Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].CCN(C(C)C)C(C)C.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C=O)C>CCOC(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:30]1[CH2:31][CH2:32][N:27]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:28][CH2:29]1)([O-:10])=[O:9]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CC1
Yield: 99.9 %

Procedure:
To a 500 mL round-bottomed flask equipped with magnetic stirring was added 2-fluoronitrobenzene (14 g, 101 mmol), DIEA (19 mL, 110 mmol), 1-benzylpiperazine (18 mL, 110 mmol) (Aldrich) and DMF (250 mL). The reaction was stirred for 18 h, diluted with 400 mL of EtOAc and washed with 300 mL each of 10% NaHCO3, H2O, and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to yield 1-(2-nitrophenyl)-4-benzylpiperazine (30 g). Calc'd for C17H19N3O2: 297.15.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][N:6]=1)=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:27]=[N+:28]=[N-:29])=[O:13])=[CH:7][N:6]=1)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(C(=O)N=[N+]=[N-])cn1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a solution of pyridine-2,5-dicarboxylic acid-2-methyl ester (0.5 g, 2.76 mmol)) (from Example 83a supra) at −10° C. in acetone (9.16 mL) was added triethylamine (0.385 mL, 2.76 mmol) (Aldrich), followed by the addition of ethyl chloroformate (0.265 mL, 2.76 mmol). (Aldrich). After the mixture was stirred at −10° C. for 30 minutes, an aqueous solution of sodium azide (0.53 g, 8.28 mmol) in water (10 mL) was added. The mixture was warmed up and stirred at room temperature for 1 hour, then concentrated to half volume, extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated to give 5-azidocarbonyl-pyridine-2-carboxylic acid methyl ester as a white solid (Yield 0.47 g, 83%).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[C:29]3[C:28]([CH3:30])=[C:27]([CH3:31])[N:26]=[C:25](OC4C=CC=CC=4)[C:24]=3[N:23]=[C:22]2[CH2:39][CH2:40][CH3:41])(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[C:29]3[C:28]([CH3:30])=[C:27]([CH3:31])[N:26]=[C:25]([NH2:5])[C:24]=3[N:23]=[C:22]2[CH2:39][CH2:40][CH3:41])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCCS(=O)(=O)c1ccc(Cl)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCCS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 28.2 %

Procedure:
Ammonium acetate (20.2 g, 0.262 mol) and 1-[5-(4-chlorobenzenesulfonyl)pentyl]-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine (2.20 g, 4.18 mmol) were stirred at 160° C. in a sealed tube for 18 hours. The solution was allowed to cool to room temperature and partitioned between chloroform (50 mL) and water (25 mL). The aqueous solution was adjusted to pH 11 with the addition of 1 M sodium hydroxide and two solid sodium hydroxide pellets. The aqueous solution was then extracted with chloroform (4×50 mL). The combined organic solutions were washed with 1 M sodium hydroxide (2×25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product as a tan foam. The crude product was purified by column chromatography on silica gel (eluting with 94:5:1 dichloromethane:methanol:triethylamine) to provide a product that was impure as determined by HPLC analysis. A second purification by column chromatography on silica gel (eluting with 96:3:1 dichloromethane:methanol:triethylamine) also resulted in impure material. The solid was recrystallized from acetonitrile, and the crystals were isolated by filtration, washed with cold acetonitrile and ethyl acetate, dried under high vacuum to provide 0.53 g of 1-[5-(4-chlorobenzenesulfonyl)pentyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine as white needles, mp 147.0–149.0° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[OH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[O:10].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:44])=[C:20]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[N:35]=[C:34]4[CH2:36][NH:37][CH2:38][CH2:39][C:33]4=[N:32][C:31]=3[NH:40][CH:41]([CH3:43])[CH3:42])[CH2:26][CH2:25]2)=[O:23])[CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([F:44])=[C:20]([CH:21]=1)[C:22]([CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[C:34]3[CH2:36][N:37]([C:5](=[O:7])[CH3:6])[CH2:38][CH2:39][C:33]3=[N:32][C:31]=2[NH:40][CH:41]([CH3:42])[CH3:43])[CH2:26][CH2:25]1)=[O:23].[C:9]([OH:10])([C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CNCC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCc2nc(NC(C)C)c(N3CCC(C(=O)c4cc(Cl)ccc4F)CC3)nc2C1
Reaction time: 1 h

Procedure:
Acetic anhydride (3 μL, 0.034 mmol) was added to a solution of (5-chloro-2-fluorophenyl)(1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone TFA salt (9.2 mg, 0.017 mmol) and pyridine (4 μL, 0.051 mmol) in DCM (170 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (4.0 mg, 40.4%) as a yellow film. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) δ ppm 1.30-1.34 (m, 6H), 1.88-2.04 (m, 4H), 2.19 (s, 1.4H), 2.21 (s, 1.6H), 2.77-2.83 (m, 0.9H), 2.87-2.92 (m, 1.1H), 2.93-3.02 (m, 2H), 3.34-3.43 (m, 1H), 3.50-3.59 (m, 2H), 3.80-3.85 (m, 1.1H), 3.85-3.90 (m, 0.9H), 4.08-4.17 (m, 1H), 4.54 (br s, 2H), 7.25-7.32 (m, 1H), 7.59-7.63 (m, 1H), 7.76 (dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 474.3.
