Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cc(Cl)ccc1N1CCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A 100 mL round-bottom flask was charged with 5-chloro-2-fluorobenzaldehyde (2.00 g, 12.6 mmol, 1.00 equiv), pyrrolidine (1.34 g, 18.8 mmol, 1.49 equiv), potassium carbonate (4.34 g, 31.4 mmol, 1.92 equiv), and dimethyl sulfoxide (10 mL). The resulting solution was stirred overnight at 100° C. in an oil bath and diluted with H2O (20 mL). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with H2O (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/10) to yield 1.80 g (68% yield) of 5-chloro-2-(pyrrolidin-1-yl)benzaldehyde as brown oil. 1H NMR 300 MHz (CDCl3) δ 10.05 (s, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.267-7.31 (m, 1H), 6.76 (d, J=9.0 Hz, 1H), 3.29-3.37 (m, 4H), 1.95-2.04 (m, 4H). LCMS (ESI, m/z): 210 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-])=O.C(N(CC)CC)C.[C:18]([Cl:22])(=[O:21])[CH2:19][CH3:20].C(O)(C)C.Cl>C1COCC1.CO.[Pd]>[ClH:22].[CH2:19]([C:18]([NH:1][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])=[O:21])[CH3:20]
Reactant: CCC(=O)Cl
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cccc(N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-nitroaniline, 4.2 g, 0.03 moles, in 100 ml THF was added ml of triethylamine followed by propionyl chloride, 3.5 g, 0.033 moles. The reaction was stirred at room temperature for 18 hours. then the triethylamine hydrochloride was removed by filtration. To the filtrate was added 100 ml of ethyl acetate, and the organic phase was then washed with 1N hydrochloric acid, 100 ml (twice), and then with 2N sodium hydroxide, 100 ml (twice). The organic phase was dried over magnesium sulfate and the solvent was evaporated to yield an oil. The oil was the dissolved in 100 ml of methanol and 20 ml of isopropanol/hydrochloric acid and to this solution was added 250 mg of 10% palladium on carbon. The reaction was then hydrogenated for 3 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was crystallized from hot isopropanol and ethyl acetate, and was collected by filtration, giving 3-((ethylcarbonyl)amino)aniline hydrochloride.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:17][OH:18])[CH2:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.Cl[Si](C)(C)C.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].N12CCCN=C1CCCCC2>N1C=CC=CC=1.O.CO>[C:24]([NH:16][C:9]1[NH:10][C:11](=[O:15])[C:12]2[N:13]=[CH:14][N:6]([CH2:5][CH2:4][CH:3]([CH2:17][OH:18])[CH2:2][OH:1])[C:7]=2[N:8]=1)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Reactant: CCCCCC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: CCCCCC(=O)Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Reaction time: 0.25 h
Yield: 14.2 %

Procedure:
To a suspension of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (0.25 g, 1.0 mmol) in pyridine (5 ml) was added chlorotrimethylsilane (0.32 ml, 2.5 mmol) and the mixture was stirred for 15 minutes. To this mixture was added hexanoyl chloride (0.18 ml, 1.3 mmol) and the mixture was stirred for 20 minutes. Methanol (2 ml) was then added and the mixture was stirred for a further 20 minutes. 1,8-Diazabicyclo[5.4.0]-undec-7-ene (0.57 ml, 3.8 mmol) and water (0.5 ml) were added and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (4:1). Product containing fractions were pooled and the solvent removed. The residue was taken up in water and passed through C18-Sep-pak cartridges to afford N2-hexanoyl-9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (50 mg, 14%), m.p. 86-88° C.; νmax (KBr) 3400, 2960, 2940, 1675, 1610, and 1560 cm−1; δH [(CD3)2SO] 0.88 (3H, t, J 6.7 Hz, CH ) 1.29 (4H, m, CH3(CH2)2), 1.46 (1H, m, 3′-H), 1.60 (2H, m, CH2CH2CO), 1.77 (2H, q, J 7.1 Hz, 2′-H), 2.46 (2H, t, J 7.4 Hz, CH2CO) 3.3-3.5 (4H, m, 2×4′-H), 4.13 (2H, t, J 7.4 Hz, 1′-H), 4.41 (2H, t, J 4.7 Hz, D2O exchangeable, 2×OH), 7.98 (1H, s, 8-H), 11.65 (1H, br, D2O exchangeable, NH), and 12.01 (1H, br, D2O exchangeable, NH); (Found: C, 53.64; H, 7.56; N, 18.95%; C16H25N5O4.0.5H2O requires: C, 53.32; H, 7.27; N, 19.43%).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[CH2:13]1)C1C=CC=CC=1>C1C=CC=CC=1>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: O=C(Cl)Cl
Reactant: Clc1cccc(Cl)c1OC1CCN(Cc2ccccc2)C1
Solvent: c1ccccc1
Product: O=C(Cl)N1CCC(Oc2c(Cl)cccc2Cl)C1
Reaction time: 72 h

