Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6].CC(C)([C@@H](OCC1C=CC=CC=1)C=C)CO.[N-:49]=[N+:50]=[N-:51].[Na+]>CS(C)=O>[N:49]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6])=[N+:50]=[N-:51]
Reactant: CCOC(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: C=C[C@H](OCc1ccccc1)C(C)(C)CO
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, 11.0 g of a mixture of (ethoxycarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (32a) and (3R)-4,4-dimethyl-3-(phenylmethoxy)-3,4,5-trihydrofuran-2-one (1) dissolved in 100 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 2.4 g (37 mmol) of sodium azide (NaN3). After work-up, the crude title compound (32b) was obtained and used in the next step without further purification. MS (ESI) m/z 524.07 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:27])=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:10]=2)=[N:7][CH:8]=1.Cl.Br[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.CC([O-])(C)C.[Na+]>CN(C=O)C.ClCCl.C1(/C=C/C(=O)/C=C/C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[C:4]([NH:27][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:10]=2)=[N:7][CH:8]=1
Reactant: COc1ccc(Cn2nc(-c3ncc(OC)c(N)n3)c3ccccc32)cc1
Reactant: Brc1ccncc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
205 mg of 5-methoxy-2-[1-(4-methoxybenzyl)-1H-indazol-3-yl]pyrimidin-4-amine (1-4-1, 0.568 mmol, 1 eq.), 121.6 mg of 4-bromopyridine hydrochloride (1:1) (0.625 mmol. 1.1 eq.), 136.5 mg of sodium 2-methylpropan-2-olate (1.42 mmol, 2.5 eq.), 106.2 mg of 1′-binaphthalene-2,2′-diylbis(diphenylphosphane) (0.171 mmol, 0.3 eq.) and 52.0 mg of (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (3:2) (0.057 mmol, 0.1 eq.) were suspended in 3 ml of dry DMF under nitrogen atmosphere. The reaction mixture was stirred for two days at 100° C. 122 mg of 4-bromopyridine hydrochloride (1:1) (0.625 mmol. 1.1 eq.), 137 mg of sodium 2-methylpropan-2-olate (1.42 mmol, 2.5 eq.), 106 mg of 1′-binaphthalene-2,2′-diylbis(diphenylphosphane) (0.171 mmol, 0.3 eq.) and 52.0 mg of (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (3:2) (0.057 mmol, 0.1 eq.) were added and stirred for further 24 hours. The mixture was cooled down to room temperature, diluted with 10 ml dichloromethane and filtered off. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography to yield 126 mg (0.23 mmol, 81%) of the analytically pure target compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[CH:23]([CH3:25])[CH3:24].[CH3:26][NH:27][CH3:28]>>[CH3:26][N:27]([CH3:28])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([CH:23]([CH3:25])[CH3:24])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(C(C)C)cc3c(=O)[nH]2)c1
Reactant: CNC
Product: CC(C)c1cc2c(N(C)C)nc(-n3cc(C(=O)O)cn3)nc2cc1F

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C17H18FN5O2, 343.1
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:21]2[CH2:22][CH2:23][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH2:19][CH2:20]2)=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(N2CCN(c3ccccn3)CC2)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 1-(2-pyridyl)-piperazine (3.5 g, 20 mmol), and K2CO3 (3.0 g, 22 mmol) in DMF (20 mL) was stirred at 110° C. for 48 h. The reaction mixture was cooled to room temperature and poured into water. The crude yellow solid was collected by vacuum filtration, air dried, and recrystallized from CHCl3 (0.36 g, 17%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:22][C:23]([OH:25])=O)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[C:38]([O:44][CH2:45][CH3:46])(=[O:43])[CH2:39]C([O-])=O.C([Mg]Cl)(C)C>C1COCC1>[Br:1][C:2]1[C:3]([CH2:22][C:23](=[O:25])[CH2:39][C:38]([O:44][CH2:45][CH3:46])=[O:43])=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)Cc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Agent: CC(C)[Mg]Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Cc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
A flask was charged with 2-(5-bromo-2-(4-phenethylthiazol-2-ylamino)pyridin-4-yl)acetic acid (0.576 g, 1.377 mmol) and THF (20 mL), and carbonyl diimidazole (0.3014 g, 1.859 mmol) was added. The mixture was heated at 50° C. for 2 hours. In a separate 50 mL scintillation vial, mono-ethyl malonate (0.2845 ml, 2.410 mmol) was dissolved in THF (15 mL) and cooled to 0° C., and isopropyl magnesium chloride (2.410 mL, 4.819 mmol) was added. This second mixture was stirred at ambient temperature for 30 minutes, then heated to 50° C. and stirred another 30 minutes. Both solutions were cooled to 0° C. and the second mixture was added to the first mixture. The combined mixture was stirred at ambient temperature overnight, then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography, eluting with 20% ethyl acetate/hexane to provide the desired product (0.337 g, 46-10% yield) as white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:17]=3[N:18]([CH3:34])[C:19](=[O:33])[CH:20]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[N:21]=2)=[CH:11][N:10]=1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:39][C:37]1[CH:36]=[CH:35][C:17]2[N:18]([CH3:34])[C:19](=[O:33])[CH:20]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[N:21]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])=[N:10][CH:11]=3)[C:16]=2[CH:38]=1
Reactant: CC(=O)OCC(=O)Nc1ccc(C2=NC(Cc3ccc4ccccc4c3)C(=O)N(C)c3ccc(Cl)cc32)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(c2ccc(NC(=O)CO)nc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.1 %