Reaction SMILES: [N:1]1([C:8]2[C:9]([O:18][CH3:19])=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][CH:29]=[C:30]([CH:32]=O)[N:31]=2)[CH2:23][CH2:22]1.C([Si]([O:41][C:42]([O:44][CH3:45])=[CH2:43])(C)C)(C)(C)C.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl.ClCCCl>[CH3:45][O:44][C:42](=[O:41])[CH2:43][CH:32]([C:30]1[N:31]=[C:27]([N:24]2[CH2:23][CH2:22][CH:21]([OH:20])[CH2:26][CH2:25]2)[S:28][CH:29]=1)[N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[C:9]([O:18][CH3:19])=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH2:2][CH2:3]1
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Reactant: O=Cc1csc(N2CCC(O)CC2)n1
Reactant: COc1ccc2cccnc2c1N1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)CC(c1csc(N2CCC(O)CC2)n1)N1CCCN(c2c(OC)ccc3cccnc23)CC1
Temperature: 55 °C
Yield: 32.4 %

Procedure:
1,2-Dichloroethane (1.02 mL) was added to a mixture of 8-[1,4]diazepan-1-yl-7-methoxy-quinoline (1.00 g, 3.88 mmol) and 2-(4-hydroxy-piperidin-1-yl)-thiazole-4-carbaldehyde (824 mg, 3.88 mmol). The reaction was heated to 55° C. and stirred until homogeneous. Freshly crushed Ti(OMe)4 (1.00 g, 5.82 mmol) was then added and the reaction was stirred at 55° C. for 1 h. tert-Butyl-(1-methoxy-vinyloxy)-dimethyl-silane (1.02 mL, 4.66 mmol) was then added and the reaction was stirred at 55° C. for 18 h. CH2Cl2 was then added, followed by sat. aq. NaHCO3, then 1 N aq. NaOH. This mixture was then stirred for 5 min and filtered through celite, washing the filter cake with CH2Cl2. The filtrate was then washed once with H2O, dried over MgSO4, filtered, and concentrated. The crude product was purified on silica gel (99:1 to 90:10 CH2Cl2:(9:1 MeOH:NH4OH)) to give the product (660 mg, 38% yield).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8](=[O:10])[CH3:9])=[N:4][CH:5]=[CH:6][N:7]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:31]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:31][CH2:9][C:8]([C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1nccnc1C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: Cc1nccnc1C(=O)CBr
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a chloroform (7.5 mL) solution of 1-(3-methylpyrazin-2-yl)ethanone (0.50 g), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (0.75 mL) and trimethylsilyl trifluoromethanesulfonate (0.80 mL) were added, and the resultant was stirred for 30 minutes. Then, N-bromosuccinimide (0.73 g) was added thereto, and the resultant was stirred for 1 hour under ice cooling. Water was added to the reaction solution, and the resultant was stirred for 10 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=95/5→85/15) to obtain the title compound (0.58 g) as a brown solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([NH2:11])[C:7]=2[CH:12]=1.O.[C:16]([OH:20])(=[O:19])[CH:17]=O.CC(O)=O>CO>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([NH:11][CH2:17][C:16]([OH:20])=[O:19])[C:7]=2[CH:12]=1
Reactant: O=CC(=O)O
Reactant: Nc1noc2ccc(C(F)(F)F)cc12
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C(O)CNc1noc2ccc(C(F)(F)F)cc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5-Trifluoromethyl-benzo[d]isoxazol-3-ylamine (2.5 g, 12.4 mmol) and glyoxylic acid monohydrate (Aldrich, 1.14 g, 12.4 mmol) in MeOH (10 mL) were treated with a few drop of AcOH and heated at 80° C. for 30 min. The reaction was then cooled to room temperature and NaBCNH3 (Aldrich, 1.17 g, 18.6 mmol) was added in one portion and the resulting solution was stirred at room temperature for another 2 hours. The solvent was removed and the residue was partitioned between ether and 1 N NaOH. The aqueous layer was then acidified with 1 N HCl to pH=3 and then extracted three times with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as white solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C([O-])([O-])=O.[K+].[K+].C([N:21]=[C:22]=[O:23])CC.CC(C)=O.C(OC(C)C)(C)C>CC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:3]([S:8]([NH:11][C:22]([NH2:21])=[O:23])(=[O:10])=[O:9])[CH2:2][CH3:7]