Procedure:
To a solution of 170 ml of 2M phosgene (0.34 mole) stirred at 15° C. was added 109.2 g (0.34 mole) of 1-benzyl-3-(2,6-dichlorophenoxy)pyrrolidine in 300 ml of benzene. The color turned from yellow to deep amber. For convenience, the solution was allowed to stir for 72 hr, then concentrated to give a deep amber colored viscous oil. The oil was triturated with 1.6 liters of 30/60 petroleum ether. The petroleum ether wash was cooled to give 101.5 g of nearly pure title compound containing a trace of benzyl chloride. The yield was nearly quantitative.
Reaction SMILES: COC1C([N+]([O-])=O)=CC=CC=1C=O.C(NC(C1CCNCC1)=O)(C)(C)C.[C:27]([NH:31][C:32]([CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([N+:47]([O-])=O)[C:42]=2[O:50][CH3:51])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][C:32]([CH:34]1[CH2:35][CH2:36][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([NH2:47])[C:42]=2[O:50][CH3:51])[CH2:38][CH2:39]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1c(CN2CCC(C(=O)NC(C)(C)C)CC2)cccc1[N+](=O)[O-]
Agent: CC(C)(C)NC(=O)C1CCNCC1
Agent: COc1c(C=O)cccc1[N+](=O)[O-]
Product: COc1c(N)cccc1CN1CCC(C(=O)NC(C)(C)C)CC1

Procedure:
The title compound is prepared according to the reactions described for BB-5 above starting from 2-methoxy-3-nitro-benzaldehyde and piperidine-4-carboxylic acid tert-butylamide yielding after reductive amination 1-(2-methoxy-3-nitro-benzyl)-piperidine-4-carboxylic acid tert-butylamide; LC-MS A: tR=0.61 min; [M+H]+=350.22 followed by reduction with stannous chloride the title compound; LC-MS A: tR=0.52 min; [M+H]+=320.27.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=2)[C:13]#[N:14])[CH2:5][CH2:4]1.C(O)(=O)C.C(N(CC)CC)C.[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH:35]=O)[CH3:30].C([BH3-])#N.[Na+]>C(O)C>[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:35][N:3]1[CH2:4][CH2:5][CH:6]([NH:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][N:17]=2)[C:13]#[N:14])[CH2:7][CH2:8]1)[CH3:30]
Reactant: N#Cc1ccnc(NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)ccc1C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(Nc3cc(C#N)ccn3)CC2)ccc1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 2.9 %

Procedure:
To a solution of 2-(piperidin-4-ylamino)-isonicotinonitrile dihydrochloride (43.0 mg, 0.18 mmol, 1.0 equiv; intermediate B15) in ethanol (2 mL), acetic acid (54.1 mg, 0.9 mmol, 5.0 equiv) and triethylamine (36.4 mg, 0.36 mmol, 2.0 equiv) was added 3-ethoxy-4-methyl-benzaldehyde (36.1 mg, 0.22 mmol, 1.2 equiv; intermediate E10) and the mixture stirred at 50° C. After 1 h, sodium cyanoborohydride (13.8 mg, 0.22 mmol, 1.2 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 50° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.8 mg (3%) of the title compound. MS (ISP): 351.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][C@H:9]2[C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1.C[O-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][C@H:9]2[C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(C)CC[C@@H]1c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CN(C)CC[C@H]1c1ccc(F)cc1
Yield: 98.5 %

