Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=1[CH2:11][OH:12])O.[N+:13]([O-])([OH:15])=[O:14]>O>[N+:13]([C:6]1[CH:7]=[C:8]([CH3:9])[CH:3]=[C:4]([CH2:11][OH:12])[C:5]=1[OH:10])([O-:15])=[O:14]
Reactant: Cc1ccc(O)c(CO)c1CO
Reactant: O=[N+]([O-])O
Solvent: O
Product: Cc1cc(CO)c(O)c([N+](=O)[O-])c1
Yield: 80 %

Procedure:
The 6-nitro-2-methylol p-cresol was prepared by charging 134.3 grams of bis-methylol para cresol (BMPC) (assay: 97.9%, melting point: 124.5 to 126.5° C.), and 3000 grams of deionized water into a 5 liter, wide mouth beaker and stirring to achieve a colloidal suspension of the BMPC before 200 grams of concentrated nitric acid was added in 30 minutes as the temperature was maintained between 20 and 30° C. The mixture was mixed an additional 24 hours at room temperature before a Buchner funnel filtration. The wetcake was washed with deionized water until the effluent achieved a pH of 6. The wetcake was then vacuum oven dried (30-35° C.,<10 torr) until the residual water assay was less than 1 percent. Yield: 80 to 85%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=2)[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:33])=O>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=2)[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([Cl:33])=[O:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(C(c2ccc(OC(C)=O)cc2)c2ccccc2C(=O)O)cc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(c2ccc(OC(C)=O)cc2)c2ccccc2C(=O)Cl)cc1
Reaction time: 2 h

Procedure:
In 50 ml of methylene chloride was dissolved 7 g of 2-[bis(4-acetoxyphenyl)methyl]benzoic acid obtained by Reference Example 1, and then 10 ml of thionyl chloride was added dropwise to the solution at room temperature. The reaction mixture was stirred for 2 hours, and the reaction mixture was concentrated under reduced pressure to afford 11.33 g of the desired compound as an oily matter.
Reaction SMILES: [CH2:1]([NH:8]/[CH:9]=[CH:10]/[C:11](=[O:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CC(O)C.O>[CH2:1]([NH:8][CH2:9][CH2:10][CH:11]([OH:17])[CH:12]([O:15][CH3:16])[O:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)C(=O)/C=C/NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COC(OC)C(O)CCNCc1ccccc1
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of (E)-4-(benzylamino)-1,1-dimethoxybut-3-en-2-one (4.71 g, 20 mmol) in a mixture of 2-Propanol (60 ml) and Water (4.80 ml) was added sodium borohydride (3.03 g, 80 mmol) in portions at 20-25° C., the mixture was stirred overnight. Quenched with 5N HCl to pH 7 (approx 10 ml), pH adjusted to 8-9 with 5N NaOH, diluted with MTBE (100 ml) and brine (50 ml). Organic phase was dried (MgSO4), evaporated, separated on a column with ethyl acetate-MeOH mixture 4:1, fractions collected to give 4-(benzylamino)-1,1-dimethoxybutan-2-ol (3.55 g, 14.83 mmol, 74.2% yield), colorless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C-]#N.[Na+].[CH3:18][O:19][CH2:20]CO>>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH2:12][CH2:18][O:19][CH3:20])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Reactant: COCCO
Agent: [C-]#N
Agent: [Na+]
Product: C=CCOc1ccc(C(=O)OCCOC)cc1

Procedure:
A mixture of methyl 4-allyloxybenzoate (1.92 g), sodium cyanide (50 mg) and 2-methoxyethanol (20 ml) was heated at reflux for 24 hours. The mixture was evaporated to give an oil which was partitioned between dichloromethane and water. The organic phase was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel using a 9:1 (v/v) mixture of pentane/ethyl acetate as eluent to give 2-methoxyethyl 4-allyloxybenzoate (1.7 g) as an oil; NMR(CDCl3): 3.44(3H,s), 3.72(2H,t), 4.44(2H,t), 4.55-4.64(2H,m), 5.27-5.48(2H,m), 5.96-6.14(1H,m), 6.93(2H,d) and 8.01(2H,d); m/z237(M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][N:21]=3)[CH:15]=2)[CH2:12][C:11]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[N:10]1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][N:21]=3)[CH:15]=2)[CH2:12][C:11]([C:28]([F:33])([F:34])[C:29]([F:32])([F:30])[F:31])=[N:10]1
Reactant: O=Cc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2,4-difluoro-phenyl)-5-[3-(5-formyl-pyridin-2-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (20 mg, 0.04 mmol) prepared in Example 79 in ethanol (1 mL), was slowly added sodium borohydride (6.0 mg, 0.16 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hour, quenched with a 1N hydrochloric acid solution, and then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a residue as a pale yellow liquid. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 3.0 mg of the titled compound as a white solid.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][N:5]([CH3:20])[C:6](=[O:19])[S:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH3:18])=[N:15]2)=[CH:10][CH:9]=1>>[CH3:20][N:5]([CH3:4])[C:6](=[O:19])[S:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH:18]=[O:2])=[N:15]2)=[CH:10][CH:9]=1
Reactant: O=[Se]=O
Reactant: Cc1ccc2ccc(SC(=O)N(C)C)cc2n1
Product: CN(C)C(=O)Sc1ccc2ccc(C=O)nc2c1
Temperature: 100 °C
Yield: 57.1 %

