Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[C:7](=[S:10])([O-:9])[CH3:8].[K+].O>CN(C=O)C.[Br-].[Na+]>[C:7](=[O:9])([S:10][CH2:2][C:3]([OH:5])([CH3:6])[CH3:4])[CH3:8]
Reactant: CC(C)(O)CCl
Reactant: CC([O-])=S
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SCC(C)(C)O
Temperature: 50 °C
Yield: 113.2 %

Procedure:
To a mixture of 1-chloro-2-methylpropan-2-ol (2.2 g, 20.26 mmol) and potassium ethanethioate (6.94 g, 60.8 mmol) in DMF (20 mL) was added 100 mg of sodium bromide and the resulting mixture was heated at 50° C. for 18 hours. The mixture was then poured into water and extracted with EtOAc. The acetate layer was washed with water, brine, dried with MgSO4 and concentrated under reduced pressure to provide 3.4 g of the title compound.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Reactant: NCCc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1cc(-c2cc3cc(CNCCc4ccccn4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 70.6 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with 2-(2-aminoethyl)pyridine (0.239 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (127 mg, 0.599 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-(1-(tert-butoxycarbonyl)-5-[(2-(pyridin-2-yl)ethyl)aminomethyl]indol-2-yl)isoindolinone (85.7 mg, yield 71%).
Reaction SMILES: NS(N)(=O)=O.Cl[CH2:7][CH2:8][CH2:9][S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]4[CH:32]=[CH:31][S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11].[NH:36]1[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>>[OH:42][CH:39]1[CH2:40][CH2:41][N:36]([CH2:7][CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[C:27]4[C:22](=[C:23]([C:33]([NH2:35])=[O:34])[CH:24]=[C:25]([C:28]5[CH:32]=[CH:31][S:30][CH:29]=5)[CH:26]=4)[NH:21][CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:37][CH2:38]1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: OC1CCNCC1
Agent: NS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCC(O)CC4)CC3)c[nH]c12
Yield: 11.9 %

Procedure:
Following the general procedure for aminosulfonamide formation outlined in example 2, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indole-7-carboxamide (40 mg, 0.13 mmol) and 4-piperidinol (0.068 mL, 0.65 mmol) were allowed to react in the presence of K2CO3 (74 mg, 0.65 mmol). The resulting residue was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (8.2 mg, 13%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1B(O)O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:29]=1[C:2]1[N:7]=[N:6][C:5]([N:8]([CH3:19])[CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][CH:3]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccc(OCc2ccccc2)c1B(O)O
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Product: COc1cccc(OCc2ccccc2)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1

Procedure:
Intermediate 1-1 (391 mg, 1.384 mmol) and (2-(benzyloxy)-6-methoxyphenyl)boronic acid (500 mg, 1.94 mmol) were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. 6-(2-(Benzyloxy)-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine was obtained as a beige solid (358 mg, 56% yield) after flash column chromatography purification. MS (M+1)=461.5.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:2]2[S:6][C:5]([NH2:7])=[N:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Nc1ncc(Br)s1
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Sc2cnc(N)s2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution of 5-bromo-thiazol-2-ylamine (70a, 10.0 g, 38.5 mmol), 4-methoxy-benzenethiol (4.70 ml, 38.5 mmol) and K2CO3 (21.0 g, 151 mmol) in DMF (100 mL) was heated at 80° C. for 1.0 hour and stirred further 16 hours at room temperature. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4(s), and concentrated under reduced pressure to give 5-(4-methoxy-phenylsulfanyl)-thiazol-2-ylamine (70b, 6.70 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:18]([N:19]([CH2:22][CH3:23])[CH2:20][CH2:21][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14])[CH3:17]
Reactant: CCN(CC)CCCl
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (400 mg, 2.08 mmol), 2-chloro-N,N-diethylethanamine hydrochloride (394 mg, 2.29 mmol) and potassium carbonate (862 mg, 6.24 mmol) in 10 mL DMF was stirred at room temperature overnight. After this time, the mixture was poured into 20 mL H2O then extracted with 2×50 mL CH2Cl2. The organic layer was separated, washed with brine and concentrated to give a yellow brown solid which was subjected to flash chromatography on silica gel using 5% MeOH/CH2Cl2 to give a yellow viscous oil (585 mg, 96.5%). 1H-NMR (CDCl3) δ: 8.16 (dd, J=2.5, 9 Hz, 1H), 8.06 (d, J=2.5 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 4.07 (t, J=7.0 Hz, 2H), 3.00 (t, J=7.0 Hz, 2H), 2.73-2.55 (m, 8H), 1.01 (t, J=7.0 Hz, 6H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17](B(O)O)[CH:18]=1)(=[O:12])[NH2:11].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO>[F:22][C:16]1[CH:17]=[CH:18][C:13]([C:10]([NH2:11])=[O:12])=[CH:14][C:15]=1[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: NC(=O)c1ccc(F)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: NC(=O)c1ccc(F)c(-c2ccc(C=O)cn2)c1
Temperature: 80 °C

