Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: OCc1ccc(F)cc1OCc1ccc(F)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)cc2OCc2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-2-[(4-fluorophenyl)methoxy]phenyl]methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C23H16F2N4O2,419; Found, 419.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:23])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:11]([CH3:14])[C:12]=1O.[NH2:24][NH2:25]>C(O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:10]2[C:9](=[O:23])[NH:24][N:25]=[C:12]([CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:11]=2[CH3:14])[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C2=C(C)C(O)=C(c3ccccc3F)C2=O)c1
Reactant: NN
Solvent: CCO
Product: COc1cccc(-c2c(C)c(Cc3ccccc3F)n[nH]c2=O)c1

Procedure:
A solution of 2-(2-fluorophenyl)-3-hydroxy-4-methyl-5-(3-methoxyphenyl)-2,4-cyclopentadienone (310 mg, 1 mmol) and hydrazine (0.2 mL) in ethanol (5 mL) was heated at reflux for 30 minutes. The resulting solution was concentrated in vacuo and the residue was dissolved in dichloromethane, dried over sodium sulfate, filtered and concentrated in vacuo to give the desired compound as a colorless oil. 1H NMR (CDCl3): 2.14 (s, 3H), 3.27 (d, J=13.8 Hz, 1H), 3.43 (d, J=13.8 Hz, 1H), 6.70–7.25 (m, 8H); MS: 325 (MH+).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][CH2:15][C@H:16]([OH:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:24](=O)[CH3:25].Cl.[NH2:28][OH:29].[OH-].[K+].C(O)(C)C>O>[CH3:25][C:24]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[N:9]=[CH:10][N:11]=[C:12]([NH:14][CH2:15][C@@H:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[OH:23])[CH:13]=3)=[CH:7][C:2]=2[O:29][N:28]=1
Reactant: NO
Reactant: CC(=O)c1ccc(-c2cc(NC[C@H](O)c3ccccc3)ncn2)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1noc2cc(-c3cc(NC[C@H](O)c4ccccc4)ncn3)ccc12
Temperature: 90 °C
Yield: 27.7 %

Procedure:
A mixture of 1-[2-fluoro-4-(6-{[(2R)-2-hydroxy-2-phenyl-ethyl]amino}-pyrimidin-4-yl)-phenyl]ethanone (88 mg, 0.25 mmol), hydroxylamine hydrochloride (41 mg, 0.60 mmol), KOH (85% aq., 0.158 mL), isopropanol (0.5 mL) and water (0.5 mL) was heated in a sealed tube at 90° C. for 10 h. An additional amount of KOH (85% aq., 2.38 mmol) was added and the temperature increased to 120° C. for an additional 21 h. The reaction mixture was diluted with water (5 mL) and extracted with DCM (5 mL×3). The combined extracts were dried (Na2SO4), concentrated, and the crude product purified (FCC) to yield the title compound (24 mg, 28%). MS (ESI): mass calcd. for C20H18N4O2, 346.14; m/z found, 347.2 [M+H]+. 1H NMR (CDCl3): 8.70 (d, J=0.8 Hz, 1H), 8.13 (dd, J=1.3, 0.8 Hz, 1H), 7.93 (dd, J=8.3, 1.3 Hz, 1H), 7.70 (dd, J=8.3, 0.8 Hz, 1H), 7.45-7.37 (m, 4H), 7.34-7.30 (m, 1H), 6.80 (d, J=1.0 Hz, 1H), 5.35-5.30 (m, 1H), 5.03-4.99 (m, 1H), 3.94-3.87 (m, 1H), 3.67-3.60 (m, 1H), 2.62 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH3:7][O:8][CH:9](OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][CH2:2][C@@H:3]1[CH2:4][O:5][C@@H:7]([O:8][CH3:9])[O:6]1
Reactant: OCC(O)CBr
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CO[C@@H]1OC[C@@H](CBr)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
To a solution of 3-bromo-1,2-propanediol (6.0 g, 38.7 mmol) in benzene (90 mL) was added trimethylorthoformate (4.23 mL, 38.7 mmol, 1 eq.) and p-toluenesulfonic acid (pTSA, few crystals). The mixture was stirred for 20 hr at 85°-90° C., then cooled to room temperature and benzene was removed under reduced pressure. The crude material was obtained in 96% yield (7.26 g) as a mixture of cis and trans isomers in a 1:1 ratio. 1H NMR (300 MHz, CDCl3) δ: 3.34 and 3.35 (2s, 3H, OCH3), 3.35 (m, 1H, CHAHBBr), 3.44 and 3.58 (dd, 0.5H, J=5.0 Hz, 15.0 Hz, and dd, 0.5H, J=5.0 Hz, 9.9 Hz, CHAHB Br), 3.92 (dd, 0.5H, J=8.3 Hz, 10.7 Hz, and d, 0.5H, J=8.2 Hz, H-5a), 4.21 (dd, 0.5H, J=6.9 Hz, 15.0 Hz, and d, 0.5H, J=8.3 Hz, H-5b), 4.45 and 4.55 (2m, 1H, H-4), 5.80 and 5.82 (2s, 1H, H-2).
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].[F:11][C:12]([F:20])([F:19])[C:13](=O)[CH2:14][C:15](=O)[CH3:16].ClCCl>C(O)C>[CH2:7]([N:9]1[C:15]([CH3:16])=[CH:14][C:13]([C:12]([F:20])([F:19])[F:11])=[N:10]1)[CH3:8]
Reactant: CCNN
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: ClCCl
Product: CCn1nc(C(F)(F)F)cc1C

