Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:20]([O:19][C:17](=[O:18])[CH2:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of ethyl 1H-indole-2-carboxylate (5.68 g, 30 mmol), tert-butyl 2-bromoacetate (6.44 g, 33 mmol), and potassium carbonate in 60 mL of DMF was heated to 80° C. for 2 days. The TLC showed that the reaction stopped at around 50% completion. The reaction was worked up by the addition of water and the aqueous phase was extracted with EtOAc (2×30 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by Combiflash (40 g silica gel cartridge, 0-30% EtOAc in hexane) to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:13][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(O)c1cc(Cl)ccc1S
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2ccc(Cl)cc12
Yield: 27 %

Procedure:
A mixture of 5-chloro-2-mercaptobenzoic acid (2.00 g, 10.6 mmol), 2-cyanopyridine (1.10 g, 10.5 mmol) and pyridine (50.0 ml) was refluxed for 9 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (0.78 g, 27%)
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].C(N(CC)CC)C.[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[N:32]=[C:33]=[O:34])([CH3:24])[CH3:23]>O1CCCC1>[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[NH:32][C:33](=[O:34])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1)([CH3:24])[CH3:23]
Reactant: C#CCN1CCCc2ccc(O)cc21
Reactant: Cc1cccc(C(C)C)c1N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN1CCCc2ccc(OC(=O)Nc3c(C)cccc3C(C)C)cc21
Temperature: 35 °C

Procedure:
A mixture of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 mL) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-isopropyl-6-methylphenyl isocyanate (558 mg/ml, 3.21 mM) was added at once and then the reaction mixture was further stirred for 30 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:19) to afford 10d as solid. Yield: 520 mg, 67.16%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd-2](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.C(#N)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1
Reactant: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Reactant: COc1ccc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2OC)cc1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(COc2ccc(-c3cnc4[nH]cc(-c5ccccc5OC)c4c3)cc2OC)cc1
Yield: 48.7 %

Procedure:
A Personal Chemistry® microwave vial (2-5 ml size) was charged with 5-bromo-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (98 mg, 0.33 mmol), 2-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (148 mg, 0.400 mmol), 6.5 mg (9.3 μmol, 5 mol %) of dichlorobis(triphenylphosphino)palladium(II), 1 ml of acetonitrile and 1 ml of a 2 M aqueous solution of sodium carbonate. The vial was sealed, evacuated and purged three times with nitrogen, then irradiated in a Personal Chemistry® microwave reactor with a temperature setting of 150° C. for 30 minutes. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 75 mg (50%) of 5-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine as a light yellow solid. 1H-NMR (d6-DMSO) δ=12.12 (br.s, 1H), 8.51 (d, 1H), 8.11 (d, 1H), 7.70 (d, 1H), 7.57 (dd, 1H), 7.38 (d, 2H), 7.27 (t, 1H), 7.25(d, 1H), 7.18 (dd, 1H), 7.11 (m, 2H), 7.02 (t, 1H), 6.95 (d, 2H), 5.03 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.75 (s, 3H); MS m/z: 467 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[C:10]=1[C:16]([O:18]CC)=O.[Na].C(O)(=O)C>C(O)C>[CH3:15][N:11]1[C:10]2[C:16](=[O:18])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9]=2[CH:13]=[C:12]1[CH3:14]
Reactant: CCOC(=O)c1c(Nc2ccccc2N)cc(C)n1C
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc2c(n1C)C(=O)Nc1ccccc1N2

Procedure:
2.73 g (0.01 mole) of ethyl 3-(2-aminophenyl)amino-1,5-dimethyl-1H-pyrrole-2-carboxylate in a solution of 0.25 g (0.011 mole) of sodium in 40 ml of dry ethanol are boiled under reflux for 2 hours. After the mixture has cooled, it is neutralized carefully with acetic acid; the solvent is stripped off in vacuo, and the yellowish residue is recrystallized from dioxane. Yield: 1.9 g.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20]COC)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>C(#N)C>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:24]=[CH:25][C:2]([NH:1][C:41]([NH:40][C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)=[O:42])=[CH:3][CH:4]=1)#[N:18]
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C#N
Yield: 68 %

Procedure:
4-(4-Aminophenoxy)-6-cyano-7-methoxyethoxyquinoline (150 mg) was added to 5.0 ml of toluene and 2.5 ml of acetonitrile, and the mixture was heated to reflux. After then adding 4-fluorophenyl isocyanate (0.12 ml), the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and washed with ethyl acetate/toluene=1/1 to obtain 150 mg of the title compound as light brown crystals (68% yield).
Reaction SMILES: [K+].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.Cl[CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[CH3:26][C:25]([CH3:28])([CH3:27])[C:24]([O:23][CH2:22][O:19][C:18]([C:10]1[NH:11][C:12]2[C:17]([C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20])=[O:29]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 50 °C
Yield: 50.8 %

