Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=C)([CH2:18][CH2:19]3)[O:16][CH2:15]4)=[N:8][C:7]=2[N:6]([CH2:24][CH2:25][CH3:26])[C:5]1=[O:27])[CH2:2][CH3:3].[O:28]1CCOCC1>CC(O)(C)C.O.O=[Os](=O)(=O)=O>[O:27]=[C:5]1[N:6]([CH2:24][CH2:25][CH3:26])[C:7]2[N:8]=[C:9]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[O:28])([CH2:18][CH2:19]3)[O:16][CH2:15]4)[NH:10][C:11]=2[C:12](=[O:13])[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: C=CC12CCC(c3nc4c([nH]3)c(=O)n(CCC)c(=O)n4CCC)(CC1)CO2
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C34CCC(C=O)(CC3)OC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1,3-Dipropyl-8-(1-vinyl-2-oxa-bicyclo[2.2.2]oct-4-yl)-3,7-dihydro-purine-2,6-dione (400 mg, 1.08 mmol) was suspended in 8 ml of dioxane and 1 ml of a 2.5% solution of OsO4 in t-BuOH was added, followed by 3 ml of H2O. After 10 min, NaIO4 was added and the reaction mixture was stirred at rt for 3 h. It was then diluted with H2O and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to afford the aldehyde intermediate, 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo[2.2.2]octane-1-carbaldehyde.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:37]=[CH:36][C:14]([O:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26]C)=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:17]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34]C)[CH:29]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:17]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=3)=[CH:36][CH:37]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Oc1cccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution was prepared of 1.5 g (2.9 mmol) of 1-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(3-methoxyphenyl)-6-methoxynaphthalene hydrochloride in 30 mL of CH2Cl2 and the solution was cooled to 0° C. under a nitrogen atmosphere. To this solution was added 1.09 mL (2.89g, 11.5 mmol) of BBr3 and the reaction was allowed to proceed for two hours at 0° C. The reaction was quenched by the addition of aqueous NaHCO3 solution (50 mL). The reaction mixture was extracted with CHCl3. The organic layer was washed with brine, dried with Na2SO4, and evaporated to dryness. The residue was suspended in THF and filtered. To the filtrate was added 1 mL of 5N HCl and the solvents were removed by evaporation. This yielded 0.99 g of the title compound as a tan amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][N:10]([C:21](=[O:22])[C:20]4[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=4)[C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)N1CCCC2=C1CCc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.78 g (40 mmol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 88 ml of methylene chloride and 7.70 g (44 mmol) of 4-chlorobenzoyl chloride in 60 ml of methylene chloride were added dropwise thereto at 0°. After stirring at room temperature for 1 hour the mixture was extracted with water, dried with magnesium sulphate and the solvent was distilled off in vacuo. Chromatography (silica gel, chloroform-hexane, 2:1) and crystallization (chloroform-hexane) gave 8-chloro-4-(p-chlorobenzoyl)-1,2,3,4,5,6-hexahydrobenzo[f]quinoline as white crystals of melting point 189°-191°.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:29])[NH:18][C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][NH:25][CH2:26]3)=[CH:21][CH:20]=2)[CH:12]=1)=[O:8].CC(O)=O.[CH:39](=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH2:39]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][C:19]([NH:18][C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][NH:9][C:7](=[O:8])[C:6]3[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:4]([O:3][CH3:2])[CH:5]=3)=[O:29])=[CH:20][CH:21]=2)[CH2:26]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CNCC4)c2)cc1OC
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CN(Cc3ccccc3)CC4)c2)cc1OC
Reaction time: 1 h

Procedure:
Suspended 3,4-Dimethoxy-N-[3-(1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide hydrochloride (50.0 mg, 0.104 mmol) in 2 mL of THF. To this was added AcOH (0.06 mL, 1.0 mmol) and benzaldehyde (0.016 mL, 0.150 mmol). The mixture stirred for 1 h. To this was added NaBH(OAc)3 (63.3 mg, 0.300 mmol). The mixture stirred for 50 h. LC-MS analysis indicated the desired product. Concentrated the mixture to dryness. Redissolved in CH2Cl2/MeOH and applied to a SiO2 prep plate. Eluted with (10% MeOH/1% NH3/CH2Cl2) to give 40.6 mg of N-[3-(2-Benzyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-3,4-dimethoxy-benzamide. MS, electrospray 536.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[Cl-].[Cl-].[Al+3].[F:15][C:16]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:18]([C:17]3[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:16]=3[F:15])=[O:19])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: COc1cccc(C(=O)Cl)c1F
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-bromo-1H-pyrrolo[2,3-b]pyridine (67, 2.00 g, 0.0102 mol) in methylene chloride (120 mL), under an atmosphere of nitrogen, was added aluminum trichloride (8.20 g, 0.0615 mol). The reaction was stirred at room temperature for 60 minutes, then 2-fluoro-3-methoxy-benzoyl chloride (34, 2.12 g, 0.0112 mol, prepared from the corresponding carboxylic acid using the protocol of Example 1, Scheme 13, Step 4), dissolved in methylene chloride (20.0 mL), was added. After 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography, eluting with 25% ethyl acetate in hexane to provide P-0265 (approx 2.6 g, 73%). MS (ESI) [M−H+]−=347, 349.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][NH:18][C:17](=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>CCOC(C)=O.[Cu]I.O1CCOCC1.CN(C=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][N:18]([C:27]4[CH:26]=[CH:25][C:24]([S:28][CH3:29])=[CH:23][CH:22]=4)[C:17](=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1cccc(Br)c1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC1CCCC1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2CC(=O)N(c3ccc(SC)cc3)C2)cc1OC1CCCC1
Temperature: 110 °C
Yield: 70.9 %

