Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[NH:10][CH2:11][C:12](=[O:40])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH2:26][O:27]C(=O)C)=[O:23])=[CH:17][C:16]=1[C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9](=[O:41])[NH:10][CH2:11][C:12](=[O:40])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH2:26][OH:27])=[O:23])=[CH:17][C:16]=1[C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OCCNC(=O)Nc1ccc(CNC(=O)CNC(=O)OCc2ccccc2)c(C(=O)c2ccccc2F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(CNC(=O)OCc1ccccc1)NCc1ccc(NC(=O)NCCO)cc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 mg of benzyl{[[2-(o-fluorobenzoyl)-4-[3-(2-acetoxyethyl)ureido]phenyl]methylcarbamoyl]methyl}carbamate dissolved in 10 ml of absolute methanol are treated with 50 mg of sodium methylate, stirred at room temperature for 1 hour and buffered with a small amount of acetic acid. The mixture is poured on to ice/10% sodium bicarbonate and extracted with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. After crystallisation from ether/ethanol, there is obtained benzyl{[[2-(o-fluorobenzoyl)-4-[3-(2-hydroxyethyl)ureido]phenyl]methylcarbamoyl]methyl}carbamate which melts at 117°-120° C.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>ClCCCl>[C:12]1([NH:11][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)c1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 4-necked RBF equipped with an overhead stirrer, J-Kem internal temperature probe, a reflux condenser and an addition funnel was placed isonicotinoyl chloride-hydrochloride (50 g, 0.28 mol). To this solid was added 500 ml of 1,2-dichloroethane and the slurry cooled to 0° C. using an ice/water bath. To the addition funnel was added a mixture of the aniline (31.4 g, 0.34 mol) and Et3N (59.5 g, 0.59 mol) in 50 ml of 1,2-dichloroethane. This mixture was slowly added to the slurry over 25 min. A slight exotherm was observed from 2.4° C. to 15° C. after the addition of the first 10 ml. The reaction mixture was observed to cool down slowly. The reaction mixture turned yellow and became heterogeneous. After 30 min., the ice bath was removed and the reaction heated to reflux for 1.5 h. Deionized water, 100 ml, was added and an off-white precipitate formed. The precipitate was collected by filtering through paper on a Buchner funnel and placed in a drying oven (60° C.) overnight to give 45 g (81% th) of an off-white crystalline solid.
Reaction SMILES: Cl[C:2]1=[N:3][C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2.[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.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>[CH:9]1[C:8]2[C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:19]([O:18][CH3:17])=[O:20])=[CH:22][CH:23]=3)=[N:3][C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[O:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: ClC1=Nc2ccccc2Oc2ccccc21
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C2=Nc3ccccc3Oc3ccccc32)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 1 (229 mg, 1.00 mmol) in DME (3 mL) was added 4-methoxycarbonylphenylboronic acid (216 mg, 1.20 mmol), Pd(PPh3)4 (0.065 mg, 0.056 mmol) and 2 N Na2CO3(aq) (1.5 mL, 3.0 mmol). The reaction mixture was stirred for 2 h at 90° C. The solution was then cooled at room temperature and poured into AcOEt. The organic layer was washed with water, brine and dried (Na2SO4), filtered and concentrated to give a yellow oil. The residue was purified by silica gel column chromatography with EtOAc (15%) in Hexanes to afford 2 (327 mg, 99%) as a yellow foam. LRMS (ESI): (calc) 329.1 (found) 330.3 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][OH:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cc(CO)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(COS(C)(=O)=O)c2ccccc21
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
A well-stirred solution of 3-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester (10, 450 mg, 1.82 mmol) [as prepared following the procedure of D. J. Oliveira and F. Coelho, Synth. Commun. 30 (12) pg. 2143 (2000)] in 10 mL of dichloromethane was cooled in an ice-bath, then treated successively with triethylamine (TEA) (283 mg, 2.18 mmole) and methanesulfonyl chloride (229 mg, 2.0 mmol). This was allowed to stir under nitrogen for 15 min. diluted with dichloromethane, then washed with saturated NaHCO3, dried (Na2SO4) and evaporated. This residue was purified by chromatography to give 0.43 g (73% yield) of the desired compound as an unstable brown solid. 1H NMR (CDCl3) δ 1.67 (s, 12H), 4.79 (s, 2H), 7.28 (t, 1H), 7.36 (t, 1H), 7.67 (m, 2H), 7.51 (bd, 1H).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([O-:15])=[O:14].[Na+].Cl>CO.O>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: O=C([O-])CCl
Reactant: Nc1ccc(S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(SCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.5 %