Procedure:
2-(5-(7-Chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)pyridin-2-ylamino)-2-oxoethyl acetate (20 mg, 0.04 mmol) was dissolved in methanol (0.5 mL) and water (0.1 mL), potassium carbonate was added and the mixture was stirred at ambient temperature for 45 minutes. The crude mixture as partitioned between ethyl acetate and water, the layers were separated, and the organic layer was dried with sodium sulfate, decanted, then concentrated in the presence of silica gel. Column chromatography eluting with a step gradient of 20-80% ethyl acetate in hexanes in 5% increments every 3 minutes provided N-(5-(7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)pyridin-2-yl)-2-hydroxyacetamide (8 mg, 43% yield). ESI m/z measured 521.1348 [M+H]+. calculated 521.1356.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].COC1C=CC2N=C(NC(=O)[CH2:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)SC=2C=1>>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH2:30][C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Product: CCOP(=O)(OCC)C(CCC(=O)c1ccccc1)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I) and acetophenone (II), MS (m/e) 420, 375, 315, 301, 287 and 283; IR (neat) 1684, 1597, 1581, 1449, 1392, 1369, 1251 and 1164 cm-1 ; NMR (CDCl3) 7.97, 7.56, 7.45, 4.18, 3.39, 2.60, 2.33 and 1.30 δ.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:15]3[NH:19][C:18]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([NH:26][C:27]5[S:28][CH:29]=[CH:30][N:31]=5)=[O:25])[C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:4][O:3]1.Cl>C1COCC1>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[C:23]([C:24]([NH:26][C:27]4[S:28][CH:29]=[CH:30][N:31]=4)=[O:25])[C:17]=3[N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC1(C)OCC(COc2cccc(-c3nc4c(C(=O)Nc5nccs5)cccc4[nH]3)c2)O1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)c1cccc2[nH]c(-c3cccc(OCC(O)CO)c3)nc12
Yield: 86 %

Procedure:
To a solution of 2-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (37; 50 mg, 0.111 mmol) in THF was added 4N HCl dropwise until precipitation was observed. The precipitate was collected via vacuum filtration and washed with anhydrous ethanol. The product (Compound 324) was dried overnight under vacuum. (Product was pale yellowish in color and yield=86%). MS (ESI) calcd for C23H22N4O4S: 410.10; found: 411 [M+H].
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)O1.[C:22]([N:25]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[CH:29][C:28]2[N:37]=[C:38](C3C=NC(OC)=CC=3)[C:39](F)=[CH:40][C:27]=2[CH2:26]1)(=[O:24])[CH3:23]>>[C:22]([N:25]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[CH:29][C:28]2[N:37]=[C:38]([C:9]3[CH:14]=[N:13][C:12]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[CH:11][CH:10]=3)[CH:39]=[CH:40][C:27]=2[CH2:26]1)(=[O:24])[CH3:23]
Reactant: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Product: CC(=O)N1Cc2ccc(-c3ccc(N4CCOCC4)nc3)nc2C=Cc2ccccc21
Yield: 91 %

