Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](OC)=[O:11])=[N:8][CH:9]=1>C1COCC1.CO>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(C)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
Sodium borohydride (4.5 g, 115. mmol) was added to a solution of methyl 5-methylpicolinate (6.0 g, 39.5 mmol) in THF (60 mL) and methanol (6 ml) at RT. The reaction mixture was stirred at RT for 2 h (the reaction was monitored by TLC). The mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The organic layer was concentrated under vacuo to afford (5-methylpyridin-2-yl)methanol (3.5 g, 72.9%) as an off-white solid. 1H NMR: 200 MHz, CDCl3: δ 8.5 (s, 1H), 7.7 (d, 1H), 7.15 (d, 1H), 5.0 (s, 3H), 3.4 (s, 3H). MS: [M+H]+: m/z=124.0.
Reaction SMILES: [O-:1][CH2:2]C.[Na+].[H-].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]([CH3:26])[CH2:13][C:12]2=[O:27].C(OCC)=O>C1C=CC=CC=1.C(O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]([CH3:26])[C:13](=[CH:2][OH:1])[C:12]2=[O:27]
Reactant: CC[O-]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To sodium ethoxide, freshly prepared from 4.8 g. of sodium hydride and 6.0 ml. of ethanol was added a solution of 14.7 g. of ethyl 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate and 19.8 ml. of ethyl formate in 150 ml. of benzene, over a 45 min. period. The reaction mixture was stirred at room temperature for 3 hrs. and then it was poured onto 250 ml. of ice water. The layers were separated, and the organic layer was extracted with 1N sodium hydroxide solution. The combined aqueous phases were washed with benzene, and then they were added dropwise to 250 ml. of 12N hydrochloric acid. This caused the product to separate in the form of an oil. Recrystallization of this oil from hexane produced 15.4 g. (96% yield) of the title compound, m.p. 98°-101° C. Further recrystallization from hexane raised the melting point to 129°-130° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[CH:28])=[CH:21][CH:20]=1.C(N(CC)CC)C.CCOC(C)=O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][C:2]2[C:3]([NH:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: C#CCOc1ccc(CCl)cc1
Reactant: N#Cc1ncc(Br)c(NC2CCCCC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ncc(C#CCOc2ccc(CCl)cc2)c(NC2CCCCC2)n1
Temperature: 65 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
5-Bromo-4-cyclohexylamino-pyrimidine-2-carbonitrile (0.19 mmol) and chloromethyl-4-prop-2-ynyloxy-benzene (0.22 mmol) in DMF (5 ml) are treated with triethylamine (0.56 mmol), copper (I) iodide (0.019 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.0093 mmol) at room temperature. The mixture is stirred for 2 h at 65° C., poured into an ice water, extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give the product in 21% yield. Rf=0.75 (n-hexanes:AcOEt=1:2). 1H-NMR (400 MHz, CDCl3) δ 1.02-1.48 (m, 5H), 1.57-1.78 (m, 3H), 1.80-1.98 (m. 2H), 3.94-4.04 (m, 1H), 4.61 (s, 2H), 5.03 (s, 2H), 5.38 (d, 1H), 7.04 (d, 2H), 7.41 (d, 2H), 8.21 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8](OC)=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][CH2:17][Cl:18].C([O-])([O-])OC.C([O-])(=O)C.[NH4+:28].[CH3:29]O>O>[CH3:1][O:2][C:3]1[CH:12]=[C:7]2[C:6](=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][CH2:17][Cl:18])[N:13]=[CH:29][NH:28][C:8]2=[O:9]
Reactant: CO
Reactant: [NH4+]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Agent: CC(=O)[O-]
Agent: COC([O-])[O-]
Solvent: O
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Temperature: 5 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
In a 1,000 mL volume stainless pressure-resistant vessel equipped with a stirrer, a thermometer and a pressure gauge were placed 161.5 g (0.59 mol) of methyl 5-methoxy-4-(3-chloropropoxy)anthranilate, 156.5 g (1.48 mol) of methyl orthoformate, 113.7 g (1.48 mol) of ammonium acetate, and 300 mL of methanol. The vessel was closed, and the reaction was carried out at 90-95° C. for 8 hours. The pressure in the vessel was 0.1-0.3 MPa (gauge pressure). After the reaction was complete, 600 mL of water was added to the reaction mixture. The aqueous reaction mixture was stirred at 0-10° C. for one hour, to precipitate a crystalline product. The crystalline product was collected by filtration, washed with 600 mL of water, and dried at 60° C. under reduced pressure, to give 152.8 g (isolated yield: 94%) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one as a white crystalline product.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[I:12].[CH3:14][NH:15][C@H:16]1[CH2:35][N:20]2[C:21]3[C:26]([C:27]([CH2:28][C:29]([O:31]CCC)=[O:30])=[C:19]2[CH2:18][CH2:17]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>>[F:13][CH:2]([F:1])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:15]([CH3:14])[C@H:16]2[CH2:35][N:20]3[C:21]4[C:26]([C:27]([CH2:28][C:29]([OH:31])=[O:30])=[C:19]3[CH2:18][CH2:17]2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:9])=[CH:5][C:4]=1[I:12]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)c1ccc(C(F)F)c(I)c1
Product: CN(C(=O)c1ccc(C(F)F)c(I)c1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 4-(difluoromethyl)-3-iodobenzoic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 539.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:12](O)=[O:13])[C:3]1=[O:15].S(Cl)([Cl:18])=O>>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:12]([Cl:18])=[O:13])[C:3]1=[O:15]
Reactant: O=S(Cl)Cl
Reactant: Cn1c(C(F)(F)F)ccc(C(=O)O)c1=O
Product: Cn1c(C(F)(F)F)ccc(C(=O)Cl)c1=O