Procedure:
To a solution of 6-bromo-3-pyridinecarboxaldehyde (336 mg, 1.80 mmol) in DME (8 mL) and EtOH (4 mL) under argon, was added (5-carbamoyl-2-fluorophenyl)boronic acid (300 mg, 1.64 mmol) followed by palladium tetrakistriphenylphosphine (190 mg, 0.16 mmol) and 2M Na2CO3 (4 mL). The mixture was heated to 80° C. for 16 h and then allowed to cool to rt. The mixture was partitioned between EtOAc (50 mL), THF (50 mL) and Na2CO3 (20 mL). The aqueous was extracted with EtOAc (50 mL) and the combined organics washed with brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (0.4% NH3: 4% MeOH: DCM) to give the title compound: RT=2.50 min; m/z (ES+)=245.0 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>ClCCl>[O:8]=[C:5]1[CH2:6][CH2:7][N:2]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:3][CH2:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of piperidin-4-one hydrochloride (1567 g, 11.56 mol) and triethylamine (1400 g, 13.87 mol) in dichloromethane (12 L) was added benzyl chloroformate (1965 g, 11.55 mol) dropwise at 0° C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. TLC (EtOAc/petroleum ether=1:5) showed the reaction was complete. The mixture was washed with water (3 L) and brine (1 L), dried over sodium sulfate and concentrated to afford benzyl 4-oxopiperidine-1-carboxylate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]#[N:22])[CH:16]=[CH:17][CH:18]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH:20][C:21]#[N:22])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: N#CC=Cc1cccc(N)c1
Product: N#CC=Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1

Procedure:
5-Bromo-2-fluoro-benzoic acid (380 mg, 1.74 mmol) was coupled to aniline (88) (250 mg, 1.74 mmol) using Method C. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH:10]=[CH:11][CH:12]=1.Cl[CH2:26][C:27]([NH2:29])=[O:28].C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][N:15]([CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH2:26][C:27]([NH2:29])=[O:28])[CH:10]=[CH:11][CH:12]=1
Reactant: Fc1cccc(COc2cccc(CCNCc3ccco3)c2)c1
Reactant: NC(=O)CCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)CN(CCc1cccc(OCc2cccc(F)c2)c1)Cc1ccco1
Yield: 99.3 %

Procedure:
A solution of 1.8 g (5.53 mmol) of [2-[3-(3-fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amine, 0.57 g (6.08 mmol) of 2-chloro-acetamide and 0.92 ml (6.62 mmol) of triethylamine in 5 ml of dry dimethylformamide was heated at 120° C. for 2 hours with microwaves. Solvent was removed under vacuum, water was added and the product was extracted with ethyl acetate. The crude reaction mixture was purified by flash chromatography (dichloromethane/methanol 95:5 v:v). 2.1 g (99% yield) of a yellow oil were isolated.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([SH:19])[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]([S:19][C:2]2[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)c1nnc(Br)s1
Solvent: CCN(CC)CC
Solvent: CCO
Product: FC(F)(F)c1nnc(Sc2ccc(Cl)c(Cl)c2)s1
Reaction time: 2 h
Yield: 67.3 %

Procedure:
130.5 g (0.66 mole) of 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole were added dropwise to a solution of 98.1 g (0.66 mole) of 3,4dichloro-thiophenol and 57.6 g (0.66 mole) of triethylamine in 500 ml of ethanol. An exothermic effect was observed and a white precipitate separated out. The mixture was stirred for a further 2 hours under reflux, concentrated to half in vacuo and introduced into 1 liter of ice water. The white precipitate was filtered off, dried over phosphorus pentoxide and recrystallized from about 300 ml of petroleum ether. 147 g (76% of theory) of 2-(3',4' -dichlorophenylthio)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 46° C were obtained.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][Si](C)(C)C)=[N:21][CH:22]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:2]2[CH:3]=[C:4]([C:8]3([CH3:15])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[N:21][CH:22]=1
Reactant: CC1(c2cccc(I)c2)COCC(N)=N1
Reactant: C[Si](C)(C)C#Cc1ccc(Cl)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(c2cccc(C#Cc3ccc(Cl)cn3)c2)COCC(N)=N1

