Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@:5]1([CH2:26][CH2:27][CH3:28])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C@@H:16](O)[CH2:17][C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH3:29][O:30][CH2:31]OC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[C:1]([O:4][C@@:5]1([CH2:26][CH2:27][CH3:28])[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][C@@H:16]([CH2:29][O:30][CH3:31])[CH2:17][C@@H:18]1[CH3:24])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CCC[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C
Reactant: COCOC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCC[C@]1(OC(C)=O)CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](COC)C[C@H](C)[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
400 mg of 17β-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3β-ol is combined in 2.8 ml of absolute dichloromethane and 1.8 ml of formaldehyde dimethylacetal with a mixture of 600 mg of kieselguhr W 20 and 300 mg of phosphorus pentoxide and stirred for 45 minutes at room temperature. The mixture is vacuum-filtered from the insoluble components and washed with dichloromethane containing 3-5% triethylamine. The crude product obtained after evaporation is chromatographed on silica gel, thus producing 280 mg of 17β-acetoxy-3β-methoxymethyl-1α-methyl-17α-n-propyl-5α-androstane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.O>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([NH:1][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[CH3:11])=[N:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Solvent: O
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1Nc1ccc(C(F)(F)F)cn1
Yield: 74016.1 %

Procedure:
3.04 g (0.02 mmol) of 2-amino-4-nitrotoluene and 7.26 g (0.04 mol) of 2-chloro-5-trifluoromethylpyridine are stirred in the molten state for 5 hours at 160° C. After cooling, 200 ml of water are added thereto and the product is taken up in methylene chloride. The solvent is evaporated off and the residue is purified by column chromatography (silica gel, methylene chloride:hexane=2:1), affording 4.4 g of N-(5-trifluoromethyl-2-pyridyl)-2-methyl-5-nitroaniline (m.p. 103°-105° C.).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:9]=2)=[C:5]([F:25])[CH:4]=1.NC1N=CN=C(OC2C=CC(NC(NC(=O)CC3C=CC(F)=CC=3)=S)=CC=2F)C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.COC1C=CC(CNC2N=C(OC3C=CC(N[C:108](=[O:120])[CH2:109][C:110]([NH:112][C:113]4[CH:118]=[CH:117][C:116]([F:119])=[CH:115][CH:114]=4)=[O:111])=CC=3F)C=CN=2)=CC=1>CN(C=O)C>[F:25][C:5]1[CH:4]=[C:3]([NH:2][C:108](=[O:120])[CH2:109][C:110]([NH:112][C:113]2[CH:118]=[CH:117][C:116]([F:119])=[CH:115][CH:114]=2)=[O:111])[CH:24]=[CH:23][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:9]=1
Reactant: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)n2)cc1
Reactant: Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1)Nc1ccc(F)cc1
Yield: 40 %