Procedure:
Into a 500 ml three-necked flask were charged 60 ml of water, 120 ml of methanol and 75 g of sodium hydroxide. 75 g of 4-aminothiphenol and 85 g of sodium chloroacetate were then slowly added to the mixture over an ice bath. Thereafter, the reaction mixture was allowed to cool to room temperature where it was then stirred for 6 hours. After reaction, concentrated hydrochloric acid was added dropwise to the reaction mixture over an ice bath until the pH value of the solution reached 1. As a result, precipitation of a solid matter was observed. The precipitate was filtered off, thoroughly washed with water, and then dried to obtain 95 g of 4-aminophenylsulfanylacetic acid (white powder).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7](N)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.N([O-])=O.[Na+].[CH:16](=[O:22])[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1>O.C(#N)C>[CH3:2][CH:1]([C:4]1[CH:10]=[CH:9][C:7]([C:20]2[O:21][C:17]([CH:16]=[O:22])=[CH:18][CH:19]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: O=Cc1ccco1
Reactant: CC(C)c1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1ccc(-c2ccc(C=O)o2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
& B. A mixture of 100 g (0.74 mole) of 4-isopropylaniline (Aldrich Chemical Co.), 100 ml of water, and 200 ml of concentrated hydrochloric acid, was cooled at 5° C. and treated dropwise with a solution of 52 g (0.75 mole) of sodium nitrite in 150 ml of water. The mixture was kept at 5° C. for 1 hour. A solution of 90 g (0.94 mole) of furfural in 150 ml of acetonitrile was added all at once followed by a solution of 30 g of CuCl2.×H2O in 125 ml of water. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was warmed at 45° C. for 30 minutes and then cooled, and extracted with ether (3×400 ml). The combined ethereal extracts were washed with water (3×200 ml), saturated NaHCO3 solution (2×200 ml) and water (2×200 ml). The ethereal extract was dried over MgSOr and the solvent removed in vacuo (water pump). The residual oil was distilled under high vacuum using a flame. The product, 5-[4-(1-methylethyl)phenyl]-2-furancarboxaldehyde (B), was obtained as an oil (26 g, 16% yield); b.p. 160-175° C./0.5 mm Hg.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[F:39][C:36]([F:37])([F:38])[C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:40])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:29][CH:28]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4′-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4′-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy} phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.04 (2H, d), 7.92 (2H, d), 7.58 (2H,dd), 7.26 (2H, m), 6.91 (2H, d), 6.79 (2H, d), 4.17 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][N:24]2[C@@H:27]2[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[C@@H:29]([OH:37])[C@H:28]2[OH:38])=[C:20]([NH:39][CH2:40][CH:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:19]=1>CN1C(=O)CCC1>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:18]2[N:26]=[C:25]3[C:21]([N:22]=[CH:23][N:24]3[C@@H:27]3[CH2:31][C@H:30]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[C@@H:29]([OH:37])[C@H:28]3[OH:38])=[C:20]([NH:39][CH2:40][CH:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[N:19]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(N[C@@H]1CCNC1)OCc1ccccc1
Solvent: CN1CCCC1=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OCc5ccccc5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
A solution of (R)-pyrrolidin-3-yl-carbamic acid benzyl ester hydrochloride (0.88 g, 3.45 mmol) in DCM is free-based using sodium hydrogen carbonate solution to yield (R)-pyrrolidin-3-yl-carbamic acid benzyl ester (0.487 g, 2.22 mmol). This amine is added to N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Example 4) (0.5 g, 0.96 mmol) and TEA (0.224 g, 2.22 mmol) and then dissolved in NMP (7 ml). The reaction mixture is heated using microwave radiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 190° C. for 1 hour. The resulting mixture is purified by chromatography on silica eluting with 5% MeOH in DCM to yield the titled compound.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:33])(=O)C.[CH3:34][CH:35]1[NH:39][C:38](=[O:40])[CH2:37][CH2:36]1>>[CH3:34][CH:35]1[CH2:36][CH2:37][C:38](=[O:40])[N:39]1[C:13]1[CH:12]=[CH:11][C:10]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:9]([N:6]2[CH2:7][CH2:8][NH:4][C:5]2=[O:33])[CH:14]=1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3nc(C)c(C)cc3C)CC2)C1=O
Reactant: CC1CCC(=O)N1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3N3CCNC3=O)CC2)nc1C
Yield: 18.9 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (182 mg) described in Preparation Example 258 and 5-methylpyrrolidin-2-one (58 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (36 mg) was obtained.
