Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](I)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:6]2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].CN(C)C=O.[CH2:31]([C:33]1([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH3:32]>[Cu]I.C(N(CC)CC)C>[NH2:1][C:2]1[N:10]=[C:9]([C:32]#[C:31][C:33]2([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:6]2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: CCC1(O)CCCCC1
Reactant: COC(=O)CCCn1c(-c2cccc(F)c2)nc2c(N)nc(I)nc21
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCCC3)nc21
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 89.6 %

Procedure:
To 162 mg of methyl 4-[6-amino-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]butanoate were added 8 ml of N,N-dimethylformamide, 30 mg of copper(I) iodide, 30 mg of dichlorobis(triphenylphosphine)palladium(II)l, 80 mg of 1-ethylcyclohexanol and 74 μl of triethylamine and the mixutre was stirred in a nitrogen stream at 70° C. for 2.5 hours. After it was allowed to cool, the solvent was evaporated and the resulting reside was subjected to a silica gel column chromatography (25 g of silica gel; chloroform-methanol (100:0-100:1-50:1) to give 144 mg of the title compound. The yield was 90%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16](O)=[O:17])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([CH:33]2[CH2:35][CH2:34]2)=[O:32])=[CH:5][CH:4]=1)#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:51]([C:53]1[CH:58]=[CH:57][C:56]([S:59]([NH2:62])(=[O:61])=[O:60])=[CH:55][CH:54]=1)#[N:52]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([CH2:15][C:16]([NH:62][S:59]([C:56]3[CH:55]=[CH:54][C:53]([C:51]#[N:52])=[CH:58][CH:57]=3)(=[O:60])=[O:61])=[O:17])[C:13](=[O:19])[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=3)[C:11]([CH3:30])=[C:10]2[C:31]([CH:33]2[CH2:35][CH2:34]2)=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)N(CC(=O)NS(=O)(=O)c2ccc(C#N)cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 48 h

Procedure:
A mixture of [6-(4-cyanophenyl)-5-(cyclopropylcarbonyl)-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (Example 31) (100 mg, 0.21 mmol), 1,3-dicyclohexylcarbodiimide (41.5 mg, 0.23 mmol), 4-cyanobenzene-1-sulfonamide (41.5 mg, 0.23 mmol) and 4-dimethylaminopyridine (28 mg, 0.23 mmol) in dichloromethane (4 ml) is stirred for 48 hours. The product is extracted with dichloromethane, washed with 2 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water 10:90→90:10).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([NH2:7])=[S:6])=[S:3].[I:8][CH3:9]>C1COCC1.C1(C)C=CC=CC=1>[IH:8].[CH3:9][SH:3]=[C:2]([NH:4][C:5]([NH2:7])=[S:6])[NH2:1]
Reactant: CI
Reactant: NC(=S)NC(N)=S
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[SH]=C(N)NC(N)=S
Product: I
Temperature: 25 °C
Reaction time: 22 h
Yield: 84.2 %

Procedure:
To a stirring solution of dithiobiuret (5.0 g, 37 mmol) in THF (75 mL) was added iodomethane (13.1 g, 92.5 mmol, 5.76 ml). After stirring at room temperature for 22 h, the solution was diluted with 150 mL of toluene and allowed to stand at 0° C. for 3 h. The crystals were collected by filtration and washed with cold 2:1 toluene/THF, then dried in vacuo to give the title compound as a white solid (8.7 g, 85%). MS (ESI): 149.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[C:21]([O:27][CH2:28][CH3:29])=[N:22][C:23]([CH3:26])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:30](Cl)([Cl:32])=[O:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:30]([Cl:32])=[O:31])[C:10]([C:20]3[C:21]([O:27][CH2:28][CH3:29])=[N:22][C:23]([CH3:26])=[N:24][CH:25]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1nc(C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Product: CCOc1nc(C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
Using the procedure as described in example 1, cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-1H-imidazole was reacted with phosgene to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2-piperazinone (Alfa) to give cis-4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one. HR-MS (ES, m/z) calculated for C27H27N6O3Cl2 [(M+H)+] 553.1516, observed 553.1515.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]=[C:22]2[CH3:46])=[CH:17][CH:16]=1>O.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4[NH:3][C:4](=[O:7])[O:5][N:42]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]=[C:22]2[CH3:46])=[CH:19][CH:20]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A mixture of hydroxylammonium chloride (3.5 g), sodium hydrogen carbonate (5.0 g) and dimethyl sulfoxide (25 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.15 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (25 mL). N,N′-carbonyldiimidazole (0.97 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.90 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.46 g, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(Cl)CCl.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Cc1cncc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 95 %