Procedure:
Referring now to FIG. 22, under a nitrogen atmosphere, selenium dioxide (67.3 mg, 0.606 mmol) was added to a solution of 17 (99.1 mg, 0.4027 mmol) in xylenes (3 mL). The mixture was heated to 100° C. for 3 h, then filtered hot through cotton, rinsing with chloroform. The product was adsorbed onto silica gel and purified by column chromatography (4:6 EtOAc/hexane) to afford 18 (60 mg, 0.230 mmol, 57%) as a white solid: 1H NMR (CDCl3) δ 10.21 (1H, s), 8.41 (1H, d, J=8.8 Hz), 8.33 (1H, d, J=8.4 Hz), 8.06 (1H, d, J=8.8 Hz), 7.91 (1H, d, J=8.8 Hz), 7.80 (1H, dd, J=1.6, 8.4 Hz) 3.17 (3H, s), 3.07 (3H, s); 13C NMR (CDCl3) δ 193.6, 165.8, 152.9, 147.7, 137.2, 136.8, 135.6, 132.21, 129.9, 127.9, 118.1, 37.0; FTIR (neat) 2922, 2876, 1705, 1661, 1366, 853, 758 cm−1; MS (ESI) m/z calculated for (C13H12N2O2S+H)+ 261, found 261; HRMS (ESI) m/z calculated for (C13H12N2O2S+H)+ 261.0692, found 261.0661.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:31])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:25]1[N:29]=[C:28]([CH3:30])[O:27][N:26]=1)[CH3:31]
Reactant: O=C(O)c1ccc(C2CCCC2)c(-c2cccc(Cl)c2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CCCC3)c(-c3cccc(Cl)c3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopentyl-pyridine-2-carboxylic acid and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=425.2 [M+H]+.
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[C:18]([F:22])=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[CH:30](=O)[CH2:31][CH2:32][CH2:33]C.OO>O.S(=O)(=O)(O)O>[CH2:30]([C:21]1[C:20]2[CH:19]=[C:18]([F:22])[C:17]([F:23])=[CH:16][C:15]=2[N:14]=[C:13]2[C:24]3[N:10]([CH2:11][C:12]=12)[C:9](=[O:27])[C:8]1[CH2:7][O:6][C:5](=[O:28])[CH2:4][C@@:3]([CH2:1][CH3:2])([OH:29])[C:26]=1[CH:25]=3)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3cc(F)c(F)cc3nc2-1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: CCCCc1c2c(nc3cc(F)c(F)cc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product of Stage 13d (100 mg; 0.25 mmol) is dissolved in a mixture of water (1.33 ml) and sulphuric acid at 95% (1 ml). Heptahydrated iron (II) sulphate (28 mg 0.10 mmol) and valeraldehyde (0.17 ml; 1.60 mmol) are added to this solution and the resulting solution is cooled down with an ice bath. The reaction medium is then treated dropwise with hydrogen peroxide at 30% (0.38 ml; 1 mmol), agitated for 5 hours at ambient temperature, then diluted with water (50 ml) and extracted with dichloromethane (4×50 ml). The combined extracts are washed with water and with a saturated aqueous solution of sodium chloride, then dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography at medium pressure (SiO2, MeOH/CH2Cl2, 5/95) in order to produce the expected solid (m.p.>275° C.).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]2)[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1.[NH4+].[Cl-]>>[CH3:7][C:6]1[N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]2)[N:4]=[CH:3][C:2]=1[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1
Reactant: Cc1c(I)cnn1[C@H]1CC[C@H](N)CC1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1[C@H]1CC[C@H](N)CC1
Reaction time: 1 h

