Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([O:28][CH3:29])=[O:27])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][CH2:37]I>CN(C)C=O.O>[CH2:36]([N:22]1[CH2:23][CH2:24][CH:19]([N:18]([CH3:25])[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([O:28][CH3:29])=[O:27])[CH:14]=3)[NH:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:20][CH2:21]1)[CH3:37]
Reactant: CCI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCNCC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCC(N(C)C2=C(c3ccc(F)cc3)Nc3ccc(C(=O)OC)cc3N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[methyl(piperidin-4-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.25 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (157.6 mg, 1.14 mmol) and CH3CH2I (71.32 mg, 0.46 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with water (200 mL) and extracted with dichloromethane (4×50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (1% methanol in dichloromethane) to afford methyl 3-[(1-ethylpiperidin-4-yl)(methyl)amino]-2-(4-fluorophenyl)-1,4-dihydroquinoxaline-6-carboxylate as light yellow oil (53 mg, 46%).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[S:23][C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:25][C:5]=2[C:4](=[O:31])[NH:3]1.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43])=[O:35].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[C:34](=[O:35])[CH2:33][N:3]1[C:4](=[O:31])[C:5]2[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:6]=2[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[C:2]1=[O:1]
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)cc1
Reactant: O=C(CBr)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(=O)c3ccc(F)cc3F)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (1.5 g), 2-bromo-1-(2,4-difluorophenyl)ethanone (0.88 g) and N,N-dimethylformamide (30 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.98 g, 49%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].C[Al](C)C.[Cl:14][C:15]1[CH:35]=[CH:34][C:18]2[C:19](=[O:33])[C:20]3[C:27]([C:28](OCC)=[O:29])=[N:26][NH:25][C:21]=3[C:22](=[O:24])[NH:23][C:17]=2[CH:16]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:35]=[CH:34][C:18]2[C:19](=[O:33])[C:20]3[C:27]([C:28](=[O:29])[N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:4][CH2:3][O:2][CH3:1])=[N:26][NH:25][C:21]=3[C:22](=[O:24])[NH:23][C:17]=2[CH:16]=1
Reactant: COCCNCCOC
Reactant: CCOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COCCN(CCOC)C(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Reaction time: 0.33 h
Yield: 330.6 %

Procedure:
Bis-(2-methoxyethyl)amine (560 μL, 3.13 mmol) was added to a solution of trimethylaluminum in toluene (1.56 mL, 3.13 mmol) and the solution was stirred for 20 minutes. A portion (403 μL) of the resulting solution was added to a solution of 7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (100 mg, 0.313 mmol) in toluene (780 μL). The resulting solution was stirred for 24 hours at room temperature and then quenched with an aqueous hydrochloric acid solution (1.8 mL, 1N) and water (15 mL). The aqueous layer was extracted with chloroform (7×25 mL). The organic layers were combined and concentrated on a rotary evaporator. The crude product was purified by flash chromatography eluting with chloroform:2-propanol (99:1-95:5) to give the title compound (421 mg, 67% yield, m.p. 207-209° C.).
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=3[N:7]([CH2:11][CH3:12])[CH:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:41]=[N+:42]=[N-:43])(=O)=O)(C)C.C(O)(=O)C>C1COCC1>[N:41]([C:9]1[N:10]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=2[N:7]([CH2:11][CH3:12])[CH:8]=1)=[N+:42]=[N-:43]
Reactant: CCN1C=CN=C(C2CC2)c2ccccc21
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN1C=C(N=[N+]=[N-])N=C(C2CC2)c2ccccc21
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
To a stirring solution of 5-cyclopropyl-1-ethyl-1H-benzo[e][1,4]diazepine (6.4 g, 0.028 mol) in THF (125 ml) cooled to −78° C. was added potassium tert-butoxide (2.05 eq, 0.057 mol, 57.2 ml of a 1 M solution in THF) dropwise over 15 min. A solution of 2,4,6-triisopropylphenyl-sulfonylazide (9.5 g, 0.031 mol) in THF (100 ml) was added over 5 min. The solution was stirred for 10 min, acetic acid (7.7 ml,0.123 mol) was added and the reaction warmed to 30° C. for 2 hour. The reaction was concentrated the residue dissolved in dichloromethane (200 mL) and washed with satd. NaHCO3 (200 ml). The aqueous layer was back extracted with dichloromethane (100 ml). The organic layers were combined, dried with Na2SO4 and evaporated to a foam. The foam was chromatographed over silica eluting with 30% ethyl acetate:hexane. The appropriate fractions were collected and evaporated under reduced pressure to give 5.83 g of a powder. MP=158-160° C.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([S:14][CH2:15][CH:16]([O:19]C)OC)[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CCOCC>[CH2:1]([S:8][C:9]1[N:13]=[C:12]2[S:14][CH2:15][CH:16]([OH:19])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CSc1nc(SCc2ccccc2)n[nH]1)OC
Agent: Cl
Solvent: CCOCC
Product: OC1CSc2nc(SCc3ccccc3)nn21

