Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:13][CH2:14][CH2:15][Cl:16]>CC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][N:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1
Reactant: ClCCCBr
Reactant: NC(=O)C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: NC(=O)C1CCN(CCCCl)CC1
Yield: 20 %

Procedure:
Piperidine-4-carboxylic acid amide (0.5 g, 3.90 mmol), acetone (1.5 ml, 3 vol), 5M NaOH solution (1.20 ml, 1.2 eq.) and 1-bromo-3-chloropropane (0.50 ml, 5.04 mmol, 1 eq.) were reacted together according to general procedure A to give the title compound (0.16 g, 20%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28][CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28]/[CH:29]=[CH:30]/[C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccc(C(F)(F)F)cc4)cc3)cc2)CC1
Temperature: 85 °C

Procedure:
1-{4′-[4-(1-Hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.2518 g, 0.603 mmol), 1-iodo-4-trifluoromethyl-benzene (0.089 mL, 0.603 mmol), and cesium carbonate (0.207 g, 11.38 mmol) were dissolved in ACN (2.6 mL) and the solution was purged with bubbling N2 (g). Palladium(II) acetate (0.008 g, 0.0302 mmol) was added, the reaction vessel was sealed, and the reaction was heated to 85° C. overnight. After cooling, the reaction was submitted to standard aqueous workup to afford the title compound.
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([Si](C)(C)C)=[CH:13][CH:12]=2)[N:7]=[C:6]([C:21]([O:23][CH3:24])=[O:22])[C:5]=1[Cl:25]>ClCCCl.S([O-])([O-])(=O)=S.[Na+].[Na+]>[NH2:3][C:4]1[C:9]([F:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([I:1])=[CH:13][CH:12]=2)[N:7]=[C:6]([C:21]([O:23][CH3:24])=[O:22])[C:5]=1[Cl:25]
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)cc2)c(F)c(N)c1Cl
Reactant: ClI
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(I)cc2)c(F)c(N)c1Cl
Temperature: 23 °C
Reaction time: 17 h
Yield: 72.3 %

