Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[C:17]1([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=C(C)C=1>[C:24]1([N:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1cccc(C)c1
Product: O=[N+]([O-])c1ccccc1-c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 47.8 %

Procedure:
A mixed solution of 2.0 g of 2-(4-chlorophenyl)nitrobenzene, 1.7 g of diphenylamine, 0.99 g of t-butoxysodium, 0.19 g of (tris-t-butylphosphine)tetrafluoroborate, 0.43 g of bis(dibenzylideneacetone)palladium(0) and 30 ml of m-xylene was heated and stirred under a nitrogen gas stream at 140° C. for 5 hours. The solution was cooled to room temperature and filtered through Celite. The filtrate was evaporated, and then the concentrate was purified by silica gel column chromatography and vacuum-dried to obtain 1.5 g of 2-(4-diphenylaminophenyl)nitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13]Cl)[CH2:9][N:8]([CH3:15])[C:7](=[S:16])[C:6]=2[CH:17]=1.[CH3:18][NH:19][CH3:20].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23]>C(O)C.C(O)(C)C>[OH2:11].[C:21]([OH:26])(=[O:25])[C:22]([OH:24])=[O:23].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13][N:19]([CH3:20])[CH3:18])[CH2:9][N:8]([CH3:15])[C:7](=[S:16])[C:6]=2[CH:17]=1
Reactant: CNC
Reactant: CN1CC(CCCl)Oc2ccc(Cl)cc2C1=S
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: CN(C)CCC1CN(C)C(=S)c2cc(Cl)ccc2O1
Product: O

Procedure:
To a solution of 8.0 g (0.027 mole) of 7-chloro-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepine-5(4H)-thione in 50 ml of absolute ethanol was added 6 ml (0.054 mole) of 40% aqueous solution of dimethylamine. The solution was heated in a steel bomb at 90° C. for 14 hr. The ethanol was removed under reduced pressure and the residue was partitioned between chloroform and aqueous sodium hydroxide. The chloroform layer was concentrated to give a viscous yellow oil. The oil was dissolved in isopropyl alcohol and reacted with oxalic acid. The oxalate salt immediately precipitated. The mixture was heated and a small amount of water was added to dissolve the salt. A white crystalline powder was obtained, mp. 150°-151° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19]>CO>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)/[CH:10]=[N:18]/[OH:19])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1cccc(Oc2ccc(F)cc2)c1
Agent: Cl
Solvent: CO
Product: O/N=C/c1cccc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
To a mixture of 3-(4-fluorophenoxy)benzaldehyde (3.0 g, 13.8 mmol, 1.0 eq) in methanol was added hydroxylamine hydrochloride (1.06 g, 15.2 mmol, 1.1 eq). The reaction mixture was stirred at ambient temperature for 12 h, before being concentrated in vacuo. The residue was taken in ethyl acetate and washed with water. The organic layer was dried with anhydrous Na2SO4 and concentrated to obtain the desired product (3 g, 94%). 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.42-7.38 (t, 1H), 7.32-7.31 (d, 1H), 7.27-7.23 (t, 2H), 7.16 (s, 1H), 7.13-7.10 (m, 2H), 7.01-6.99 (m, 1H). MS (ESI): 232.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH:10]=[C:9]([O:13]CC)[CH2:8][C:7]=2[C:6]([O:16][CH3:17])=[CH:5][CH:4]=1.Cl>C(O)C>[CH3:1][O:2][CH:3]1[C:12]2[CH:11]=[CH:10][C:9](=[O:13])[CH2:8][C:7]=2[CH:6]([O:16][CH3:17])[CH2:5][CH2:4]1
Reactant: CCOC1=CCc2c(OC)ccc(OC)c2C1
Agent: Cl
Solvent: CCO
Product: COC1CCC(OC)C2=C1C=CC(=O)C2
Temperature: 25 °C
Yield: 85.5 %