Procedure:
In a manner analogous to that described in Example 42, the reaction of (RS)-5-(3-iodo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (intermediate XII-2) with 5-chloro-2-trimethylsilanylethynyl-pyridine (EP385210) was performed. In addition, after combination of solution 1 and 2, a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 0.47 ml) was added. The 5-[3-(5-chloro-pyridin-2-ylethynyl)-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as a white foam. MS (ISP): m/z=326.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added tert-butyl (aminooxy)acetate 88 (0.13 g, 0.86 mmol, Organic Letters, 2002, 4(6) 869-872), 1-hydroxybenzotriazole (0.15 g, 1.11 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.10 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl [({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetate 89 (0.23 g, 79%) as a white solid.
Reaction SMILES: O1CCOCC1.Cl.Cl[C:9]1[C:14]([C:15]2[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=2)=[CH:13][C:12]([O:23][CH3:24])=[CH:11][N:10]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=1>>[CH3:24][O:23][C:12]1[CH:13]=[C:14]([C:15]2[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=2)[C:9]([NH:25][C:26]2[CH:31]=[N:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:10][CH:11]=1
Reactant: COc1cnc(Cl)c(-c2nc(C)nc(N)n2)c1
Reactant: COc1ccc(N)cn1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N)n2)c1
Temperature: 140 °C

Procedure:
1,4-dioxane (0.1 mL, 1.169 mmol) and 2N HCl (0.219 mL, 0.437 mmol) was added to a mixture of 4-(2-chloro-5-methoxypyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (110 mg, 0.437 mmol) and 5-amino-2-methoxypyridine (Aldrich, St. Louis, Mo.) (81 mg, 0.656 mmol) in a microwave reaction vessel and the mixture was sealed and heated at 140° C. for 60 min in a Personal Chemistry microwave unit under microwave irradiation. After cooling, the resulting dark mixture was concentrated. Flash column chromatographic purification (short column, SiO2, pure DCM to 5% MeOH in DCM) provided the title compound mixed with starting material. This was washed with methanol several times and finally the solid was recrystallized from MeOH to give 4-(5-methoxy-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (21 mg, 0.062 mmol, 14.16% yield) as a yellow-green powder. LCMS (API-ES) m/z 340 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 11.47 (s, 1H) 8.52 (d, J=2.74 Hz, 1H) 8.39 (d, J=3.33 Hz, 1H) 8.13-8.18 (m, 1H) 8.12 (d, J=3.13 Hz, 1H) 7.86 (br s., 1H) 7.73 (br. s., 1H) 6.79 (d, J=8.80 Hz, 1H) 3.83 (s, 3H) 3.82 (s, 3H) 2.44 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([CH3:17])([CH3:16])[O:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[CH2:18]([O:20][C:21]([C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28](Cl)=[O:29])=[O:22])[CH3:19]>C1COCC1.C(OCC)(=O)C>[CH2:18]([O:20][C:21]([C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([S:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][Si:7]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:17])[CH3:16])[CH:10]=1)=[O:29])=[O:22])[CH3:19]
Reactant: CCOC(=O)[C@H]1CCCN1C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CCCN1C(=O)Sc1cccc(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 0.17 h

