined, washed with water and brine, dried (MgSO4), and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to yield 14.2 g (95%) of white solid, mp 122°-124° C.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:19][N:18]=4)[N:14]=[CH:15][C:10]=3[C:9]([CH3:30])=[C:8]([C:31]([O:33]CC)=[CH2:32])[C:7]2=[O:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(Cl)(Cl)Cl>[C:31]([C:8]1[C:7](=[O:36])[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)=[CH:19][N:18]=3)[N:14]=[CH:15][C:10]=2[C:9]=1[CH3:30])(=[O:33])[CH3:32]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 107.9 %

Procedure:
To a solution of 8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (237 mg, 0.48 mmol) in chloroform (5 ml) was added hydrogen chloride (2 M ethereal solution, 2.0 ml, 4.0 mmol). The reaction mixture was stirred at RT for 12 h. The solvents were evaporated and the residue was dissolved in ethanol. The ethanol was evaporated to give 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (239 mg mmol). MS (APCI+) 462 (M+1, 100); 1H NMR δ (400 MHz, DMSOd6) 10.83 (m, 2H), 9.00 (s, 1H), 8.1 (m, 1H), 7.88–7.82 (m, 2H), 5.89–5.80 (m, 1H), 3.88–3.85 (m, 2H), 3.23–3.11 (m, 4H), 2.83–2.82 (m, 3H), 2.43 (s, 3H), 2.34 (s, 3H), 2.23–2.11 (m, 2H), 1.93 (br, 2H), 1.81–1.77 (m, 2H), 1.60–1.59 (m, 2H); Anal. Calc'd for C25H31N7O2, 2.70 HCl 1.05 C2H5OH: C, 53.50; H, 6.63; N, 16.12. Found: C, 53.45; H, 6.47; N, 15.85.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([CH3:16])[N:3]=1.P(Cl)(Cl)([Cl:19])=O>>[CH2:9]([C:5]1[C:6]([Cl:19])=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(N)nc(O)c1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(N)nc(Cl)c1Cc1ccccc1
Temperature: 90 °C
Yield: 53.7 %

Procedure:
A mixture of 2-amino-5-benzyl-6-methylpyrimidine-4-ol (1.2 g, 5.57 mmol) and phosphorous oxychloride (9 ml) was kept to warm at 90° C. for 6 hours. The reaction mixture was concentrated in vacuo. Ice-water was added to the residue and an aqueous ammonia was cautiously added thereto. The solution was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate=8:2) to give the object compound (700 mg, 53.7%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([N:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[S:31]([NH2:34])(=[O:33])=[O:32])=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:12][C:11]([C:35]([F:38])([F:37])[F:36])=[N:10]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>CO.[Pd]>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]([N:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[S:31]([NH2:34])(=[O:32])=[O:33])=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:12][C:11]([C:35]([F:36])([F:37])[F:38])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(-n2nc(C(F)(F)F)cc2C(=O)N2CCc3cc(-c4ccccc4S(N)(=O)=O)ccc32)c1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NCc1cccc(-n2nc(C(F)(F)F)cc2C(=O)N2CCc3cc(-c4ccccc4S(N)(=O)=O)ccc32)c1
Yield: 15 %

Procedure:
1-[[1-[3-Cyanophenyl]-3(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl]-5-[2-(aminosulfonyl)phenyl]-2,3-dihydro-1H-indole (0.2 g, 0.34 mmol), prepared according to Example 4, was reduced under an atmosphere of hydrogen gas (55 psi) in methanol (5 mL) and trifluoroacetic acid in the presence of 10% palladium on carbon catalyst for 18 h at ambient temperature. The reaction mixture was filtered through a pad of Celite® and washed with methanol (3×). This product was treated with trifluoroacetic acid (1 mL) at 80° C. over 1 h, then purified by HPLC utilizing gradient elution with a mixture of water:acetonitrile with 0.05% of trifluoroacetic acid on a reverse phase C18 (60 angstrom) column to give the title product (28 mg, 15%). LRMS (ES+): 598.2 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[N:14][C:15]([N+:18]([O-])=O)=[CH:16][CH:17]=2)[CH2:8]1>CO.[Pd]>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[N:14][CH:13]=2)[CH2:8]1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc([N+](=O)[O-])nc2)C1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc(N)nc2)C1
Yield: 92.8 %