Procedure:
The title compound was prepared from a mixture of 4-(4-amino-2-fluorophenoxy)-N-(2-morpholinoethyl)pyridin-2-amine, hydrochloride salt (15 mg, 0.043 mmol), 3-(4-fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1, 10 mg, 0.052 mmol), TBTU (17 mg, 0.052 mmol), DIPEA (30 μL), and DMF (1 mL) using a similar procedure described for the preparation of Compound C of Example 1. The crude product was purified by preparative HPLC (Shimadzu S5 VP-ODS 20×100 mm). The product obtained from HPLC purification was treated with 1 M HCl and lyophilized to give the title compound (10 mg, 40%) as a white solid. 1H NMR (DMSO-d6) δ 10.37 (s, 1H), 10.05 (s, 1H), 9.90 (br s, 1H), 7.90 (d, 1H, J=6.1 Hz), 7.75 (d, 1H, J=13.2 Hz), 7.58-7.55 (m, 2H), 7.53-7.50 (m, 1H), 7.40 (d, 1H, J=8.8 Hz), 7.24 (t, 1H, J=8.8 Hz), 7.08-7.03 (m, 3H), 6.39 (d, 1H, J=6.1 Hz), 6.11 (s, 1H), 3.80-3.81 (m, 4H), 3.67-3.65 (m, 2H), 3.47 (br s, 2H), 3.20 (br s, 4H); MS (ESI+) m/z 512.12 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:35][C:36](=[NH:47])[CH2:37][S:38]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:40])=[O:39]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:47]=[C:36]([CH2:37][S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:40])=[O:39])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N=C(CS(=O)(=O)c1ccccc1)NO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CS(=O)(=O)c2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (300 mg, 1.00 mmol) in dichloromethane (15 ml) was treated with 1,1′-carbonyldiimidazole (162 mg, 1.00 mmol) and the solution was stirred at room temperature for 2 hours. N-hydroxy-2-(phenylsulfonyl)ethanimidamide (J.Heterocycl.Chem.; 16; 1979; 1197-1200) (214 mg, 1.00 mmol) was then added and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 130° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound (78 mg).
Reaction SMILES: [C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[Na+].[Na+].[C:11]([N:15]=[N:16][C:17](Cl)([CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:18])([CH3:14])([CH3:13])[CH3:12]>CN(C)C=O>[C:1]([O:8][C:17]([N:16]=[N:15][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH2:19][CH:20]([CH3:21])[CH3:22])(=[O:7])[CH2:2][CH2:3][C:4]([O:6][C:17]([N:16]=[N:15][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:5]
Reactant: CC(C)CC(C)(Cl)N=NC(C)(C)C
Reactant: O=C([O-])CCC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CC(C)(N=NC(C)(C)C)OC(=O)CCC(=O)OC(C)(CC(C)C)N=NC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
To a slurry of 5.97 grams (.0221 moles) of sodium succinate in 75 mls. of dimethylformamide in a 200 beaker, warmed to 35°C in a water bath, was added 9.0 grams (.0442 moles) of 2-t-butylazo-2-chloro-4-methylpentane dropwise. After the addition was complete, the reaction was stirred for 3 hours at room temperature, poured into 200 ml. of cold water and extracted with pentane. The pentane solution was washed with water, dried over anhydrous Na2SO4, filtered, stirred over alumina, filtered and the pentane evaporated to leave 6.0 grams (60% yield) of a light yellow liquid. The crude product was purified by column chromatography using pentane as eluent. The infrared spectrum of the purified product was in agreement with the structure of the desired product.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].[Sn](Cl)(Cl)(Cl)Cl.Cl>ClCCl>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[C:7]([C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)=[O:8]
Reactant: COc1ccccc1OC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(C(F)(F)F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-Trifluoromethylbenzoyl chloride (200 grams), 1,2-dimethoxybenzene (128 mL), and dichloromethane (1800 mL) were combined in a reaction flask under a nitrogen atmosphere. Tin (IV) chloride (168 mL) was added to the reaction mixture slowly drop-wise over 45 minutes. The reaction mixture was heated to reflux for 11 hours. It was subsequently cooled to room temperature and slowly poured into a mixture of 200 mL of hydrochloric acid and 1800 mL of ice water. The layers were phase separated. The organic layer was washed with 4 portions of water (1 L each) and then with 1.5 L of 20% saturated aqueous sodium hydroxide (w/v). The organic layer was dried over anhydrous sodium sulfate and then concentrated by rotary evaporation. The residue was recrystallized in 1 L of 15% ethyl acetate/85% hexanes. The crystalline solid was collected by vacuum filtration yielding 132 grams of 3,4-dimethoxy-4′-trifluoromethylbenzophenone. This material was not purified further but was used directly in the next step.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[N:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=2)=[C:8]([CH3:21])[CH:7]=1.C([O-])([O-])=[O:23].[K+].[K+].OO>CS(C)=O>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[N:12]=[CH:13][C:14]([C:17]([NH2:18])=[O:23])=[N:15][CH:16]=2)=[C:8]([CH3:21])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C2OCCO2)ccc1Oc1cnc(C#N)cn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C2OCCO2)ccc1Oc1cnc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 137.6 %