Procedure:
1,2-dihydro-1-methyl-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid (17.8 g, 80.5 mmol) was dissolved in thionyl chloride (70 mL), and this mixed solution was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 1,2-dihydro-1-methyl-2-oxo-6-(trifluoromethyl)pyridine-3-carbonyl chloride. The obtained acid chloride was dissolved in acetonitrile (80 mL), and added dropwise to a mixed solution of 5-hydroxy-1-methyl-1H-pyrazole hydrochloride (10.8 g, 80.3 mmol), triethylamine (20.4 g, 201 mmol) and acetonitrile (20 mL), under ice cooling. After stirring this mixed solution for a day at room temperature, acetonecyanhydrin (0.69 g, 8.05 mmol) and triethylamine (9.8 g, 96.6 mmol) were added thereto, and the mixture was stirred overnight at room temperature. To a residue obtained by concentrating the reaction solution under reduced pressure, a mixture of aqueous saturated sodium bicarbonate and ethyl acetate was added for extraction and separation. Thus obtained aqueous layer was added with diluted hydrochloric acid to give a pH of 3 to 4, and extracted with chloroform. The obtained organic layer was dried over anhydrous magnesium sulfate, and the inorganic substance was separated by filtration. The solvent was distilled off under reduced pressure to obtain 10.4 g of a crude product of a subject compound.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:40])[CH2:22][CH2:21]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(C(=O)c4ccccc4)CC3)n[nH]c12
Reaction time: 8 h
Yield: 49.9 %

Procedure:
A mixture of 5-phenyl-3-(4-piperidinyl)-1H-indazole-7-carboxamide hydrochloride (0.051 g, 0.17 mmols), triethylamine (0.1 mL, 0.71 mmols), DMAP (0.0021 g, 0.017 mmols), and benzoylchloride (0.020 mL, 0.17 mmols) in DMF (3 mL) was kept at ambient temperature overnight. The mixture was concentrated in vacuo and the resulting residue purified via preparative HPLC, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give 0.036 g of a white solid. LC/MS-M+H 425
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)([OH:8])[CH2:5][O:6][CH3:7].C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C1COCC1>[Cl:24][CH2:25][C:26]([NH:1][CH2:2][CH2:3][C:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)([OH:8])[CH2:5][O:6][CH3:7])=[O:27]
Reactant: COCC(O)(CCN)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(O)(CCNC(=O)CCl)c1ccc(Cl)c(Cl)c1
Reaction time: 0.33 h