Reactant: NS(=O)(=O)c1ccccc1I
Reactant: CCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)OC(C)C
Solvent: CC(C)=O
Product: CCCS(=O)(=O)NC(N)=O
Product: Ic1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-iodo benzene sulfonamide (4 g) in acetone (40 mi) solid K2CO3 (3.92 g) is added in one portion and the mixture is refluxed under N2 -atmosphere, n-propyl isocyanate is added dropwise to the heated mixture. After 2 hours reflux, the reaction is cooled to room temperature and concentrated to dryness. Water (200 ml) is added and the cooled mixture is acidified with 2N HCl to pH 4 and filtered. The precipitate obtained is recristallised with acetone/isopropyl ether mixture to give 4.1 g solid of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].[Cl:15][C:16]1[CH:28]=[N:27][C:19]2[NH:20][C:21]3[CH2:26][CH2:25][NH:24][CH2:23][C:22]=3[C:18]=2[CH:17]=1.O>N1C=CC=CC=1>[Cl:15][C:16]1[CH:28]=[N:27][C:19]2[NH:20][C:21]3[CH2:26][CH2:25][N:24]([S:11]([C:4]4[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])(=[O:13])=[O:12])[CH2:23][C:22]=3[C:18]=2[CH:17]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(OC)c(S(=O)(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
2,5-Dimethoxybenzenesulfonyl chloride (63 mg, 0.26 mmol) was added to a solution of 3-chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) in pyridine (2 mL), and the reaction was stirred overnight at room temperature. The reaction mixture was added to water (20 mL), and the resulting precipitate was filtered and dried under vacuum to provide 36 (94 mg, 96% yield) as a yellow solid. LC-MS (M+H=408, obsd.=408).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.C([S:14][CH2:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18])(=O)C.[OH-].[Na+].CCOC(C)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:9][S:14][CH2:15][C@@H:16]([CH3:20])[C:17]([OH:19])=[O:18]
Reactant: CC(=O)SC[C@@H](C)C(=O)O
Reactant: Cc1cc(Br)cc(CBr)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(CSC[C@@H](C)C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.55 g (21 mmol) 1-bromo-3-bromomethyl-5-methyl-benzene and 2.90 ml (21 mmol) (S)-3-acetylsulfanyl-2-methyl-propionic acid in 32 ml methanol is cooled in an ice bath and 4N aqueous sodium hydroxide (15.8 ml, 63 mmol) are added. The reaction mixture is stirred at rt for 3 hrs. EtOAc is added to the mixture and the organic layer is washed with water and brine and evaporated. Filtration over silica gel (flashmaster, hexane to hexane/EtOAc 4/6) gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:22][CH:23]([F:33])[O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:29][C:28]2[CH:27]=[CH:26][C:25]([O:24][CH:23]([F:22])[F:33])=[CH:32][CH:31]=2)[C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: FC(F)Oc1ccc(CBr)cc1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: O=C1NCCC(F)(F)C[C@H]1N(Cc1ccc(OC(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 4-(difluoromethoxy)benzyl bromide analogous to Example 1 to afford 4-chloro-N-(4-difluoromethoxy-benzyl)-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[H-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.C(OC(=O)C)C>[C:20]1([S:26]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2[C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Fc1cccc(F)c1-c1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(-c2c(F)cccc2F)nc2ccccc21
Reaction time: 0.08 h
Yield: 83 %

Procedure:
