Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:16]=2)[NH:11][C:10](=[O:23])[C:9]1=[O:24].[N+:25]([O-])([OH:27])=[O:26].[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[CH:13][C:14]([N+:25]([O-:27])=[O:26])=[C:15]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:16]=2)[NH:11][C:10](=[O:23])[C:9]1=[O:24]
Reactant: O=[N+]([O-])O
Reactant: NCCCCn1c(=O)c(=O)[nH]c2ccc(-n3ccnc3)cc21
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NCCCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccnc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice-cooling, 1-(4-aminobutyl)-7-(1H-imidazol-1-yl)-2,3(1H,4H)-quinoxalinedione dihydrochloride (1.00 g) was dissolved in concentrated sulfuric acid (10 ml) to which was subsequently added dropwise fuming nitric acid (94 μl). The reaction solution was gradually warmed up to room temperature and stirred overnight. Ice water was added to the reaction solution, followed by neutralization using 15% sodium hydroxide aqueous solution. The thus precipitated solid was collected by filtration and dried to give 1-(4-aminobutyl)-7-(1H-imidazol-1-yl)-6-nitro-2,3(1H,4H)-quinoxalinedione (0.40 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Br:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:20]([O-])=O)(=[O:3])[CH3:2]>C(#N)C.[Pt]>[C:1]([O:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Br:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH2:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: CC#N
Product: CC(=O)OCCCNc1c(N)cnc2cc(Br)ccc12
Yield: 97.8 %

Procedure:
To a hydrogenation flask was added a solution of 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propyl acetate (60.8 g, 165.1 mmol) in acetonitrile (600 mL) followed by 5% platinum on carbon (6.7 g) and the reaction was hydrogenated at 40 psi (2.8×105 Pa) overnight. The reaction was filtered through CELITE filter aid and the filtrate was collected. The solvent was removed under reduced pressure to afford 3-[(3-amino-7-bromoquinolin-4-yl)amino]propyl acetate (54.6 g) as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])O.[Na+].[N:30]#[C:31]Br>ClCCl.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:31]#[N:30])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:23][CH:24]=1)(=[O:3])=[O:4]
Reactant: N#CBr
Reactant: CS(=O)(=O)c1ccc(OCc2ccc(C3CCNCC3)cn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(OCc2ccc(C3CCN(C#N)CC3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of 4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidine (124 mg, 0.358 mmol) in dichloromethane (1 mL) was added a solution of sodium hydrogen carbonate (60 mg, 0.716 mmol) in water (0.5 mL). The mixture was cooled in an ice bath followed by the addition of a solution of cyanogen bromide (45 mg, 0.430 mmol) in dichloromethane (1 mL). The mixture was stirred at 0° C. for 30 minutes and then stirred at room temperature for an additional 1 hour. The mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (114 mg, yield 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[N:6][C:7]=1F.[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1.CN1CCOCC1.O>CN1CCCC1=O>[Cl:1][C:2]1[C:7]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:6][C:5]([N:9]2[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[N:22][CH:21]=[C:20]([CH3:24])[N:19]=4)[N:14]=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(F)n2)n1
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Yield: 69 %

Procedure:
A mixture of 1-(5-chloro-6-fluoro-2-pyridyl)-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine; (0.6372 mmol; 217.1 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (1.912 mmol; 382.9 mg), and N-Methylmorpholine (3.186 mmol; 326 mg; 0.354 mL) in 1-methyl-2-pyrrolidinone (3 mL) in a sealed pressure vial was heated at 100° C. overnight. The mixture was poured into water. The precipitate was collect by filtration, then purified on silica eluted with 0 to 6% MeOH in DCM to afford tert-butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (229.4 mg, 69%).