Procedure:
The title compound (26.2 mg, 91%) was prepared from 13C (20.0 mg, 0.07 mmol) and 5A (30.5 mg, 0.105 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.159 min; LCMS Found: (M+H)+=413.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([OH:12])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]2=[CH:3][CH:2]=1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S(=O)(=O)(O)O>C(OCC)(=O)C.O>[CH2:13]([O:12][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]([OH:11])=[CH:9][CH:8]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Oc1ccc(O)c2ccccc12
Reactant: CCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOc1ccc(O)c2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
112 g of naphthohydroquinone and 560 ml of n-decanol were placed in a 1 l three-necked flask and 56 ml of concentrated sulfuric acid was dropwisely added thereto for 30 minutes under nitrogen gas stream while stirring. Thereafter, the mixture was further stirred for 30 minutes and, then, heated at 50° C. for 1 hour and 30 minutes. After cooling, ethyl acetate-water was added to the reaction mixture and the precipitated crystals were filtered off. An aqueous sodium hydroxide solution was added to the filtrate so as to water layer reach pH of 5 to 6. Then, the ethyl acetate layer was washed with water and dried with MgSO4 overnight. The dried ethyl acetate solution was evaporated under reduced pressure to remove ethyl acetate and n-decanol. The residue was dissolved in 1 l of ethyl acetate and treated with 26 g of active carbon followed by concentration under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane and, further, recrystallized from benzene to obtain 73 g of white crystals having a melting point of 89° to 90° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:14]([N:21]1[CH2:25][CH2:24][C@@H:23]([NH2:26])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH2:14]([N:21]1[CH2:25][CH2:24][C@@H:23]([NH:26][C:3]2[C:2]([Cl:1])=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=2)[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(Cl)c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 97.5 %

Procedure:
A mixture of ethyl 5,6-dichloronicotinate (10.0 g), (3R)-(−)-1-benzyl-3-aminopyrrolidine (9.61 g), K2CO3 (8.38 g) and CuO (371 mg) in DMF (60 ml) was stirred at 100° C. for 10 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and water and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-Hexane (7:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-chloronicotinate (15.95 g)
Reaction SMILES: [CH2:1]([NH:5][C:6](=[S:9])[NH:7][NH2:8])[CH2:2][CH2:3][CH3:4].C[O-].[Na+].[CH:13](OCC)=O>CO>[SH:9][C:6]1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:13]=[N:8][N:7]=1
Reactant: CCOC=O
Reactant: CCCCNC(=S)NN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCn1cnnc1S
Reaction time: 24 h
Yield: 55 %

Procedure:
4-n-Butylthiosemicarbazide (20.0 g. or 0.136 mole) was heated to reflux with a solution of methanol (100 ml.), sodium methoxide (7.55 g. or 0.140 mole) and ethyl formate (20.7 g. or 0.280 mole). After 8 and 16 hours, 10 ml. and 5 ml. of ethyl formate was added to the refluxing solution. After 24 hours total reflux, the solvent was removed under reduced pressure and the residue was dissolved in water (100 ml.). The pH of the solution was adjusted to about 12 with 50% sodium hydroxide solution. This solution was then heated on a steam bath for 45 minutes, cooled and acidified with dilute hydrochloric acid. The resulting oil was extracted into ether. The ether was dried over sodium sulphate and removed under vacuum. The resulting oil was crystallized from ether-hexane to give 11.8 g. (55% yield) of 3-mercapto-4-n-butyl 1,2,4-triazole, m.p. 67°-69° C. The structure was confirmed by its nuclear magnetic resonance spectrum and its mass spectrum.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[CH2:15][CH2:16][C@H:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C[C@@H](CCCCC)CCC(O)=O>>[CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[CH2:15][CH2:16][C@@H:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC[C@@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Agent: CCCCC[C@H](C)CCC(=O)O
Product: CCCCC[C@H](C)CCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Yield: 100 %

Procedure:
A procedure similar to that used to prepare compound 155 was used except that (S)-4-methylnonanoic acid 163 (5.56 g, 32.27 mmol) was used as a reactant to give 164 as an oil (10.70 g 100%). 1H NMR (400 MHz, CDCl3) δ7.42-7.34 (m, 3H), 7.28 (d, J=6.59 Hz, 2H), 5.64 (d, J=7.33 Hz, 1H), 4.74 (quin, J=6.78 Hz, 1H), 2.94-2.85 (m, 2H), 1.73-1.67 (m, 1H), 1.47-1.43 (m, 1H), 1.39-1.22 (m, 7H), 0.90-0.84 (m, 8H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.[CH:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1>>[CH3:19][N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:24]([CH:21]4[CH2:23][CH2:22]4)=[O:25])[CH:8]=[N:7][CH:6]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:20]
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3)ccc21
Reactant: O=C(O)C1CC1
Product: CN1C(=O)CCc2cc(-c3cncc(CNC(=O)C4CC4)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 37, 6-(5-aminomethyl-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one (example 36) has been reacted with cyclopropanecarboxylic acid to give the title compound as a white solid. MS: 336.3 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:20]=1)[C:8]([N:10]=[S@@:11]([CH3:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])#[CH:2].I[C:22]1[CH:23]=[N:24][NH:25][CH:26]=1>>[CH3:19][S@:11](=[O:18])([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[N:10][C:8](=[O:9])[C:7]1[CH:20]=[C:3]([C:1]#[C:2][C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)[CH:4]=[N:5][CH:6]=1
Reactant: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Reactant: Ic1cn[nH]c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cn[nH]c2)c1)c1ccccc1