Procedure:
5,8-Dihydro-1,4-dimethoxy-6-ethoxynaphthalene (XII) (3.5 g, 15 mmole) was dissolved in 88 ml hot ethanol and then cooled to room temperature. The suspension was stirred with hydrochloric acid (2 N) (17.5 ml) for fifteen minutes. The reaction mixture was poured onto ice water and filtered to give as a tan solid 1,4-dimethoxy-6-tetralone (XIII) (2.67 g, 86.5% yield). m.p. 99°-100° C. (ethanol).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].Br[CH:29]([CH2:37][CH3:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([CH:29]([CH2:37][CH3:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N(C(CC)C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one (77 mg, 0.205 mmol, Example 124, Step C) in DMF (0.3 mL) was added slowly 9.5 mg (0.24 mmol) of a dispersion of 60% sodium hydride in mineral oil followed by tert-butyl 2-bromobutanoate (92 mg, 0.410 mmol). The reaction was stirred at ambient temperature overnight, quenched with MeOH/HOAc, was diluted with EtOAc and water and extracted to EtOAc. The organics were dried over Na2SO4, filtered and the filtrate was concentrated. Purification by reversed phase preparatory HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.) (eluent: 70% acetonitrile, water, 0.1% TFA) provided the title compound, as well as its stereoisomer, (R)-tert-butyl 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-1-yl)butanoate.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]>N1C=CC=CC=1>[C:1]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CN
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CNC(C)=O
Yield: 34.4 %

Procedure:
31 gm of acetic acid anhydride were slowly added to a solution of ethyl glycinate (prepared from 31 gm ethyl glycinate hydrochloride in ether and sodium hydroxide) in 70 ml of pyridine, while stirring and cooling the solution. The resulting mixture was then stirred for one hour at room temperature and subsequently evaporated, yielding 15 gm (55% of theory) of ethyl N-acetyl-glycinate.
Reaction SMILES: COC([C:5]1[S:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[NH2:15])=O.CN1CCNCC1.CN1CCCC1=O>O>[NH2:15][C:6]1[C:7]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:8]=2[S:9][CH:5]=1
Reactant: COC(=O)c1sc2cc(F)ccc2c1N
Agent: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1csc2cc(F)ccc12
Temperature: 176 °C
Yield: 62.5 %

Procedure:
A mixture of methyl-6-fluoro-3-aminobenzo[b]thiophene-2-carboxylate (20.1 g), 1-methylpiperazine (13.1 g), and 1-methyl-2-pyrrolidinone (100 ml) was heated at 176° C. for 2 hrs, under nitrogen. The solution was diluted with water (400 ml) and extracted with ether. The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 9.32 g of 3-amino-6-fluorobenzo[b]thiophene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[OH:9].O.[CH2:11](OC(OCC)OCC)C>Cl>[O:9]1[C:3]2[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=2[N:1]=[CH:11]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cc(O)ccc1O
Agent: Cl
Solvent: O
Product: Oc1ccc2ocnc2c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a solution of 2-aminobenzene-1,4-diol (2.40 g, 19.2 mmol) in triethylorthoformate (10 mL) was added 3 drops of concentrated HCl. After heating to 65° C. for 30 minutes and stirring at room temperature for 16 hours, the mixture was poured into water and extracted with ethyl acetate (2×). The organic phase was washed with HCl (2N) and saturated NaHCO3, dried, and concentrated under reduced pressure to provide the product (2.09 g, 81%) as red-black solid.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5]([S:19][C:20]([F:29])([F:28])[C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])=[N:4][CH:3]=1.C([O:32][C:33](=[O:36])[CH2:34][NH2:35])C.BrC1N(C2C3C(=CC=CC=3)C(C#N)=CC=2)C(SC(F)(F)C(O)=O)=NC=1.NCC(NCC(OCC)=O)=O>>[Br:1][C:2]1[N:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]#[N:18])=[CH:9][CH:8]=2)[C:5]([S:19][C:20]([F:29])([F:28])[C:21]([NH:23][CH2:24][C:25]([NH:35][CH2:34][C:33]([OH:32])=[O:36])=[O:26])=[O:22])=[N:4][CH:3]=1
Reactant: N#Cc1ccc(-n2c(Br)cnc2SC(F)(F)C(=O)NCC(=O)O)c2ccccc12
Reactant: CCOC(=O)CN
Agent: CCOC(=O)CNC(=O)CN
Agent: N#Cc1ccc(-n2c(Br)cnc2SC(F)(F)C(=O)O)c2ccccc12
Product: N#Cc1ccc(-n2c(Br)cnc2SC(F)(F)C(=O)NCC(=O)NCC(=O)O)c2ccccc12

Procedure:
2-(2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)acetamido)acetic acid is prepared via either of the two routes shown below. In the first, 2-(2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetamido)acetic acid (see eg 14) is coupled with glycine ethyl ester and then hydrolyzed to the acid. In the second, (see eg 10), 2-(5-bromo-1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)-2,2-difluoroacetic acid is coupled with NH2-Gly-Gly-OEt, which is then hydrolyzed to the acid.
Reaction SMILES: [CH2:1]([C:5]([CH2:11][CH:12]([CH3:14])[CH3:13])([CH2:8][O:9][CH3:10])[CH2:6][OH:7])[CH:2]([CH3:4])[CH3:3].[CH3:15][Si:16](Cl)([CH3:18])[CH3:17]>>[CH2:1]([C:5]([CH2:11][CH:12]([CH3:14])[CH3:13])([CH2:6][O:7][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH2:8][O:9][CH3:10])[CH:2]([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: COCC(CO)(CC(C)C)CC(C)C
Product: COCC(CO[Si](C)(C)C)(CC(C)C)CC(C)C