Procedure:
To a solution of (2RS)-4-amino-2-(3,4-dichlorophenyl)-1-methoxybutan-2-ol (3.00 g) and triethylamine (1.60 mL) in THF (50 mL) was added dropwise chloroacetyl chloride (0.91 ml) under ice-cooling, and the mixture was stirred for 20 min. The reaction mixture was quenched with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-100%)) to give the title compound (2.13 g).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][S:5][CH2:6][CH2:7][CH2:8][S:9][C@H:10]1[C:14](=[O:15])[CH2:13][C@@H:12]([OH:16])[C@@H:11]1/[CH:17]=[CH:18]/[C@@H:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].P([O-])([O-])([O-])=O>CC#N>[OH:16][C@@H:12]1[CH2:13][C:14](=[O:15])[C@H:10]([S:9][CH2:8][CH2:7][CH2:6][S:5][CH2:4][C:3]([OH:26])=[O:2])[C@H:11]1/[CH:17]=[CH:18]/[C@@H:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1SCCCSCC(=O)OC
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1SCCCSCC(=O)O
Temperature: 23 °C
Reaction time: 16 h
Yield: 10.9 %

Procedure:
Methyl ester 8 (50 mg, 0.124 mmol) was dissolved in CH3CN (10 mL) and pH 7.2 phosphate buffer (3.0 mL) was added. The mixture was treated with PLE (400 μL, 1.34 mol/L) and stirred for 16 h at 23° C. The reaction mixture was extracted with EtOAc (3×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 100% EtOAc) gave 5.3 mg (11%) of the above titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[S:28](=[O:30])(=[O:29])[N:27](COCC[Si](C)(C)C)[C:26](=[O:39])[CH2:25]2)=[C:20]([Br:40])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:39])[CH2:25]2)=[C:20]([Br:40])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(C2CC(=O)N(COCC[Si](C)(C)C)S2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a round-bottom flask was added methyl (2S)-2-[(benzyloxy)carbonyl]amino-3-[3-bromo-4-(1,1-dioxido-3-oxo-2-[2-(trimethylsilyl)ethoxy]methylisothiazolidin-5-yl)phenyl]-propanoate (165 mg, 0.252 mmol), dichloromethane (5 mL), and trifluoroacetic acid (2.5 mL). After stirring at room temperature for 30 minutes, the solvent was removed. The resulting residue was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1>C(OCC)(=O)C.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:6]
Reactant: NNC(=O)c1cccc(Cl)c1
Reactant: O=C1CCC(=O)O1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(O)CCC(=O)NNC(=O)c1cccc(Cl)c1
Yield: 94.2 %