Procedure:
In a manner similar to that describe in Example 431 a mixture of (S)-5-ethynyl-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 4-iodopyrazole were reacted to give the title compound as a white film (15 mg, 17%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35](Cl)=[C:30]3[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][CH:24]([N:27]2[C:31]3=[N:32][CH:33]=[N:34][C:35]([O:1][C:2]4[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[N:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=4)=[C:30]3[CH:29]=[N:28]2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CN(C)S(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 160 °C
Yield: 29.1 %

Procedure:
A mixture of 4-hydroxy-N,N-dimethyl-benzenesulfonamide (ChemService Inc., West Chester, Pa., USA; 18 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(4-dimethylsulfamoyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (13 mg, 28%) as a white solid. Mass spectrum MH+=503.
Reaction SMILES: C([N:8]1[C:13]([CH3:15])([CH3:14])[CH2:12][N:11]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:25][CH:24]=3)[N:20]=[C:19]3[N:33]([CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)[N:34]=[C:35]([CH3:36])[C:18]=23)[C:10]([CH3:44])([CH3:43])[CH2:9]1)C1C=CC=CC=1>ClCCl>[CH3:32][O:31][CH2:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[N:20]=[C:19]3[N:33]([CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)[N:34]=[C:35]([CH3:36])[C:18]3=[C:17]([CH2:16][N:11]3[CH2:12][C:13]([CH3:15])([CH3:14])[NH:8][CH2:9][C:10]3([CH3:44])[CH3:43])[CH:22]=2)=[CH:28][CH:27]=1
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)N(Cc4ccccc4)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Solvent: ClCCl
Product: COCOc1ccc(-c2cc(CN3CC(C)(C)NCC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Reaction time: 5 h
Yield: 92.4 %

Procedure:
1.44 g of 4-(4-benzyl-2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine were dissolved in 16 ml dichloromethane and purged with argon. 1.44 g Palladium (10% on charcoal) were added and the mixture was hydrogenated at r.t. for 5 h. The catalyst was filtered off using celite and the solvents were evaporated. 1.13 g (93%) of the crude title compound were obtained, which were used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[NH:5][N:4]=1.CC([O-])(C)C.[K+].C1(P(O[NH2:37])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1.CCOC(C)=O>[NH2:37][N:5]1[N:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:13]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]nc(C(F)(F)F)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reaction time: 1 h

Procedure:
A mixture of Example 11A and KOtBu (1 M in THF, 2.8 mL, 2.8 mmol) in THF (5 mL) was stirred for 60 min, and O-(diphenylphosphoryl)hydroxylamine (0.680 mg, 0.348 mmol) was added and stirred for 1 hour. The mixture was diluted with EtOAc, washed with 1 N NaOH and water, dried (Na2SO4), and concentrated to give the title compound as a white solid (402 mg) which was used without purification. 1H NMR (300 MHz, DMSO-d6) δ 8.45-8.35 (m, 1H), 8.10-7.92 (m, 3H), 6.58 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7](=S)[NH:8][CH3:9].[NH2:13][NH2:14]>CS(C)=O.C(OCC)(=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:11]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:14][N:13]=[C:7]2[NH:8][CH3:9]
Reactant: CNC(=S)c1cc(Br)ccc1F
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1n[nH]c2ccc(Br)cc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A mixture of 5-bromo-2-fluoro-N-methylbenzothioamide (480 mg, 1.9 mmol) and anhydrous hydrazine (0.61 mL, 19 mmol) in dimethylsulfoxide (6 mL) was heated to 80° C. and stirred for 1 hour. The temperature was increased to 100° C. and the reaction was stirred for 40 minutes. The temperature was increased further to 130° C. and the reaction was stirred for another 45 minutes. The reaction was cooled to room temperature and diluted with ethyl acetate and brine. The layers were separated and the aqueous was extracted with ethyl acetate (4×). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (20-70% ethyl acetate/heptanes) gave the title compound (103 mg, 23%) as a white solid. +ESI (M+H+1) 228.0; 1H NMR (400 MHz, CD3OD, δ): 7.78 (dd, J=1.85, 0.68 Hz, 1H), 7.29-7.40 (m, 1H), 7.17 (dd, J=8.88, 0.68 Hz, 1H), 2.94 (s, 3H).