Procedure:
Stir at 50° C. a mixture of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid potassium salt (1.0 g, 3.43 mmol), KI (0.16 g) 2,2-dimethyl-propionic acid chloromethyl ester (0.63 g, 4.16 mmol) in DMF (20 mL) for 1.5 h. Cool, and partition between H2O-EtOAc. Wash the extract with aqueous NaHCO3 solution, dry the extract (MgSO4), filter and concentrate under vacuum to afford the crude product. Chromatography the product on a silica gel column eluting with 8% MeOH/EtOAc to obtain 0.64 g of the title compound as a solid; MS 326(M+H), m.p. 223–224° C. TLC (silica gel, 8% MeOH/EtOAc) Rf=0.30.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][CH2:23][CH2:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([NH:30][C:27]2[CH:28]=[CH:29][N:25]([CH2:24][CH2:23][O:22][CH3:21])[N:26]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COCCn1ccc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Yield: 64.1 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.37 mmol) and 1-(2-methoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 72, 0.054 g, 0.38 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.19 g, 0.44 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) dropwise and the resulting solution stirred at room temperature over night. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (15 mL), a saturated sodium chloride solution (20 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-40 g column, 50-70% ethyl acetate/hexanes) to give (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (94 mg, 65%) as an off white solid: [α]29D=−62.6°, (C=0.31, chloroform); HR-ES(+) m/e calcd for C22H28N4O3 [M+Na]+ 419.2053, observed 419.2055; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-2.09 (m, 7H), 3.18 (s, 4H), 3.61 (t, J=5.28 Hz, 2H), 4.12 (t, J=5.13 Hz, 2H), 4.38-5.23 (m, 4H), 6.37 (d, J=2.11 Hz, 1H), 7.32-7.84 (m, 7H), 10.84 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[OH:12])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CCOc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1ccc(C=O)cc1OCc1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
16.6 grams of 4-ethoxy-3-hydroxybenzaldehyde (100 mmol.) and 200 ml of absolute ethyl alcohol are added to a three-necked flask and then heated to 40° C. for being dissolved, 9 grams of potassium carbonate (65.07 mmol.) is added, 15 ml of benzyl chloride (130.13 mmol.) is added under stirring, heating reflux is performed for 1 hour, the reaction product is cooled to 50° C. after complete reaction is detected by TLC and then filtered while it is hot, the filtrate is put in a refrigerator for being cooled over night, crystals are separated out and pump-filtered, filter cakes are washed with 30 mL of absolute ethyl alcohol and then vacuum-dried to obtain 21.5 grams of white needle crystals, and the yield is 83.9%.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[CH:4][C:3]=1[CH3:15].[O:16]=[C:17]([CH:19]=[C:20]([CH3:22])[CH3:21])[CH3:18]>>[CH3:21][C:20]([CH3:22])([CH2:19][C:17](=[O:16])[CH3:18])[CH:8]([C:6](=[O:7])[C:5]1[CH:13]=[CH:14][C:2]([F:1])=[C:3]([CH3:15])[CH:4]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: CC(=O)C=C(C)C
Reactant: COC(=O)CC(=O)c1ccc(F)c(C)c1
Product: COC(=O)C(C(=O)c1ccc(F)c(C)c1)C(C)(C)CC(C)=O
Reaction time: 120 h

Procedure:
A mixture of methyl 4-fluoro-3-methylbenzoylacetate (1a) (26.95 g, 0.128 mol) and mesityl oxide (2) (19.3 g, 0.192 mol) was kept at 0°-5° C. for 5 days, poured onto cold saturated NaHC3 and extracted with ether. The combined extracts were washed with H2O and brine and dried (MgSO4). Removal of the volatiles in vacuo furnished 3a which was used without further purification.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[CH:8][CH2:9][C:10]3[C@H:11]4[C@:23]([CH3:31])([CH2:24][CH2:25][C:26]=32)[C@@H:14]([C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]4)[CH2:6]1)(=[O:3])[CH3:2].B.CSC.[OH2:36].[Na]>C(OCC)C>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([C@@H:8]([OH:36])[CH2:9][C:10]3[C@H:11]4[C@:23]([CH3:31])([CH2:24][CH2:25][C:26]=32)[C@@H:14]([C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:13][CH2:12]4)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CCC3=C2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]32)C1
Agent: B
Agent: [Na]
Solvent: CSC
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC[C@]2(C)C3=C(C[C@H](O)[C@H]2C1)[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC3
Temperature: 0 °C