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:27])[NH:25][OH:26].ClC(Cl)(Cl)C(O)=O>CC(C)=O>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24](=[O:27])[N:25]([OH:26])[CH:7]1[CH2:1][CH2:2][O:3][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[NH:6]1
Reactant: O=C(NO)Nc1ccccc1Br
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1Br)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1
Reaction time: 48 h

Procedure:
560 mg (2 mmol) of 4-hydroxycyclophosphamide in 10 ml of acetone were treated with 460 mg of 3-o-bromophenyl-1-hydroxyurea and a catalytic amount of trichloroacetic acid and let to stand at -25° C. After 2 days, the crystals were drawn off by suction and recrystallized from acetone.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][CH:9]=1)#[N:2].C(O)C.CC1CCCO1.[O-]CC.[Na+].[C:31]([O:35][CH2:36][CH3:37])(=[O:34])[CH:32]=[CH2:33]>>[C:13]([O:12][C:11]([NH:10][C:7]1[N:8]=[CH:9][C:4]([CH:3]([C:1]#[N:2])[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH3:37])=[O:34])=[N:5][CH:6]=1)=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)Nc1cnc(CC#N)cn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC1CCCO1
Product: CCOC(=O)CCC(C#N)c1cnc(NC(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
To tert-butyl 5-(cyanomethyl)pyrazin-2-ylcarbamate (0.32 g, 1.37 mmol) in a mixture solvent of ethanol/2-methyltetrahydrofuran (5 mL/5 mL) was added freshly prepared sodium ethoxide (1 M, 1.366 mL), and the mixture was stirred at 0° C. for 10 min, followed by addition of ethyl acrylate (145 ul, 1.366 mmol) and the mixture was stirred at 0° C. for 2 h. The reaction was quenched at this point by adding sat. NaHCO3 (5 mL), and the reaction mixture was stirred for another 10 min, diluted with EtOAc (20 mL), filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (20 mL), washed with pH 7.0 sodium phosphate buffer, and EtOAc layer was concentrated, and the light brown residual oil was purified by flash column eluted with gradient EtOAc/heptane (0-50%) to afford ethyl 4-(5-(tert-butoxycarbonylamino)pyrazin-2-yl)-4-cyanobutanoate (100 mg, 22% yield). LCMS (m/z): 279.2 (MH+-tBu), 0.86 min.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH: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.[C:21]1([NH:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]1([NH:27][C:28]2[N:32]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:31]=[CH:30][N:29]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(Nc2ncc[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(Nc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trityl chloride (2.79 g, 10 mmol) was added to an ice-cooled solution of phenyl amino imidazole (c) (1.59 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in methylene dichloride (50 mL). The reaction mixture was allowed to warm to RT and stirred overnight. The mixture was diluted with methylene dichloride, washed successively with H2O, saturated NaHCO3, brine and dried with MgSO4. Filtration and evaporation of the solvent followed by chromatography separation gave the product (d). 1H NMR (500 MHz, CDCl3) δ 7.52-7.35 (m, 5H), 7.28-7.43 (m, 15H), 6.85 (s, 2H), 6.41 (s, 1H), 6.08 (s, 1H). MS: 1399.8 (M−H)−; 402.8 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:19]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)=[CH:18]2)(=O)=O)C=CC=CC=1>>[CH:1]1([NH:7][C:28]2[N:27]=[C:26]([C:19]3[C:20]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:17][CH:18]=3)[CH:31]=[CH:30][N:29]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: c1cnc2[nH]cc(-c3ccnc(NC4CCCCC4)n3)c2c1
Yield: 41.7 %

Procedure:
Using the procedure of example 1, cyclohexylamine (88 mg) was reacted with compound 1f (100 mg) to provide compound 13 (33 mg, 42%). 1H NMR (400 MHz, CD3OD) δ 8.91 (d, J=8.4 Hz, 1H), 8.26 (d, J=4.8 Hz, 1H), 8.16 (s, 1H), 8.10 (d, J=5.6 Hz, 1H), 7.22 (dd, J=8.0 Hz, 4.8 Hz, 1H), 6.97 (d, J=5.6 Hz, 1H), 3.86 (m, 1H), 2.13-1.27 (m, 10H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[F:21])[N:17]=[C:16]([C:22]([OH:24])=O)[C:15]([OH:25])=[N:14]2.[Cl:26][C:27]1[CH:28]=[C:29]([CH:36]=[CH:37][CH:38]=1)[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:36]=[CH:37][CH:38]=1)[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:22]([C:16]1[C:15]([OH:25])=[N:14][C:13]2[C:18](=[CH:19][C:20]([F:21])=[C:11]([F:10])[CH:12]=2)[N:17]=1)=[O:24]