Procedure:
A solution of 25.0 g (grams) (167 mmol) (millimoles) of ethylhydrazine oxalate in 50 mL (milliliters) of ethanol was added to a solution of 25.0 g (162 mmol) of 1,1,1-trifluoro-2,4-pentanedione in 200 mL of ethanol at ambient temperature with stirring. The mixture was heated to reflux with stirring for 18 hours and was then allowed to cool. The volatile components were removed by evaporation under reduced pressure and the residue obtained was taken up in 150 mL, of dichloromethane. The resulting solution was washed twice with 100 mL portions of water, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 19.1 g (66 percent of theory) of the title compound as an amber oil
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]2[S:25][C:24]3[N:26]4[C:17](=[CH:18][N:19]=[C:20]4[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)=[O:14])[CH2:5][CH2:4]1.C(N(CC)CC)C.Br[CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(O)C>[C:38]1([CH2:37][CH2:36][CH2:35][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([C:15]3[S:25][C:24]4[N:26]5[C:17](=[CH:18][N:19]=[C:20]5[CH:21]=[CH:22][CH:23]=4)[CH:16]=3)=[O:14])[CH2:5][CH2:4]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(NCCCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCCCC1CCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 1.0 g (2.41 mM) of N-[3-(4-piperidyl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.7 ml (12.2 mM) of triethylamine in ethanol (10 ml) was added 0.45 ml (2.96 mM) of 1-bromo-3-phenylpropane at room temperature and the mixture was refluxed under nitrogen for 20 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 30-50-100%) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([NH2:15])=[CH:4][CH:3]=1.[CH3:16]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]=[CH:16][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1ccc(Br)cc1Nc1ccccc1
Solvent: O
Solvent: COC(OC)OC
Product: Brc1ccc2ncn(-c3ccccc3)c2c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 5-bromo-N1-phenylbenzene-1,2-diamine (650 mg, 2.47 mmol) in HC(OMe)3 (15 mL) was added TsOH.H2O (38 mg, 0.2 mmol). The mixture was stirred at 100° C. for 4 h. Upon completion, the reaction solution was concentrated, the residue was extracted with EtOAc and washed with water. The organic layer was concentrated to give the crude 6-bromo-1-phenyl-1H-benzo[d]imidazole which was used in next step without further purification. LCMS (m/z): 273.1/274.1 [M+H]+/[M+2H]+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[NH:19]1[CH2:29][CH2:28][CH:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:21][CH2:20]1.C(O)C>O>[CH2:26]([O:25][C:23]([CH:22]1[CH2:28][CH2:29][N:19]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:3]=2)[CH2:20][CH2:21]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Fc1ccc2nc(-c3ccccc3)cc(Cl)c2c1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1

