Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][SH:6].[H-].[Na+].Cl[C:10]1[N:15]=[CH:14][C:13](/[C:16](/[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:18][CH3:19])=[CH:12][CH:11]=1>C1COCC1>[CH3:2][NH:3][CH2:4][CH2:5][S:6][C:10]1[N:15]=[CH:14][C:13](/[C:16](/[C:26]2[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=2)=[C:17](\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)/[CH2:18][CH3:19])=[CH:12][CH:11]=1
Reactant: CNCCS
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(SCCNC)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a stirred solution of 2-(methylamino)ethanethiol hydrochloride (217 mg, 10 eq) in 20 mL anhydrous THF was added NaH (120 mg, 12 eq) at 0° C. After the mixture was stirred at rt for 1 h, (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)-phenol (80 mg, 1.0 eq, made from example 1) was added. The reaction mixture was heated under reflux for 48 h, cooled, quenched with sat. NH4Cl, and extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (75 mg, 81% yield). 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J=2.4 Hz, 0.8 Hz, 1H), 7.13-7.21 (m, 3H), 7.05-7.10 (m, 4H), 6.95 (dd, J=8.4 Hz, 2.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 2H), 3.23 (t, J=6.4 Hz, 2H), 2.84 (t, J=6.4 Hz, 2H), 2.50 (q, J=7.2 Hz, 2H), 2.41 (s, 3H), 0.93 (t, J=7.2 Hz, 3H); m/z=391[M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH:20]1([CH2:26][NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl.CO>[CH:20]1([CH2:26][NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:16](=[O:18])[C:15]#[C:14][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:13][CH:12]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: Nc1ccc(CNCC2CCCCC2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(CNCC2CCCCC2)cc1

Procedure:
Prepared analogously to Example 3.8. from (4′-chlorobiphenyl-4-yl)propynoic acid and 4-[(cyclohexylmethylamino)methyl]phenylamine hydrochloride. Yield: 60 mg (13% of theory); melting point: 205° C.-210° C.; C29H29ClN2O (M=457.01); calc.: molecular ion peak (M+H)+: 457/459 (Cl); found: molecular ion peak (M+H)+: 457/459 (Cl); Rf value: 0.60 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [CH3:1][N:2]([CH:15](Cl)[CH:16]([CH3:18])C)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[C-:20]#[N:21].[K+].C1OCCOCCOCCOCCOCCOC1.O>C(#N)C>[CH3:1][N:2]([CH:15]([CH2:16][CH3:18])[C:20]#[N:21])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COc1ccc(CCN(C)C(Cl)C(C)C)cc1OC
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCC(C#N)N(C)CCc1ccc(OC)c(OC)c1
Yield: 87 %

Procedure:
4.67 g of 3-((N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-amino)- 2-methylpropyl chloride was dissolved in 40 ml of acetonitrile, followed by the addition of 2.13 g of potassium cyanide and 0.1 g of 18-crown-6. The obtained mixture was heated under reflux for 40 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: n-hexane/ethyl acetate (1:1)] to obtain 3.93 g of the title compound as a pale yellow oil (yield: 87%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:34]1[CH2:39][CH2:38][CH:37]([C:40]([NH2:42])=[O:41])[CH2:36][CH2:35]1>>[NH:2]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1)[N:34]1[CH2:39][CH2:38][CH:37]([C:40]([NH2:42])=[O:41])[CH2:36][CH2:35]1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: NC(=O)C1CCNCC1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCC(C(N)=O)CC1
Yield: 40 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalents of piperidine-4-carboxamide as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[OH:12])=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:20])[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[C@H:8]([OH:12])[CH2:9][N:10]([C:17]([N:16]([CH3:20])[CH3:15])=[O:18])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: OC1CNCC1Oc1ccc(Cl)cc1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1C[C@@H](O)[C@H](Oc2ccc(Cl)cc2)C1