Procedure:
To a stirred suspension of sodium hydride (0.25 g, 6.3 mmol) in anhydrous THF (20 mL) is added 3-(t-butyl-dimethyl-silanyloxy)-benzenethiol (1.3 g, 5.22 mmol) at RT. After 10 min, the title A compound, (R)-1-chlorocarbonyl-pyrrolidine-2-carboxylic acid ethyl ester (1.1 g, 5.22 mmol) is added and the reaction is stirred for 24 h. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 25% ethyl acetate in hexane to yield (R)-1-[3-(t-butyl-dimethyl-silanyloxy)-phenyl-sulfanylcarbonyl]-pyrrolidine-2-carboxylic acid ethyl ester as a clear oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[C:5]([Cl:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([C:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH:32]=2)[C:24]([N+:34]([O-:36])=[O:35])=[CH:23][C:21]=1[NH2:22].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CO>C1COCC1>[Cl:17][C:5]1[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:7][C:2]([NH:22][C:21]2[CH:23]=[C:24]([N+:34]([O-:36])=[O:35])[C:25]([C:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH:28]=3)=[CH:26][C:20]=2[O:19][CH3:18])=[N:3][CH:4]=1
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1N
Reactant: Clc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A mixture of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 21, 575 mg, 1.86 mmol) and 2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline (Intermediate 3, 490 mg, 1.86 mmol) was stirred in THF (30 mL) and cooled in an ice/water bath. Lithium bis(trimethylsilyl)amide (4.10 mL, 4.10 mmol, 1M in THF) was then added dropwise and the mixture was stirred for 1 h. CH3OH was added and the mixture was concentrated in vacuo. The crude material was suspended in CH3OH and the mixture was filtered. The collected solid was washed with CH3OH and diethyl ether and dried on the filter to give the title compound (660 mg, 72%) as a yellow powder; 1H NMR: 2.29 (3H, s), 2.30-2.38 (2H, m), 2.58 (2H, t), 2.97 (2H, dd), 3.96 (3H, s), 5.60-5.68 (1H, m), 7.00 (1H, s), 7.16 (1H, td), 7.36-7.45 (1H, m), 8.49-8.56 (3H, m), 8.87 (1H, d), 8.90 (1H, s), 8.97 (1H, s); m/z: ES+ MH+ 492.4.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][OH:11]>C1(C)C=CC=CC=1>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3]1
Reactant: OCCCBr
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C., ice bath) solution of morpholine (31.5 ml, 0.36 mole) in toluene (300 ml) was added 3-bromopropanol (25 g, 0.18 mole) under argon. The cooling bath was then removed, the resulting mixture was warmed to room temperature, and stirred at room temperature for 1 hr. The mixture was heated at 100° C. (bath temperature) for 3 hrs under argon. After cooling, the mixture was diluted with ethyl acetate. The organic layer was washed (brine), dried (MgSO4), and concentrated. The residue was chromatographed (silica gel, elution by 1:1 CH2Cl2-hexane) to give the title compound as a clear oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Br:42]Br>C(#N)C.C(OCC)C>[Br:42][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:10][CH:11]=1
Reactant: BrBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCO)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCBr)cc1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 2-(4-(tert-butyldimethylsilyloxy)phenyl)ethanol (1250 mg, 4.95 mmol) in acetonitrile (50 mL) and diethyl ether (25 mL) was sequentially added triphenylphosphine (3.44 mL, 14.8 mmol), 1H-imidazole (1011 mg, 14.8 μmol), and bromine (765 μl, 14.8 mmol). The clear solution was stirred at 23° C. for 18 h. The mixture was concentrated directly onto silica (20 g) under reduced pressure then purified on 120 grams of silica eluting with 0-5% EtOAc/Hexane. MS (ESI pos. ion) m/z (MH+): 315/317. Calc'd exact mass for C14H23BrOSi: 314. 1H NMR (400 MHz, Chloroform-d) δ ppm 0.19 (s, 6 H) 0.98 (s, 9 H) 3.08 (t, J=7.78 Hz, 2 H) 3.47-3.57 (m, 2 H) 6.78 (d, J=8.53 Hz, 2 H) 7.05 (d, J=8.53 Hz, 2 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[NH:36]1[C:32]([C:31]2[CH:30]=[CH:29][C:28]([C:13]3[N:9]4[N:10]=[CH:11][CH:12]=[C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:8]4=[N:15][C:14]=3/[CH:16]=[CH:17]/[C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:35][CH:34]=2)=[N:33][N:38]=[N:37]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C(=C/c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(-c2nnn[nH]2)cc1)\c1ccc2ccccc2n1
Temperature: 130 °C

Procedure:
A mixture of compound 13a (95 mg, 0.21 mmol), sodium azide (20 mg, 0.31 mmol) and ammonium chloride (16 mg, 0.31 mmol) in DMF (3 mL) was heated at 130° C. overnight. The reaction mixture was cooled to rt and water (20 mL) was added. The mixture was extracted with DCM/MeOH (9:1 v/v, 2×100 mL). The combined organic layers were washed with brine, and dried over Na2SO4. The mixture was filtered and concentrated to obtain a residue, which was washed with MeOH (2×2 mL). The resulting solid was purified by flash column chromatography on silica gel (0-20% MeOH/DCM) to give compound 13b as an orange solid. 1H-NMR (400 MHz, CDCl3+CD3OD) δ (ppm): 8.27 (d, J=8.3 Hz, 2H), 8.09-8.14 (m, 1H), 8.02-8.07 (m, 1H), 8.00 (d, J=5.6 Hz, 1H), 7.84-7.92 (m, 3H), 7.73-7.80 (m, 2H), 7.65-7.72 (m, 2H), 7.46-7.53 (m, 1H), 6.12 (d, J=5.6 Hz, 1H), 4.04-4.11 (m, 4H), 3.96-4.02 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H23N9O: 502.2 (M+H). Found 502.5.