Procedure:
A mixture of 4-(3-cyclopentyloxy-4-methoxy-phenyl)-pyrrolidin-2-one (276 mg, 1 mmol), 1-bromo-3-methylsulfanylbenzene (1.4 mmol), K3PO4 (1.5 mmol), DMF (3 mL), dioxane (3 mL) and 1,2-trans-cyclohexanediamine (25 μL) was stirred under N2 for 5 min before CuI (35 mg) was added. The reaction mixture was heated at 110° C. for 20 h under N2 with stirring, then cooled down to r.t. The mixture was diluted with EtOAc, washed with saturated NH4Cl (3×10 mL) and dried over Na2SO4. Concentration and chromatography of the residue on silica gel gave 282 mg of pure product. Yield: 71%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3ncccc3o2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2nc3ncccc3o2)c1

Procedure:
A mixture of 700mg. of 2-(3-nitrophenyl)oxazolo[4,5-b]pyridine in 50 ml. of ethanol was hydrogenated over 150 mg. of 5% palladium-on-carbon catalyst. The catalyst was removed by filtration and the solvent was concentrated to dryness. The residue was recrystallized from chloroform-petroleum ether to give 2-(3-aminophenyl)oxazolo[4,5-b]pyridine, m.p. 179°-180.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:12]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Br:12])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: BrP(Br)Br
Product: Clc1ccc(CCBr)cc1

Procedure:
In Stage 1, the 2-(4′-chlorophenyl)ethanol was reacted with phosphorous tribromide to give 2-(4′-chlorophenyl)ethyl bromide. The product was isolated directly from an aqueous quench without the need of an extractive solvent.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.Br[CH2:27][CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:29][CH2:28][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:23][CH:24]=2)=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCCC(=C(c1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Reactant: BrCCOCc1ccccc1
Product: OCCC(=C(c1ccc(OCCOCc2ccccc2)cc1)c1ccc(OCCOCc2ccccc2)cc1)c1ccccc1

Procedure:
is prepared from 4,4-bis(4-hydroxyphenyl)-3-phenylbut-3-en-1-ol (example 1c) and benzyl 2-bromoethyl ether by PTC reaction according to the method described in the example 1 a.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCCCC>[CH:1]([C@@H:14]1[O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][CH2:20]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCC
Product: O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Yield: 68.6 %

Procedure:
(1R,4R,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane (0.05 g, 0.19 mmol) was treated with LiAlH4 (0.036 g, 0.94 mmol) (Procedure I) in dry pentane to yield trans-(3S,6R)-6-benzhydryl-tetrahydro-pyran-3-ol 33b 0.035 g (70%, [α]D=(+)61.7, c=1, MeOH).
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[C:19]([NH2:24])([CH2:22][CH3:23])([CH3:21])[CH3:20]>>[CH3:20][C:19]([NH:24][C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:21])[CH2:22][CH3:23]
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Reactant: CCC(C)(C)N
Product: CCC(C)(C)Nc1c(-c2ccc(OC)cc2)c(=O)c1=O
Yield: 84.1 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and tert-amyl amine (0.48 mL, 4.11 mmol) were converted to the title compound (0.14 g, 84%) m.p.: 133-135° C.; 1H NMR (DMSO-d6) δ8.28(br s,1H), 8.04(m,2H), 7.11(m,2H), 3.83(s,3H), 1.80(q,2H), 1.42(s,6H), 0.85(t,3H); IR (KBr) 2980, 1765, 1725, 1600, 1423, 1310, 1260, 1175, 1030, 850 cm−1; MS (m/z) 273 [M+].
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([S:15]([CH3:18])(=[O:17])=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([O:13][CH3:14])[CH:7]=1.C(=O)(O)[O-]>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:13][CH3:14])[N:5]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:4]=[CH:3]2
Reactant: COc1cc(N(CC(OC)OC)S(C)(=O)=O)ccc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: COc1cc2c(ccn2S(C)(=O)=O)cc1F
Temperature: 70 °C