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:6][N:5]=1)([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([C:4]1[S:8][C:7]([N:9]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=2)(=[O:11])=[O:12])=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(S(=O)(=O)Nc2nnc(C(C)C)s2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Oc1ccc(S(=O)(=O)N(COCC[Si](C)(C)C)c2nnc(C(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
3.3 g Acetic acid 4-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl ester were dissolved in 12 ml dichloromethane. 2.69 ml N,N-diisopropylethylamine, 78 mg 4-dimethylaminopyridine and 2.1 g 2-(trimethylsilyl)ethoxymethyl chloride were added. The reaction mixture was stirred at room temperature for one hour. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel with the eluents n-heptane:ethyl acetate=1:1=>1:3 to obtain 2.7 g acetic acid 4-[(5-isopropyl-[1,3,4]thiadiazol-2-yl)-(2-trimethylsilanyl-ethoxymethyl)-sulfamoyl]-phenyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:33]2[CH2:35][CH2:34]2)[C:15]([C:17]2[CH:18]=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:33]1([N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15](=[O:16])[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[CH:27][CH:28]=3)=[N:19][CH:18]=2)[CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)c2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)C2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccc(C(=O)N(C3CCNCC3)C3CC3)cn2)cc1

Procedure:
The title compound is prepared from 4-{cyclopropyl-[6-(4-methanesulfonyl-phenyl)-pyridine-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester by treatment with trifluoroacetic acid in dichloromethane. LC (method 6): tR=0.70 min; Mass spectrum (ESI+): m/z=400 [M+H]+.
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH:9]1[NH:18][C:19](=[O:23])[O:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C>C(#N)C.ClCCl>[NH2:33][CH2:32][CH2:31][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH:9]([NH:18][C:19](=[O:23])[O:20][CH2:21][CH3:22])[CH:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCOC(=O)NC1Cc2ccc(O)cc2C1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)NC1Cc2ccc(OCCN)cc2C1Cc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of ethyl 1-benzyl-6-hydroxy-2,3-dihydro-1H-inden-2-ylcarbamate (620 mg, 1.991 mmol) and caesium carbonate (1298 mg, 3.98 mmol) in acetonitrile (15 ml) was stirred at 80° C. under argon for 1 h, cooled down to 50° C. and tert-butyl 2-bromoethylcarbamate (669 mg, 2.99 mmol)dissolved in acetonitrile was slowly added. Stirred at 80° C. for 2 h. Evaporated acetonitrile, re-dissolved in dichloromethane, washed with water, co-extracted aqueous layer twice with dichloromethane and the combined organic layers were dried, filtered and evaporated and purified by flash silica gel chromatography on 40 g SiO2-cartridge using 30% ethyl acetate in cyclohexane to afford the titled compound as a brown oil. m=624 mg
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:23]=[C:22]4[CH2:24][CH2:25][CH2:26][C:27](=[CH:30]N(C)C)[C:28](=O)[C:21]4=[CH:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.O.[NH2:42][NH2:43]>C(O)C>[C:34]1([C:19]2[CH:20]=[C:21]3[C:28]4=[N:42][NH:43][CH:30]=[C:27]4[CH2:26][CH2:25][CH2:24][C:22]3=[N:23][C:18]=2[C:15]2[CH:14]=[CH:13][C:12]([C:8]3([NH2:7])[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:16]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NN
Reactant: CN(C)C=C1CCCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Solvent: O
Solvent: CCO