2-(2,6-difluorophenyl)benzimidazole (Example 12) (0.31 g, 1.34 mmol) dissolved in THF (5 mL) was added to NaH (0.10 g, 190 M%). After 5 min, benzenesulfonyl chloride (0.25 mL, 0.35 g, 2.00 mmol, 150 M%) was added. After stirring for 2 h, the reaction was dissolved in ethylacetate, and washed with NaHCO3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na2SO4), filtered, and concentrated. The product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2 and then recrystallized from diethylether/hexane (3:1), to yield white powders of 1-benzenesulfonyl-2-(2,6-difluorophenyl)benzimidazole (0.41 g, (1.10 mmol, 83% yield). M.p. 104-106° C. 1H-NMR (300 MHz, CD2Cl2): δ8.09 (m, 1H, PhSO2), 7.77 (m, 1H, PhSO2), 7.69 (m, 2H, PhSO2), 7.66-7.53 (m, 2H, H4,7), 7.51-7.39 (m, 4H, PhSO2, H3,5), 7.07 (m, 2H, H3′,5′).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[CH2:11]([C@H:13]1[NH:18][CH2:17][C@@H:16]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:20])[O:15][CH2:14]1)[CH3:12].CCN(C(C)C)C(C)C>CC#N.O>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][CH3:10])[N:3]=[C:2]([N:18]2[C@H:13]([CH2:11][CH3:12])[CH2:14][O:15][C@H:16]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[CH2:17]2)[CH:7]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: CC[C@@H]1CO[C@H](C(=O)Nc2ccccc2)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC[C@@H]1CO[C@H](C(=O)Nc2ccccc2)CN1c1cc(Cl)nc(NC)n1
Temperature: 100 °C
Yield: 129.1 %

Procedure:
4,6-Dichloro-N-methyl-2-pyrimidinamine (0.150 g, 0.845 mmol) was added to a 20 mL microwave vial followed by the addition of (2S,5R)-5-ethyl-N-phenyl-2-morpholinecarboxamide (0.198 g, 0.845 mmol) in CH3CN (5 mL) and Hunig's base (0.738 mL, 4.23 mmol). The reaction was irradiated at 150° C. for 10 minutes. The reaction was left in the 20 mL sealed microwave vessel and heated to 100° C. over the weekend. The reaction mixture was diluted with water and extracted with EtOAc (2×). The organic layers were combined and dried to afford the crude title compound (0.410 g). LC-MS (ES) m/z=376 [M+H]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C@H:19]1[C@@H:26]2[C@@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[O:21][C@:20]1([CH2:38][OH:39])[CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@H:19]1[C@@H:26]2[C@@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[O:21][C@@:20]1([CH2:29][O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH:38]=[O:39])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1(C)O[C@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1(C)O[C@H]2O[C@](C=O)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O1
Reaction time: 0.5 h

Procedure:
DMSO (1.65 mL, 23.6 mmol) was added drop-wise to a cold (−78° C.) solution of oxalyl chloride (1.05 mL, 12.0 mmol) in dichloromethane (50 mL). After stirring for 30 min, a solution of compound 2 (3 g, 7.5 mmol) in dichloromethane (25 mL) was added to the reaction. The stirring was continued for 45 min at −78° C., and triethylamine (3.5 mL, 25.0 mmol) was added to the reaction. The reaction was stirred at −78° C. for 15 min, after which the ice-bath was removed and the reaction was allowed to gradually warm over 45 min. The reaction was diluted with dichloromethane and the organic phase was sequentially washed with 5% aqueous HCl solution, saturated aqueous NaHCO3 solution, brine, dried (Na2SO4) and concentrated under reduced pressure to provide 3 (2.2 g, crude), which was used without any further purification. LC-MS (M+H)+=399.1
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:31])=[C:4]([CH:8]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)=[O:22])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:32][N+:33]([CH3:35])=[CH2:34].[I-].O.[OH-].[Na+].[C:40](O)(=O)C>CCOC(C)=O>[CH3:34][N:33]([CH2:35][CH:20]([CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH3:31])[C:9](=[CH2:40])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[O:11])[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)=[O:22])[CH3:32]
Reactant: CC(=O)O
Reactant: C=[N+](C)C