Procedure:
(±)-cis-4-(4'-Fluorophenyl)-3-methoxycarbonyl-1-methylpiperidine (2.0 g), prepared as in Example 2(a), in dry toluene was added to sodium methoxide in toluene and refluxed for 7 hours. After cooling to 0° and filtration, evaporation gave the title compound as an oil (1.97 g, 99%), purity 85-90%.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([C:14]1[S:15][C:16]2[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20][CH2:19][C:17]=2[N:18]=1)[CH3:13]>>[CH2:12]([C:14]1[S:15][C:16]2[CH2:22][CH:21]([CH2:23][O:24][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH2:20][CH2:19][C:17]=2[N:18]=1)[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1nc2c(s1)CC(CO)CC2
Product: CCc1nc2c(s1)CC(COS(=O)(=O)c1ccc(C)cc1)CC2
Yield: 65 %

Procedure:
The compound is prepared by action of p-toluenesulfonyl chloride on the above derivative (IV), according to the procedure described in Example 1. M.p.=54°-56° C. Yield: 65%.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18]>ClC(Cl)C>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1
Reactant: Nc1ccccn1
Reactant: O=Cc1ccc(B(O)O)cc1
Solvent: CC(Cl)Cl
Product: OB(O)c1ccc(CNc2ccccn2)cc1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
A mixture of 4-formylphenylboronic acid (1 g, 6.67 mmol) and 2-pyridinylamine (2.51 g, 26.7 mmol) in dichloroethane (25 mL) was stirred under argon at room temperature. To this mixture was added NaB(OAc)3 (1.84 g, 8.67 mmol). The reaction mixture was quenched with H2O after 3 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with water. The organic layer was then dried and concentrated in vacuo. The crude product was then purified by column chromatography (gradient from 20% to 80% EtOAc/hexane) to give product as colorless liquid (0.39 g, 30%). HPLC/MS: (M+H)+ 229.1 m/z. Retention time (LC-MS)=4.54 min. 1H NMR (CD3OD): 7.90 (1H, d); 7.59 (2H, s); 7.43 (1H, m); 7.30(2H, d); 6.55 (2H, m); 4.47 (2H
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:5]2[C:10]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: OB(O)c1cccnc1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Oc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(-c2cccnc2)c2c(Oc3cccc([N+](=O)[O-])c3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a vial was added 2-chloro-5-iodo-4-(3-nitrophenoxy)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (333.7 mg, 0.61 mmol), pyridin-3-ylboronic acid (79 mg, 0.64 mmol, 1.05 mol eq), 1,4-dioxane (4 mL), water (1 mL), Na2CO3 (78 mg, 0.73 mmol, 1.2 mol eq) and Pd(PPh3)2Cl2 (21 mg, 0.05 mol eq). The reaction vial was capped, stirred at rt for 1 hr and was then heated to 60° C. (block temperature) for 2 days (note: the reaction progress was monitored by LCMS after couple hours and more pyridin-3-ylboronic acid was added as needed). The reaction was diluted with ethyl acetate (100 mL) and water (20 mL) and the organic layer was separated, washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and evaporated to give crude product (TLC: Rf 0.3 in 50% ethyl acetate-50% heptane). The crude product was purified on silica gel to give the title compound as a light yellow solid (266 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.01 (d, J=2.01 Hz, 1H) 8.54 (dd, J=4.78, 1.51 Hz, 1H) 8.38 (t, J=2.14 Hz, 1H) 8.23 (dd, J=8.06, 2.01 Hz, 2H) 8.15 (s, 1H) 7.86-7.93 (m, 1H) 7.77-7.85 (m, 1H) 7.50 (dd, J=7.93, 4.66 Hz, 1H) 5.68 (s, 2H) 3.58-3.74 (m, 2H) 0.83-1.02 (m, 2H) 0.00 (s, 9H). m/z (APCI+) for C23H24ClN5O4Si 498.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:3]=1[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>CO>[CH3:24][N:25]([CH3:27])[CH:26]=[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][C:3]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:2]=1[F:1])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)Cc1ccccc1SCc1cc(F)ccc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)C(=CN(C)C)c1ccccc1SCc1cc(F)ccc1F