Procedure:
A mixture of 9.0 g of 4-chloro-6-fluoro-2-phenylquinoline prepared according to the procedure described in example 9(b) and 18 ml of ethyl isonipecotate was stirred and heated in an oil bath at 160°-165° for 2 hr. It was then cooled and diluted with water. Addition of ethanol caused a solid to form which was collected to give 7.2 g of product as white prisms, mp 120°-124°.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][O:6][C:4]([C:3]1[C:2]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:20]=2)=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COC(=O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1ccccc1-c1cccc([N+](=O)[O-])c1

Procedure:
n.m.r. (DMSO-d6) δ values include 3.61 (s, 3 H), 7.51 (d, 1 H), 7.58 (t, 1 H), 7.69 (m, 3 H), 7.88 (d, 1 H), 8.24 (d, 1 H); from methyl 2-bromobenzoate (1.53 g), tetrakis(triphenylphosphine)palladium(0) (270 mg) and 3-nitrophenylboronic acid (1.44 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH2:8][CH3:9])[CH:3]1[NH:6][C:4]1=[O:5].C(=O)([O-])O.[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.O>[CH2:15]([O:22][C:23]([NH:1][C@@H:2]([CH2:7][CH2:8][CH3:9])[CH:3]1[NH:6][C:4]1=[O:5])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC[C@H](N)C1NC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@H](NC(=O)OCc1ccccc1)C1NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution obtained by dissolving 3(S)-amino-2-caprolactam (5.00 g, 39.01 mmol) in THF (20 ml) and water (40 ml), sodium hydrogen carbonate (4.92 g, 58.56 mol) and benzyloxycarbonyl chloride (5.57 ml, 39.01 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 18 hours.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.[OH:12][CH:13]1[CH2:17][C:16](=[O:18])[CH:15]=[CH:14]1>O1CCCC1>[CH2:1]([C:16]1([OH:18])[CH2:17][CH:13]([OH:12])[CH:14]=[CH:15]1)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: O=C1C=CC(O)C1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC1(O)C=CC(O)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
30 ml of tetrahydrofuran was put in a reaction tube and cooled to -78° C., and n-butyllithium (as a 1.6M hexane solution; 13.8 ml, 22.08 mmmoles) was added dropwise. Then a solution of 4-hydroxy-2-cyclopentenone (987 mg; 10.1 mmoles) in 20 ml of tetrahydrofuran was added dropwise over about 20 minutes. The reaction mixture was washed with 8 ml of tetrahydrofuran. After 60 minutes, 40 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was vigorously shaken. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 ml×6). The extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column (Merck silica gel 30 g; hexane:ethyl acetate=4:1) to obtain 1.55 g (yield about 90%) of 4-butylcyclopent-2-ene-1,4-diol.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]=[C:15]([C:17]([N:19]3[CH2:23][CH2:22][C@@H:21]([O:24][CH3:25])[CH2:20]3)=[O:18])[S:16][C:9]=12.[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([OH:36])=[CH:31][CH:30]=2>CN(C=O)C>[CH3:25][O:24][C@@H:21]1[CH2:22][CH2:23][N:19]([C:17]([C:15]2[S:16][C:9]3[C:10](=[N:11][CH:12]=[CH:13][C:8]=3[O:36][C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:26])=[CH:35]4)[CH:14]=2)=[O:18])[CH2:20]1
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5[nH]c(C)cc5c4)c3s2)C1
Temperature: 90 °C
Yield: 84 %