Procedure:
Take up 5-(4-[1,3]dioxolan-2-yl-2-methylphenoxy)pyrazine-2-carbonitrile (0.082 g, 0.305 mmol) and K2CO3 (0.020 g, 0.152 mmol) in DMSO (3.0 mL). Add 30% H2O2 (0.090 mL, 0.792 mmol) and stir at room temperature for 1.5 hours before quenching with water (10 mL). Extract with ethyl acetate (50 mL). Wash the organic layer with water (1×10 mL), dry over Na2SO4 filter and concentrate. Purify by flash chromatography eluting with 40% ethyl acetate in dichloromethane to give the title compound (0.063 g, 68.6%): MS ES+ 302.0 (M+H)+; TLC [silica gel 60 F254, 40% ethyl acetate in dichloromethane] Rf=0.17.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH3:20])[C:18]([C:21]34[CH2:28][CH2:27][C:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([CH2:25][CH2:26]3)[CH2:23][CH2:22]4)=[N:17][N:16]=2)=[C:11]([C:35]([F:38])([F:37])[F:36])[CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[CH3:20][N:19]1[C:18]([C:21]23[CH2:22][CH2:23][C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([CH2:25][CH2:26]2)[CH2:27][CH2:28]3)=[N:17][N:16]=[C:15]1[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[C:35]([F:37])([F:36])[F:38]
Reactant: Cn1c(-c2ccc(OCc3ccccc3)cc2C(F)(F)F)nnc1C12CCC(c3ccccc3)(CC1)CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1c(-c2ccc(O)cc2C(F)(F)F)nnc1C12CCC(c3ccccc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 3-[4-(Benzyloxy)-2-(trifluoromethyl)phenyl]-4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (8-E) (27 mg, 0.05 mmol) was dissolved in ethyl acetate/methanol (1:1, 4 mL) to which 10% palladium-on-carbon (4 mg) was added. The reaction was then placed under hydrogen atmosphere and stirred for 3 h at room temperature and pressure. After appropriate evacuation of the hydrogen atmosphere, the palladium was filtered through a filter aid with methanol (40 mL). The filtrate was collected and the solvent removed in vacuo to afford 4-[4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazol-3-yl]-3-(trifluoromethyl)phenol (8-F). MS: m/z 428 (M+1); 1H NMR (500 MHz, CDCl3): δ 1.92 (6H, m), 2.11 (6H, m), 3.41 (3H, s), 7.17 (2H, m), 7.24 (1H, m), 7.31 (2H, m), 7.38 (3H, m) ppm.
Reaction SMILES: CC1[N:3]([C:7]2[CH:8]=[C:9]([C:13]3[CH:22]=[N:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17]C)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH2:4][CH2:5][N:6]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C@H:27]1[O:29][CH2:28]1.[OH-].[Na+].Cl>C1(C)C=CC=CC=1.CO>[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:27]([OH:29])[CH2:28][NH:6][CH2:5][CH2:4][NH:3][C:7]2[CH:8]=[C:9]([C:13]3[CH:22]=[N:21][CH:20]=[CH:19][C:14]=3[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: COC(=O)c1ccncc1-c1cccc(N2CCN=C2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(O)c1ccncc1-c1cccc(NCCNC[C@H](O)c2cccc(Cl)c2)c1
Temperature: 110 °C
Yield: 57.7 %

Procedure:
A solution of methyl 3-[3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)phenyl]isonicotinate (0.25 g) and (R)-3-chlorostyrene oxide (0.13 g) in anhydrous toluene (2 ml) was heated at reflux (ca. 110° C.) for 18 h. The mixture was cooled to ca. 50° C., 1M sodium hydroxide solution (4.8 ml) and methanol (3 ml) were added over 5-10 min. The apparatus was configured to distill out 4 ml of solvents under atmospheric pressure. The homogeneous mixture obtained was heated at reflux for 2 h. The mixture was cooled to <50° C., and concentrated hydrochloric acid (36%, 0.3 ml) was added dropwise to adjust pH to 7. The aqueous solution was loaded on to silica gel column and eluted with a mixture of dichloromethane and methanol (8/2, v/v). The product was isolated as 0.2 g (57%) of hygroscopic brown solid.
Reaction SMILES: [Na].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([O:38][CH3:39])=[N:13][N:14]([CH3:37])[C:15]=3[N:16](S(C3C=CC(Cl)=CC=3)(=O)=O)[S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3]1.[Cl-].[NH4+].O>CO.ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([O:38][CH3:39])=[N:13][N:14]([CH3:37])[C:15]=3[NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COc1nn(C)c(N(S(=O)(=O)c2ccc(Cl)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1-c1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1nn(C)c(NS(=O)(=O)c2ccc(Cl)cc2)c1-c1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 66.7 %