Procedure:
To a solution of (5-bromopyridin-3-yl)acetic acid (1.00 g, 4.63 mmol) and morpholine (0.50 mL, 5.73 mmol) in DCM (50 mL) was added EDC (1.78 g, 9.30 mmol) and 1-hydroxybenzotriazole (1.25 g, 9.26 mmol). The reaction mixture was allowed to stir at rt for 50 min and then diluted with DCM (50 mL) and 1N HCl (100 mL). The organic solution was separated and discarded. The aqueous solution was neutralized with sat. aq. NaHCO3 (100 mL) and was extracted with DCM (3×50 mL). The organic solutions were combined, dried over MgSO4, filtered and concentrated to give 4-[(5-bromopyridin-3-yl)acetyl]morpholine (1.26 g, 4.40 mmol, 95%) as a light brown solid. LCMS (FA): Rt=1.11 min, m/z=287.0 (M+H).
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.COC(=O)C1C=CC(N2C=C(C3[C:47]([C:55]4[CH:60]=[CH:59]C=CC=4)=[N:48]OC=3C(F)(F)F)N=C2)=CC=1>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:48][CH2:47][CH:55]5[CH2:60][CH2:59]5)=[O:31])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:21])([F:23])[F:22])[O:18][N:17]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Product: O=C(NCC1CC1)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)nc1
Yield: 83 %

Procedure:
As described for Example 10, 6-{4-[3-(4-chloro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), instead of 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester was converted, to the title compound (90 mg, 83%) which was obtained as a white solid. MS: m/e=488.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14](CC(O)=O)[NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C:29]1[NH:30]C=CN=1)(C1NC=CN=1)=O.[OH-:34].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH2:22][C:29]([NH2:30])=[O:34])=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)Cc1cc2ccc(OCc3ccccc3)cc2[nH]1
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC(=O)Cc1c[nH]c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-benzyloxyindole-acetic acid (4.72 g, 16.7 mmol) in tetrahydrofuran (100 mL), was added carbonyl diimidazole (2.85 g, 17.6 mmol). The resulting solution was stirred at room temperature for 1.5 hr. Ammonium hydroxide (14 mL) was added and the reaction was allowed to stir at room temperature for 18 h. The mixture was concentrated to ½ volume and the resulting solid filtered and washed with cold methanol to give 2-[6-(benzyloxy)-1H-indol-3-yl]acetamide (4.7 g, quantitative) as a off-white solid. Mp: 189-192° C.; 1H NMR (DMSO-d6) 400 MHz δ: 10.65 (brs, 1H), 7.46 (d, J=7.4 Hz, 2H), 7.37-7.35 (m, 2H), 7.31 (m, 1H), 7.26 (brs, 1H), 7.14 (d, J=2.3 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 6.79 (m, 2H), 5.04 (s, 2H), 3.39 (s, 2H); LCMS [M+H]: 281.
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:3]([N:5]([CH2:14][C:15]1[C:20]2[N:21]=[CH:22][S:23][C:19]=2[CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:4].[CH2:36]([NH:43][C:44](=[O:52])[NH:45][C@H:46]([CH3:51])[CH2:47][C:48](O)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[S:23]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:14][N:5]([CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:3]([CH:2]([NH:1][C:48](=[O:49])[CH2:47][CH:46]([NH:45][C:44]([NH:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:52])[CH3:51])[CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:29][CH:30]=3)=[O:4])[C:20]=2[N:21]=[CH:22]1
Reactant: C[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1cccc2scnc12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CN(Cc1cccc2scnc12)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)NC(=O)NCc1ccccc1)OCC
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-N-benzothiazol-4-ylmethyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide in CH2Cl2 (50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-butyric acid (1.44 g, 6.1 mmol), EDCI (1.17 g, 7.32 mmol, 1.2 eq), HOBt (0.93 g, 7.32 mmol, 1.2 eq), DIEA (2.13 mL, 12.2 mmol, 2.4 eq) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 718 (M+H), 740 (M+Na).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6](=[O:12])[N:5]3[CH2:13][C@@H:14]([CH2:15][N:16]4[CH2:21][CH2:20][C:19]([NH:23]C(=O)OCC5C=CC=CC=5)([CH3:22])[CH2:18][CH2:17]4)[N:3]1[C:4]=23.[H][H]>C(O)C.[Pd]>[NH2:23][C:19]1([CH3:22])[CH2:18][CH2:17][N:16]([CH2:15][C@H:14]2[N:3]3[C:4]4[N:5]([C:6](=[O:12])[CH2:7][CH2:8][C:9]=4[CH:10]=[CH:11][C:2]3=[O:1])[CH2:13]2)[CH2:21][CH2:20]1
Reactant: [H][H]
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Agent: [Pd]
Solvent: CCO
Product: CC1(N)CCN(C[C@@H]2CN3C(=O)CCc4ccc(=O)n2c43)CC1
Yield: 99.8 %

