Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[N:8]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:7]=[N:6][CH:5]=1.[CH3:17][N:18](C)C=O.CN.N>ClC(Cl)Cl.CO>[ClH:2].[ClH:1].[CH3:17][NH:18][CH2:3][C:4]1[N:8]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:7]=[N:6][CH:5]=1
Reactant: CC(c1ccccc1)n1cncc1CCl
Reactant: CN(C)C=O
Agent: CN
Agent: Cl
Agent: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNCc1cncn1C(C)c1ccccc1
Yield: 44.5 %

Procedure:
Through a stirred mixture of 3 parts of 5-(chloromethyl)-1-(1-phenylethyl)-1H-imidazole monohydrochloride and 45 parts of N,N-dimethylformamide were bubbled 3 equivalents of gaseous methanamine at room temperature during a 1 hour-period: exothermic reaction, the temperature rose to 50° C. The reaction mixture was taken up in trichloromethane and methanol, previously saturated with ammonia, was added. The formed precipitate was filtered off and the filtrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off, washed with 2-propanol, dried and crystallized from 2-propanol, yielding 1.6 parts (44.5%) of (±)-N-methyl-1-(1-phenylethyl)-1H-imidazole-5-methanamine dihydrochloride.monohydrate; mp. 109° C. (compound 8.38).
Reaction SMILES: [CH:1]1([PH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14](Br)[CH2:15]Br>>[CH2:8]([P:7]([CH:15]1[CH2:14][CH2:10][CH2:11][CH2:12][CH2:13]1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:9][P:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C1CCC(PC2CCCCC2)CC1
Reactant: BrCCBr
Product: C1CCC(P(CCP(C2CCCCC2)C2CCCCC2)C2CCCCC2)CC1

Procedure:
Dicyclohexyl phosphine (40 g, 0.2 mole) was reacted with ethylene dibromide (18 g, 0.1 mole) for 2 hours at 90°-100° C. to form ethylenebis(dicyclohexylphosphine). The phosphine compound was then oxidized with 25 g of 30% hydrogen peroxide to give the phosphine oxide. The crude product was recrystallized from isopropanol/water to give 20 grams of the subject compound, m.p. 199°-201° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:23][S:24]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25].C(O)(=O)C.[CH3:37][CH:38]([CH3:41])[CH:39]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[O:12])=[CH:21][CH:22]=2)=[N:4][C:3]=1[CH2:23][S:24]([CH:27]1[CH2:28][CH2:29][N:30]([CH2:37][CH:38]([CH3:41])[CH3:39])[CH2:31][CH2:32]1)(=[O:25])=[O:26]
Reactant: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCNCC1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)C1CCN(CC(C)C)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
A solution of 4-[5-methyl-4-[(piperidine-4-sulfonyl)methyl]-1,3-oxazol-2-yl]-N-(pyridin-3-ylmethyl)benzamide (300 mg, 0.66 mmol, 1.00 equiv), acetic acid (59.3 mg, 0.99 mmol, 1.50 equiv) and 2-methylpropanal (57 mg, 0.79 mmol, 1.20 equiv) in 1,2-dichloroethane (3 mL) was stirred at room temperature for 4 h. Sodium triacetoxyborohydride (420 mg, 1.98 mmol, 3.00 equiv) was added in small batches and the resulting solution was stirred overnight at 30° C. The resulting mixture was concentrated under vacuum and the residue was diluted with 2 mL of methanol. The solution was loaded onto a C18 column and eluted with acetonitrile/water to give 200 mg (59%) of 4-(5-methyl-4-[[1-(2-methylpropyl) piperidine-4-sulfonyl]methyl]-1,3-oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS (ES, m/z): 511 [M+H]+, 306, 256; 1HNMR (300 MHz, CD3OD, ppm) δ 8.60 (s, 1H), 8.47 (d, 1H), 8.11 (d, 2H), 7.99 (d, 2H), 7.89 (d, 1H), 7.47-7.43 (m, 1H), 4.65 (s, 2H), 4.41 (s, 2H), 3.33-3.08 (m, 3H), 2.50.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1([C:12]2[C:13]3[NH:20][CH:19]=C(C(O)=O)[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:11]=[CH:10][CH:9]=[N:8]1>C(Cl)Cl.CN(C=O)C>[N:7]1([C:12]2[C:13]3[NH:20][CH:19]=[C:1]([C:2]([Cl:4])=[O:3])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH:11]=[CH:10][CH:9]=[N:8]1