Procedure:
An aqueous solution of sodium hydroxyde (2M, 270 □l), was added at room temperature to a solution of N-[4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazol-5-yl]-4-chloro-N-[(4-chlorophenyl)sulfonyl]benzenesulfonamide (Preparation 43) (32 mg) in a mixture of methanol (1 ml) and dichloromethane (1 ml). After 1 h, an aqueous saturated solution of ammonium chloride (4 ml) and water (4 ml) were added and the mixture was extracted with dichloromethane (3×5 ml). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (silica) eluted with dichloromethane:methanol (95:5) to yield the title compound as colourless oil (15.1 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[C:15]1=[O:33])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH:24][C:25]([C:27]2[S:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[O:26])[C:15]1=[O:33]
Reactant: CC(C)(C)OC(=O)NCCCCCCN1C(=O)c2cccc(NC(=O)c3ccc(Cl)s3)c2C1=O
Solvent: O=C(O)C(F)(F)F
Product: NCCCCCCN1C(=O)c2cccc(NC(=O)c3ccc(Cl)s3)c2C1=O

Procedure:
was obtained analogously by reacting tert-butyl-6-(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)hexylcarbamate with trifluoroacetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>CC(O)C.O.CCOCC.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]>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: CCOCC
Product: COC(=O)c1cc(C(=O)OC)cc(-c2ccccc2OC)c1

Procedure:
To dimethyl 5-bromoisophthalate (1.5 g, 5.5 mmol, Aldrich) in i-PrOH (33.3 ml) and water (16.7 ml), 2-methoxy phenyl boronic acid (Aldrich), triethyl amine (841 mg, 8.25 mmol) and PdCl2(dppf) (180 mg, 0.22 mmol) were added and the reaction mixture was refluxed for 4 h. Then reaction mixture was diluted with ether, washed with water, brine and dried. Volatiles were removed under vacuum and the crude residue was column chromatographed (30% ethylacetate/70% hexanes) to yield 650 mg of dimethyl 2′-methoxybiphenyl-3,5-dicarboxylate as white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([S:25]([CH3:24])(=[O:27])=[O:26])[C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CNC(=O)N1c1cccc(I)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CC(=O)N(c2cccc(I)c2)C1=O

Procedure:
A solution of 3-(3-iodophenyl)imidazolidine-2,4-dione (950 mg) and N,N-diisopropylethylamine (1.1 ml) in DCM (20 ml) was treated with methanesulfonyl chloride (0.453 ml) at 20° C. After 2 h the reaction mixture was diluted with DCM and washed with aqueous 2M HCl (3×20 ml) and NaHCO3 and dried (MgSO4). The solvent was removed under reduced pressure to give the title compound (1.15 g). LCMS RT=2.91 min.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[C:15]([O:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]O)=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:15]([O:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH2:26][N:10]2[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=3[CH:8]=[C:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:28][CH:29]=1)([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)Oc1ccc(OCCO)cc1
Reactant: COC(=O)c1cc2c(Cl)nccc2[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(Cl)nccc2n1CCOc1ccc(OC(C)(C)C)cc1
Yield: 104.6 %