Procedure:
The product of stage (a) was heated under reflux with dilute hydrochloric acid (15 ml conc. plus 100 ml water) for 3 hours. The mixture was then cooled and stirred with ether. The precipitated solid was filtered off to give 5.4 g of desired product, mp 136°-138° C.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][NH:10][CH2:11][C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1.[CH:14]([O:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:19]=1[C:20](O)=[O:21])([CH3:16])[CH3:15]>>[O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][N:10]([C:20]([C:19]4[CH:23]=[C:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[CH:26][C:18]=4[O:17][CH:14]([CH3:16])[CH3:15])=[O:21])[CH2:11][C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1
Reactant: c1c2c(cc3c1OCO3)CNCC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc3c(cc2C1)OCO3

Procedure:
Prepared in analogy to example 1.1 from 5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (CA [94143-83-6]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 418.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17](=S)[CH2:18][C:19](=O)[CH3:20])=[O:4].[C:23]1([CH2:29][CH2:30][NH:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:17]1[N:31]([CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:32]=[C:19]([CH3:20])[CH:18]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1C(=S)CC(C)=O
Reactant: NNCCc1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)CC2CC2)CN1c1cc(C)nn1CCc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-cyclopropylmethanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 445c) was reacted with 1-(2-phenylethyl)hydrazine (CAS Reg. No. 51-71-8) to give the title compound as brown solid. MS (ESI): m/z=432.6 [M+H]+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@@H:29]3[C@@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH:31]3[CH2:36][CH2:35][N:34](C4C=CC([N+]([O-])=O)=CC=4)[CH2:33][CH2:32]3)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].O>C(OCC)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@@H:29]3[C@@H:24]([CH2:25][CH:26]=[CH:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH:31]3[CH2:36][CH2:35][N:34]([CH2:8][C:5]4[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=4)[CH2:33][CH2:32]3)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(C2=NN(C3CCN(c4ccc([N+](=O)[O-])cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COc1ccc(C2=NN(C3CCN(Cc4ccncc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Reaction time: 0.5 h

Procedure:
Prepared from starting compound A1 and 4-picolylchloride hydrochloride as described for compound 11. After the addition of 100 ml of water, 20 ml of diethyl ether is added and the resulting mixture stirred for 30 min. The precipitate is filtered off and dried. M.p. 196-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cccc(OC)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-methoxyacetophenone. 1H-NMR (CDCl3) δ: 8.25 (1H, d, J=1.5 Hz), 7.53 (1H, d, J=8.4 Hz), 7.36-7.26 (4H, m), 7.05-7.01 (1H, m), 5.78 (2H, s), 3.84 (3H, s), 3.78 (2H, q, J=7.0 Hz), 0.89 (3H, t, J=7.0 Hz).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3[N:13]=[CH:14][N:15]4[C:20](=[O:21])[N:19]([CH2:22][C:23]#[CH:24])[N:18]=[N:17][C:16]=34)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:27]I>CN(C=O)C>[CH3:27][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[C:12]1[N:13]=[CH:14][N:15]2[C:20](=[O:21])[N:19]([CH2:22][C:23]#[CH:24])[N:18]=[N:17][C:16]=12
Reactant: CI
Reactant: C#CCn1nnc2c(-c3nc(-c4ccccc4)c[nH]3)ncn2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCn1nnc2c(-c3nc(-c4ccccc4)cn3C)ncn2c1=O
Reaction time: 0.17 h
Yield: 8.5 %

