Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[F:24][CH:25]([F:37])[C:26]1[NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:28]=2[N:27]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CCOC(C)=O>CS(C)=O.O>[F:37][CH:25]([F:24])[CH:26]1[N:27]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[N:11][CH:12]=[N:13][CH:14]=3)[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:3]=2)[C:28]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:29]=2[NH:30]1
Reactant: O=[N+]([O-])c1c(Nc2cncnc2)nc(Cl)nc1N1CCOCC1
Reactant: COc1cccc2[nH]c(C(F)F)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc2c1N(c1nc(Nc3cncnc3)c([N+](=O)[O-])c(N3CCOCC3)n1)C(C(F)F)N2
Temperature: 120 °C
Yield: 85.5 %

Procedure:
A mixture of 0.465 g (1.38 mmol) of the above nitro compound, 0.368 g (1.86 mmol) of 2-difluoromethyl-4-methoxy-1H-benzimidazole (Example 2) and 0.762 g (5.52 mmol) of powdered K2CO3 in 5 mL of DMSO was heated at 120° C. for 8 hrs. The reaction mixture was diluted with water, and extracted with EtOAc (×4). The organic layer was washed with brine, dried, and concentrated. Chromatography on silica, eluting first with hexanes/EtOAc (7:3) and then with CH2Cl2/EtOAc (1:2), gave 0.592 g (86% yield) of 2-[2-(difluoromethyl)-7-methoxy-2,3-dihydro-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-5-nitro-N-(5-pyrimidinyl)-4-pyrimidinamine, as a yellow powder: 1H NMR (CDCl3) δ 10.26 (s, 1H), 9.16 (s, 1H), 8.98 (s, 2H), 7.38 (dd, J=8.4, 0.6 Hz, 1H), 7.20 (t, J=8.4 Hz, 1H), 7.12 (t, JHF=53.5 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 4.01 (s, 3H), 3.87 (t, J=4.8 Hz, 4H), 3.70 (t, J=4.8 Hz, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[NH:10][C:9]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:22][O:21]1>CN(C=O)C>[CH3:1][O:2][C:3]1[C:11]2[N:10]([CH2:19][C:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)([OH:21])[CH3:22])[C:9]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC1(c2ccncc2)CO1
Reactant: COc1cccc2c3c([nH]c12)CCN(C)C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c3c(n(CC(C)(O)c4ccncc4)c12)CCN(C)C3
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 6-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.3 mmol) in DMF (10 mL) was added sodium hydride (276 mg, 6.9 mmol) and stirred for 10 min at RT, followed by addition of 4-(2-methyl-oxiranyl)-pyridine (468 mg, 3.4 mmol) and stirring continued for another 16 h. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with water, dried over sodium sulfate and concentrated to afford crude material, which was re-crystallized in ether and hexane to yield 1-(6-methoxy-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol. 1H NMR (CD3OD, TFA salt) d (ppm): 8.60 (m, 2H), 7.95 (m, 2H), 6.95 (m, 2H), 6.50 (m, 1H), 4.65 (m, 2H), 4.30 (m, 2H), 3.90 (m, 2H), 3.80 (s, 3H), 3.60 (m, 2H), 3.10 (s, 3H), 1.70 (s, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH2:21][CH2:22][CH2:23][CH:24]([NH2:25])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)C(N)CCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Yield: 5 %