Procedure:
A solution of 3.5 g. of 4-(4-chlorophenoxy)-3-pyrrolidinol, 1.8 g. of dimethylcarbamyl chloride and 1.7 g. of triethylamine in 300 ml of methylene chloride was stirred for 60 hr. The solvent was removed under vacuum, 300 ml of benzene was added and the mixture was refluxed for 2 hr., then filtered. After solvent evaporation, the residue was dissolved in cyclohexane-benzene and charcoaled. The product was then crystallized, collected by filtration and recrystallized from cyclohexane-benzene; m.p. 137°-142° C. Analysis: Calculated for C13H17N2O3Cl: C, 54.84; H, 6.02; N, 9.84. Found: C, 54.64; H, 6.01; N, 9.77.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[CH:14](OCC)=[O:15]>>[OH:15][CH:14]=[C:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: CCOC=O
Reactant: COc1ccc2c(c1)C(=O)CCC2
Product: COc1ccc2c(c1)C(=O)C(=CO)CC2

Procedure:
The expected product is prepared from 7-methoxy-1-tetralone and ethyl formate according to the procedure described in Organic Synthesis 1959, 39, 27.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[C:11]2=[O:26])[S:5][C:6]=1[C:7](O)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:40][C:41](=[NH:43])[CH3:42]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=3)[C:11]2=[O:26])[S:5][C:6]=1[C:7]1[O:8][N:43]=[C:41]([CH3:42])[N:40]=1
Reactant: CC(=N)NO
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(-c2sc(N3CCN(Cc4ccc(C(F)(F)F)cc4)C3=O)nc2C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid (0.39 g, 1.00 mmol) in N,N-dimethylformamide (10 mL) was added 1,1′-carbonyldiimidazole (0.24 g, 1.50 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes, and N-hydroxyacetamidine (0.08 g, 1.1 mmol) was added. The stirring was continued at ambient temperature for 6 hours, and another portion of N-hydroxyacetamidine (0.08 g, 1.1 mmol) was added. The reaction mixture was heated for 23 hours at 110° C. and cooled to ambient temperature, diluted with ethyl acetate and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, and filtered and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound in 15% yield (0.06 g): mp 163-164° C. (ethyl acetate): 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.1 Hz, 2 H), 7.41 (d, J=8.1 Hz, 2H), 4.55 (s, 2H), 4.15-4.09 (m, 2H), 3.51-3.45 (m, 2 H), 2.68 (s, 3H), 2.41 (s, 3H): 13C NMR (75 MHz, CDCl3) δ 170.8, 167.3, 160.5, 155.3, 154.5, 139.6. 128.5, 125.9, 125.8, 122.1, 109.0, 47.6, 421 41.9, 17.5, 11.6: MS (ES+) m/z 424.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([OH:23])=O)=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:24][C:25]([CH3:29])([CH3:28])[C:26]#[N:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([C:25]([NH:24][C:21]([C:18]1[C:16]2=[N:17][C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)=[CH:13][N:14]=[C:15]2[NH:20][CH:19]=1)=[O:23])([CH3:29])[CH3:28])#[N:27]
Reactant: CC(C)(N)C#N
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C#N)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.6 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (60 mg, 0.193 mmol), 2-amino-2-methylpropanenitrile (25 mg, 0.29 mmol), HATU (217 mg, 0.57 mmol) and DIEA (74 mg, 0.57 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Then the mixture was filtered and the cake was washed with DMSO and MeOH to give N-(2-cyanopropan-2-yl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (15 mg, 20.5%) as light yellow solid. MS: (M+H)+=400; 1H NMR (300 MHz, DMSO): δ 13.03 (s, 1H), 9.13 (s, 1H), 8.58 (s, 1H), 8.54-8.50 (m, 1H), 8.35 (s, 1H), 7.32-7.69 (m, 1H), 7.23-7.22 (m, 1H), 4.17 (s, 3H), 1.88 (s, 6H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=O)[CH3:19])[CH:2]=1.Cl.[NH2:22][OH:23].Cl>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[N:22][OH:23])[CH3:19])[CH:2]=1
Reactant: CC(=O)c1ccccc1Oc1cnc2ccccc2c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccccc1Oc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.1 %