Procedure:
8-(4-Phenyl-1H-imidazol-2-yl)-3-(prop-2-ynyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (1.07 mmol) was dissolved in dry DMF (35 mL) and cooled in ice under a nitrogen atmosphere. A 60% suspension of sodium hydride in mineral oil (1.18 mmol) was added in one portion and the reaction stirred on ice for 10 minutes. Methyl iodide (2.14 mmol) was then added dropwise to the reaction and the mixture stirred at room temperature for 48 hours. The mixture was poured onto ice water (140 mL) and the precipitate was filtered, washed with water, ethyl acetate, and diethyl ether, and purified by column chromatography (hexane:ethyl acetate 4:3) to give the title compound (0.030 g; 89%). δH (DMSO-d6) 8.97 (1H, s), 7.90 (1H, s), 7.83 (2H, d, J=7.2), 7.40 (2H, t, J=7.6), 7.25 (1H, t, J=7.2), 5.13 (2H, d, J=2.0), 3.99 (3H, s), 3.52 (1H, J=2.0).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:20])=[C:4]([C:16]([F:19])=[CH:17][CH:18]=1)[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([O:14][CH3:15])=[O:13])=[O:6].[CH3:21][O:22][C:23]1[C:24](=O)[C:25](=[O:29])[C:26]=1[O:27]C>CO>[F:20][C:3]1[C:2]([NH:1][C:24]2[C:25](=[O:29])[C:26](=[O:27])[C:23]=2[O:22][CH3:21])=[CH:18][CH:17]=[C:16]([F:19])[C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([O:14][CH3:15])=[O:13])=[O:6]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1c(F)ccc(N)c1F
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C(=O)c1c(F)ccc(Nc2c(OC)c(=O)c2=O)c1F
Temperature: 60 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
A mixture of methyl (S)-1-(3-amino-2,6-difluorobenzoyl)pyrrolidine-2-carboxylate (prepared above) and 4.20 g (29.55 mmol) of 3,4-dimethoxycyclobut-3-ene-1,2-dione in solution in 50 ml of methanol was heated at 60° C. for one hour and then stirred at ambient temperature for 4 hours. The reaction medium was concentrated and the residue (6.29 g) was chromatographed on silica gel (300 g prepacked column, eluted with heptane/ethyl acetate, from 70% to 100% of ethyl acetate). 2.30 g of methyl (S)-1-[2,6-difluoro-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzoyl]-pyrrolidine-2-carboxylate were obtained. Yield=79%.
Reaction SMILES: [C:1]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][O:7][C:6]1=[O:17])(=[O:4])[CH2:2][CH3:3].[CH:18](=[O:20])[CH3:19]>>[CH3:3][C@@H:2]([C@H:18]([OH:20])[CH3:19])[C:1]([N:5]1[C@@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][O:7][C:6]1=[O:17])=[O:4]
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC=O
Product: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@@H](C)O