Procedure:
To a solution of (2S,3′S)-2-methyl-1′-(6-nitro-pyridin-3-yl)-[1,3′]bipyrrolidinyl (0.110 g, 0.398 mmol) in methanol (30 mL) in a 250 mL parr bottle was added 5% Pd/C (0.030 g). The reaction mixture was allowed to shake under a hydrogen atmosphere (55 psi) at room temperature for 3 hours. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to afford 0.091 g (93%) of title compound.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:9]1[CH:8]=[C:7]2[C:12]([N:13]=[C:14]([CH3:15])[C:5]3[N:6]2[C:2]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=2)=[N:3][C:4]=3[CH3:17])=[CH:11][CH:10]=1
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(-c2nc(C)c3c(C)nc4ccc(F)cc4n23)c1
Yield: 49.8 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 3-methoxyphenylboronic acid (46 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (40 mg, 50% yield). EIMS 322.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH:16]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH3:18])[CH3:17].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([CH:16]([CH3:18])[CH3:17])=[CH:20][CH:21]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: CC(C)c1ccc(N)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccc(C(C)C)cc2)c1C(=O)OC
Yield: 70 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 4-isopropylaniline (0.42 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.70 g of the product at 85:15 hexanes-ethyl acetate, in 70% yield: 1H NMR (CDCl3) δ 1.25 (s, J=6.8 Hz, 6H), 2.90 (m, 1H), 3.86 (s, 3H), 3.88 (s, 3H), 7.01-7.13 (m, 3H), 7.27-7.34 (m, 4H), 8.07 (br, 1H).
Reaction SMILES: [H-].[Na+].[C:3](OC)(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.[CH:16]1([C:21](=[O:36])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:34])([CH3:33])[C:31]#[N:32])=[C:26]([F:35])[CH:25]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>C1COCC1>[CH:16]1([C:21]2([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:34])[C:31]#[N:32])=[C:26]([F:35])[CH:25]=3)[CH2:7][C:5](=[O:6])[CH2:4][C:3](=[O:8])[O:36]2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)(C#N)c1ccc(OCC(=O)C2CCCC2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(OCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Sodium hydride (60%) (0.49 g, 12.3 mmol) was magnetically stirred in dry THF (33 mL) and cooled to 0° C. The mixture was then treated with Methyl acetoacetate (1.34 mL, 12.3 mmol) dropwise over 15 min. The reaction was allowed to stir for 30 min at 0° C. To the resulting clear solution was added nBuLi (1.6M in Hexanes) (7.71 mL, 12.3 mmol). The reaction was then allowed to stir for 30 min at 0° C. To the yellow solution was added 2-[4-(2-Cyclopentyl-2-oxo-ethoxy)-2-fluoro-phenyl]-2-methyl-propionitrile (1.19 g, 4.1 mmol) as a solution in dry THF (15 mL). The result was stirred at 0° C. for 15 min and then at room temperature for 90 min. The solution was next poured into 0.5N HCl (100 mL) and extracted with EtOAc (2×50 mL). The organics were concentrated and the residue dissolved in MeOH (33 mL) and treated with K2CO3 (1.5 g). The mixture was heated to 65° C. and maintained for 1 hr. The reaction was cooled and poured into 0.5N HCl (100 mL) and extracted with EtOAc (2×50 mL). The organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel) eluting with CH2Cl2 through 1% MeOH in CH2Cl2 to yield the title compound as a white solid (1.21 g, 79%). 1H NMR (300 MHz, DMSO-d6) δ: 1.55 (m, 8H), 1.69 (s, 6H), 2.37 (m, 1H), 2.62 (s, 2H), 3.33 (s, 2H), 4.10 (m, 2H), 6.87 (m 2H), 7.34 (m 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1ccccc1N
Reactant: O=C=Nc1ccccc1I
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1NC(=O)Nc1ccccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of 2-iodophenyl isocyanate (3.36 g, 13.7 mmol) in THF (250 mL) was added ethyl 2-aminobenzoate (5.1 mL, 34.5 mmol). The resulting mixture was stirred at room temperature for 8 hours, evaporated and chromatographed (silica gel, 10% EtOAc in hexanes) to give 4.4 g (78%) of ethyl 2-(2-iodophenylureido)benzoate as a white solid, mp 162°-164° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([C:21]2[N:22]=[C:23]([SH:32])[NH:24][C:25]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>CN(C)C=O>[C:15]1([C:21]2[N:22]=[C:23]([S:32][C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[NH:24][C:25]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 85.5 %

Procedure:
Under stirring and a layer of argon, a solution of 7.45 g of 4-chloro-3-nitrotrifluoromethylbenzene in 40 ml of dimethylformamide is added dropwise to a solution of 7.94 g of 4,5-diphenyl-2-mercaptoimidazole and 0.45 g of sodium hydride (80% strength in white oil) in 150 ml of dimethylformamide. The mixture is agitated for 20 minutes, concentrated under vacuum, and the residue distributed between water and ethyl acetate. The organic solution is dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from ether, thus obtaining 11.87 g of 4,5-diphenyl-2-(2-nitro-4-trifluoromethylphenylthio)imidazole, mp 234°-236°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2)=[CH:22][CH:21]=1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: Oc1ccc(F)cc1
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(F)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 4-fluorophenol and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[C:13](=O)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[O:14]C(Cl)C>C1COCC1>[C:19]([O:18][C:13]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:14])([CH3:22])([CH3:21])[CH3:20]
Reactant: C1CCNCC1
Reactant: CC(Cl)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1