Procedure:
A solution of phenylmethyl (1-{[(2R)-4,9-dioxo-1,2,8,9-tetrahydro-4H,7H-imidazo[1,2,3-ij]-1,8-naphthyridin-2-yl]methyl}-4-methyl-4-piperidinyl)carbamate (1.848 g, 4.10 mmol) in ethanol at rt under argon was treated with palladium on carbon (10% paste) (0.462 g, 4.34 mmol) (20% w/w) and stirred under 1 atmosphere of hydrogen for 2 h, reaction mixture was filtered through a thin pad of Kielselguhr eluting with ethanol (100 ml). The filtrate was treated with palladium on carbon (10% paste) (0.462 g, 4.34 mmol) and stirred under 1 atm of hydrogen for 18 h. The reaction mixture was filtered through a thin pad of Kielselguhr eluting with ethanol (500 ml) and the filtrate was then evaporated to give the product as a yellow solid (1.294 g, 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:12][C:13]1([F:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>C(O)C>[F:12][C:13]1([F:19])[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: FC1(F)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1ccc(N2CCC(F)(F)CC2)nc1
Temperature: 70 °C

Procedure:
To a slurry of 2-chloro-5-nitropyridine (5 g, 31.5 mmol) and 4,4-difluoropiperidine hydrochloride (4.97 g) in ethanol (40 mL) at ambient temperature was added N,N-diisopropylethylamine (12.00 mL, 69.4 mmol) and the mixture heated to 70° C. for 18 hours. The reaction was concentrated, partitioned between CH2Cl2 and 1M NaOH. The organic phase concentrated and purified by chromatography (elution with 2% MeOH—CH2Cl2 then 3% MeOH—CH2Cl2) to provide the title compound as a yellow oil. MS (DCI) m/z 261 (M+NH4)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]3[C:20]([C:21]4[CH:26]=[C:25]([S:27][CH3:28])[N:24]=[C:23]([CH3:29])[N:22]=4)=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1.CO>C(Cl)Cl.CN(C=O)C.C([O-])(O)=O.[Na+].C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11]3[C:20]([C:21]4[CH:26]=[C:25]([S:27]([CH3:28])=[O:38])[N:24]=[C:23]([CH3:29])[N:22]=4)=[N:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cc(-c2nc3ccccc3nc2Nc2cccc3[nH]ncc23)nc(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc3ccccc3nc2Nc2cccc3[nH]ncc23)cc(S(C)=O)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
A 50 mL round-bottomed flask was charged with N-(1H-indazol-4-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)quinoxalin-2-amine (150 mg, 0.375 mmol) in DCM-DMF(5:1, 6 mL). mCPBA (130 mg, 0.751 mmol, Aldrich) was added to this solution at 0° C., the mixture was stirred at 0° C. for 2 h, then warmed to room temperature and diluted with saturated NaHCO3. The aqueous layer was extracted with DCM (3×), and the combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 2% to 10% 2M NH3.MeOH in DCM to give N-(1H-indazol-4-yl)-3-(2-methyl-6-(methylsulfinyl)pyrimidin-4-yl)quinoxalin-2-amine (36 mg, 0.087 mmol, 23% yield) as an orange solid. m/z (ESI, +ve ion) 416 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=[C:11]3[CH:10]=[CH:9]2)[CH2:3][CH2:2]1.[Cl:21]N1C(=O)CCC1=O>CC#N>[Cl:21][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([S:17]([NH2:20])(=[O:18])=[O:19])[CH:16]=2)[N:8]([CH2:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: NS(=O)(=O)c1cnc2c(ccn2CC2CCOCC2)c1
Solvent: CC#N
Product: NS(=O)(=O)c1cnc2c(c1)c(Cl)cn2CC1CCOCC1

Procedure:
A mixture of EXAMPLE 388C (0.15 g) and N-chlorosuccinimide (0.081 g) in CH3CN (8 mL) was heated at 90° C. for 16 hours. The solvent was removed, and the residue was purified by flash column chromatography on silica to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[CH:17][C:16]=1[N+:28]([O-:30])=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:15]2[C:16]([N+:28]([O-:30])=[O:29])=[CH:17][C:18]([C:24]([F:27])([F:25])[F:26])=[CH:19][C:20]=2[N+:21]([O-:23])=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2c([N+](=O)[O-])cc(C(F)(F)F)cc2[N+](=O)[O-])C1