Procedure:
To a solution of trans-4-(4-iodo-5-methyl-1H-pyrazol-1-yl)cyclohexanamine (170.0 mg, 0.5571 mmol) in THF (4 mL, 60 mmol) at rt was added 1.3 M of isopropylmagnesium chloride in THF (1.7 mL, 2.2 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.46 mL, 2.8 mmol), and allowed to stir at rt for 2 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was concentrated in vacuo to afford the title compound, and was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:8](I)[C:7]1=[O:22].[Li+].[Cl-].[CH3:28][Sn](C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][N:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:8]([CH3:28])[C:7]1=[O:22]
Reactant: O=c1c(I)c(OCc2ccc(F)cc2)ccn1Cc1cccc(F)c1
Reactant: C[Sn](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccc(F)cc2)ccn(Cc2cccc(F)c2)c1=O

Procedure:
To a degassed solution of 1-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(1H)-one (0.804 g, .7 mmol) in DMF (10 mL) and LiCl (0.25 g, .9 mmol) was added tetramethyltin (0.49 mL, 3.54 mmol) followed by bistriphenylphosphine-palladium chloride catalyst (0.124 g, 0.177 mmol). The reaction mixture was heated in an oil bath (85°-90° C.) under nitrogen for 3 hours. The solvent was concentrated and the residue was diluted with ethyl acetate and washed with water. The organic extracts were dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by flash column chromatography (20% ethyl acetate in hexane). The appropriate fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 7.59 (d, 1H, J=7.6 Hz), 7.46 (m, 2H), 7.34 (m, 1H), 7.10 (m, 4H), 6.46 (d, 1H, J=7.6 Hz), 5.17 (s, 2H), 5.15 (s, 2H), 1.99 (s, 3H); ES-HRMS m/z 342.1314 (M+H calculated for C20H18NO2F2 requires 342.1300).
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:33][CH2:34][O:35]C)[N:18]([CH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl.C(#N)C>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:33][CH2:34][OH:35])[N:18]([CH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:25])=[O:24])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1ccc(C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)NCCCn2c(CCO)nc3c(N)nc4ccccc4c32)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Boron tribromide (5.50 mL of 1 M in dichloromethane) was added dropwise to a chilled (0° C.) suspension of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-4-methylbenzenesulfonamide (1.0 g, 2.2 mmol; U.S. Pat. No. 6,677,349, Example 253) in dichloromethane (20 mL). The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched with methanol. Hydrochloric acid (about 10 mL of 6 N) was added and the mixture was stirred at 50° C. overnight. The mixture was diluted with water (50 mL) and ethyl acetate (100 mL) and then brought to neutral pH with solid sodium hydroxide. The layers were separated and the aqueous was extracted with ethyl acetate (×2). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide a yellow solid. This material was purified by prep HPLC (COMBIFLASH system eluting first with a gradient of 0 to 5% methanol in dichloromethane containing 1% ammonium hydroxide and then with a gradient of 5 to 10% methanol in dichloromethane containing 1% ammonium hydroxide) to provide a white solid. This material was suspended in hot acetonitrile, allowed to cool, and then the solvent was decanted. The resulting material was dried under vacuum to provide about 200 mg of N-{3-[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-4-methylbenzenesulfonamide as a white solid, m p. 231-232° C. Anal. calcd for C22H25N5O3S.0.20 CH4O: % C, 59.79; % H, 5.85; % N, 15.70. Found: % C, 59.44; % H, 5.89; % N, 15.52.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:16][C:3]1[C:2]([NH:1][S:22]([C:18]2[S:17][CH:21]=[CH:20][CH:19]=2)(=[O:24])=[O:23])=[C:10]2[C:6]([CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc2ccc(C)c(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2ccc(C)c(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.1 %

Procedure:
To a mixed solution of ethyl 7-amino-6-methyl-1H-indole-2-carboxylate (0.50 g) and pyridine (10 mL) was added 2-thiophenesulfonyl chloride (0.54 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-1:3), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (677 mg, yield 81%) as colorless needle crystals. melting point 184-185° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.[CH2:15]([C:22]1[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:14][C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]3)=[C:2]([F:1])[CH:3]=2)[N:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cn(-c2ccc(N)cc2F)cn1
Reactant: Clc1nccc(Cc2ccccc2)n1
Product: Cc1cn(-c2ccc(Nc3nccc(Cc4ccccc4)n3)cc2F)cn1