Reactant: O=C(O)c1c[nH]c2c(-n3cccn3)ncnc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1c[nH]c2c(-n3cccn3)ncnc12
Reaction time: 14 h
Yield: 1042.6 %

Procedure:
Oxalyl chloride (4.5 mL, 51 mmol) was added to a solution of diazaindole carboxylic acid 50 (1.08 g, 4.7 mmol) in CH2Cl2 (8 mL) and the reaction mixture was stirred 14 h. Catalytic DMF (3 drops) was added to the reaction mixture and after 3 h the reaction was quenched with MeOH. The crude reaction mixture was concentrated to dryness to yield 51 (1.21 g, 49 mmol, 96%) as a tan solid with was used without further purification. 1H NMR: (500 MHz, DMSO-d6) δ 12.45 (br s, 1H), 8.87 (s, 1H), 8.87 (d, J=2.6 Hz, 1H), 8.32 (d, J=3.3 Hz, 1H), 8.14 (d, J=1.5 Hz, 1H), 6.77 (dd, J=2.6, 1.5 Hz, 1H); Methyl ester (obtained by stirring 51 in MeOH): LC/MS: (ES+) m/z (M+H)+=244; HPLC Rt=0.95 min., column 0, conditions B.
Reaction SMILES: [CH2:1]([CH:4]1[C:9]([O:10][CH3:11])=[N:8][C@H:7]([CH:12]([CH3:14])[CH3:13])[C:6]([O:15][CH3:16])=[N:5]1)[CH:2]=[CH2:3].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]I)=[C:20]([Cl:27])[CH:19]=1.O>O1CCCC1>[CH2:1]([C@:4]1([CH2:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][C:20]=2[Cl:27])[C:9]([O:10][CH3:11])=[N:8][C@H:7]([CH:12]([CH3:14])[CH3:13])[C:6]([O:15][CH3:16])=[N:5]1)[CH:2]=[CH2:3]
Reactant: Clc1cc(Br)ccc1CCI
Reactant: C=CCC1N=C(OC)[C@@H](C(C)C)N=C1OC
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@]1(CCc2ccc(Br)cc2Cl)N=C(OC)[C@@H](C(C)C)N=C1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
Under an argon atmosphere, an n-butyllithium-hexane solution (1.60 mol/L, 11.16 mL) was added at −78° C. to a solution of (5R)-2-allyl-3,6-dimethoxy-5-isopropyl-2,5-dihydropyrazine (3.64 g) in tetrahydrofuran (60 mL) to form a reaction solution. This reaction solution was then stirred at −78° C. for 30 minutes. A solution of 4-bromo-2-chloro-1-(2-iodoethyl)benzene (6.73 g) in tetrahydrofuran (20 mL) was added to the reaction solution, and the reaction solution was stirred at −78° C. for 30 minutes and then at 0° C. for 1 hour. Water was added to the reaction solution, and the reaction solution was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and then the solvent was removed by distillation under reduced pressure. The resultant product was purified by silica gel column chromatography (hexane:ethyl acetate=70:1) to obtain the target product (6.04 g) as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([N:26]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CO>[CH2:19]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN[C@H]3CCN(Cc4ccccc4)C3)cc2)nc1
Yield: 43.6 %

Procedure:
Using a method similar to Example 334, and using 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.300 g, 1.24 mmol), (3S)-1-benzylpyrrolidin-3yl amine (0.21 mL, 1.22 mmol), and sodium borohydride (0.108 g, 2.85 mmol) in methanol (12 mL) provides 0.214 g (43%) of the title compound as a white foam (chromatography solvent: ethyl acetate→19:1 ethyl acetate:methanol): high resolution mass spectrum (electrospray): m/z calc for C24H27N4O2 403.2134, found 403.2144; 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.9, 8.8 Hz), 7.48-7.42 (m, 2H), 7.40-7.27 (m, 5H), 7.17-7.12 (m, 2H), 7.02 (d, 1H, J=9.3 Hz), 3.79 (d, 1H, J=13.2 Hz), 3.76 (d, 1H, J=13.7 Hz), 3.69 (d, 1H, J=12.7 Hz), 3.67 (d, 1H, J=12.7 Hz), 3.44-3.36 (m, 1H), 2.92 (dd, 1H, J=7.3, 9.8 Hz), 2.69 (t, 2H, J=6.8 Hz), 2.44 (dd, 1H, J=6.3, 10.2 Hz), 2.25-2.14 (m, 1H), 1.77-1.67 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:18])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([O:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([C:37](Cl)=[O:38])=[CH:32][CH:31]=[CH:30]3)[CH:21]=1.