Procedure:
3-Chloro-benzoic acid hydrazide (3.4 g, 20 mmol) and succinic anhydride (2. g, 20 mmol) was mixed in ethyl acetate (50 ml) at room temperature for 15 min. The reaction mixture was diluted with ether and the precipitate was filtered to give 5.1 g of 4-[N′-(3-chloro-benzoyl)-hydrazino]-4-oxo-butyric acid. 1H-NMR(CDCl3+DMSO-d6) d(ppm): 10.01 (s, 1H), 9.53 (s, 1H), 7.68 (s, 1H), 7.55 (d, 1H), 7.21 (d, 1H), 7.12 (t, 1H) and 2.35 (m, 4H). This solid was mixed with conc. H2SO4 and stirred at room temperature for 45 min and the reaction mixture was carefully added to crashed ice (400 g). The precipitate was filtered to give 4.07 g (80.6%) of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid as white solid. 1H-NMR(DMSO-d6) d(ppm): 12.4 (w, 1H), 7.96 (s, 1H), 7.91 (d, 1H), 7.71 (d, 1H), 7.63 (t, 1H), 3.15 (t, 2H) and 2.82 (t, 2H). Step 2: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid hydrazide: 3-[5-(3-Chloro-phenyl)-[1,3,4)oxadiazol-2-yl]-propionic acid (2.52 g, 10 mmol) was mixed with iodomethane (5.68 g, 40 mmol) and K2CO3 (5.52 g, 40 mmol) in DMF (25 ml) at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water 3 times, dried with MgSO4 and concentrated to give 2.57 g of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid methyl ester. The methyl ester (2.54 g, 9.52 mmol) was mixed with 98% hydrazine hydrate (4.76 g, 95.2 mmol) in methanol (10 ml) for an h. The reaction mixture was concentrated, diluted with water, filtered to give 2.17 g (81.4%) of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid hydrazide as white solid. 1H-NMR(CDCl3+DMSO-d6) d(ppm): 8.75 (w, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.42 (m, 2H), 3.45 (w, 2H), 3.19 (t, 2H) and 2.68 (t, 2H).
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].ClCCO[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1OC)[CH:19]=[C:18]([C:25](OCC)=O)[C:17](/[N:30]=C/N(C)C)=C2.[Cl:35][CH2:36][CH2:37][O:38][C:39]1[CH:48]=[C:47]2[C:42]([CH:43]=[C:44](/[N:54]=[CH:55]/N(C)C)[C:45]([C:49]([O:51]CC)=O)=[CH:46]2)=[CH:41][C:40]=1[O:59][CH3:60]>O1CCCC1>[N:8]1[C:15]2[C:20](=[CH:21][CH:22]=[CH:13][CH:14]=2)[CH:19]=[C:18]([C:17]#[N:30])[CH:25]=1.[Cl:35][CH2:36][CH2:37][O:38][C:39]1[C:40]([O:59][CH3:60])=[CH:41][C:42]2[CH:43]=[C:44]3[C:45]([C:49](=[O:51])[C:7]([C:6]#[N:8])=[CH:55][NH:54]3)=[CH:46][C:47]=2[CH:48]=1
Reactant: CCOC(=O)c1cc2cc(OCCCl)c(OC)cc2cc1/N=C/N(C)C
Reactant: CCOC(=O)c1cc2cc(OC)c(OCCCl)cc2cc1/N=C/N(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2cc3[nH]cc(C#N)c(=O)c3cc2cc1OCCCl
Product: N#Cc1cnc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To 2.5 mL of dry tetrahydrofuran at −78° C. is added 1.8 mL of 2.5 M n-butyllithium (4.4 mmol). Then 0.24 mL of dry acetonitrile in 4.5 mL of dry tetrahydrofuran is added dropwise over 10 minutes. This is stirred and additional 15 minutes at −78° C., then the ethyl 6-(2-chloroethoxy)-3-{[(E)-(dimethylamino)methylidene]-amino}-7-methoxy-2-naphthoate and ethyl 7-(2-chloroethoxy)-3-{[(E)-(dimethylamino)methylidene]amino}-6-methoxy-2-naphthoate (1:1 mixture) is dissolved in 3 mL of tetrahydrofuran and added dropwise over 15 minutes. The reaction mixture is stirred for 30 minutes at −78° C., then quenched with 0.57 mL of glacial acetic acid, and warmed to room temperature. To the yellow mixture is added 10 mL of water. The solids are filtered, washed with water and dried to give 0.502 g of 8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo]quinoline-3-carbonitrile and 7-(2-chloroethoxy)-8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile (1:1 mixture) as a yellow green solid (76%), m.p. 260–73° C. dec.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([O:13]CC)=[O:12])[C:3]=1/[CH:16]=[CH:17]/[Si:18]([CH3:21])([CH3:20])[CH3:19].CO.O.O.[OH-].[Li+]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]=1/[CH:16]=[CH:17]/[Si:18]([CH3:19])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1nc(C2CC2)nc(N)c1/C=C/[Si](C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)/C=C/c1c(N)nc(C2CC2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.2 %