Procedure:
The title compound was prepared from 3-fluoro-4-(4-methyl-imidazol-1-yl)-phenylamine (94 mg, 0.49 mmol) and 4-benzyl-2-chloro-pyrimidine (100 mg, 0.49 mmol) in analogous manner to the procedure described in example 1e). Obtained as a pale-yellow solid (50 mg, 29%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>O1CCOCC1.O.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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:38]4[CH:39]=[CH:40][C:35]([CH2:34][OH:33])=[CH:36][CH:37]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CO)cc4)cc23)CC1
Temperature: 160 °C
Yield: 30.2 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (20.0 mg, 0.048 mmol), K3PO4 (21.0 mg, 0.096 mmol) and [4-(hydroxymethyl)phenyl]boronic acid (30.0 mg, 0.193 mmol) in dioxane/H2O (2 mL/0.7 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (5.0 mg, 0.0048 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160° C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgSO4, filtered, concentrated, and purified by reverse phase HPLC method A (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (6.4 mg, 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]2[CH3:26])=[C:4]([F:28])[CH:3]=1.[CH3:29][C:30]1[C:34]([CH2:35][C:36](O)=[O:37])=[C:33]([CH3:39])[O:32][N:31]=1>>[CH3:29][C:30]1[C:34]([CH2:35][C:36]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][N:10]3[C:14](=[O:15])[C:13]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]3[CH3:26])=[C:4]([F:28])[CH:3]=2)=[O:37])=[C:33]([CH3:39])[O:32][N:31]=1
Reactant: CCCC1(c2ccc(F)cc2)N=C(C)N(CC(=O)c2ccc(N)cc2F)C1=O
Reactant: Cc1noc(C)c1CC(=O)O
Product: CCCC1(c2ccc(F)cc2)N=C(C)N(CC(=O)c2ccc(NC(=O)Cc3c(C)noc3C)cc2F)C1=O

Procedure:
Synthesis in analogy to Example 14 and Example 1 starting from enantiomerically pure 3-[2-(4-amino-2-fluoro-phenyl)-2-oxo-ethyl]-5-(4-fluoro-phenyl)-2-methyl-5-propyl-3,5-dihydro-imidazol-4-one and (3,5-dimethylisoxazol-4-yl)-acetic acid to yield (−)-2-(3,5-dimethyl-isoxazol-4-yl)-N-(3-fluoro-4-{2-[4-(4-fluoro-phenyl)-2-methyl-5-oxo-4-propyl-4,5-dihydro-imidazol-1-yl]-acetyl}-phenyl)-acetamide. LC/MS at 254 nm; [M+H] 523; Rt 3.417 min; optical rotation αD25−1.4°, c=0.5 in methanol.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH:13]=[C:12]([OH:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C>[Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH2:13][CH:12]([OH:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)=CC(=O)O1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCC1CC(O)CC(=O)O1
Yield: 96 %

Procedure:
6-t-Butyldimethylsilyloxymethyl-5,6-dihydro-4-hydroxy pyran-2-one (26.3 parts) was dissolved in ethanol (500 parts) and heated to 45° C.-55° C. Raney nickel (6.6 parts) was washed caustic free with water and then water free with ethanol and added to the pyran-2-one solution under a blanket of nitrogen. Hydrogen was passed through the rapidly stirred mixture until the reaction was complete, as judged by GC analysis. The catalyst was filtered off and the solvent removed at 40° C./20 mm to leave 6-t-butyldimethylsilyloxymethyl-4-hydroxytetrahydro pyran-2-one (25.7 parts, 96%, cis/trans ratio 82/18) as a greenish oil which solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[C:29]([O:35][CH3:36])[CH:28]=1)=[O:26]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[N:11]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][C:29]=3[O:35][CH3:36])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)c(OC)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
An amount of 800 mg (3.39 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one (preparation as per WO 2007/134862 Example 36A) and 1.66 g (5.09 mmol) of caesium carbonate were suspended in 10 ml of acetone and admixed with 1.14 g (4.41 mmol) of methyl-4-(bromomethyl)-3-methoxybenzenecarboxylate. The mixture was stirred at 60° C. for 2 h. The suspension was diluted with water. It was extracted with twice 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. Purification by flash chromatography over silica gel with elution with cyclohexane/ethyl acetate (gradient 4:1→1:1) gave 910 mg (64% of theory) of the target compound.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].S(Cl)([Cl:15])(=O)=O>ClCCl>[Cl:15][C:2]([CH3:4])([CH3:3])[C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CC(=O)C(C)(C)Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of ethyl isobutyrylacetate (2 g, 12.6 mmol) in dichloromethane (12 mL) at 0° C. was added a 1M solution of sulfuryl chloride in dichloromethane (13.9 mL, 13.9 mmol). The reaction mixture was warmed to 25° C. and stirred for 2.5 h. The reaction mixture was diluted with dichloromethane (80 mL) and washed in turn with water (2×60 mL) and brine (75 mL). The organic extract was dried (MgSO4), filtered, concentrated to yield ethyl 2-chloroisobutyrylacetate (2.8 g, 66% product, 34% ethyl isobutyrylacetate) as a yellow oil which was used as is in the step below.