Procedure:
0.46 g of 1-[2-(quinolin-3-yloxy)-phenyl]-ethanone and 0.15 g of hydroxylamine hydrochloride were dissolved in 3 ml of pyridine and then the mixture was stirred for 24 hours at room temperature. After the reaction mixture was treated with dilute hydrochloric acid and separated with ethyl acetate, the organic layer was concentrated to obtain 0.54 g of 1-[2-(quinolin-3-yloxy)-phenyl]-ethanone oxime (Compound Number 23).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH:13]1[NH:14][CH:15]=[C:16]2[C:21]=1[CH:20]=[CH:19][CH:18]=[CH:17]2>O1CCOCC1>[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][N:14]1[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: c1ccc2c[nH]cc2c1
Solvent: C1COCCO1
Product: c1ccc2c(c1)CN(CCc1c[nH]c3ccccc13)C2

Procedure:
A solution of 3-(2-bromo-ethyl)-1H-indole (4.48 g, 20 mmol) and isoindole (4.76 g, 40 mmol) in abs. dioxane (50 ml) was stirred at 80° C. for 6 h. The solvent was then removed i. vac., CHCl3 (100 ml) was added to the residue and the mixture was washed twice with water. The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (20:1).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH:18]([N:13]1[C:12]([C:34]2[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)n1nc2c(c1-c1ccc(C(F)(F)F)cc1)CCNCC2
Yield: 68.4 %

Procedure:
The title compound (103 mg) was prepared as in Example 177, Steps C and D, using 199 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 265 mg of 4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated for C17H20F3N3, 323.16. found, m/z 324.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.86 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 4.34 (m, 1H), 3.43-3.40 (m, 2H), 3.20-3.18 (m, 2H), 2.80-2.78 (m, 2H), 1.40 (d, J=6.6 Hz, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH:59][C:8](=[O:10])[CH2:7][CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[S:56][C:46]=2[C:47]([N:50]2[CH2:51][CH2:52][O:53][CH2:54][CH2:55]2)=[N:48][CH:49]=1
Reactant: O=C(O)CC1CCOCC1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)CC3CCOCC3)nc12

Procedure:
From tetrahydropyran-4-yl-acetic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 393 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:13](=[O:17])[CH2:14][CH2:15][CH3:16])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22](B(O)O)=[C:21]([O:29][CH3:30])[CH:20]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O>[CH2:11]([C:9]1[N:10]=[C:3]2[C:2]([C:20]3[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[CH:22][C:21]=3[O:29][CH3:30])=[N:7][CH:6]=[CH:5][N:4]2[C:8]=1[C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH3:12]
Reactant: COc1cc(C)cc(C)c1B(O)O
Reactant: CCCC(=O)c1c(CC)nc2c(Cl)nccn12
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CCCC(=O)c1c(CC)nc2c(-c3c(C)cc(C)cc3OC)nccn12
Yield: 77.5 %