Procedure:
Iodine monochloride (280 mg, 1.7 mmol, 2.0 equiv) was added to a stirred solution of methyl 4-amino-3-chloro-5-fluoro-6-(4-(trimethylsilyl)phenyl)picolinate (300 mg, 0.85 mmol, 1.0 equiv) in 1,2-dichloroethane (5.7 mL) at 23° C. The resulting brown solution was stirred at 23° C. for 17 h. The reaction mixture was diluted with saturated solution of sodium thiosulfate (100 mL) and extracted with dichloromethane (4×40 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (33% ethyl acetate in hexanes) to afford the title compound as a pale purple powder (250 mg, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH2:17][CH3:18])[CH:3]=1
Reactant: CCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cccc(Br)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In DMF (100 ml) was dissolved 3-bromophenol (10 g). To the mixture were added potassium carbonate (10.4 g) and bromopropane (6.0 ml), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=10/1) to give 1-bromo-3-propoxybenzene (11.2 g).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.[NH:34]1[CH2:39][CH2:38][CH2:37][C@@H:36]([OH:40])[CH2:35]1>>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:34]3[CH2:39][CH2:38][CH2:37][C@@H:36]([OH:40])[CH2:35]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O[C@@H]1CCCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Agent: Cl
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 85 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and (R)-piperidin-3-ol hydrochloride and was obtained as a white solid. UPLC-MS (Condition 3) tR=0.99 min, m/z=464.1[M+H]+, m/z=508.1[M+formic acid-H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.35 (m, 1H) 1.37-1.52 (m, 1H) 1.56-1.69 (m, 1H) 1.79-1.93 (m, 1H) 2.52-2.62 (m, 1H) 2.65-2.79 (m, 1H) 3.43 (d, J=12.72 Hz, 1H) 3.50-3.61 (m, 1H) 3.65 (d, J=12.23 Hz, 1H) 4.76 (d, J=4.52 Hz, 1H) 6.55-6.67 (m, 1H) 7.34 (d, J=8.93 Hz, 2H) 7.52-7.86 (m, 1H) 7.88 (d, J=9.17 Hz, 2H) 8.14-8.36 (m, 1H) 8.72 (d, J=2.32 Hz, 1H) 10.32-10.44 (m, 1H) 12.96-13.18 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Cl[CH2:20][S:21][CH3:22]>CN(C=O)C>[CH3:20][S:21][CH2:22][N:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)c1cc2[nH]ccc2cn1
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCn1ccc2cnc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
To a mixture of tert-butyl 1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1.0 g, 4.6 mmol) in DMF (20 ml) was added sodium hydride (60% in oil) (0.41 g, 10 mmol) and stirred at room temperature for 3 h. To the mixture, (chloromethyl)(methyl)sulfane (0.89 g, 9.2 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was extracted with EtOAc/H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was purified by chromatography (SiO2, hexanes:EtOAc=50:50) to give tert-butyl 1-(methylthiomethyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (8A, 920 mg, 3.3 mmol, 72% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.61 (s, 9 H) 1.94 (s, 3 H) 5.15 (s, 2 H) 6.64 (d, J=3.28 Hz, 1 H) 7.34 (d, J=3.28 Hz, 1 H) 8.15 (s, 1 H) 8.93 (d, J=1.01 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[CH:11][C:4]=2[CH:3]=1.[H-].[Na+].[Br-].[Li+].[CH3:24]I>COCCOC.CN(C=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:24])[C:5]2[N:9]([C:12]3[C:13]([F:19])=[CH:14][CH:15]=[CH:16][C:17]=3[F:18])[N:10]=[CH:11][C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=c1[nH]c2c(cnn2-c2c(F)cccc2F)cc1Br
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
5-Bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (11.3 g, 34.7 mmol) in DME (78 mL) and DMF (7.7 mL) was cooled to 0° C. under argon. NaH (1.24 g of 95% wt., 49 mmol) was then added in small portions and the solution was allowed to stir at 0° C. for 10 min. Finely ground lithium bromide (8.83 g, 102 mmol) was then added and the solution stirred at RT for 20 min at which point MeI (4.37 ml, 68.9 mmol) was added. The suspension was heated at 40° C. for 16 h then cooled to RT. The reaction mixture was quenched with water and extracted with EtOAc (3×100 mL). The combined organic solution was washed with 2×50 mL brine, dried over MgSO4, filtered and concentrated. The resulting crude solid was then suspended in 300 mL of 1:1 solution of EtOAc:Hexanes with stirring over 30 min. The solution was then allowed to precipitate in the freezer for 2 h. The resulting solid was then collected by filtration washing with MTBE affording 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (5.27 g) in >95% purity as a beige solid. The mother liquor was then concentrated to ca. 15 ml in vacuo (rotary evaporator) and treated with 50 mL of MTBE and again chilled in the freezer overnight. The resulting solid was collected by filtration and washing with MTBE to afford a second crop of 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (1.54 g) in ca. 95% purity. MS (ESI, pos.ion) m/z: 340.0/342.0 (M+1). For a related reference, see: Liu, H.; Ko, S.-B.; Josien, H.; Curran, D. P. Tetrahedron Lett. 1995, 36, 8917-8920.
Reaction SMILES: [CH2:1]([N:26]1[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[N:28]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:35]=2)[C:27]1=[O:46])/[CH:2]=[CH:3]\[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)[C:6]1=[O:25].C(Cl)Cl.CC[OH:52].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[O:52]1[C@@H:2]([CH2:1][N:26]2[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[N:28]([C:34]3[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:35]=3)[C:27]2=[O:46])[C@H:3]1[CH2:4][N:5]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[N:7]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:23])([F:24])[F:22])[CH:14]=2)[C:6]1=[O:25]
Reactant: CCO
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C/C=C\CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C[C@@H]1O[C@@H]1CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 50 %