Procedure:
According to the procedure as described in Example 1,2,2-di-iso-butyl-1-methoxy-3-[(trimethylsilyl)oxy]propane was prepared from intermediate 2,2-di-iso-butyl-3-methoxy-1-propanol and reagent trimethylsilyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9](O)=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2.[Cl-].[NH4+].C1C=CC2N([OH:36])N=[N:33]C=2C=1.C(Cl)CCl.C(N(C(C)C)C(C)C)C.CN([CH:53]=[O:54])C>>[C:53]([OH:54])([C:21]([F:24])([F:23])[F:22])=[O:36].[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH2:33])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2
Reactant: CN(C)C=O
Reactant: On1nnc2ccccc21
Reactant: COc1nc(C(=O)O)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(C(N)=O)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To 6-methoxy-5-(6-(trifluoromethyl)-1H-indazol-4-yl)picolinic acid (0.020 g, 0.059 mmol) in DMF (3 mL) were added ammonium chloride (0.016 g, 0.297 mmol), HOBt (0.011 g, 0.083 mmol), and EDC (0.017 g, 0.089 mmol), followed by N-ethyl-N-isopropylpropan-2-amine (0.052 mL, 0.297 mmol). The reaction mixture was stirred for 1 hour at room temperature. The crude reaction mixture was purified by preparative HPLC, eluting with a gradient of 30-40% acetonitrile (containing 0.035% TFA) in H2O (containing 0.05% TFA) over a period of 7 minutes. The product-containing fractions were combined and the volatiles removed in vacuo to give a TFA salt of the title compound as white solid (0.012 g, 60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.99 (s, 3H), 7.45-7.51 (m, 1H), 7.70-7.83 (m, 1H), 7.98 (s, 1H), 8.03-8.12 (m, 2H), 8.13 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C15H11F3N4O2, 337.1. found 337.15.
Reaction SMILES: [CH3:1][CH:2]([CH2:24][CH3:25])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([CH3:23])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:6][CH2:5]1.NN.O.[CH3:29][CH2:30][CH2:31]CCC.CCOC(C)=O>CCO>[CH3:1][C:2]1[C:24]([CH3:25])=[CH:31][CH:30]=[CH:29][C:3]=1[N:4]1[CH2:5][CH2:6][N:7]([CH:10]([CH3:23])[CH2:11][NH2:12])[CH2:8][CH2:9]1
Reactant: CCC(C)CN1CCN(C(C)CN2C(=O)c3ccccc3C2=O)CC1
Reactant: CCCCCC
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCN(C(C)CN)CC2)c1C
Temperature: 70 °C
Yield: 44.7 %

Procedure:
2-{2-[4-(2,3-dimethylpropyl)piperazin-1-yl]propyl}isoindole-1,3-dione (3.0 g, 7.95 mmol) prepared in Reference 2 was dissolved in 50 ml EtOH, then H2NNH2.H2O (1.54 ml, 31.80 mmol) was added and stirred at about 70° C. The reaction progress and completion were confirmed using TLC (hexane: EtOAc=1:1). Upon completion of the reaction, while the temperature was kept at room temperature, the resulting solution was filtered to remove insolubles. The solvent was removed by distilling it under reduced pressure, followed by adding water and extracting the aqueous layer with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:11]=[CH:10]C=[CH:8][C:7]=1O.[C:13](OCC)(=[O:15])C>C1(C)C=CC=CC=1>[N:5]([C:6]1[CH:11]=[CH:10][C:1]([OH:2])=[CH:8][CH:7]=1)=[C:13]=[O:15]
Reactant: Nc1ccccc1O
Reactant: CCOC(C)=O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of phosgene (20% in Toluene, 24 mL, 45.9 mmol) (Aldrich) in ethyl acetate (25 mL) at 0° C. was added aminophenol (0.5 g, 4.59 mmol) (Aldrich). The reaction mixture was stirred at 0° C. for 30 minutes and then heated at 80° C. for 3 hours. The mixture was cooling down to room temperature to give crude 4-isocyanato-phenol as 0.18 M solution in toluene and used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:21]3[CH2:24][CH2:23][CH2:22]3)=[N:9][C:10]=2[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])=O)[CH:5]=[CH:6][N:7]=1>C(O)(=O)C>[NH:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:11]1[C:10]1[N:9]=[C:8]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=12
Reactant: Nc1ccccc1NC(=O)c1nc(C2CCC2)n2ccnc(N)c12
Solvent: CC(=O)O
Product: Nc1nccn2c(C3CCC3)nc(-c3nc4ccccc4[nH]3)c12