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:37]([C:33]2[C:34]3[C:29](=[CH:28][C:27]([O:26][C:22]4[CH:21]=[C:20]([Cl:19])[N:25]=[CH:24][N:23]=4)=[CH:36][CH:35]=3)[CH:30]=[CH:31][CH:32]=2)=[O:38])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(Cl)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)c2cccc3cc(Oc4cc(Cl)ncn4)ccc23)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.9 g (12 mMol) 5-tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine and 3.8 g (12 mMol) 6-(6-chloropyrimidin-4-yloxy)-naphthalene-1-carbonyl chloride (described under Step 19.3) are dissolved in 10 ml CH2Cl2 and cooled to 0° C. 0.99 ml (12 mMol) Pyridine are added dropwise and after complete addition the reaction is allowed to warm to rt. It is stirred for 2 h at ambient temperature. The reaction is worked up by addition of 150 ml CH2Cl2 and aq. extraction with sat. Na2CO3 solution. The organic layer is subsequently washed with brine and dried. After removal of the solvents the remaining crude product is purified by flash chromatography (SiO2; hexanes/EtOAc, gradient 3:1 to 2:1) to give the title compound as a yellow solid: m.p.: 163-164° C.
Reaction SMILES: [C:1]([CH:3]([C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:41])[C:4]1[N:9]=[N:8][C:7]([S:10][C:11]2[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=2[CH2:13][NH:14][C:15](=[O:29])[C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[C:18]([F:28])[CH:17]=2)=[CH:6][CH:5]=1)#[N:2].S(=O)(=O)(O)[OH:43]>>[NH2:2][C:1](=[O:43])[CH:3]([C:4]1[N:9]=[N:8][C:7]([S:10][C:11]2[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=2[CH2:13][NH:14][C:15](=[O:29])[C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[C:18]([F:28])[CH:17]=2)=[CH:6][CH:5]=1)[C:34]1[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=1[Cl:40]
Reactant: O=S(=O)(O)O
Reactant: N#CC(c1ccc(Sc2ccccc2CNC(=O)c2cc(F)cc(N3CCOCC3)c2)nn1)c1c(Cl)cccc1Cl
Product: NC(=O)C(c1ccc(Sc2ccccc2CNC(=O)c2cc(F)cc(N3CCOCC3)c2)nn1)c1c(Cl)cccc1Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
N-[2-({6-[Cyano(2,6-dichlorophenyl)methyl]pyridazin-3-yl}sulfanyl)benzyl]-3-fluoro-5-(morpholin-4-yl)benzamide (92 mg, 0.15 mmol) was treated with concentrated sulfuric acid (2 mL) and the mixture was stirred at 70° C. for 30 min. The solution was cooled to RT, quenched with ice-water and extracted into DCM. The organic layer was washed with aqueous saturated NaHCO3, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. Purification by flash column chromatography (DCM:MeOH from 97.3:2.7 to 95:5) afforded the title compound (63 mg, 67%) which co-exists in solution as a mixture of the amide and the enol-amine. LCMS (Method 3): Rt 10.15 & 11.27 min, m/z 626 [MH−]. 1H NMR (400 MHz, CD3OD) (ratio amide/enol-amine 1:0.8): 7.65 (1H, dd, J 7.6, 1.2), 7.57-7.43 (5.4H, m), 7.42-7.37 (3.6H, m), 7.36-7.29 (3.6H, m), 7.21 (0.8H, t, J 1.8), 7.17-7.13 (2H, m), 6.99 (0.8H, ddd, J 9, 2.3, 1.4), 6.95-6.93 (1H, m), 6.85-6.80 (1.8H, m), 6.58 (0.8H, d, J 9.9), 6.15 (0.8H, d, J 9.9), 5.98 (1H, s), 4.73 (1.6H, s), 4.71 (2H, d, J 1.8), 3.82 (7.2H, t, J 4.8), 3.22-3.17 (7.2H, m).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([S:11]([OH:14])(=[O:13])=[O:12])[C:7]([O:9]C)=[O:8])=[N+:2]=[N-:3]>Cl>[N:1]([CH2:4][CH2:5][CH:6]([S:11]([OH:14])(=[O:12])=[O:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3]