Procedure:
1-(8-Chloro-2-ethylimidazo[1,2-a]pyrazin-3-yl)-1-butanone (226 mg, 0.90 mmol) and 4,6-dimethyl-2-methoxybenzeneboronic acid (198 mg, 1.1 mmol) were dissolved in a mixed solvent of 1,2-dimethoxyethane (4.5 mL) and water (0.75 mL). Barium hydroxide octahydrate (347 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium complex (79 mg, 0.068 mmol) were added thereto, and the mixture was heated under reflux for 4 hours under nitrogen atmosphere. After being allowed to cool, the reaction mixture was filtered and washed with ethyl acetate. Then, the filtrates were combined and washed with a 1N aqueous sodium hydroxide solution. It was extracted with ethyl acetate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give 1-[2-ethyl-8-(2-methoxy-4,6-dimethylphenyl)imidazo[1,2-a]pyrazin-3-yl]-1-butanone (245 mg) as a white amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[O:22][CH3:31])=[O:14])=[CH:6][CH:7]=1
Reactant: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)cc1-c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ncc(C(=O)N[C@@H]2CCCC[C@H]2OC)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a suspension of 5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-6-(2-methoxy-ethoxy)-nicotinamide (example 16, 50 mg) in THF (0.5 ml) was added sodium hydride dispersion (60% in mineral oil, 5.4 mg) at 0° C. The mixture was stirred at room temperature for 1 h. Methyl iodide (18.4 mg) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo. The product was purified by flash chromatography (SiO2, CH2Cl2=>CH2Cl2MeOH 9:1) to give 5-(4-chloro-phenyl)-N-((1R,2R)-2-methoxy-cyclohexyl)-6-(2-methoxy-ethoxy)-nicotinamide (27 mg) as a colorless oil. MS (ISP) 419.4 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][NH:25][CH2:24]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][N:25]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:24]2
Reactant: Clc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3Cc4ccc(Cl)cc4C3)c(F)cc2c1=O
Temperature: 110 °C
Yield: 62.6 %

Procedure:
A mixture of 136 mg of 1-cyclopropyl-6,7-difluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 123 mg of 5-chloroisoindoline, 122 mg of DBU, and 1.5 ml of anhydrous DMF was heated at 110° C. for 1.5 hours while stirring. The resulting reaction mixture was evaporated under reduced pressure to dryness. 20 ml of chloroform and 10 ml of 5% acetic acid were added to the residue thus obtained, and the mixture was stirred. The deposited crystals were collected by filtration and washed with water and then ethanol. The chloroform layer was separated, and washed with water, dried over anhydrous sodium sulfate, and condensed. The residue was crystallized by the addition of hot ethanol. After cooling the mixture, the crystals were collected by filtration. These crystals, combined with the crystals obtained above, were recrystallized from a mixed solvent of chloroform, methanol, and ethanol to obtain 128 mg of the target compound.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)(=O)=O.[I-:17].[K+]>CN(C)C=O>[I:17][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(I)C1
Temperature: 100 °C