Procedure:
Cholesta-5,8-diene-3β-yl acetate (1.0 g) is dissolved in 250 ml diethylether. The reaction mixture is cooled to 0° C. and 2.35 ml of borane-dimethylsulphide-complex (2 M solution in tetrahydrofuran) is added. The reaction mixture is warmed to room temperature within 2 hours. Then, 26 ml water, 26 ml sodium hydroxyde solution (10% aqueous) and 3.65 ml hydrogen-peroxyde (30%) are added at 0° C. After aqueous work-up and column chromatography 3β-(acetyloxy)-5α-cholest-8-ene-6α-ol (140 mg) is isolated.
Reaction SMILES: ClC1C(Cl)=NC2C(=CC=C([N+]([O-])=O)C=2)N=1.Cl[C:17]1[C:26](Cl)=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([Cl:28])[CH:23]=2)[N:18]=1.[K][S:30][C:31](=[C:34]([C:37]#[N:38])[C:35]#[N:36])[S:32][K]>>[Cl:28][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]1[S:30][C:31](=[C:34]([C:37]#[N:38])[C:35]#[N:36])[S:32][C:26]1=[N:25]2
Reactant: N#CC(C#N)=C(S[K])S[K]
Reactant: Clc1ccc2nc(Cl)c(Cl)nc2c1
Agent: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Product: N#CC(C#N)=C1Sc2nc3ccc(Cl)cc3nc2S1
Yield: 78 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 3.0 g of 2,3,6-trichloroquinoxaline and 3.5 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a dark brown powder weighing 3.0 g with a calculated yield of 78 percent and has a melting point greater than 300° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1>>[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-proline methyl ester hydrochloride (Bachem), the title compound was prepared as an oil. The reaction was monitored by tlc (Rf=0.12 in 50% EtOAc/hexanes).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[C:9]([CH2:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][C:9]1[O:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:29])[F:30])=[CH:23][CH:24]=3)[C:3]=2[N:10]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Clc1cccc(Cl)c1Cc1nc2c(Cl)ncnc2o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1ccc(Nc2ncnc3oc(Cc4c(Cl)cccc4Cl)nc23)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A mixture of 7-chloro-2-(2,6-dichloro-benzyl)-oxazolo[5,4-d]pyrimidine (42 mg, 0.13 mmol), 4-trifluoromethyl-phenylamine (22 mg, 0.13 mmol), and p-TsOH.H2O (51 mg, 0.27 mmol) in toluene (2 mL) was heated to 120° C. in a sealed tube. After 2 h, the solution was cooled purified by preparative reverse-phase HPLC to afford the title compound as a colorless solid (20 mg, 34%). MS (ESI): mass calcd. C19H11Cl2F3N4O, 438.0; m/z found, 439.1 [M+H]+. 1H NMR (CDCl3): 8.57 (s, 1H), 7.90 (d, J=8.6 Hz, 2H), 7.76 (s, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.31-7.27 (m, 1H), 4.66 (s, 2H).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][N:6]1[S:20]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)(=[O:22])=[O:21])=O.O.[NH2:34][NH2:35]>CO>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:10][C@H:8]2[CH2:7][N:6]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[C@H:5]([C:3]([NH:34][NH2:35])=[O:2])[CH2:9]2)=[CH:13][CH:14]=1
Reactant: NN
Reactant: COC(=O)[C@@H]1C[C@@H](SCc2ccc(OC)cc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Solvent: O
Solvent: CO
Product: COc1ccc(CS[C@@H]2C[C@@H](C(=O)NN)N(S(=O)(=O)c3ccc4ccccc4c3)C2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(step 8) To a solution of 5 g (10.6 mmol, 1 eq) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester in 20 ml methanol were added 6.45 ml (110 mmol, 10 eq) hydrazine-hydrate and the solution was stirred at RT for 3 days. The solvent was evaporated, followed by solving and evaporating with EtOH, ether and hexane. The light yellow solid was dried in vacuo giving (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid hydrazide, mp 130° C., MS: 472 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][O:9][CH2:10][CH:3]1[CH2:4][N:5]([C:11]1[CH:12]=[N:13][C:14]([N+:17]([O-])=O)=[CH:15][CH:16]=1)[CH2:6]2.[H][H]>C1COCC1.CO.[Pd]>[CH3:1][N:2]1[CH:7]2[CH2:8][O:9][CH2:10][CH:3]1[CH2:4][N:5]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[N:13][CH:12]=1)[CH2:6]2
Reactant: CN1C2COCC1CN(c1ccc([N+](=O)[O-])nc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN1C2COCC1CN(c1ccc(N)nc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a solution of 112i (800 mg, 3.0 mmol) in THF (80 ml) was added Pd/C (50 mg) in MeOH (20 ml) at room temperature. The reaction mixture was hydrogenated at atmospheric hydrogen pressure and stirred at room temperature overnight. The mixture was filtered and the filtrate was evaporated to give 112j as a colorless oil (680 mg, 90%). MS: [M+H]+: 235
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[CH:4][CH:3]=1.I[CH2:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:33][CH3:34])[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[CH:30][CH:31]=1
Reactant: CCI
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(nc(Oc3cccc(C(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (50 mg, 0.11 mmol, example 1) in DMF (1 mL) was added iodoethane (18.7 mg, 0.12 mmol) followed by potassium carbonate (23 mg, 0.16 mmol). Then the mixture was stirred at 50° C. for 3 h. The mixture was diluted with ethyl acetate and extracted with brine and saturated aqueous ammonium chloride solution. The organic phase was dried and concentrated to give crude solid product which was collected and washed with ethanol to give 7-(4-chlorobenzyl)-1-ethyl-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (15 mg, 26.7% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.77 (s, 1H), 7.69-7.73 (m, 3H), 7.43 (s, 4H), 5.46 (s, 2H), 3.91-3.93 (q, 2H), 3.29 (s, 3H), 1.11-1.14 (t, 3H). LCMS retention time 3.109 min; LCMS MH+ 479.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=S)[CH2:21][C:22](=O)[CH3:23])=[O:4].[Cl:26][C:27]1[CH:32]=[C:31]([NH:33][NH2:34])[CH:30]=[CH:29][N:28]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:33]([C:31]2[CH:30]=[CH:29][N:28]=[C:27]([Cl:26])[CH:32]=2)[N:34]=[C:22]([CH3:23])[CH:21]=1)=[O:4]
Reactant: NNc1ccnc(Cl)c1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1-c1ccnc(Cl)c1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 253c) was reacted with (2-chloro-pyridin-4-yl)-hydrazine (CAS Reg. No. 700811-29-6) to give the title compound as colorless solid. MS (ESI): m/z=495.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:13])=[O:12].[CH3:21][N:22]1[CH2:27][C@@H:26]2[CH2:28][C@H:23]1[CH2:24][NH:25]2>>[CH3:21][N:22]1[CH2:27][C@@H:26]2[CH2:28][C@:23]1([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=1[CH:4]=[CH:5][N:6]3[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:13])=[O:12])[CH2:24][NH:25]2
Reactant: CN1C[C@@H]2C[C@H]1CN2
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(Br)cccc21
Product: Cc1ccccc1S(=O)(=O)n1ccc2c([C@@]34CN[C@H](CN3C)C4)cccc21
Yield: 19 %