Procedure:
A mixture of methyl [2-(2,5-difluorobenzylthio)phenyl]acetate, (15.6 g), dimethylformamide dimethylacetal (23 ml) and pyridinium tosylate (0.2 g) was heated on an oil bath at 140° with distillation of methanol for 4 hours. Excess dimethylformamide dimethylacetal was evaporated under reduced pressure and the residue purified by silica gel column chromatography to give an oil which was recrystallised from diisopropyl ether to give methyl 3-dimethylamino-2-[2-(2,5-difluorobenzylthio)phenyl]prop-2-enoate, mp 97.5°-99° (compound 1A). A mixture of this product (7.26 g), dissolved in acetone (500 ml) and water (15 ml), and Amberlyst 15 (an acidic ion-exchange resin) was stirred at room temperature for 24 hours. The mixture was filtered and the filtrate evaporated, extracted with ether and the extract worked up to give methyl 3-hydroxy-2-[2-(2,5-difluorobenzylthio) phenyl]prop-2-enoate, as a yellow oil, (compound 1B). This (5.3 g) was dissolved in tetrahydrofuran (70 ml) and sodium hydride (0.495 g of 80% dispersion in oil) was added and the mixture stirred for 30 minutes at room temperature. Methyl iodide (2.34 g) was added and the mixture stirred at room temperature overnight and then heated under reflux for 4 hours. Solvent was evaporated and the resulting oil was partitioned between ethyl acetate/ether and water and the organic phase dried and evaporated. The resulting oil was applied to a silica gel chromatography column and eluted with hexane/ethyl acetate to give crude methyl 3-methoxy-2-[2-(2,5-difluorobenzylthio) phenyl]prop-2-enoate, one fraction as the Z-isomer and another fraction as E-isomer. The Z-isomer (2.6 g) was dissolved in toluene (70 ml) and two drops of concentrated sulphuric acid added. The mixture was heated under reflux for two hours, whereby the Z-isomer was converted to the E-isomer. The mixture was washed with water, dried and evaporated and the resulting oil combined with the previously obtained E-isomer. The combined fractions were further purified by column chromatography to give pure methyl (E)-3-methoxy-2-[2-(2,5-difluorobenzylthio) phenyl]prop-2-enoate, as a light brown oil. (Compound 1C).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:36]([CH3:35])(=[O:38])=[O:37])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(C)(=O)=O)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (69.1 mg, 150 μmol; Example 6) was initially charged in THF (2 ml), and sodium hydride (60% in mineral oil; 7.2 mg, 180 μmol) was added at 0° C. The mixture was warmed to RT and stirred for 20 min. A solution of methanesulfonyl chloride (20.6 mg, 180 μmol, 1.2 eq.) in THF (1 ml) was then slowly added dropwise. After a reaction time of 16 h, more methanesulfonyl chloride (6.7 mg, 60 μmol, 0.4 eq.) was added, and the mixture was again stirred at RT for 60 min. The reaction mixture was then concentrated, and the crude product was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). This gave the title compound as a colorless solid (47 mg, 58% of theory).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[OH:35]>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:35][C:29]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=2[F:27])=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Oc1cc(F)ccc1F
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cc(F)ccc1F)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 2,5-difluorophenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.12 (1H, d, J=2.6 Hz), 8.00–7.87 (3H, m), 7.43–7.37 (2H, m), 7.25–7.11 (2H, m), 7.05–6.96 (1H, m), 5.42–5.32 (1H, m), 1.61–1.58 (12H, m); MS (ESI) m/z 489 (M+H)+, 487 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:26][CH2:25][C:22]2[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=2)=[O:17])[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Cc1ncc(CN)cn1
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)O)c2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(Br)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Reaction time: 3 h