Procedure:
(E)-ethyl 6-amino-2-cyclopropyl-5-(2-(trimethylsilyl)vinyl)pyrimidine-4-carboxylate (0.666 g, 2.180 mmol) was dissolved in THF (8.7 mL), MeOH (8.7 mL), and Water (4.4 mL). Lithium hydroxide hydrate (0.274 g, 6.54 mmol) was added as a solid. The reaction mixture was stirred for 15 min at room temperature. The solvent was removed under vacuum. The resulting solid was partitioned between 1 N HCl and ethyl acetate. The aqueous phase was extracted with ethyl acetate three times. The combined organics were washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The solid was triturated with hexane (15 mL) and gently heated with heat gun. The solid from the resulting suspension was collected via filtration and dried under vaccum to provide the title compound as an off-white solid (0.104 g, 17% yield): mp 146-149° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.12 (s, 9H), 0.91-1.03 (m, 4H), 2.02 (tt, J=7.8, 5.1 Hz, 1H), 6.22 (d, J=19.3 Hz, 1H), 6.74 (d, J=19.3 Hz, 1H), 7.34 (s, 2H); ESIMS m/z 278 ([M+H]+), 276 ([M−H]−)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].CC(C)([O-])C.[K+].Br[C:17]1[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[N:21][CH:22]=1>CC(N(C)C)=O.O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([O:9][C:17]2[CH:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[CH:3][C:2]=1[NH2:1]
Reactant: Nc1cc(O)ccc1F
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cc(Oc2ccc(C(F)(F)F)nc2)ccc1F
Temperature: 75 °C
Yield: 26.8 %

Procedure:
In DMA (8 mL) was placed 3-amino-4-fluorophenol (281 mg, 2.21 mmol), potassium t-butoxide (248 mg, 2.21 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (500 mg, 2.21 mmol). The mixture was warmed to 75° C. overnight, then cooled to RT and diluted with water (75 mL). The mixture was extracted with ethyl acetate (2×40 mL) and the combined organic phases washed with brine (40 mL), dried (Na2SO4), concentrated in vacuo and purified by column chromatography to yield 2-fluoro-5-(6-(trifluoromethyl)pyridin-3-yloxy)benzenamine (161 mg, 26% yield) as an oil which was used without further purification. MS (ESI) m/z: 273.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1>CN(C=O)C>[CH:18]1([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH:12]=3)[N:9]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nccn2c(C3CCC3)nc(-c3cccc(OCc4ccc(F)cc4)c3)c12
Temperature: 40 °C
Reaction time: 12 h

Procedure:
An anhydrous DMF (2 mL) solution of 3-(8-amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol (50 mg, 0.179 mmol) and K2CO3 (27 mg, 0.197 mmol) was charged with 1-bromomethyl-4-fluoro-benzene (7) (24 μL, 0.197 mmol) and stirred 12 h at 40° C. The reaction mixture was partitioned between CHCl3 and H2O and separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined organic fractions were washed with H2O (1×), brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. The crude mixture was purified by MDP resulting in a light tan/waxy solid; 1H NMR (CDCl3, 400 MHz) δ 1.99-2.08 (m, 1H), 2.11-2.25 (m, 1H), 2.44-2.55 (m, 2H), 2.58-2.70 (m, 2H), 3.75-3.88 (m, 1H), 5.06 (brs, 2H), 5.10 (s, 2H), 6.98-7.15 (m, 5H); 7.20-7.34 (m, 3H), 7.35-7.47 (m, 3H); MS (ES+): m/z 389.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH2:18])[NH:16][N:17]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH:19]1([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:39]=[CH:38][C:32]([C:33](OCC)=[O:34])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH2:22][CH2:21][CH2:20]1.C[Al](C)C.CC(C)=O>C1(C)C=CC=CC=1.C(#N)C>[CH:19]1([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:39]=[CH:38][C:32]([C:33]([NH:18][C:15]4[NH:16][N:17]=[C:13]([O:12][CH2:11][C:5]5[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=5)[CH:14]=4)=[O:34])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)c1ccc(N2CCN(C3CCC3)CC2)cc1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: CC#N
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCN(C5CCC5)CC4)cc3)[nH]n2)cc(OC)c1
Yield: 23.3 %

Procedure:
4-(4-Cyclobutylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide was prepared following the procedure as outlined for Example 100, starting from 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.173 g, 0.69 mmol), ethyl 4-(4-cyclobutylpiperazin-1-yl)benzoate (0.2 g, 0.69 mmol) and a 2M solution of trimethylaluminium in toluene (1.387 mL, 2.77 mmol) in toluene (10 ml) at room temperature for 20 h. The reaction mixture was poured into acetone (20 mL), quenched with excess damp sodium sulphite, filtered and evaporated to afford a yellow solid. Acetonitrile (10 ml) was added and this was filtered to afford the title compound (0.079 g, 23.17%) as a white solid.