Procedure:
The title compound was prepared according to the procedure described in Example 2, Step C except using 4-benzyl-1-tert-butoxycarbonyl-2(S)-(4-tert-butoxycarbonylaminobutyl)-piperazine (3.74 g, 8.36 mmol), 10% palladium on carbon (0.50 g) in methanol (50 mL) for 48 h at 60 psi hydrogen. The title compound (Rf 0.3 in 5% methanol in chloroform) was obtained as an oil (3.14 g). NMR (300 MHz, CDCl3) d 4.59 (1H, m), 4.00 (1H, m), 3.83 (1H, br d J=12 Hz), 3.12 (2H, m), 2.90 (4H, m), 2.70 (1H, dt, J=4, 13 Hz), 1.0-1.9 (25H, m).
Reaction SMILES: S(Cl)(Cl)=O.CC1C(C)=CC=CC=1C(O)=O.CC1C(C)=CC=CC=1C(Cl)=O.[CH3:27][C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=1[C:35]([N:37]=[C:38]=[S:39])=[O:36].[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1)[NH2:44]>C(O)C.C1(C)C=CC=CC=1>[Cl:40][C:41]1[CH:42]=[C:43]([NH:44][C:38]([NH:37][C:35](=[O:36])[C:29]2[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:28]=2[CH3:27])=[S:39])[CH:45]=[CH:46][C:47]=1[O:48][C:49]1[C:58]2[C:53](=[CH:54][C:55]([O:61][CH3:62])=[C:56]([O:59][CH3:60])[CH:57]=2)[N:52]=[CH:51][CH:50]=1
Reactant: Cc1cccc(C(=O)N=C=S)c1C
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: Cc1cccc(C(=O)Cl)c1C
Agent: Cc1cccc(C(=O)O)c1C
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4C)cc3Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,3-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,3-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 2,3-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 2,3-Dimethyl-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 96%).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][CH:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=2[S:28]([CH3:31])(=[O:30])=[O:29])[C:4]=1[C:32](OCC)=[O:33].[CH3:37][NH:38][NH2:39]>O1CCOCC1>[CH3:37][N:38]1[CH2:2][C:3]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[C:7](=[O:19])[NH:6][CH:5]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[S:28]([CH3:31])(=[O:30])=[O:29])[C:4]=2[C:32](=[O:33])[NH:39]1
Reactant: CNN
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(C)(=O)=O
Solvent: C1COCCO1
Product: CN1CC2=C(C(=O)N1)C(c1ccc(C#N)cc1S(C)(=O)=O)NC(=O)N2c1cccc(C(F)(F)F)c1

Procedure:
Ethyl 6-(bromomethyl)-4-[4-cyano-2-(methylsulphonyl)phenyl]-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (150 mg, 0.256 mmol; Example 19A) was initially charged in dioxane (3.5 ml). Methylhydrazine (35.4 mg, 0.767 mmol) was added dropwise to the reaction mixture, and the mixture was then stirred at boiling point for 3 h. The reaction mixture was then separated directly by preparative HPLC (Method 12). This gave 55 mg (39% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.CN(C=O)C.[OH-].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Br>[Cl-].[Na+].O>[O:30]1[CH2:29][CH:28]1[CH2:26][N:6]1[C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:16]=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1S2
Reactant: BrCC1CO1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2c(c1)N(CC1CO1)c1ccccc1S2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(trifluoromethyl)-10H-phenothiazine (5.0 g, 18.8 mmol) and DMF (15 mL) at RT was added finely powdered KOH (2.1 g, 37.5 mmol) and (±)-epibromohydrin (3.9 mL, 48.9 mmol). The reaction mixture was stirred at RT for 48 h. Once no starting material was observed by analytical LCMS, EtOAC (250 mL) and brine (250 mL) were added. The organic layer was separated, and the aqueous layer was washed with EtOAC (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried over MgSO4, and concentrated to afford the title compound.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=O)[CH2:5]1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18](=[O:39])[CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:16][O:17][C:18](=[O:39])[CH2:19][C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([C:1](=[O:3])[CH3:2])[CH:5]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)N(C(C)=O)CC2=O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cn(C(C)=O)c2cc(OC)ccc12
Yield: 50 %