Procedure:
The compound was prepared from 4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane according to Method 1 to give 25 mg (19%) of a white solid: 1H NMR (CD3OD) δ 7.91–6.44 (m, 9H), 4.67–4.63 (m, 1H), 4.35–4.33 (m, 1H), 4.09–4.07 (m, 1H), 3.99–3.95 (m, 1H), 3.72–3.70 (m, 1H), 3.21–3.17 (m, 1H), 2.95 (s, 3H), 2.33–2.31 (m, 2H); MS (ESI) 382.1 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[N:16]1CC[CH2:18][CH2:17]1)=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2].C(N)C.C(O)C>O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[N:8]([CH2:22][CH3:23])[C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH3:18])=[CH:13][CH:12]=[C:11]([CH3:21])[N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(CC)c1=O
Agent: CCN
Solvent: O
Solvent: CCO
Product: CCNc1c(C(=O)OCC)c(=O)n(CC)c2nc(C)ccc12

Procedure:
A stirred mixture of 5.88 g. (0.02 mole) of 1-ethyl-1,2-dihydro-4-chloro-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (Example 30) and 2.6 g. (0.04 mole) of 70% aqueous ethyl amine in 25 ml. of ethanol was heated under reflux for 5 hours. The solution was cooled and was diluted with water to the cloudy point. The precipitate which formed was collected, air dried, and was recrystallized from heptane to give 1.6 g. of product, m.p. 133°-136° C.