Procedure:
The compound of Example 21 (90 mg, 0.139 mmol) is mixed under argon with 3-metachloroperbenzoic acid (72.5 mg, 0.210 mmol) in anhydrous dichloromethane (10 ml). The mixture is stirred at ambient temperature. The progression of the reaction is monitored by TLC (eluent DCM/EtOH: 95/05). After 4 days, starting compound remains. A fresh quantity of metachloroperbenzoic acid (0.124 g, 0.36 mmol) is added to the reaction medium and the reaction medium is stirred at ambient temperature for another 4 days. The solvent is evaporated off under reduced pressure and the residue is purified by flash chromatography (BIOTAGE 25+M column, gradient dichloromethane/acetone: 0% to 8% of acetone). The expected compound is obtained in the form of a white solid, with a yield of 50%. Melting point: 108-110° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]O)=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:24])[F:25])=[CH:20][CH:19]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)ccc1O
Reactant: OCCc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)ccc1OCCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
1.79 g (10.5 mmol) of methyl 5-fluorosalicylate, 20 g (10.5 mmol) of 2-(4-trifluoromethylphenyl)ethanol and 2.76 g (10.5 mmol) of triphenylphosphine are introduced into 50 ml of THF and, at 0° C., a solution of 1.83 g (10.5 mmol) of diethyl azodicarboxylate in 10 ml of THF is added dropwise. The mixture is stirred at RT overnight and then the volatile components are removed in vacuo. The resulting crude product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:1). 2.09 g (58% yield) of the title compound are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[CH:15][C:16]([CH2:18][C:19](OC(C)(C)C)=[O:20])=[N:17][C:9]1=2)=O)(C)(C)C.[BH4-].[Li+]>C1COCC1>[O:11]1[CH2:12][CH2:13][NH:8][C:9]2[N:17]=[C:16]([CH2:18][CH2:19][OH:20])[CH:15]=[CH:14][C:10]1=2
Reactant: CC(C)(C)OC(=O)Cc1ccc2c(n1)N(C(=O)OC(C)(C)C)CCO2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1ccc2c(n1)NCCO2
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
To a solution of 6-tert-butoxycarbonylmethyl-2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (350 mg, 1 mmol) in THF (4.0 ml) was added a solution of lithium borohydride (0.6 ml, 2.0 m in thf). The mixture was refluxed overnight, then cooled in an ice-bath. Aqueous solution of naoh (0.36 ml, 5%) was added. The ice-bath was removed. Additional h2O (0.36 ml) was added and the mixture stirred for 10 min. Celite and na2so4 were added. The mixture was filtered through celite, and the celite washed with etoac. The filtrate and washing were combined, dried over na2so4, concentrated, and flash chromatographed on silica gel, eluting with meoh/dcm (1, 2, 3, 4%) to give the product (171 mg, 94% yield) as a yellow oil. 1H NMR(CDCl3) δ6.90 (d, 1H, J=7.8 Hz), 6.39 (d, 1H, J=7.7 Hz), 4.85 (bs, 1H), 4.20 (t, 2H, J=4.4 Hz), 3.91 (t, 2H, J=5.5 Hz), 3.69–3.52 (m, 2H), 2.78 (t, 2H, J=5.6 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)=O)=[CH:7][CH:6]=1.[C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=O)[CH2:22][CH3:23]>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=2)=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][CH3:23])=[CH:7][CH:6]=1
Reactant: O=C(c1ccc(OCCCl)cc1)c1ccc(O)c(F)c1
Reactant: CCC(=O)c1ccccc1
Product: CCC(=C(c1ccc(OCCCl)cc1)c1ccc(O)c(F)c1)c1ccccc1

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, (4-(2-chloroethoxy)phenyl)(3-fluoro-4-hydroxyphenyl)methanone (350 mg, 1.19 mmol) was reacted with propiophenone (319 mg, 2.38 mmol) to give the desired product (quant.) as a yellow solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[C:21]([F:33])[CH:20]=4)=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][CH:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:33][C:21]1[CH:20]=[C:19]([CH2:18][C:15]2[C:16](=[O:17])[N:11]([C@H:8]3[CH2:9][CH2:10][C@H:5]([OH:4])[CH2:6][CH2:7]3)[C:12]3[N:13]([N:37]=[CH:38][CH:39]=3)[C:14]=2[CH2:34][CH2:35][CH3:36])[CH:24]=[CH:23][C:22]=1[C:25]1[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile (4.3 g) in tetrahydrofuran (40 mL) was added 3M hydrochloric acid (40 mL), and the mixture was stirred at 70° C. for 2 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 8M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (15 mL)-tetrahydrofuran (15 mL). Thereto was added sodium borohydride (0.25 g) at 0° C. After stirring for 2 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (3.0 g, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)CCl)([O-:3])=[O:2].Cl.[OH-].[K+].[H-].[Na+]>CN(C)P(N(C)C)(N(C)C)=O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1

Procedure:
A derivative of 3-nitrobenzyl chloride (IV) and a compound of the formula (V) are reacted in a solvent such as dimethylformamide, hexamethylphosphoramide, etc., in the presence of a hydrogen chloride acceptor such as KOH, NaH, etc., at a temperature in the range from -10° to 150° C., preferably from 0° to 80° C., for 0.1 to 20 hours, preferably 0.5 to 10 hours, to obtain a nitrobenzene derivative of the formula (VI). This nitrobenzene derivative is reduced into an aniline derivative (VII) by a conventional method, for example, by adding hydrazine hydrate to said nitrobenzene derivative in an alcohol and heating the solution under reflux in the presence of palladium-charcoal for 1 to 10 hours.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:17]3[CH:18]=[C:19]([C:22]([O:24]C)=[O:23])[S:20][CH:21]=3)=[N:9][N:10]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=[CH:4][NH:3]1.[OH-].[Na+]>CO>[O:1]=[C:2]1[C:7]2[C:8]([C:17]3[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[S:20][CH:21]=3)=[N:9][N:10]([CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: COC(=O)c1cc(-c2nn(C3CCOCC3)c3cc[nH]c(=O)c23)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(-c2nn(C3CCOCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 50 °C
Reaction time: 6 h
Yield: 99.1 %