Procedure:
The procedure is as in Example 7, but with 8.5 g (0.1 mole) of piperidine, 60 ml of THF, 20 ml of saturated aqueous K2CO3 solution and 0.11 mole of α-chloroethyl tert-butyl carbonate.
Reaction SMILES: [F:1][C:2]([F:18])([C:14]([F:17])([F:16])[F:15])[CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][CH:6]=1.C1(C2C=CC(C(O)=O)=NC=2OCC(F)(F)C(F)(F)F)CC1.[NH2:40][C:41]([CH2:48][CH3:49])([CH2:46][CH3:47])[C:42]([NH:44][CH3:45])=[O:43]>>[CH2:46]([C:41]([NH:40][C:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([O:4][CH2:3][C:2]([F:1])([F:18])[C:14]([F:17])([F:16])[F:15])[N:10]=1)=[O:13])([C:42](=[O:43])[NH:44][CH3:45])[CH2:48][CH3:49])[CH3:47]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1cccc(OCC(F)(F)C(F)(F)F)n1
Agent: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1
Product: CCC(CC)(NC(=O)c1cccc(OCC(F)(F)C(F)(F)F)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid and 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (Example 297b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, the product was isolated by preparative HPLC; LC-MS (UV peak area/ESI) 100%, 398.1488 (M+H)+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([C@@H:26]([NH2:29])[CH2:27][CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C@@H:26]([NH:29][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH2:27][CH3:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: CC[C@H](N)c1ccccc1
Product: CC[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1ccccc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with (S)-1-phenylpropylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 330.3 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.49 (br s, 1H); 8.38 (d, J=5.5 Hz, 1H); 7.83 (d, J=7.6 Hz, 1H); 7.27-7.44 (m, 6H); 6.77 (d, J=5.5 Hz, 1H); 5.88 (br s, 1H); 4.97 (br s, 1H); 1.97 (m, 2H); 1.03 (t, J=7.5 Hz, 3H).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[NH2:22].[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][N:32]=1)[C:27](Cl)=O>>[Br:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[C:27]([C:26]3[CH:30]=[CH:31][N:32]=[C:24]([F:23])[CH:25]=3)[N:22]=[C:16]2[CH:17]=1
Reactant: O=C(Cl)c1ccnc(F)c1
Reactant: Nc1cc(Br)cc[n+]1N
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Fc1cc(-c2nc3cc(Br)ccn3n2)ccn1
Yield: 77.6 %

Procedure:
The product was prepared in the same manner as described in example 1b using 1,2-diamino-4-bromopyridinium 2,4,6-trimethylbenzenesulfonate (2.2 g, 5.67 mmol) and 2-fluoroisonicotinoyl chloride (1.81 g, 11.3 mmol) as starting materials. The reaction affords 7-bromo-2-(2-fluoropyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (1.29 g, 77.7%) as white powder. MS: m/z=294.9 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1)([O-:3])=[O:2]
Reactant: Nc1ccc(CO)cc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1Nc1ccc(CO)cc1

Procedure:
In a manner similar to Preparation Al 88.5 g of 3-nitro-4-chloropyridine, 68.7 g of 4-aminobenzyl alcohol and 46.9 g of sodium bicarbonate in 500 ml of ethanol to give 56.3 g of the titled intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][C:10]1[C:9]([C:21]([F:24])([F:23])[F:22])([O:16][Si](C)(C)C)[CH2:8][CH2:7][CH2:6][C:5]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][C:10]1[C:9]([C:21]([F:23])([F:22])[F:24])([OH:16])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)CCCc2c1[nH]c1c(Cl)cc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(C(F)(F)F)CCCc2c1[nH]c1c(Cl)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
6,8-Dichloro-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.4 g, 1.0 mmol) was dissolved in THF (5 mL) and KOH (280 mg, 5.0 mmol) in H2O (5 mL), was added. The resulting mixture stirred at room temperature for 2 h, diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were then dried over Na2SO4 and concentrated under reduced pressure to give the crude residue which was purified by column chromatography [EtOAc-hexane (1:19) as eluant] to provide the title compound as a white solid (100 mg, 26%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.03 (s, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.32 (d, J=1.5 Hz, 1H), 6.6 (s, 1H), 2.72-2.64 (m, 2H), 2.23-2.19 (m, 1H), 2.0-1.9 (m, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:15]#[N:16])=[C:10]([CH3:14])[NH:11]2)=[CH:7][CH:6]=1.[CH2:17](I)[CH3:18]>CN(C=O)C>[CH2:17]([N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([O:4][CH3:3])[CH:13]=2)[C:9]([C:15]#[N:16])=[C:10]1[CH3:14])[CH3:18]
Reactant: CCI
Reactant: COc1ccc2c(C#N)c(C)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(C)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a suspension of NaH (0.6 g, 2 eq.) in DMF (7 mL) is added a solution of 6-methoxy-2-methyl-1H-indole-3-carbonitrile (1.3 g, 7.0 mmol) in DMF (8 mL) followed by ethyl iodide (1.2 mL, 2 eq.) at 0° C. After stirring for 1 h, the mixture is poured into ice water and then extracted with CH2Cl2. The organic layer is washed with brine and dried with Na2SO4. The solvent is evaporated under vacuum and purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 92% of 1-ethyl-6-methoxy-2-methyl-1H-indole-3-carbonitrile.