Procedure:
Prepared from (4S)-N-propionyl-4-benzyl-2-oxazolidinone and acetaldehyde according to the procedure described in Example 1, paragraph A. 1H-NMR (360 MHz, CDCl3): δ 7.2–7.4 (m,5H); 4.71 (m,1H); 4.12–4.25 (m,2H); 3.76 (dq,1H); 3.26 (dd,1H); 2.79 (dd,1H); 1.30 (d,3H), 1.21 (d,3H).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=1.[OH-].[Na+]>>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:27][CH:26]=1)(=[O:32])[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)C(=O)c1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)C(C)C)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 1-(4-Hydroxy-phenyl)-2-methyl-propan-1-one from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C23H28O6 [M+NH4]+: 423 [M+H]+: 401.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:12]([OH:13])=[N:11][N:10]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:31][CH:32]1[CH2:35][O:34][CH2:33]1>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:12]([O:13][CH2:31][CH:32]3[CH2:35][O:34][CH2:33]3)=[N:11][N:10]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:15])=[O:16])[C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2nc(O)c3cc([N+](=O)[O-])cnc32)cc1
Reactant: ICC1COC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2nc(OCC3COC3)c3cc([N+](=O)[O-])cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
5-Nitro-1-tosyl-1H-pyrazolo[3,4-b]pyridin-3-ol (0.05 g, 0.150 mmol) was dissolved in DMF (1.5 mL). Cesium carbonate (0.146 g, 0.450 mmole) was added, and then 3-(iodomethyl)oxetane (0.030 g, 0.150 mmol; prepared according to US 2008/0021032) was added to the mixture. The mixture was stirred at room temperature for 16 hours. The mixture was then diluted with water and extracted with EtOAc (2×50 mL), and the extracts were washed with brine (1×), dried over sodium sulfate and concentrated under reduced pressure. Preparative TLC (0.5 mm plate, 1:1 ethyl acetate/hexanes) afforded 5-nitro-3-(oxetan-3-ylmethoxy)-1-tosyl-1H-pyrazolo[3,4-b]pyridine (15 mg, 19%) as a solid. 1H NMR (400 MHz, CDCl3) δ 9.54-9.52 (m, 1H), 8.83-8.81 (m, 1H), 8.05-7.99 (m, 2H), 7.34-7.28 (m, 2H), 4.93-4.86 (m, 2H), 4.78-4.72 (m, 2H), 4.62-4.55 (m, 2H), 3.57-3.48 (m, 1H), 2.40 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:14]=[C:13]([N+:23]([O-])=O)[CH:12]=1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]>[Pd].CO>[NH2:23][C:13]1[CH:12]=[C:11]([C:2]([CH3:10])([CH3:1])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:14]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)c1cc(-c2ccncc2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)c1cc(N)cc(-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.9 %

Procedure:
To a 250 ml was added tert-butyl 2-methyl-2-(3-nitro-5-(pyridin-4-yl)phenyl)propanoate 63.1.A (1.9 g, 5.5 mmole) 4 g 10% of Pd/C and 50 ml of MeOH. The air from the reaction vessel was removed and purged with hydrogen gas via a balloon. This was repeated three times to ensure all air was removed from the reaction vessel. The reaction was stirred at room temperature under an atmosphere of hydrogen for 6 hours. The reaction mixture was filtered over a pad of celite (elute with MeOH) and the solvent removed to give tert-butyl 2-(3-amino-5-(pyridin-4-yl)phenyl)-2-methylpropanoate 63.1.B as a light brown solid (1.15 g, 66% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1)=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][OH:16])=[CH:12][CH:13]=1
Reactant: COC(=O)CCC(=O)c1ccc(CCO)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCc1ccc(CCO)cc1
Reaction time: 12 h
Yield: 37.6 %