Procedure:
A solution of 8-amino-N-(2-aminophenyl)-3-cyclobutylimidazo[1,5-a]pyrazine-1-carboxamide (40.0 mg, 0.124 mmol) in acetic acid (1.2 mL) was microwaved at 120° C. for 10 min (300 W). The resulting solution was purified mass directed preparative HPLC to afford 1-(1H-benzimidazol-2-yl)-3-cyclobutylimidazo[1,5-a]pyrazin-8-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92-2.05 (m, 1H) 2.07-2.21 (m, 1H) 2.53-2.59 (m, 4H) 3.91-4.06 (m, 1H) 7.08 (d, J=4.80 Hz, 1H) 7.16-7.26 (m, 2H) 7.38 (d, J=4.80 Hz, 1H) 7.44 (br. s., 1H) 7.55 (d, J=8.08 Hz, 1H) 7.62 (d, J=6.82 Hz, 1H) 10.49 (br. s., 1H) 12.76 (s, 1H); MS (ES+): m/z 305.15 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4](Cl)[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(O)C>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: C1COCCN1
Reactant: N#Cc1c(-c2ccccc2)cc(Cl)nc1Cl
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)cc(N2CCOCC2)nc1Cl
Yield: 86.1 %

Procedure:
A suspension of 24.9 gm (0.1 mol) of 2,6-dichloro-4-phenyl-3-cyano-pyridine in 400 ml of ethanol was slowly admixed with 17.4 gm (0.2 mol) of morpholine, and the resulting mixture was refluxed for about two hours. Even while refluxing, but primarily upon subsequent cooling (optionally on an ice water bath) of the reaction mixture, a colorless crystalline precipitate formed which was collected by suction filtration, very thoroughly washed with water and dried. 25.8 gm (86% of theory) of 2-chloro-6-morpholino-4-phenyl-3-cyano-pyridine, m.p. 198°-200° C., were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([NH:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:21][CH2:22][CH2:23][C:24]1[C:28]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=2[O:26][N:25]=1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:9]([N:11]([CH2:21][CH2:22][CH2:23][C:24]3[C:28]4[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=4[O:26][N:25]=3)[C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2scc(Nc3ccncc3)c12
Reactant: Fc1ccc2c(CCCCl)noc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(CCCN(c3ccncc3)c3csc4cccc(Cl)c34)noc2c1
Temperature: 70 °C
Yield: 36.3 %

Procedure:
A solution of 4-chloro-3-[(4-pyridinyl)amino]benzo[b]thiophene (2.26 g, 8.67 mmole) in 25 mL DMF was added to a suspension of NaH (0.416 g of 60% in oil, 10.4 mmole, washed with heptane). To this mixture was added 3-(3-chloropropyl)-6-fluorobenzisoxazole (2.04 g, 9.53 mmole) and the reaction mixture was heated at 70° C. for 3 hours. The reaction mixture was quenched into water and extracted with ethyl acetate (3×). The organics were washed with water and dried (MgSO4). The compound was purified via flash chromatography (EtOAc) to give 2.8 g of a partially solidified oil. This was recrystallized from methanol/water to give 1.38 g of a white powder, mp: 135-136° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].F[C:15]1[CH:16]=[C:17]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])[C:18]([N+:27]([O-:29])=[O:28])=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:20]=1.O>CN(C=O)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:15]1[CH:16]=[C:17]([O:30][CH2:31][C:32]([F:34])([F:35])[F:33])[C:18]([N+:27]([O-:29])=[O:28])=[C:19]([O:21][CH2:22][C:23]([F:24])([F:26])[F:25])[CH:20]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: O=[N+]([O-])c1c(OCC(F)(F)F)cc(F)cc1OCC(F)(F)F
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1cc(OCC(F)(F)F)c([N+](=O)[O-])c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of diethyl malonate (18.0 g, 114.9 mmol) in DMF (50 mL) was added sodium hydride (60% in mineral oil, 3.0 g, 125.0 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h and a solution of 5-fluoro-2-nitro-1,3-bis-(2,2,2-trifluoro-ethoxy)-benzene (18.0 g, 53.4 mmol) in DMF (30 mL) was added dropwise. The reaction mixture was heated 100° C. for 24 h. After cooling the reaction mixture was poured into water (300 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of the solvent under reduced pressure gave 2-[4-nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-malonic acid diethyl ester as a brown oil (20.8 g, 80%). The crude product was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 6.91 (s, 2H), 4.62 (s, 1H), 4.48 (q, J=8.0 Hz, 4H), 4.28-4.16 (m, 4H), 1.31-1.25 (m, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ 166.4, 149.2, 136.7, 132.3, 122.3 (q, 1JCF=276.6 Hz), 109.5 (two signals), 67.0 (q, 2JCF=36.7 Hz), 61.4, 41.6, 14.0.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][Cl:22])=[N:19]C(C(O)=O)=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:28](CC)CC)C.C(Cl)(=O)[O:34][CH2:35][CH3:36].N>O.O1CCCC1>[C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][Cl:22])=[N:19][C:36]([C:35]([NH2:28])=[O:34])=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1nc(CCl)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Reaction time: 0.17 h