Procedure:
A mixture of 1-acetyl-6-methoxy-1,2-dihydro-3H-indol-3-one (3.96 g, 19.3 mmol) (Example 12) and methyl(triphenylphosphoranylidene)acetate (19.75 g, 57.9 mmol) in toluene (60 mL) was heated at reflux under argon for 24 h. The mixture was loaded on silica gel and eluted with EtOAc/hexane (1/5) to yield a thick oil (2.52 g, 50%). LC/MS m/z 262 (M+H)+; 1H NMR (400 MHz, CDCl3) 8.04 (br s, 1H), 7.38 (d, 1H), 7.31 (s, 1H), 6.92 (dd, 1H), 3.89 (s, 3H), 3.74 (s, 3H), 3.71 (d, 2H), 2.62 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1.[CH3:22][N:23]([CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)[C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:27]=2[N:28]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[CH3:22][N:23]([CH2:34][CH:39]1[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38]1)[C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([NH:33][C:17](=[O:19])[CH:16]=[CH:15][C:12]3[CH:11]=[CH:10][C:9]([C:8]([F:7])([F:21])[F:20])=[CH:14][CH:13]=3)=[CH:29][C:27]=2[N:28]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)C=Cc4ccc(C(F)(F)F)cc4)ccc3o2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 115.3 %

Procedure:
Add oxalyl chloride (0.20 mL, 2.30 mmol) and 3 drops of DMF to a stirring suspension of 3-(4-trifluoromethyl-phenyl)-acrylic acid (0.249 g, 1.15 mmol) in CH2Cl2 (5.0 mL). Stir the reaction mixture at room temperature for 2 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 3-(4-trifluoromethyl-phenyl)-acryloyl chloride solution to a mixture of rac-N2-methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.158 g, 0.607 mmol) and pyridine (0.06 mL) in CH2Cl2 (5.0 mL). Shake the reaction mixture overnight at room temperature. Filter the reaction mixture and wash the product with CH2Cl2. Dry the product on high vacuum to yield the desired product as an off-white solid (0.321 g, 91%). mass spectrum (m/e): 459.0 (M+1), 457.0 (M−1). 1H NMR (400 MHz, CD3OD): δ 8.93-8.89 (m, 1H), 8.71 (dt, J=8.0, 1.8 Hz, 1H), 8.17-8.13 (m, 1H), 7.85-7.72 (m, 4H), 7.55 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.8, 1.8 Hz, 1H), 6.94 (d, J=15.8 Hz, 1H), 4.57-4.47 (m, 1H), 3.75-3.67 (m, 2H), 3.36-3.29 (m, 2H), 3.28 (s, 3H), 2.96 (s, 3H), 2.41-2.28 (m, 2H), 2.27-2.18 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[CH:7]2.[Li]CCCC.[C:17](=[O:19])=[O:18].O>C1COCC1.CCCCCC>[CH3:11][C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: Cc1cc2cccc(Br)c2[nH]1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1cc2cccc(C(=O)O)c2[nH]1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
1000 mg of 7-bromo-2-methyl-indole (4.8 mmol) were dissolved in 15 ml THF and 8.9 ml of a 1.6 molar solution of n-BuLi in hexane were added at −78° C. The reaction mixture was then allowed to warm to 0-5° C. and was stirred at this temperature for 30 min. Then it was cooled again to −78° C., dry ice was added and the mixture was allowed to warm to rt. After 15 min at rt it was poured into water and extracted twice with ether. The aqueous phase was then acidified with 1 N HCl solution and extracted several times with DCM. The combined DCM extracts were then dried with magnesium sulfate, filtered and the solvent was evaporated. The remaining residue was triturated with pentane. Final filtration yielded 157 mg (31%) of 2-methyl-1H-indole-7-carboxylic acid as an off-white solid. MS (ISP) 174.3 (M−H)−.