Procedure:
Cs2CO3 (0.495 g, 1.52 mmol) was added to a solution of (3R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-methoxy-pyrrolidin-1-yl)-methanone (0.228 g, 0.76 mmol) and 2-methyl-1H-indol-5-ol (0.223 9, 1.52 mmol) in DMF (5 mL), and the resulting solution was heated to 90° C. After 20 h the reaction was quenched with water, EtOAc was added, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over Na2SO4 then concentrated. The resulting material was purified on silica gel by flash column chromatography, eluting with CH2Cl2/MeOH (98/2) to afford the title compound as a white solid (0.26 g, 84%). MS: 408.8 (MH+); HPLC Rf: 5.394 min.; HPLC purity: 97%.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH3:2].Br[CH2:13][C:14]#[N:15]>>[CH2:10]([N:3]([CH2:1][CH3:2])[CH:4]1[CH2:5][CH2:6][N:7]([CH2:13][C:14]#[N:15])[CH2:8][CH2:9]1)[CH3:11]
Reactant: CCN(CC)C1CCNCC1
Reactant: N#CCBr
Product: CCN(CC)C1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of Diethyl-piperidin-4-yl-amine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=196.2: 1HNMR(DMSO-d6) 3.65 (s, 2H), 2.80-2.75 (m, 2H), 2.45-2.30 (m, 5H), 2.15-2.05 (m, 2H), 1.70-1.60 (m, 2H), 1.45-1.35 (m, 2H), 0.95 (t, 6H).
Reaction SMILES: [ClH:1].[OH:2][C:3]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1>C(O)C.CO.[Pt]=O>[ClH:1].[OH:2][C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[OH:14])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCOC(=O)C(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A solution of 5.64 g (0.01 mole) of ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetate hydrochloride in 200 ml of absolute ethanol and 50 ml of methanol and 0.5 g of platinum oxide is hydrogenated at about 50 psi for about 1 hour until the infrared showed no evidence of a ketone carbonyl function. The solution is filtered and the filtrate concentrated leaving a residue which is recrystallized from butanone and methanol-butanone to give ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate HCl, M.P. 185°-187° C.
Reaction SMILES: CN(C(ON1N=[N:16][C:11]2[CH:12]=CC=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N)C.[F:29][CH:30]([F:62])[O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[N:36]=[C:35]2[C:42]1[N:43]=[C:44]2[C:50]([C:51]([OH:53])=O)=[CH:49][N:48]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[C:45]2=[N:46][CH:47]=1>CN(C=O)C>[F:62][CH:30]([F:29])[O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[N:36]=[C:35]2[C:42]1[N:43]=[C:44]2[C:50]([C:51]([NH:16][CH:11]([CH3:12])[CH3:10])=[O:53])=[CH:49][N:48]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:59])([CH3:60])[CH3:61])[C:45]2=[N:46][CH:47]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (28.0 mg, 73.5 μmol.20) and propan-2-amine (14.5 mg, 21.0 μL, 245 μmol) then 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (30 mg, 61.3 μmol) and DMF (2 mL). The reaction mixture was stirred at 25° C. for 15 h. Propan-2-amine (14.5 mg, 21.0 μL, 245 μmol) and HATU (28.0 mg, 73.5 μmol) were added. After 3 h the solvents were evaporated and the residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco, 0 to 50% EtOAc in hexanes over 30 min) to yield 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (32.5 mg, 61.3 μmol, 100%) as a light yellow solid. MS (M+Na)+=553.1; 1H NMR (CDCl3) δ: 9.25 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=2.3 Hz, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.45-7.53 (m, 1H), 7.36 (dd, J=8.9, 2.1 Hz, 1H), 6.53 (t, J=74.0 Hz, 1H), 5.73 (s, 2H), 4.38-4.59 (m, 1H), 4.21 (s, 3H), 3.55-3.64 (m, 2H), 1.42 (d, J=6.4 Hz, 6H), 0.88-1.03 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH2:12]Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C1C=CC=CC=1.O>[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH2:12][C:5]([CH3:12])([CH3:6])[CH:4]=[O:1]
Reactant: [OH-]
Reactant: COc1ccc(CCl)c(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(CC(C)(C)C=O)c(Br)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 103.7 %