Reactant: COC(=O)C(CCN=[N+]=[N-])S(=O)(=O)O
Agent: Cl
Product: [N-]=[N+]=NCCC(C(=O)O)S(=O)(=O)O
Temperature: 100 °C
Yield: 117.2 %

Procedure:
Methyl 4-azido-2-sulfo-butyrate (1.00 g, 4.08 mmol) in the mixture of HCl (50 ml, 1.0 M) and HAC (5 ml) was heated at 100° C. for 8 hrs. The mixture was evaporated and co-evaporated 3×50 ml of water, and crystallized with water/acetone to afford 1.0 g (99%) of the title compound. 1H NMR (DMF-d7): 3.60 (m, 2H), 3.52 (m, 1H), 2.24 (m, 2H). 13C NMR 170.96, 63.04, 50.66, 29.12. ESI MS m/z− 207.7 (MW−H); HRMS m/z− (C4H7N3O5S—H) calcd 208.0028. found 208.0021.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][S:6]([C:9]1[C:13]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:12][S:11][N:10]=1)(=[NH:8])=[O:7])[CH3:2].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH2:19]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6]([C:9]1[C:13]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:12][S:11][N:10]=1)(=[N:8][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:7])[CH3:20]
Reactant: CCN(CC)CCS(=N)(=O)c1nsnc1-n1ccnc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCN(CC)CCS(=O)(=NC(=O)OCc1ccccc1)c1nsnc1-n1ccnc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of S-[2-(diethylamino)ethyl]-S-[4-(1H-imidazol-1-yl)-1,2,5-thiadiazol-3-yl]sulfoximine (10 mmol), benzyl chloroformate (12 mmol) and potassium carbonate(32 mmol) in methylene chloride is stirred at ambient temperature for 5 hr.The mixture is filtered and the filtrate concentrated to obtain the productwhich is purified using standard laboratory procedures.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25]>CS(C)=O.[I-].[K+]>[CH3:25][O:24][CH:23]([O:26][CH3:27])[CH2:22][CH2:21][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1
Reactant: COC(CCBr)OC
Reactant: COC(=O)c1cccc2cc[nH]c12
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc2ccn(CCC(OC)OC)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 1H-indole-7-carboxylate (3.3 g, 18.8 mmol) in DMSO (18 mL) was added potassium tert-butoxide (2.1 g, 18.8 mmol) in portions. After stirring at room temperature for 1 h, a solution of 3-bromo-1,1-dimethoxypropane (10 g, 54.6 mmol) and potassium iodide (188 mg, 1.1 mmol) in DMSO (15 mL) was added and the mixture was stirred for 15 h. The reaction was quenched with saturated aqueous ammonium chloride and adjusted to pH 6. The aqueous phase was extracted with ethyl acetate (3×) and the combined extracts were washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 90:10 hexanes/ethyl acetate) to give methyl 1-(3,3-dimethoxypropyl)-1H-indole-7-carboxylate (4.8 g, 92%) as a light yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.79 (d, J=7.5 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.12 (d, J=3.0 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 6.56 (d, J=3.5 Hz, 1H), 4.49 (t, J=7.0 Hz, 2H), 4.09 (t, J=6.0 Hz, 1H), 3.97 (s, 3H), 3.25 (s, 6H), 1.97 (q, J=6.0 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]=[C:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([F:28])[C:25]([Br:29])=[CH:24][C:23]=3[F:30])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][N:15]=[C:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([F:28])[C:25]([Br:29])=[CH:24][C:23]=3[F:30])[CH2:18][CH2:17]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(Br)cc3F)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cc(N2CCC(=NOC3CCNCC3)CC2)c(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 77a (300 mg, 0.61 mmol) was dissolved in 20% TFA/DCM (2 mL) and stirred at r.t. for 2 h. The solvents were removed in vacuo and the residue re-dissolved in DCM. This solution was washed with 2M NaOH then water and dried over MgSO4 and concentrated to give 1-(4-bromo-2,5-difluoro-phenyl)-piperidin-4-one O-piperidin-4-yl-oxime 77b.