Reaction SMILES: [OH-].[Na+].Cl[O-].[Na+].[NH2:6][C:7]1[C:16]([CH3:17])=[CH:15][C:14](Br)=[CH:13][C:8]=1[C:9]([NH:11][CH3:12])=[O:10].C1(C)C=C(C)C=C(C)C=1.[C-]#N.[Na+].[CH2:31]([N:33]1C=CN=C1)C>[Cu]I.O>[NH2:6][C:7]1[C:16]([CH3:17])=[CH:15][C:14]([C:31]#[N:33])=[CH:13][C:8]=1[C:9]([NH:11][CH3:12])=[O:10]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: CCn1ccnc1
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: Cc1cc(C)cc(C)c1
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 500-mL four-necked flask equipped with a mechanical stirrer, thermocouple, condenser, side-arm addition funnel and sodium hydroxide/sodium hypochlorite scrubber was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (24.6 g, 0.10 mol, 99% purity) and mesitylene (100 g) while maintaining an atmosphere of nitrogen through a gas inlet line connected to the condenser. The mixture was stirred at room temperature and sodium cyanide (ground to a powder just prior to use) (7.7 g, 0.15 mol, assuming 95% purity) and copper(I) iodide (2.9 g, 0.015 mol, 98% purity) and 1-ethyl-1H-imidazole (5.9 g, 0.06 mol, 98% purity) were added, after which time the nitrogen inlet line was attached directly to the reaction flask. The reaction mixture was heated at reflux (about 166-170° C.) for 8 h, while venting through the scrubber. After cooling overnight, water (100 mL) was added, and stirring was continued for 1 h. The mixture was filtered, and the solid collected was washed with water (3×50 mL), mesitylene (50 g) and dried to a constant weight in a vacuum-oven at 55° C. to give the title compound as a light yellow solid (18.0 g).
Reaction SMILES: C1(S(N2CCNC(=O)[C@H]2CC#C)(=O)=O)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[C@H:31]2[CH2:37][C:38]#[CH:39])(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([N:30]2[CH2:35][CH2:34][NH:33][C:32](=[O:36])[C@H:31]2[CH2:37][C:38]#[CH:39])(=[O:29])=[O:28])=[CH:25][CH:26]=1
Reactant: C#CC[C@@H]1C(=O)NC=CN1S(=O)(=O)c1ccc(Cl)cc1
Agent: C#CC[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccccc1
Product: C#CC[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Using the procedure described for compound 51, (R)-4-(4-chlorobenzenesulfonyl)-3-(prop-2-ynyl)-3,4-dihydropyrazin-2(1H)-one afforded the title compound as a tan solid. 1H NMR (300 MHz, CDCl3): δ 2.02 (s, 1H), 2.45 (s, 3H), 2.85 (m, 1H), 2.97 (m, 1H), 3.24 (m, 2H), 3.81 (m, 2H), 4.48 (t, 4.7 Hz, 1H), 6.47 (s, 1H), 7.55 (d, 8.0 Hz, 2H), 7.78 (d, 8.0 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Zn]>[C:14]1([S:11]([CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])(=[O:12])=[O:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)c2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Nc1cccc(CS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A solution of 1-nitro-3-[(phenylsulfonyl)methyl]benzene (5.15 g) in ethanol (55 mL) and water (11.4 mL) was treated with ammonium chlorid (4.99 g) at 0° C. Then zinc powder (6.10 g) was cautiously added in portions and stirred for 3 hours at RT. Then the mixture was filtered over Cellite, washed with ethanol, condensed to dryness, treated with ethyl acetate, washed with brine, dried with sodium sulfate and condensed to dryness. Crystallization of the crude product (5.20 g) from diethyl ether furnished the pure title compound (3.80 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C.Cl.[NH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.O>CN(C=O)C>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:18])[F:19])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:33][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: NN1CCCC1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NN1CCCC1