Procedure:
To a solution of N-(2,2-dimethoxyethyl)-N-methanesulphonyl-4-fluoro-3-methoxyaniline (1.91 g, 0.65 mmol) in dry toluene at 0° C. under argon, was added slowly a solution of TiCl4 (0.173 g, 0.911 mmol) in dry toluene (10 ml). The solution was then heated to 70° C. for 1 h. cooled and poured onto ice/sat. sod. bicarbonate solution (20 ml). The organic layer was separated, washed with sat. sod. bicarbonate solution, 0.5% hydrochloric acid (2×20 ml) and water (2×20 ml). The solution was dried (MgSO4) and evaporated in vacuo to give 5-fluoro-1-methanesulphonyl-6-methoxyindole ((0.102 g)
Reaction SMILES: C(OC(=O)CC[CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=2)=[C:15]([CH3:17])[N:16]=1)=[O:10])C.[CH2:30]([O:32][C:33](=[O:39])[CH2:34]CN=C=O)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:39])[CH2:34][CH2:7][NH:8][C:9]([NH:11][C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[C:20]([F:28])[CH:19]=2)=[C:15]([CH3:17])[N:16]=1)=[O:10])[CH3:31]
Reactant: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Reactant: CCOC(=O)CCN=C=O
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1

Procedure:
The title compound is prepared by the same procedure as 4-{3-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:14])[O:12][CH3:13])[CH:5]=[C:6]([Br:9])[C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:11](=[O:14])[O:12][CH3:13])[CH:5]=[C:6]([Br:9])[C:7]=1[F:8]
Reactant: COC(=O)Nc1cc(Br)c(F)c(Br)c1
Reactant: COc1ccc(CCl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1ccc(OC)cc1)c1cc(Br)c(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A stirred solution of methyl (3,5-dibromo-4-fluorophenyl)carbamate (0.82 g, 2.508 mmol) in DMF (20 mL) was treated with sodium bis(trimethylsilyl)amide (3.01 mL, 3.01 mmol), stirred at rt for 30 minutes, then 1-(chloromethyl)-4-methoxybenzene (0.410 mL, 3.01 mmol) was added, stirred at 70° C. for two hours. The reaction mixture was partitioned between NH4Cl solution and EtOAc. The organic layer was washed with NaHCO3 solution (2×), then brine, then dried over MgSO4, filtered and evaporated to dryness to give 1.40 g colorless film, which was purified by column chromatography on silica (120 g silica, gradient from 100% hexanes to 20% EtOAC in hexanes) to give methyl (3,5-dibromo-4-fluorophenyl)(4-methoxybenzyl)carbamate (1.01 g)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([OH:25])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=3)[N:10]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:9]=2)=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](=[O:25])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=3)[N:10]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: OC(Cc1ccccc1)c1ccc2c(c1)c(-c1ccc(F)cc1)nn2C1CCCCO1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1ccc2c(c1)c(-c1ccc(F)cc1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
A suspension of 1-[3-(4-fluorophenyl)-1-(tetrahydropyran-2-yl)-1H-indazol-5-yl]-2-phenylethan-1-ol (0.223 g, 0.54 mmol) and pyridinium chlorochromate (1.0 g, 4.6 mmol) in dried dichloromethane (10 mL) under nitrogen was stirred at ambient temperature for 6 hours. It was diluted with dichloromethane and washed with saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15–30% ethyl acetate/hexane) to provide the title compound (0.112 g, 51% yield): 1H NMR (CDCl3) δ 8.62 (d, 1H), 8.10 (dd, 1H), 7.85–7.90 (m, 2H), 7.65 (dd, 1H), 7.19–7.37 (m, 7H), 5.77 (dd, 1H), 4.35 (s, 2H), 4.06 (m, 1H), 3.77 (m, 1H), 2.59 (m, 1H), 2.14 (m, 2H), 1.70 (m, 3H); ES-MS (m/z) 415 [M+1]+.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[C:9]=12)#[N:13]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)c(F)c2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(Cc3ccc(F)c(F)c3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(3,4-difluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 387 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[N:9][CH:10]=[CH:11][N:5]2[N:4]=[CH:3]1.Br[C:13]1[CH:14]=[CH:15][C:16]([F:28])=[C:17]([C:19]2[C:20]([C:26]#[N:27])=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH:18]=1.C([O-])(=O)C.[K+]>CN(C)C(=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:25][C:22]1[CH:21]=[C:20]([C:26]#[N:27])[C:19]([C:17]2[CH:18]=[C:13]([C:11]3[N:5]4[C:6]([C:7](=[O:8])[N:2]([CH3:1])[CH:3]=[N:4]4)=[N:9][CH:10]=3)[CH:14]=[CH:15][C:16]=2[F:28])=[CH:24][CH:23]=1
Reactant: Cn1cnn2ccnc2c1=O
Reactant: N#Cc1cc(F)ccc1-c1cc(Br)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cn1cnn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3)cnc2c1=O
Temperature: 120 °C
Yield: 77 %