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[CH2:12]Br)(=O)C.[C:15]([NH2:23])(=[S:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1>CC(C)=O>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]2[S:22][CH:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[OH:4])[N:23]=2)[CH:17]=1
Reactant: NC(=S)c1cccnc1
Reactant: CC(=O)Oc1ccccc1C(=O)CBr
Solvent: CC(C)=O
Product: Oc1ccccc1-c1csc(-c2cccnc2)n1
Temperature: 20 °C
Yield: 36 %

Procedure:
o-(Bromoacetyl)phenyl acetate (2.57 g, 10 mmol) in dry acetone (30 mL) was treated with thionicotinamide (1.38 g, 10 mmol). The mixture was refluxed 16 hours, cooled to about 20° C. at which point a precipitate formed (2.46 g). The precipitate was filtered and dried in vacuo. The precipitate was dissolved in MeOH (50 mL) and treated with 10% NaOH in H2O (20 mL) for 1 hour at about 20° C. to hydrolyze the acetate ester. The pH was adjusted to neutrality with 6N HCl while chilling on ice/H2O and the volume was reduced to about 35 mL in vacuo. After cooling to about 4° C., an orange solid precipitate formed, which was removed by filtration and dried in vacuo to constant mass to yield 36-50% product (LSIMS m/s 254 (MH+)).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[C:22]([F:27])=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:28].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][N:16]3[C:21]4[C:22]([F:27])=[C:23]([F:26])[CH:24]=[CH:25][C:20]=4[O:19][CH2:18][C:17]3=[O:28])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: C1CC(OCC2CC2)CCN1
Reactant: O=C1COc2ccc(F)c(F)c2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2ccc(F)c(F)c2N1CCCN1CCC(OCC2CC2)CC1
Yield: 53.7 %

Procedure:
4-Cyclopropylmethoxypiperidine (0.037 g, 0.24 mmol), 4-(3-chloropropyl)-5,6-difluoro-4H-benzo[1,4]oxazin-3-one (0.065 g, 0.25 mmol), K2CO3 (0.066 g, 0.48 mmol), and KI (0.072 g, 0.48 mmol) were mixed according to GP3. Purified by prep TLC (SiO2; heptanes/EtOAc 1:1) to give the title compound (0.049 g, 54%). Rf=0.21 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) δ 6.84-6.70 (m, 2H), 4.48 (s, 2H), 4.48 (s, 2H), 4.08-4.02 (m, 2H), 3.34-3.26 (m, 1H), 3.24 (d, J=6.8 Hz, 2H), 2.75-2.68 (m 2H), 2.38 (t, J=7.2 Hz, 2H), 2.18-2.06 (m, 2H), 1.92-1.81 (m, 4H), 1.63-1.52 (m, 2H), 1.06-0.96 (m, 2H), 0.52-0.47 (m, 2H), 0.18-0.14 (m, 2H); 13C NMR (CDCl3) δ 165.0, 147.5 (dd, J=242.3 Hz, J=13.2 Hz), 143.9, 140.7 (dd, J=250.2 Hz, J=17.3 Hz), 119.9, 111.7 (dd, J=7.3 Hz, J=3.5 Hz), 110.9 (d, J=18.9 Hz), 74.5, 72.7, 68.5, 55.5, 51.2, 42.7 (d, J=10.4 Hz), 31.1, 25.5, (d, J=2.6 Hz), 11.1, 3.2.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:20])[CH:18]=[CH:17][O:16][C:15](=[O:19])[CH2:14]1>>[O:9]1[CH:17]2[CH:18]1[C:13]([CH3:20])([CH3:12])[CH2:14][C:15](=[O:19])[O:16]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)C=COC(=O)C1
Product: CC1(C)CC(=O)OC2OC21
Yield: 81.3 %

Procedure:
A solution of 43.15 g of m-chloroperbenzoic acid in 25.2 g of 4,4-dimethyl-3,4-dihydro-2-pyrone at 0° C. was stirred for 3 hours while allowing the temperature to rise to room temperature and was then vacuum filtered. The product was empasted with methylene chloride and the filtrate was washed with an aqueous sodium thiosulfate, then with water. The organic phase was dried and evaporated to dryness under reduced pressure to obtain 28.5 g of raw product which was chromatographed over silica gel and eluted with an hexane-isopropyl ether to obtain 23.08 g of racemic 5,6-epoxy-4,4-dimethyl-tetrahydro-pyr-2-one melting towards 22° C.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:28][C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[N:17][CH:18]=[C:19]([CH2:21][N:22]4[CH2:27][CH2:26][S:25][CH2:24][CH2:23]4)[CH:20]=3)[N:12]=[C:11]([CH3:37])[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O.OS(C(F)(F)F)(=O)=O>[CH3:36][O:35][C:32]1[N:31]=[CH:30][C:29]([NH:28][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:37])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([CH2:21][N:22]3[CH2:27][CH2:26][S:25][CH2:24][CH2:23]3)=[CH:18][N:17]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCSCC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CN3CCSCC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 54.8 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(thiomorpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (86 mg, 0.129 mmol) in 2 mL of TFA was treated with 2 drops of triflic acid. The brown solution was heated in an oil bath at 80° C. for 5 h. The volatiles were removed on and the dark residue was basified with 1 N NaOH and extracted with EtOAc twice followed by DCM once. The combined organic extracts were concentrated and purified on a Redi-Sep pre-packed silica gel column (12 g) eluting with a gradient of 2-6% MeOH in DCM to give 4-(2-(6-methoxypyridin-3-ylamino)-5-(thiomorpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (30 mg, 55% yield) as an orange crystalline solid. 1H NMR (400 MHz, d6-DMSO) δ 11.75 (1H, s); 8.68 (1H, d, J=2.4 Hz); 8.54 (1H, d, J=2.7 Hz); 8.18 (1H, d, J=2.5 Hz); 8.16 (1H, d J=2.9 Hz); 7.87 (1H, br. s); 7.73 (1H, br. s); 6.82 (1H, d, J=9.0 Hz); 3.84 (3H, s); 3.46 (2 H, s); 2.67-2.60 (8H, m); 2.44 (3H, s). m/z (ESI, +ve ion) 425 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.Cl.[CH3:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH2:19][CH2:20][NH2:21].[CH3:22][N:23]1[CH:28]=[C:27]([CH2:29]Cl)[C:26]([C:31](OC)=[O:32])=[C:25]([Cl:35])[C:24]1=[O:36]>CO.CC#N>[Cl:35][C:25]1[C:24](=[O:36])[N:23]([CH3:22])[CH:28]=[C:27]2[CH2:29][N:21]([CH2:20][CH2:19][C:11]3[N:10]([CH3:9])[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[N:12]=3)[C:31](=[O:32])[C:26]=12
Reactant: COC(=O)c1c(CCl)cn(C)c(=O)c1Cl
Reactant: Cn1c(CCN)nc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1nc3ccccc3n1C)C2
Temperature: 90 °C
Reaction time: 5 h
Yield: 54.2 %

Procedure:
K2CO3 (8.35 g, 60.4 mmol) was added rapidly to a suspension of 2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethanamine dihydrochloride (5 g, 20.15 mmol) in MeOH (50 ml) and the reaction was stirred for about 5 h. The mixture was filtered and the filtrate was concentrated. The residue and TEA (28.1 ml, 201 mmol) were added to a solution of 1-methyl-2-oxo-1,2-dihydro-3-chloro-4-methoxycarbonyl-5-chloromethyl-pyridine (5.04 g, 20.15 mmol, see compound (6) of Example b1)) in MeCN (100 ml). The mixture was heated at about 90° C. overnight. The reaction was cooled to r.t. and the mixture was filtered through a sintered glass funnel. The solid was washed with water and dried to afford the title compound (3.9 g, 10.93 mmol, 54.2% yield).