Procedure:
A mixture of 5.0 g (0.013 mol) of product of Example 28, 3.42 g (0.034 mol) of triethylamine, 2.08 g (0.017 mol) of N-aminopyrrolidine hydrochloride in 30 ml of DMF were reacted at 45° C. for 1 hour. The reaction mixture was poured into water, extracted with ether, washed with diluted HCl, dried (MgSO4) and concentrated in vacuo to 4.06 g of light yellow solid. This solid was recrystallized in hot hexane affording 3.47 g (59.9%) of product as a beige solid; mp 101°-103° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:14]1([C:6]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:2]([N:33]3[CH2:34][CH2:35][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH2:31][CH2:32]3)[N:3]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: FC(F)(F)c1nc(Cl)c(-c2ccccc2)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1nc(-c2ccccc2)c(-c2ccccc2)c(N2CCN(c3ccccn3)CC2)n1
Temperature: 28 °C
Yield: 69.66 %

Procedure:
To a solution of 4-chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.5 g, 1.49 mmol, prepared according to the procedure described in PCT/IB03/02879) in DMF (5 ml) was added 1-pyridin-2-yl piperazine (0.107 g, 0.66 mmol) and anhydrous potassium carbonate (0.2 g) under stirring at 28° C. The reaction mixture was stirred for 4 hours and when TLC confirmed the completion, it was poured onto ice. The solid thus obtained was filtered and washed with water (20 ml). The above solid was then dissolved in dichloromethane (50 ml) and dried over anhydrous sodium sulphate. Evaporation of the solvent afforded the title compound (0.48 g, yield 69.66%, purity by HPLC 99.8%). m.p. 165-167° C. 1H-NMR (CDCl3) δ: 3.43 (s, 8H), 6.58-6.64 (m, 2H), 7.14-7.21 (m, 7H), 7.26-7.29 (m, 3H), 7.45-7.49 (t, 1H), 8.14-8.15 (d, 1H); IR cm−1 (KBr): 3436, 2839, 1591 and 1557; MS m/z: 462.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[N:11][CH:12]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.Br[CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CC#N>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[N:11]([CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:12]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)nc2)n1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1cc(N)n(-c2ccc(=O)n(CCO[Si](C)(C)C(C)(C)C)c2)n1

Procedure:
To a solution of 5-(5-amino-3-(tert-butyl)-1H-pyrazol-1-yl)pyridin-2-ol (1.10 g, 4.74 mmol) in MeCN (10.0 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (1.28 mL, 5.68 mmol) and K2CO3 (0.785 g, 5.68 mmol) and the mixture heated to reflux for 6 hr. The resulting mixture was cooled and was loaded directly onto silica and purified by flash column chromatography (SiO2, 40 g, 0-100% EtOAc in isohexane, gradient elution) to afford the title compound, Intermediate A15, as a pale yellow solid (1.11 g, 60%); Rt 2.61 min (Method 2, acidic); m/z 391 (M+H)+, (ES+).
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:14].[C:15](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:15][O:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:14]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(I)c2c(c1O)CNC2=O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(I)c2c(c1OC)CNC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
4-Hydroxy-5-methoxy-7-iodoisoindolinone (30.0 mg, 0.0983 mmol) was dissolved in DMF (2 mL), and the solution was treated with potassium carbonate (26.0 mg, 0.188 mmol) and methyl iodide (0.020 mL, 0.32 mmol), followed by stirring at room temperature for 1.5 hours. The reaction mixture was added with water and the precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4,5-dimethoxy-7-iodoisoindolinone (22.0 mg, yield 70%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:12]([N:9]([CH2:8][C:7]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[CH:3][C:4]=1[F:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(N)c(F)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(F)cc1Br
Temperature: 100 °C

Procedure:
A suspension of 4-bromo-2-fluoro-5-methylbenzenamine (1 g, 4.9 mmol), (bromomethyl)benzene (2.5 g, 14.7 mmol) and potassium carbonate (2 g, 14.7 mmol) in acetonitrile (80 mL) was heated in a sealed tube at 100° C. for 16 hours. After concentration, the residue was diluted with ethyl acetate (80 mL), washed with water (20 mL), dried over anhydrous sodium sulfate filtered, and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 50/1 petroleum ether/ethyl acetate to give the title compound. MS: 384 (M+H+).
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:8]([C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[O:25])[CH2:7]1)(=[O:4])=[O:3].CO.[H][H]>[Pd].O1CCCC1>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][NH:9][C@H:8]([C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[O:25])[CH2:7]1)(=[O:4])=[O:3]
Reactant: [H][H]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@H]1CN[C@H](C(=O)N2CCNC2=O)C1
Yield: 81.9 %

Procedure:
A mixture of (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)carbonylpyrrolidine (30 g), 10% palladium on carbon (10 g), methanol (300 ml) and tetrahydrofuran (150 ml) was stirred for 5 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filtrate was evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (250 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-(2-oxoimidazolidin-1-yl)carbonylpyrrolidine (14.92 g).