Procedure:
3-Methyl-3H-imidazo[2,1-f][1,2,4]triazin-4-one (75 mg, 0.5 mmol), 5′-bromo-4,2′-difluorobiphenyl-2-carbonitrile (prepared according to the procedure described in WO 02/38568) (220 mg, 0.75 mmol) and potassium acetate (74 mg, 0.75 mmol) were suspended in N,N-dimethylacetamide (2 ml) and degassed with nitrogen for 10 min. Palladium(II) acetate (5.6 mg, 0.025 mmol) and triphenylphosphine (6.6 mg, 0.025 mmol) were added and the mixture heated at 120° C. for 1 h. The mixture was allowed to cool to ambient temperature, diluted with ethyl acetate (100 ml), washed with water (50 ml) and brine (30 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give a brown solid. The solid was purified by flash column chromatography on silica, eluting with dichloromethane on a gradient of methanol (0-2%). The appropriate fractions were collected and concentrated, and the residue triturated with diethyl ether, which gave 4,2′-difluoro-5′-(3-methyl-4-oxo-3,4-dihydroimidazo[2,1-f][1,2,4] triazin-7-yl)biphenyl-2-carbonitrile (139 mg, 77%) as a white solid: δH (500 MHz, CDCl3) 3.55 (3H, s), 7.27 (1H, dd, J9 and 9), 7.35 (1H, ddd, J8, 8 and 3), 7.45 (1H, dd, J8 and 3), 7.47-7.49 (1H, m), 7.71 (1H, s), 7.73 (1H, s), 7.89-7.92 (2H, m); m/z (ES+) 364 (M++H).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][CH:15]2[CH2:20][CH2:21][CH:22]([OH:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>>[OH:30][CH:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:21][CH2:20][CH:15]1[CH2:16][CH2:17][C:18](=[O:19])[N:14]1[CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:31])=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(OCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Yield: 85.6 %

Procedure:
Analogous to the procedure described for Example 1A, Step F, 4-{2-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-ethoxy}-benzoic acid ethyl ester (52 mg, 0.122 mmol) was hydrolyzed with 6N NaOH (1 mL) to yield the title compound (41.5 mg). 1H NMR (CDCl3) δ7.98 (d, 2H), 7.32-7.16 (m, 5H), 6.85 (m, 2H), 4.13 (m, 2H), 3.92 (m, 1H), 3.81 (m, 1H), 3.75 (m, 1H), 3.40 (m, 1H), 2.82 (m, 1H), 2.66 (m, 1H), 2.36 (m, 2H), 2.10 (m, 2H), 1.70-1.34 (m, 5H); MS 398.4 (M+1), 396.3 (M−1).
Reaction SMILES: [C:1]([S:4][CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].C[O-].[Na+].CO.S(OCC1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(C)(=O)=O.CS(Cl)(=O)=O.OCSCC1CCN(C(OC(C)(C)C)=O)CC1>CO.O1CCCC1.O.C(N(CC)CC)C>[CH2:9]([O:8][P:6]([CH2:5][S:4][CH2:1][CH:2]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27][CH2:26]1)([O:11][CH2:12][CH3:13])=[O:7])[CH3:10]
Reactant: CCOP(=O)(CSC(C)=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: CC(C)(C)OC(=O)N1CCC(CSCO)CC1
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CCOP(=O)(CSCC1CCN(C(=O)OC(C)(C)C)CC1)OCC
Reaction time: 0.33 h

Procedure:
To a solution of 1.529 g (6.759 mM) of S-(diethoxyphosphorylmethyl) thioacetate in 30 ml of methanol was added 1.30 g (6.76 mM) of 28% sodium methoxide-methanol under ice-cooling and the mixture was stirred at the prevailing temperature for 20 minutes. To this reaction mixture was added crude tert-butyl 4-(mesyloxymethyl)piperidine-1-carboxylate [which was prepared by adding 0.73 ml (9.46 mM) of methanesulfonyl chloride to a solution of 1.75 g (8.11 mM) of tert-butyl 4-(hydroxymethylthiomethyl)piperidine-1-carboxylate and 1.51 ml (10.8 mM) of triethylamine in 30 ml of tetrahydrofuran with ice-cooling, stirring the mixture at the prevailing temperature for 0.5 hour, pouring the mixture in water, extracting it with 2 portions of ethyl acetate, drying the pooled organic layer over MgSO4, and concentrating it], and the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure and the residue was diluted with water and extracted with 2 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate: 3/1 to ethyl acetate) to provide the title compound.