Procedure:
A mixture of tert-butyl 3-[(methylsulfonyl)oxy]-1-azetidinecarboxylate (prepared as described in Synlett 1998, 379; 5.0 g, 19.9 mmol), and potassium iodide (16.5 g, 99.4 mmol) in N,N-dimethylformamide (25 mL), was heated at 100° C. for 42 h. The cooled mixture was partitioned between water and ethyl acetate, and the layers separated. The organic phase was dried over MgSO4, concentrated under reduced pressure and the residue azeotroped with xylene. The crude product was purified by flash column chromatography (dichloromethane as eluant) to give the title compound, 3.26 g.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[NH:4][N:3]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:40][C:41]1[CH:42]=[C:43]([C:48]2[CH:52]=[CH:51][N:50]([CH2:53][CH2:54][NH2:55])[N:49]=2)[CH:44]=[CH:45][C:46]=1[Cl:47]>C(Cl)Cl>[Cl:40][C:41]1[CH:42]=[C:43]([C:48]2[CH:52]=[CH:51][N:50]([CH2:53][CH2:54][NH:55][C:7]([C:5]3[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=3)=[O:9])[N:49]=2)[CH:44]=[CH:45][C:46]=1[Cl:47]
Reactant: Cc1cc(C(=O)O)[nH]n1
Reactant: NCCn1ccc(-c2ccc(Cl)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCn2ccc(-c3ccc(Cl)c(Cl)c3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a stirred solution of 3-methyl-1H-pyrazole-5-carboxylic acid (104 mg, 0.83 mmol) in DCM (2.0 ml) was added DIPEA (0.144 mL 0.81 mmol). EDCI (159 mg, 0.83 mmol) and HOBt (112 mg, 0.83 mmol). After 10 min 2-(3-(3,4-dichloro-phenyl)-1H-pyrazol-1-yl)ethanamine (102 mg, 0.40 mmol) was added to the reaction mixture as a solution in DCM (2.0 ml). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution and water. The organic phase was dried over Na2SO4, evaporated and purified by chromatography (CombiFlash, 1st column silica, eluent: 0-10% MeOH/DCM; 2nd column C-18 RP, eluent: 0-100% MeCN/water) to obtain 65 mg (45%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.24 (s, 3H), 3.64 (q, 2H), 4.31 (t, 2H), 6.36 (s, 1H), 6.81 (d, 1H), 7.65 (d, 1H), 7.77 (d, 1H), 7.80 (dd, 1H), 8.00 (d, 1H), 8.23 (s, 1H), 12.88 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]1[C:11]([Cl:12])=[C:10]([C:13]2[O:17][N:16]=[C:15]([CH2:18][OH:19])[C:14]=2[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2Cl)=[O:21])[N:9]=[N:8]1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CCOC(C)=O>[F:36][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1)[CH2:6][N:7]1[C:11]([Cl:12])=[C:10]([C:13]2[O:17][N:16]=[C:15]([CH2:18][OH:19])[C:14]=2[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:21])[N:9]=[N:8]1
Reactant: O=C(c1ccccc1Cl)c1c(CO)noc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1N1CCOCC1)c1c(CO)noc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Dissolve {5-[1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazol-4-yl]-3-hydroxymethyl-isoxazol-4-yl}-(2-chloro-phenyl)-methanone (0.10 g, 018 mmol) in morpholine (1.0 mL) and stir at 80° C. for 20 hours. Dilute the solution with EtOAc (25 mL) and wash with 1N HCl (20 mL), water (20 mL), and saturated NaHCO3 (20 mL) then dry, filter, and concentrate. Purify the crude material by flash chromatography to give the title compound: MS (IS) 615.9 (M+1), MS (ES−) 613.9 (M−1): 1HNMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.74 (s, 2H), 7.45 (dd, 1H, J=1.4, 7.5), 6.93 (dt, 1H, J=1.5, 7.4), 6.83 (dt, 1H, J=1.0, 7.4), 6.40 (m, 1H), 5.42 (s, 2H), 4.85 (d, 2H, J=7.3), 3.80 (t, 1H, J=7.3), 3.44 (m, 4H), 2.64 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)[CH:5]=[C:4]([F:19])[CH:3]=1.[Li]CCCC.[CH:25](N1CCCCC1)=[O:26].O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:12][CH:13]=2)[CH:5]=[C:4]([F:19])[C:3]=1[CH:25]=[O:26]
Reactant: O=CN1CCCCC1
Reactant: CCCCCc1ccc(-c2cc(F)cc(F)c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCc1ccc(-c2cc(F)c(C=O)c(F)c2)cc1
Yield: 78.9 %

Procedure:
In a 500-ml three-neck flask equipped with a stirrer, a thermometer and a dropping funnel, 15.0 g (57.6 mmol) of 2,6-difluoro-4-(4-pentylphenyl)benzene was dissolved in 100 ml of THF under nitrogen atmosphere, and 43 ml (69.1 mmol) of n-BuLi (1.6M cyclohexane solution) was added dropwise at −65° C. or lower while stirring, followed by further stirring for one hour. Then, 7.2 g (63.4 mmol) of formylpiperidine was added dropwise thereto at −65° C. or lower, and the solution was further stirred for 2 hours. 200 ml of water was added to the reaction mixture, which was extracted with 400 ml of toluene, and the toluene layer was washed twice with 200 ml of water and then dried over anhydrous magnesium sulfate. Toluene was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography with toluene as a developing solvent to obtain 13.1 g of 2,6-difluoro-4-(4-pentylphenyl)benzaldehyde.