Procedure:
Methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (500 mg, 2.374 mmole), 2-(4-tert-butoxyphenoxy)ethanol (624 mg, 2.97 mmole), and PPh3 (778 mg, 2.97 mmole) were combined in toluene (10 mL) at RT. To this was added DIAD (0.58 mL, 2.98 mmole) slowly at RT. After 3 hr the mixture was concentrated. Flash column chromatography (Biotage-SNAP-50 g SiO2, 0-25% EtOAc/hexanes) gave the title compound (1.0 g, 105%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J=6.0 Hz, 1 H); 7.44 (d, J=1.0 Hz, 1 H); 7.43-7.38 (m, 1 H); 6.85-6.81 (m, 2 H); 6.64-6.60 (m, 2 H); 4.92 (t, J=5.0 Hz, 2 H); 4.31 (t, J=5.0 Hz, 2 H); 3.95 (s, 3H); 1.26 (s, 9 H).
Reaction SMILES: [NH2:1][C:2](=S)[C:3]([O:5][CH2:6][CH3:7])=[O:4].F[B-](F)(F)F.C([O+](CC)CC)C.C([O-])(=O)C.[Na+].Cl.[NH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O>ClCCl.C(O)(=O)C>[CH2:6]([O:5][C:3]([C:2]1[NH:27][CH:28]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:1]=1)=[O:4])[CH3:7]
Reactant: NCC(=O)c1ccccc1
Reactant: CCOC(=O)C(N)=S
Agent: CC(=O)[O-]
Agent: CC[O+](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(-c2ccccc2)c[nH]1
Temperature: 75 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
A solution of ethyl aminothioxoacetate (7.4 g) in 74 ml of dichloromethane was stirred in a water bath at room temperature and treated dropwise with triethyloxonium tetrafluoroborate in dichloromethane (1.0 M, 74 ml). The mixture was stirred for 16 h and then evaporated to dryness to give a yellow oil. Anhydrous sodium acetate (9.10 g), 2-aminoacetophenone hydrochloride (9.54 g), and glacial acetic acid (110 ml) were added to the oil and the mixture was stirred and heated at 75° C. under an atmosphere of nitrogen. After 2 h the reaction mixture was evaporated and the residue was suspended in water (50 ml), slowly basified with potassium carbonate, and then extracted with ethyl acetate. The organic extracts were washed with water and brine, dried over magnesium sulphate and evaporated to dryness. The residue was crystallized from dichloromethane-diethyl ether to give 7.63 g of 4-phenyl-1H-imidazole-2-carboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[N:44][CH:43]=[CH:42][N:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[N:44][CH:43]=[CH:42][N:41]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K14) (224 mg, 0.75 mmol) according to the general procedure M. Obtained as an orange foam (370 mg, 82%).
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.C[O:34][C:35](=O)[CH2:36][C:37]1[CH:76]=[CH:75][CH:74]=[CH:73][C:38]=1[CH2:39][CH2:40][C:41]1[C:46]([C:47]([F:50])([F:49])[F:48])=[CH:45][N:44]=[C:43]([NH:51][C:52]2[CH:72]=[CH:71][C:55]([C:56]([N:58]3[CH2:63][CH2:62][N:61]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:60][CH2:59]3)=[O:57])=[CH:54][CH:53]=2)[N:42]=1.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:7][C:35](=[O:34])[CH2:36][C:37]1[CH:76]=[CH:75][CH:74]=[CH:73][C:38]=1[CH2:39][CH2:40][C:41]1[C:46]([C:47]([F:50])([F:48])[F:49])=[CH:45][N:44]=[C:43]([NH:51][C:52]2[CH:72]=[CH:71][C:55]([C:56]([N:58]3[CH2:59][CH2:60][N:61]([C:64]([O:66][C:67]([CH3:68])([CH3:69])[CH3:70])=[O:65])[CH2:62][CH2:63]3)=[O:57])=[CH:54][CH:53]=2)[N:42]=1
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
HOBt (0.068 g, 0.50 mmol), EDCl.HCl (0.096 g, 0.50 mmol) and DIPEA (0.34 mL, 1.9 mmol) were added to a stirred solution of tert-butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoyl)piperazine-1-carboxylate (A25) (0.28 g, 0.39 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (0.19 g, 1.9 mmol) was added in one portion and the resulting solution was stirred at room temperature for 17 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (65 mL) and saturated aqueous NaHCO3 (65 mL). The aqueous layer was extracted with EtOAc (2×50 mL) then the combined organic layers were washed with brine (50 mL) and dried over MgSO4. The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-20% MeOH in EtOAc) to give the title compound A26 as a white solid (0.18 g, 77%); 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 7.91 (s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.31-7.21 (m, obscured), 5.43 (br. s, 2H), 3.74 (s, 2H), 3.71-3.35 (m, 8H), 3.18-3.03 (m, 4H), 1.47 (s, 9H). LCMS-A: rt 6.120 min; m/z 613.3 [M+H]+.