Procedure:
A mixture of NaOH (4.9 g), and (Bu)4NI (1 g) in benzene (14 mL) and water (4.9 mL) was heated at 70° C. under argon to obtain a homogeneous mixture. To this mixture was added dropwise a mixture of isobutylaldehyde (10.1 g, 140 mmoles), and the product of Step 1 (25 g, 106 mmoles) in benzene (38 mL). After the addition, the resulting mixture was stirred at 70° C. for 6 h under argon. It was cooled, diluted with water, and extracted with EtOAc (3×150 mL). The combined organic extracts were washed with water, dried (Na2SO4) and concentrated to dryness. This residue was purified by silica gel flash chromatography using 5% EtOAc in hexane. The appropriate fractions (monitored by TLC) were combined and concentrated to dryness to give the desired product (14.9 g, ˜50%). NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: O[C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:10][CH3:11])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:10][CH3:11])=[CH:4][N:3]=1
Reactant: COc1cnc(O)c(OC)n1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cnc(Cl)c(OC)n1

Procedure:
Treatment of the above-obtained 2-hydroxy-3,5-dimethoxypyrazine with phosphorus oxychloride by the method described in Preparation 13, Step B, gives 2-chloro-3,5-dimethoxypyrazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[ClH:8].[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([NH:17][C:18](C1SC(C#N)=CC=1)=[O:19])[CH2:10]2>>[ClH:8].[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([NH:17][C:18]([C:5]1[S:4][C:3]([O:2][CH3:1])=[CH:7][CH:6]=1)=[O:19])[CH2:10]2
Reactant: N#Cc1ccc(C(=O)N[C@H]2CN3CCC2CC3)s1
Reactant: COc1cccs1
Agent: Cl
Product: COc1ccc(C(=O)N[C@H]2CN3CCC2CC3)s1

Procedure:
This compound is prepared from 2-methoxythiophene according to the procedure used to make the compound of Example 18, making non-critical variations. Yield for 2 steps 33%. HRMS (FAB) calculated for C13H18N2O2S+H 267.1167, found 267.1167.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)N.[Cl:9][C:10]1[CH:15]=[C:14]([C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:13]=[CH:12][N:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]2[NH:1][C:3]3=[N:4][CH:5]=[CH:6][N:7]=[C:8]3[C:17]=2[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:13]=[CH:12][N:11]=1
Reactant: O=C(Cc1ccc(F)cc1)c1ccnc(Cl)c1
Reactant: NNc1cnccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Fc1ccc(-c2c(-c3ccnc(Cl)c3)[nH]c3nccnc23)cc1
Reaction time: 2 h
Yield: 26.5 %

Procedure:
Hydrazinopyrazine (6.2 g, 57 mmol) and 1-(2-chloropyridin-4-yl)-2-(4-fluorophenyl)ethanone (14 g, 57 mmol) were suspended in benzene (250 ml) and p-toluenesulfonic acid monohydrate (0.68 g) was added. The reaction mixture was then refluxed with azeotropic removal of water via Dean Stark trap. After 2 h, the benzene was removed in vacuo and di-ethylene glycol was added. The reaction mixture was heated at reflux. After 2 h, the reaction mixture was poured into ether with vigorous stirring. Water was added and the product was extracted into ether. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Methanol was added and the solid was filtered off to give 6-(2-chloropyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine (4.9 g) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:20][C:21]1[O:25][C:24]([CH3:26])=[N:23][CH:22]=1>CN(C)C=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:20][C:21]2[O:25][C:24]([CH3:26])=[N:23][CH:22]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: Cc1ncc(CBr)o1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(NCc2cnc(C)o2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 57 %

Procedure:
To a solution of 33.63 parts of 1-amino-4-methoxy-2-nitrobenzene in 282 parts of N,N-dimethylformamide there were added 21.2 parts of sodium carbonate and a solution of 35.2 parts of 5-bromomethyl-2-methyloxazole in 94 parts of N,N-dimethylformamide. The whole was stirred for 20 hours at 70° C. and was then evaporated. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2C2 /CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from petroleum ether. The product was filtered off and dried, yielding 30 parts (57.0%) of N-(4-methoxy-2-nitrophenyl)-2-methyl-5-oxazolemethanamine (interm. 14).