Procedure:
deprotonating (R)-3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester and further reacting the resultant compound with 2-chloro-1,3-dinitro-5-trifluoromethylbenzene to form (R)-3-(2,6-dinitro-4-trifluoromethylphenoxy)pyrrolidine-1-carboxylic acid tert-butyl ester;
Reaction SMILES: [CH2:1]([C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:10]([OH:14])(=[O:13])C=C.[CH2:15](C(C)=O)[CH3:16]>>[CH2:1]([C:5]12[CH2:9][CH:8]([CH:15]=[CH:16]1)[CH2:7][CH:6]2[C:10]([OH:14])=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=CC=CC1
Reactant: C=CC(=O)O
Reactant: CCC(C)=O
Product: CCCCC12C=CC(CC1C(=O)O)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
n-Butylcyclopentadiene (12.22 g: 100 mmol) was dissolved in methyl ethyl ketone (10 mL), to which acrylic acid (7.93 g: 110 mmol) was added dropwise at 0° C. over 1 hour. The thus-obtained mixture was stirred at room temperature for 3 hours. Light components, such as the solvent and unreacted acrylic acid, were then distilled off under reduced pressure from the reaction mixture, whereby n-butyl-5-norbornene-2-carboxylic acid (15.9 g: 82 mmol) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:7]=3[O:8][C:4]=2[CH:3]=1.[C:16]1(=[O:21])[O:20][CH2:19][CH2:18][CH2:17]1.[H-].[Na+].[H][H]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH:12]=[C:11]([O:13][CH:17]([CH2:18][CH3:19])[C:16]([OH:21])=[O:20])[CH:10]=[CH:9][C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: O=C1CCCO1
Reactant: Oc1ccc2oc3cc(Cl)ccc3c2c1
Agent: [H-]
Agent: [Na+]
Product: CCC(Oc1ccc2oc3cc(Cl)ccc3c2c1)C(=O)O
Temperature: 120 °C

Procedure:
110 g (0.5 mole) 7-Chloro-2-hydroxydibenzofuran is dissolved in 200 g (2.3 mole) of butyrolactone. To this solution is added 27.5 g (0.57 mole) sodium hydride 50% dispersion in oil (prewashed with petroleum ether) in small increments. When hydrogen evolution ceases the solution is heated to 120° C. for 2 hours. The excess butyrolactone was distilled off under high vacuum. The crude product was dissolved in water and precipitated into dilute acid. The product was filtered and redissolved in sodium bicarbonate solution. The solution was charcoal treated and precipitated in dilute acid filtered and dried. 137 g., m.p. 143°-145° C. were obtained. This Example corresponds to Example 69 in Table I.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:22][CH:23]([CH3:25])[CH3:24]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)CCSc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)CCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 26 %

Procedure:
A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol), 2-cyano-6-isopentylthiopyridine (1.48 g, 7.2 mmol), triethylamine (1.5 ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure to give the precipitated crystals, which were recrystallized from ethyl acetate-hexane to give the titled compound (0.64 g, 26%).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10](=[O:12])[CH3:11])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O>CC#N>[C:24]([O:23][C:21](=[O:22])[CH2:20][N:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10](=[O:12])[CH3:11])=[N:2]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(=O)c1n[nH]c2cnccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1nn(CC(=O)OC(C)(C)C)c2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(1H-pyrazolo[3,4-c]pyridin-3-yl)-ethanone (Sphinx Scientific laboratory LLC, catalog number: PPY-1-CS01) (2.45 g 14.44 mmol) in CH3CN (50 mL) were added potassium carbonate (3.99 g, 28.9 mmol) and tert-butyl bromoacetate (2.34 mL, 15.88 mmol). The reaction mixture was stirred at RT overnight. The crude mixture was poured into water and extracted with EtOAc (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 0:1) to give the title compound. TLC, Rf (EtOAc)=0.7; MS: 276 [M+H]+; tR (HPLC conditions c): 2.06 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[NH:26][C:27](=[O:29])C)[CH2:7][C:8]([NH:19]C(C)=O)(C(OCC)=O)[C:9]([O:11]CC)=[O:10])([O-])=O.C(Cl)([Cl:32])=O>>[ClH:32].[N:26]1[C:27](=[O:29])[N:1]=[C:4]2[CH:5]=[C:6]([CH2:7][C@@H:8]([C:9]([OH:11])=[O:10])[NH2:19])[CH:23]=[CH:24][C:25]=12
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)C(Cc1ccc(NC(C)=O)c([N+](=O)[O-])c1)(NC(C)=O)C(=O)OCC
Product: Cl
Product: N[C@@H](Cc1ccc2c(c1)=NC(=O)N=2)C(=O)O
Yield: 54 %

Procedure:
Following the procedure for the production of the racemic mixture in Example 1, diethyl 2-(3-nitro-4-acetamidobenzyl)-2-acetaminomalonate is hydrolyzed and cyclized with phosgene to produce pure Example 3 title compound in 54% yield: m.p. 259° (decomp).