Reactant: COc1cccc(C(=O)CC(CC(=O)c2cccc(OC)c2)c2cccc(F)c2C)c1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C(=O)c1cccc(OC)c1)C(c1cccc(F)c1C)C(CN(C)C)C(=O)c1cccc(OC)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(3-fluoro-2-methylphenyl)-1,5-bis(3-methoxyphenyl)pentane-1,5-dione (71.6 g, 170 mmol) and (145 g, 782 mmol) in acetic acid (300 mL) was stirred at 120° C. under nitrogen for 16 h. An additional 5 g (27.0 mmol) of Eschenmoser's salt was added and the mixture heated an additional 2 h. The solution was allowed to cool to room temperature and concentrated in vacuo to give a brown solid. The residue slurried with water and then treated with NaOH (s) until the pH reached 10. EtOAc (100 mL) was added, and the pH was adjusted to 10 with NaOH (s). The vigorously stirred mixture was diluted with 200 mL of EtOAc followed by 300 mL of hexanes. The pale yellow solid was isolated by filtration, washed with water (200 mL), hexanes (200 mL), and ethyl acetate (100 mL), and dried under vacuum at 45° C. overnight to give 91 g of desired 2-((dimethylamino)methyl)-3-(3-fluoro-2-methylphenyl)-1,5-bis(3-methoxyphenyl)-4-methylenepentane-1,5-dione product as a crude yellow solid, (characterized by LCMS and 1H NMR), LRMS (M+H+) m/z=490.5.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][Si:6]([CH3:22])([CH3:21])[CH2:7][CH2:8][O:9][CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH2:20])[N:19]=[C:14]2[CH:13]=[CH:12]1.C(N(C(C)C)CC)(C)C.Cl.[CH3:33][C@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]1[NH2:40]>ClCCl>[CH3:33][C@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]1[NH:40][C:1]([NH:20][C:18]1[N:19]=[C:14]2[CH:13]=[CH:12][N:11]([CH2:10][O:9][CH2:8][CH2:7][Si:6]([CH3:22])([CH3:21])[CH3:5])[C:15]2=[N:16][CH:17]=1)=[O:2]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(N)cnc21
Reactant: C[C@H]1CCCC[C@H]1N
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CCCC[C@H]1NC(=O)Nc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Reaction time: 0.17 h
Yield: 55 %

Procedure:
Phosgene (ca. 20% in toluene, 0.9 mL) was added to a 0° C. solution of 5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine (0.300 g, 1.1 mmol) and diisopropylethylamine (0.6 mL, 3.4 mmol) in 10 mL of dichloromethane. The mixture was stirred for 10 min., then cis-2-methylcyclohexylamine hydrochloride (prepared as in Knupp, G. Chem. Ber. 1984, 117(6), 2076-98, using racemic α-methylbenzylamine) (0.249 g, 1.6 mmol) was added as a solution in 2 mL of dichloromethane with a few added drops of diisopropylethylamine. The mixture was stirred for 40 min., then concentrated to a residue. Column chromatography afforded 0.25 g (55%) of 1-(cis-2-methyl-cyclohexyl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S].N1CC[O:20]CC1.[OH2:23]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:20])=[O:23])=[C:7]([O:14][CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: COc1cc(C(C)(C)C)ccc1C(C)=O
Reactant: C1COCCN1
Agent: [S]
Product: COc1cc(C(C)(C)C)ccc1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.76 g (27.9 mmol) of 1-(4-tert-butyl-2-methoxyphenyl)ethanone (described in patent applications WO 01/02366; WO 99/52857; WO 99/21836; WO 97/48683), 1.1 g (34.3 mmol) sulfur and 15 mL morpholine (0.172 mol) was refluxed overnight under a nitrogen atmosphere. The reaction mixture was cooled and poured into 200 mL water containing 30 g sodium hydroxide and the resulting mixture was again refluxed overnight. The reaction mixture was then cooled to room temperature, diluted with an equal volume of water, and filtered through a pad of Celite filter aid. The filtrate was then cooled with an external ice water bath and acidified. The resulting precipitate was filtered, washed with water and air dried. The residue was then suspended in EtOAc and filtered to remove insoluble material and the filtrate was concentrated in vacuo to afford the title compound.