Procedure:
Under cooling with ice and stirring, to a solution of 7.5 parts of 1-(2-benzoyl-4-chlorophenyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxylic acid and 2.8 volume parts of triethylamine in 100 volume parts of dry tetrahydrofuran, 2.0 volume parts of ethyl chlorocarbonate is added dropwise. The solution is then added dropwise to 200 volume parts of ice-cooled concentrated aqueous ammonia (28 %). After stirring for 10 minutes, the mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed with water and the solvent is distilled off. The residue is treated with ether to obtain 1-(2-benzoyl-4-chlorophenyl)-5-chloromethyl-1H-1,2,4-triazole-3-carboxamide as crystals. Recrystallization from ethanol gives colorless crystals melting at 122°-124°C (this product includes 1/2 ethanol of crystallization).
Reaction SMILES: [Cl:1][C:2]1[N:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[C:4]([NH:6][C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5].CN([CH:24]=[O:25])C>C1COCC1>[Cl:1][C:2]1[C:3]2[C:4](=[O:5])[N:6]([C:7]([CH3:15])([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:8])[CH:24]([OH:25])[C:16]=2[C:17]([Cl:20])=[CH:18][N:19]=1
Reactant: CC(C)(NC(=O)c1cc(Cl)cnc1Cl)c1ccccc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2c(Cl)ncc(Cl)c2C1O
Yield: 71.7 %

Procedure:
In a similar manner to Step 2 of Example 16, 2,5-dichloro-N-(1-methyl-1-phenylethyl)nicotinamide (400 mg, 1.29 mmol) was dissolved in THF (16 mL), and the solution was treated with n-butyllithium-hexane solution (2.71 mol/L, 1.20 mL, 3.23 mmol) and DMF (0.250 mL, 3.23 mmol), followed by purification by slurry (diisopropylether) and flash column chromatography (hexane/ethyl acetate=60/40 to 50/50) to obtain 4,7-dichloro-1-hydroxy-2-(1-methyl-1-phenylethyl)-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (312 mg, yield 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[N:29]=[CH:28][N:27]=[C:26]5[N:30](C6CCCCO6)[N:31]=[CH:32][C:25]=45)=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.Cl.O1CCOCC1>CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][C:24]4[N:29]=[CH:28][N:27]=[C:26]5[NH:30][N:31]=[CH:32][C:25]=45)=[CH:21][CH:22]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(Oc3ncnc4c3cnn4C3CCCCO3)cc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(Oc3ncnc4[nH]ncc34)cc2)CC1
Yield: 62.4 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added N-(4-fluorophenyl)-N′-(4-{[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide (0.050 mg, 0.10 mmol, 1.0 eq.) and 4M HCl/Dioxane (5 ml). After 5 minutes ether was added. The resulting solid was filtered and washed twice with ether. The solid was further dried under vacuum to give N-(4-fluorophenyl)-N′-[4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl]cyclopropane-1,1-dicarboxamide (0.027 g, 67% yield). 1H NMR (400 MHz, DMSO): 10.20 (s, 1H), 10.10 (s, 1H), 8.50 (s, 1H), 8.06 (s, 1H), 7.75 (m, 2H), 7.67 (m, 2H), 7.27 (m, 2H), 7.13 (m, 2H), 4.47 (bs, 1H), 1.47 (s, 4H); MS (ESI) for C22H17FN6O3: 433 (MH+).