Reactant: O=C(O)c1nc2cc(F)c(F)cc2nc1O
Reactant: Clc1cccc(CC2CCCN2)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1nc2cc(F)c(F)cc2nc1O)N1CCCC1Cc1cccc(Cl)c1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
Diisopropylethylamine (0.32 mL, 1.8 mmol) was added dropwise to a mixture of 6,7-difluoro-3-hydroxyquinoxaline-2-carboxylic acid (100 mg, 0.44 mmol), racemic 2-(3-chlorobenzyl)pyrrolidine (72 mg, 0.37 mmol) and O-HATU (210 mg, 0.55 mmol) in anhydrous DMF (2.0 mL) at room temperature under nitrogen, after which the mixture was heated to 85° C. and stirred for 4 h. The cooled mixture was directly purified by flash column chromatography on silica gel, eluting with 10% concentrated ammonium hydroxide in methanol/methylene chloride (gradient from 2:98 to 10:90), to provide a yellow solid. The residue was further purified by preparative reverse phase HPLC to provide (+/−)-[2-(3-chlorobenzyl)pyrrolidin-1-yl](6,7-difluoro-3-hydroxyquinoxalin-2-yl)methanone as a light yellow solid: 1H NMR (400 MHz, CDCl3, ˜2:1 mixture of rotamers) δ 7.72-7.63 (m, 2H, rotamers A and B), 7.38-7.21 (m, 2H, rotamers A and B), 7.10-7.03 (m, 1H, rotamers A and B), 6.90-6.79 (m, 1H, rotamers A and B), 4.63-4.56 (m, 1H, rotamers A and B), 3.89-3.82 (m, 1H, rotamer B), 3.76-3.69 (m, 1H, rotamer A), 3.56-3.47 (m, 1H, rotamers A and B), 3.33 (dd, 1H, rotamer A), 3.17 (q, 1H, rotamer B), 2.94-2.89 (m, 1H, rotamer A), 2.86-2.63 (m, 1H, rotamer B), 2.12-1.92 (m, 2H, rotamers A and B), 1.91-1.73 (m, 2H, rotamers A and B) ppm; ESI MS m/z 404 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[Cl-].[Al+3].[Cl-].[Cl-].C(S)CCCCCCC>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCc1ccc(OC)cc1F
Agent: CCCCCCCCS
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-methoxyphenyl)propanoate (57.4 g, 254 mmol) and aluminum chloride (101 g, 761 mmol) in dichloromethane (250 mL) was added dropwise 1-octanethiol (74.3 g, 508 mmol) and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice water and the mixture was stirred for 30 min. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4:1) to give the title compound (44.6 g, yield 83%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:4]1[N:8]2[C:9](=[S:13])[NH:10][N:11]=[CH:12][C:7]2=[CH:6][N:5]=1)[CH2:2][CH3:3].[Na].[CH3:15]I>CO>[CH2:1]([C:4]1[N:8]2[C:9]([S:13][CH3:15])=[N:10][N:11]=[CH:12][C:7]2=[CH:6][N:5]=1)[CH2:2][CH3:3]
Reactant: CI
Reactant: CCCc1ncc2cn[nH]c(=S)n12
Agent: [Na]
Solvent: CO
Product: CCCc1ncc2cnnc(SC)n12

Procedure:
A 3.98 gm. portion of 6-n-propyl-imidazo[1,5-d]-as-triazine-4(3H)-thione is added to a solution of 0.46 gm. of sodium in 15 ml. of methanol under nitrogen. A 1.56 ml. portion of methyl iodide is added. The reaction procedes as described in Example 30 giving the desired product, m.p. 132°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH2:10][C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=O.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1)[CH2:10]/[C:11](/[C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[N:32]\[OH:33]
Reactant: Cn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2cc(Cl)ccc2Cl)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(S(C)(=O)=O)cc2)c2cc(Cl)ccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-(3-(2,5-dichlorophenyl)-3-(4-(methylsulfonyl)-phenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing 3% of the corresponding Z isomer as a colourless solid, MS (ESI+): m/z=479.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12].[OH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:17]=2)[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc(Cl)nc1Oc1cccc(-c2ccccc2)c1

Procedure:
Methyl α-[6-methyl-2,4-dichloro-5-pyrimidinyl]-acetate (4 g, 18 mmol), 3-hydroxybiphenyl (3 g, 18 mmol) and potassium carbonate (11 g, 80 mmol) in dimethylformamide (50 ml) are stirred at +80° C. for 2 hours. Workup as for example 1a) gives pure methyl α-[6-methyl-2-chloro-4-(3-phenylphenoxy)-5-pyrimidinyl]-acetate. 1H (CDCl3):7.65-7.05 (m, 9H); 3.82 (s, 2H); 3.76 (s, 3H); 2.52 (s, 3H).