Procedure:
A mixture of Example 1A (2.50 g, 11 mmol), 10% Pd/C (0.25 g, 0.23 mmol of Pd metal) in anhydrous methanol (25 mL) was first degassed to remove air (two vacuum/H2 cycles) after which it was capped and a balloon filled with H2 was applied to it for 12 hours. After this time the reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure to give 2.32 g of crude material. Column chromatography [silica gel; eluent hexanes-ethyl acetate (2:1)] provided the desired product (0.92 g, 39%). 1H(CDCl3) δ(ppm): 1.91-1.96 (m, 2H); 2.32 (t, 2H); 2.62 (t, 2H); 2.83 (t, 2H); 3.66 (s, 3H); 3.85 (t, 2H); 7.11-7.15 (m, 4H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:17]>C(C(C)=O)C(C)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[CH:19][CH:20]=1
Reactant: COC(=O)CN
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: COC(=O)CNCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of glycine methyl ester hydrochloride (5.00 g, 39.8 mmol) in 80 ml methyl isobutyl ketone is treated with 12.6 g of sodium carbonate and the mixture stirred overnight at RT. Next, a solution of 2-bromo-1-(4-chlorophenyl)ethanone (8.37 g, 35.8 mmol) in 40 ml methyl isobutyl ketone is added dropwise to this suspension. The mixture is stirred for 1 hr more at RT, then the solid is suction-filtered and washed with 55 ml methyl isobutyl ketone. The filtrate is acidified with 12 ml of 6 N hydrochloric acid, then treated with 6.4 ml isopropanol. The precipitated solid is filtered off at the pump, washed with a little methyl isobutyl ketone, then stirred in 240 ml of acetonitrile and again suction-filtered. 3.41 g (34% of theory) of the pure title compound are thus obtained.
Reaction SMILES: S1C23C=CC=CC2=NC=CC3=C(C(O)=[O:15])C1.[S:17]1[C:21]23[CH:29]=[CH:28][CH:27]=[CH:26][C:22]2=[N:23][CH:24]=[CH:25][C:20]3=[C:19]([C:30]([N:32]2[CH:37]([CH3:38])CC[CH2:34][CH:33]2C)=[O:31])[CH2:18]1>>[S:17]1[C:21]23[CH:29]=[CH:28][CH:27]=[CH:26][C:22]2=[N:23][CH:24]=[CH:25][C:20]3=[C:19]([C:30]([N:32]2[CH2:37][CH2:38][O:15][CH2:34][CH2:33]2)=[O:31])[CH2:18]1
Reactant: CC1CCCC(C)N1C(=O)C1=C2C=CN=C3C=CC=CC32SC1
Reactant: O=C(O)C1=C2C=CN=C3C=CC=CC32SC1
Product: O=C(C1=C2C=CN=C3C=CC=CC32SC1)N1CCOCC1

Procedure:
By following the same procedure as above using benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid as the starting material, 1-(benzo[b]thieno[2,3-c]pyridine-3-carbonyl)-2,6-dimethyl-piperidine and 4-(benzo[b]thieno[2,3-c]pyridine-3-carbonyl)-morpholine were obtained. (See Table 13-1, Table 13-2, Table 13-3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(c2ccnc(C#N)c2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccnc(C#N)c4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile following a procedure analogous to that described in Example 28. LC (method 10): tR=1.73 min; Mass spectrum (ESI+): m/z=407 [M+H]+.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([NH2:18])[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:29]=1)[C:26](O)=[O:27]>>[CH:1]1([C:6]2[CH:7]=[C:8]([NH:18][C:26](=[O:27])[C:25]3[CH:29]=[C:21]([O:20][CH3:19])[CH:22]=[N:23][CH:24]=3)[CH:9]=[N:10][C:11]=2[O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: COc1cncc(C(=O)O)c1
Product: COc1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(C3CCCC3)c2)c1
Yield: 55.9 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 1c) (100 mg, 0.33 mmol) and 5-methoxy-nicotinic acid (50.49 mg, 0.33 mmol) as starting materials. The title compound (73 mg, 48.2%) was isolated as off white solid; MS (ESI): 396 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH:1]1([CH2:4][C:5](=[O:15])[CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([S:13]([CH3:14])=[O:24])[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(CC(=O)CC2CC2)n1
Solvent: ClCCl
Product: CS(=O)c1nccc(CC(=O)CC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a solution of 1-cyclopropyl-3-[2-(methylsulfanyl)pyrimidin-4-yl]propan-2-one (2) (3.00 g, 13.49 mmol) in DCM (54.0 mL) at rt, mCPBA (3.99 g, 16.19 mmol) was added in portions. The reaction mixture was stirred at rt for 1 hour. The reaction was partitioned between saturated sodium carbonate solution and DCM and the aqueous layer was back-extracted. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was purified by Biotage™ silica gel chromatography [100% DCM to 5% MeOH/DCM] to afford the desired product as a viscous yellow oil (1.88 g, 58.5% yield), which was still contaminated with residual m-chlorobenzoic acid and carried on to the next step. MS (ES+): m/z=239.2 (100) [MH+2]. HPLC: tR=0.73 minute over 3 minutes. Purity: 67.7% [HPLC (LC/MS) at 220 nm].