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]cc3CCC4)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To a solution of tert-butyl(1-(4-(6-((dimethylamino)methylene)-5-oxo-3-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-2-yl)phenyl)cyclobutyl)carbamate (90 mg, 0.17 mmol) in anhydrous ethanol (2 mL) was added hydrazine hydrate (25 μL, 0.5 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was concentrated to dryness under reduced pressure, purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 99:1 to 60:40) and preparative HPLC (Method G, gradient 5 to 95% 0.1% FA/ACN in 0.1% FA/H2O, 20 minutes run) to give the desired product as a white solid (50 mg, 58% yield). 1H NMR (500 MHz, CDCl3) 7.49 (s, 1H), 7.38 (d, 2H), 7.29 (d, 2H), 7.21-7.25 (br m, 5H+1H), 3.25 (m, 2H), 2.94 (t, 2H), 2.53-2.61 (br m, 1H), 2.42-2.52 (m, 2H), 2.31-2.41 (br m, 1H), 2.14-2.21 (m, 2H), 1.98-2.10 (m, 1H), 1.74-1.85 (m, 1H), 1.30-1.43 (br s, 9H). LCMS (Method A): RT=6.09 min, M+H+=507.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9][CH2:10][OH:11])[C:7]([CH:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[N:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[N+:1]([C:4]1[N:8]([CH2:9][CH2:10][O:11][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[C:7]([CH:12]=[CH:13][N:14]([CH3:15])[CH3:16])=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C)C=Cc1ncc([N+](=O)[O-])n1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCn2c([N+](=O)[O-])cnc2C=CN(C)C)cc1

Procedure:
2.26 g. (0.01 mole) of 5-nitro-1-(2-hydroxyethyl)-2-(2-dimethylaminovinyl)-imidazole and 1.9 g. (0.01 mole) of p-toluenesulfochloride were agitated in 20 ml. of pyridine at 20° C. for 2 hours. Then, the mixture was poured on ice water and vacuum-filtered; m.p. 116°-118° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH2:11]([O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[F:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)c(F)c1
Yield: 80.9 %

Procedure:
A mixture of 3-fluoro-4-hydroxybenzaldehyde (4.264 g, 30.0 mmol), benzyl bromide (5.986 g, 35.0 mmol, 4.16 mL) and K2CO3 (820 g, 59.0 mmol) in DMF (50 mL) was stirred for 48 hours at room temperature before EtOAc (100 mL) and water (50 mL) were added. The organic layer was separated, washed with water (2×50 mL), brine (30 mL) and dried (Na2SO4). Concentration in vacuo gave a white solid residue. Recrystallization from CH2Cl2/n-hexane afforded CAB06038 as colorless needles (5.59 g, 81%). Mp. 94-95° C.; 1H NMR (400 MHz, CDCl3) δ 524 (s, 2H), 7.12 (dd, J=8.2, 8.2 Hz, 1H), 734-7.48 (m, 5H), 7.59-7.66 (m, 2H), 9.85 (d, J=2.0 Hz, 1H); LRMS (ES+): m/z 231.1 (100%, [M+H]+).
Reaction SMILES: CO[C:3]([C:5]1[N:10]=[CH:9][C:8]2[N:11]=[CH:12][NH:13][C:7]=2[CH:6]=1)=[O:4].[CH3:14][O:15][CH2:16][CH2:17][NH2:18]>CO>[CH3:14][O:15][CH2:16][CH2:17][NH:18][C:3]([C:5]1[N:10]=[CH:9][C:8]2[N:11]=[CH:12][NH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]cnc2cn1
Reactant: COCCN
Solvent: CO
Product: COCCNC(=O)c1cc2[nH]cnc2cn1

Procedure:
In a similar manner as described for example D5, 2.0 g of methyl-1H-imidazo[4,5-c]pyridine-6-carboxylate (example D2) and 8.5 g of 2-methoxyethanamine in 50 ml methanol yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[H-].[Na+].CN(C)C=O>O>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: Clc1ccccn1
Reactant: CCOC(=O)c1c[nH]nc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccccn2)nc1C
Temperature: 180 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of ethyl 3-methyl-1H-pyrazole-4-carboxylate (7.95 g), 2-chloropyridine (5 ml), sodium hydride (0.60%, oil, 2.32 g) and N,N-dimethylformamide (150 ml) was stirred overnight at 180° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3-methyl-1-(2-pyridyl)-1H-pyrazole-4-carboxylate (8.31 g, yield 73%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 79-80° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.[O:28]1[CH2:31][C:30](=O)[CH2:29]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:28]1[CH2:31][CH:30]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@@H:16]([NH:18][C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[N:21]=[CH:22][NH:23]4)[CH3:17])[CH2:3][CH2:2]2)[CH2:29]1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(C2COC2)CC1