Procedure:
A round bottom flask was charged with 5-bromo-4′-methylbiphenyl-3-carboxylic acid (1.00 g, 2.75 mmol), (2-methylpyrimidin-5-yl)methanamine (0.406 g, 3.30 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumh (2.40 g, 6.32 mmol), N,N-diisopropylethylamine (1.91 mL, 11.0 mmol) and N,N-dimethylformamide (10 mL, 100 mmol) and the reaction stirred for 3 hours. The reaction was then quenched with water and extracted with ethyl acetate and washed with brine. The solvents were removed under reduced pressure and the residue purified by flash chromatography followed by prep HPLC to get the product as light yellow solid.
Reaction SMILES: [I:1][C:2]1[C:3](=O)[NH:4][C:5]([S:12][CH3:13])=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>P(Cl)(Cl)(Cl)=O>[Cl:16][C:3]1[C:2]([I:1])=[C:7]([C:8]([F:11])([F:10])[F:9])[N:6]=[C:5]([S:12][CH3:13])[N:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CSc1nc(C(F)(F)F)c(I)c(=O)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1nc(Cl)c(I)c(C(F)(F)F)n1
Yield: 98 %

Procedure:
5-Iodo-2-methylthio-6-trifluoromethyl-3H-pyrimidin-4-one (11.8 g) was dissolved in phosphoryl chloride (40 ml) and phosphorous pentachloride (7.9 g) was added at room temperature with stirring. The mixture was refluxed for 3 hr and the phosphoryl chloride was removed under reduced pressure. The residue was poured onto icy water and extracted with chloroform. The chloroform layer was washed with water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 4-chloro-5-iodo-2-methylthio-6-trifluoromethylpyrimidine (12.2 g) as pale brown crystalline solid, mp 55-56° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:14]2)#[N:10]>CCO>[OH:3][NH:2][C:9](=[NH:10])[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:14]2
Reactant: NO
Reactant: CCOC(=O)CCc1cc2cc(C#N)ccc2[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCc1cc2cc(C(=N)NO)ccc2[nH]1
Temperature: 50 °C
Reaction time: 72 h
Yield: 96.8 %

Procedure:
Hydroxylamine hydrochloride (121 mg) and sodium bicarbonate (293 mg) was added to a solution of ethyl 3-(5-cyano-1H-indol-2-yl)propanoate (D30) (200 mg) in EtOH (15 mL), in that sequence. The reaction mixture was heated to 50° C. and stirred for 72 hours at that temperature. Another portion of hydroxylamine hydrochloride (60 mg) was added, followed by addition of sodium bicarbonate (150 mg). The resulting suspension was stirred at 50° C. for 24 hours. The inorganics was filtered off. The solid was washed with dichloromethane. The filtrate was concentrated to afford a pale yellow oil. Trituration of the residue provided ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indol-2-yl}propanoate (D31) (220 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7]1)[CH:2]=[CH2:3].Br[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=1>CC(N(C)C)=O.[Cu]=O>[O:12]=[C:8]1[NH:7][C:6]([CH2:5][O:4][CH2:1][CH:2]=[CH2:3])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:14]=2)[C:10](=[O:11])[N:9]1[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([C:32]([F:33])([F:35])[F:34])[CH:25]=1
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Reactant: C=CCOCC1(c2cccc(C(F)(F)F)c2)NC(=O)NC1=O
Agent: O=[Cu]
Solvent: CC(=O)N(C)C
Product: C=CCOCC1(c2cccc(C(F)(F)F)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 130 °C

Procedure:
To a solution of 4-[(2-propenyloxy)methyl]-4-(3-trifluoromethylphenyl)imidazolidin-2,5-dione (1.45 g) and 4-bromo-2-(trifluoromethyl)benzonitrile (1.15 g) in DMAC (7 mL) is added copper oxide (528 mg). The mixture is refluxed overnight at 130° C. The mixture is concentrated, taken in ethyl acetate, washed with a 10% aqueous ammonia solution and brine. The organic phase is dried over magnesium sulfate, concentrated under vacuum and purified on silica gel (ethyl acetate/cyclohexane 0/100 to 50/50) to give the desired compound.