Procedure:
To a solution of methyl 4-(4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (125 mg) obtained in Example 21 in methanol (20 mL) was added 1N aqueous sodium hydroxide solution (5 mL) under ice-cooling, and the mixture was stirred at 50° C. for 6 hr. The reaction mixture was concentrated under reduced pressure to evaporate the methanol, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid (6 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (119 mg).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:6]1=2)=[O:4].C(N(CC)CC)C.[CH2:29]([N:31]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][NH:36]1)[CH2:32][CH3:33])[CH3:30]>CN(C)C=O>[CH2:29]([N:31]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][N:36]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2[N:17]([CH3:21])[CH:18]=[C:19]([CH3:20])[C:6]1=2)=[O:4])[CH2:32][CH3:33])[CH3:30]
Reactant: Cc1cn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Reactant: CCN(CC)CC1CCCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccccc2NC(=O)c2c1c(C)cn2C

Procedure:
A mixture of 4-(chloroacetyl)-1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]-benzodiazepin-10-one (2.0 g, 0.0066 mol), dimethylformamide (30 ml), triethylamine (1 ml, 0.0071 mol) and 2-[(diethylamino)methyl]piperidine (1.7 g, 0.01 mol) is heated to 30°-40° C. for two hours with stirring. The solvent is distilled off under water jet vacuum, the residue taken up in water (10 ml), made alkline with potassium carbonate and extracted exhaustively with dichloromethane. The combined methylene chloride extracts are dried over sodium sulfate and concentrated. The crude product thus obtained is purified by chromatography on silica gel using dichloromethane/methanol (9:1 v/v). After recrystallization from ethyl acetate/methanol (95:5) the desired compound (1.4 g) is obtained in the form of colorless crystals, Mp. 176°-178° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N+:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[N+:11]([C:14]1[CH:19]=[C:18]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2ncnc3[nH]ccc23)c1
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (10 g, 65 mmol), 3-nitrophenylboronic acid (17.4 g, 104 mmol), Pd(dppf)Cl2—CH2Cl2 (2.13 g, 2.60 mmol), and 2 M sodium carbonate (81.5 mL, 163 mmol) in DMF (217 mL) was degassed for 10 minutes and then heated at 115° C. for 1 hour. After the reaction mixture was cooled to room temperature, water (700 mL) and sorbitol (20 g) were added which led to the precipitation of the desired product. After 30 minutes of stirring, the precipitate was filtered to give the crude product which was then slurried from EtOAc (100 mL) and hexanes (150 mL) for 30 minutes. Filtration of the precipitate gave 4-(3-nitrophenyl)-7H-pyrrolo[2,3-d]pyrimidine. LRMS (ESI) calc'd for C12H9N4O2 [M+H]+: 241, found 241.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl.Cl.[F:16][C:17]1[CH:26]=[C:25]([C:27]2[C:32]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:31][CH:30]=[CH:29][N:28]=2)[CH:24]=[CH:23][C:18]=1[C:19]([NH:21][CH3:22])=[O:20]>>[F:16][C:17]1[CH:26]=[C:25]([C:27]2[C:32]([CH:33]3[CH2:38][CH2:37][N:36]([C:2]4[CH:11]=[CH:10][C:9]5[C:4](=[C:5]([F:12])[CH:6]=[CH:7][CH:8]=5)[N:3]=4)[CH2:35][CH2:34]3)=[N:31][CH:30]=[CH:29][N:28]=2)[CH:24]=[CH:23][C:18]=1[C:19]([NH:21][CH3:22])=[O:20]
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CCNCC2)cc1F
Reactant: Fc1cccc2ccc(Cl)nc12
Agent: Cl
Product: CNC(=O)c1ccc(-c2nccnc2C2CCN(c3ccc4cccc(F)c4n3)CC2)cc1F

Procedure:
The title compound was prepared analogously to Example 8 by using 2-chloro-8-fluoroquinoline (Combi-blocks) and 2-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide trihydrochloride (prepared according to Step 2 of Example 1) in Step 3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.85 (d, J=11.93 Hz, 2H) 2.04-2.19 (m, 2H) 2.91-3.03 (m, 2H) 3.09 (d, J=4.50 Hz, 3H) 3.22 (tt, J=11.61, 3.74 Hz, 1H) 4.72 (d, J=13.50 Hz, 2H) 6.80 (d, J=7.43 Hz, 1H) 7.05 (d, J=9.19 Hz, 1H) 7.08-7.15 (m, 1H) 7.20-7.25 (m, 1H) 7.32-7.39 (m, 2H) 7.44 (dd, J=8.02, 1.37 Hz, 1H) 7.88 (dd, J=9.19, 1.17 Hz, 1H) 8.27 (t, J=8.02 Hz, 1H) 8.50 (d, J=2.35 Hz, 1H) 8.55 (d, J=2.35 Hz, 1H). m/z=460 (M+1).