Reaction time: 4 h

Procedure:
To a mixture of (S)—N-(1-(1-(piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)ethyl)-9H-purin-6-amine from Example 113 (99 mg, 0.273 mmol) in anhydrous DCE (10 mL) was added oxetan-3-one (32 μL, 0.546 mmol) followed by AcOH (16 μL, 0.273 mmol) and 4 Å (angstrom) powdered molecular sieves (0.1 g). After stirring for 4 h, sodium triacetoxyborohydride (116 mg, 0.546 mmol) was added and stirring was continued for 48 h. The crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then triturated with diethyl ether and MeOH affording 129 as a white solid (50 mg, 44%). LCMS: RT 1.61 min [M+H]+ 419.1. 1H NMR (DMSO, 400 MHz, 80° C.): δ 8.25 (1H, s), 8.05 (1H, s), 7.65-7.59 (2H, m), 7.44 (1H, bs), 7.20-7.13 (2H, m), 6.16-6.04 (1H, m), 4.63-4.39 (6H, m), 3.50-3.42 (1H, m), 2.93-2.85 (1H, bd, J=10.45 Hz), 2.76-2.69 (1H, bd, J=10.45 Hz), 2.40-2.28 (1H, m), 2.04-1.93 (1H, t, J=11.60 Hz), 1.90-1.81 (1H, m), 1.76-1.53 (6H, m)
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[C:16]([Cl:17])=[N:15][S:14][N:13]=1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[K+]>C1COCC1.CO>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]([C:12]2[C:16]([Cl:17])=[N:15][S:14][N:13]=2)=[C:5]([CH2:4][NH2:1])[CH:10]=1
Reactant: [N-]=[N+]=NCc1cc(Cl)ccc1-c1nsnc1Cl
Agent: [K+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(Cl)ccc1-c1nsnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-[2-(azidomethyl)-4-chlorophenyl]-4-chloro-1,2,5-thiadiazole (0.205 g, 0.72 mmol) and water (0.01 mL, 0.72 mmol) in THF (1.5 mL) was added triphenyl phosphine (0.188 g, 0.72 mmol). The solution was refluxed 1 h then stirred at ambient temperature for 16 h. The solution was reduced in vacuo and the residue was dissolved in MeOH. KOH (1 pellet) was added and the solution was refluxed 5 min. The solution was reduced in vacuo and partitioned between 1 M HCl and EtOAc. The aqueous phase was separated, basified with 1 M NaOH and extracted into ether. The organic phase was separated, dried (Na2SO4) and reduced in vacuo. The residue was purified by flash chromatography on silica (eluting with EtOAc/hexanes gradient, 5–10% EtOAc followed by 0.9% MeOH/0.1% NH4OH/chloroform). 1-[5-Chloro-2-(4-chloro-1,2,5-thiadiazole-3-yl)phenyl]methanamine was isolated as a yellow oil. MS m/z=260.5.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])(C)(C)C.C([O:32][C:33](=[O:53])[CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[C:38]=1B1OC(C)(C)C(C)(C)O1)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61].C(Cl)Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[F:63][C:62]([F:65])([F:64])[C:60]([OH:66])=[O:61].[C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:38]3[C:39]([CH3:43])=[CH:40][CH:41]=[CH:42][C:37]=3[CH2:36][O:35][CH2:34][C:33]([OH:53])=[O:32])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)(=[NH:9])[NH2:7]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: Cc1cccc(COCC(=O)OC(C)(C)C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2COCC(=O)O)c1
Yield: 22 %

Procedure:
The procedure used in Example 1: step c was followed using {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 27: step c) 123 mg, 0.25 mmol), [3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyloxy]-acetic acid tert-butyl ester ((Example 299: step c) 270 mg, 0.75 mmol), Na2CO3 (2M, 1.5 mL, 3 mmol), Pd(PPh3)4 (66 mg, 0.06 mmol), ethanol (1.5 mL) and toluene (3 mL). Analogous aqueous workup yielded 417 mg of crude material which was treated with 1:1 TFA/DCM as described in Example 1: step d. Analogous purification by C18-HPLC yielded the title compound (26.8 mg, 22%) as a white solid. 1H-NMR (CD3OD): δ 8.35 (s, 1H), 8.07 (ddd, 1H, J=1.2, 1.9, 7.9 Hz), 7.86 (t, 1H, J=1.6 Hz), 7.71 (t, 1H, J=7.9 Hz), 7.10–7.43 (m, 3H), 4.25 (m, 2H), 4.07 (br s, 1H), 3.78 (br s, 1H), 2.73 (s, 3H), 2.35 (s, 3H), 2.02 (s, 3H). ESI-MS (m/z): Calcd. for C22H22N2O5S3 (M+H): 490.1; found: 490.1.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]([CH2:12][CH2:13][O:14][Si](C(C)(C)C)(C)C)[C:9](=[O:11])[CH3:10].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][N:8]([CH2:12][CH2:13][OH:14])[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)N(CCO[Si](C)(C)C(C)(C)C)CCC1OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N(CCO)CCC1OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a stirred solution of N-(2-(1,3-dioxolan-2-yl)ethyl)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)acetamide (0.65 g, 2.04 mmol) in THF (5 mL) was added a solution of tetrabutylammonium fluoride (1.0 M in THF, 2.24 mL). The reaction mixture was stirred at RT for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 0 to 100% ethyl acetate/iso-hexane to afford the title compound (0.287 g, 69%) which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.I[CH:10]1[CH2:13][O:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:10]2[CH2:13][O:12][CH2:11]2)[C:4](=[O:8])[CH:3]=1
Reactant: IC1COC1
Reactant: O=c1cc(Br)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(Br)ccn1C1COC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromopyridin-2(1H)-one (173 mg), 3-iodooxetane (184 mg), and K2CO3 (414 mg) in N,N-dimethylformamide (15 mL) was stirred at 100° C. for 2 h. The reaction mixture was stirred at room temperature for one more hour and then quenched with H2O (30 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL) and the combined organic phase was dried (Na2SO4) and concentrated to give the crude product, which was purified by preparative TLC to give the title compound. Yield: 68 mg (30% of theory).
Reaction SMILES: [CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][NH:5][C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2].F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:11])[CH2:7][CH2:6][N:5]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:22])([F:24])[F:23])[CH:14]=2)[C@H:4]1[CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: CC[C@]1(O)CCN[C@H]1C(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)c(C(F)(F)F)c2)[C@H]1C(C)C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-isopropylpyrrolidin-3-ol 0.5 oxalate (203 mg), 4-fluoro-2-(trifluoromethyl)benzonitrile (189 mg) and lithium carbonate (163 mg), the title compound was obtained as colorless oil (yield: 180 mg, yield: 55%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[CH3:9][C:10]([S@@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11].O>C1COCC1>[CH3:9][C:10]([S@@:13](/[N:15]=[CH:7]/[C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: Cn1cc(C=O)cn1
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(/C=N/[S@@](=O)C(C)(C)C)cn1
Temperature: 65 °C
Yield: 97.2 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-4-carbaldehyde (3.0 g, 27 mmol) in THF (100 mL) was added (S)-2-methylpropane-2-sulfinamide (6.6 g, 54 mmol) and Ti(OEt)4 (22.3 g, 98.0 mmol). The reaction mixture was heated at 65° C. for 12 h. After cooling, the mixture was poured into water. The solid was filtered, and the filtrate was extracted with EtOAc (3×100 mL). The organic layer was washed with water (3×50 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (4:1) to afford 5.6 g (98%) of (S,E)-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide 40 as colorless oil. LCMS (ESI) m/z: 214.1 [M+H]+.