Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.C1(P(=[CH:33][CH:34]=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:33]/[CH:34]=[O:35])=[CH:6][CH:5]=1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: O=C/C=C/c1ccc(OC(F)(F)F)cc1
Yield: 59.7 %

Procedure:
570 mg (3.0 mmol) of 4-(trifluoromethoxy)benzaldehyde and 913 mg (3.0 mmol) of (triphenylphosphoranylidene)acetaldehyde were heated under reflux in 7.5 ml of toluene under nitrogen atmosphere for 1 hour and 45 minutes. The toluene was distilled off under reduced pressure and the thus obtained residue was purified over column chromatography using 20 g of silica gel. The fractions eluted with a mixed solvent of acetic acid-hexane (1:10) were collected to obtain 387 mg (yield: 60%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:46])[NH:5][C:6]1[C:10]2[CH:11]=[N:12][C:13]([NH:15][C:16]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])=[O:17])=[CH:14][C:9]=2[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:7]=1)[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([NH:3][C:4](=[O:46])[NH:5][C:6]1[C:10]2[CH:11]=[N:12][C:13]([NH:15][C:16]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:20])=[O:17])=[CH:14][C:9]=2[NH:8][N:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-1-(3-(3-ethylureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (0.046 mmol) was taken up in TFA (1 ml) and the reaction mixture stirred at room temperature for 1 h. Triethylsilane (0.008 ml, 0.046 mmol) was added drop wise, and the reaction mixture stirred for an additional 5 minutes. The mixture was concentrated, re-dissolved in DMSO (1.5 mL) and submitted for purification by mass-triggered preparative HPLC to afford (R)-1-(3-(3-ethylureido)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. TFA (9.2 mg, 0.019 mmol, 41.2% yield) as a white solid. MS ESI calc'd. For C18H27N7O2 [M+H]+ 368. found 368. 1H NMR (ppm, 600 MHz, DMSO): δ 9.67 (s, 1H); 9.08 (s, 1H); 7.81 (s, 1H); 7.36 (s, 1H); 7.31-7.32 (m, 4H); 7.19-7.22 (m, 1H); 4.81-4.86 (m, 1H); 3.16-3.20 (m, 2H); 1.39 (d, J=7.0 Hz, 3H); 1.07 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][N:11]3C2CCCCO2)=[C:5]([C:26](OCC)=[O:27])[N:4]([CH2:31][C:32]2[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=2)[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH3:1][C:2]1[C:6]([C:7]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][NH:11]3)=[C:5]([CH2:26][OH:27])[N:4]([CH2:31][C:32]2[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=2)[N:3]=1
Reactant: CCOC(=O)c1c(-c2cc(C(F)(F)F)cc3c2cnn3C2CCCCO2)c(C)nn1Cc1cnn(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nn(Cc2cnn(C)c2)c(CO)c1-c1cc(C(F)(F)F)cc2[nH]ncc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
A 100 mL round bottom flask was charged with ethyl 3-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-4-yl)-1H-pyrazole-5-carboxylate (0.745 g, 1.442 mmol) in THF (10 mL). The mixture was cooled to 0° C. A 1M solution of lithium aluminum hydride (4.33 mL, 4.33 mmol) in ether was added, and the reaction mixture was stirred at 0° C. for 1 hour. The reaction was quenched with 1N HCl (6 mL) at 0° C. and the product was extracted into EtOAc. The organic phase was washed with brine and dried over Na2SO4. The volatiles were removed by evaporation. The crude residue was dissolved in MeOH (5 mL). HCl (0.5 mL) was added and the mixture was stirred for 2 hours. The product was purified by LCMS, eluting with 30% ACN in H2O (containing 10 mM NH4HCO3) over a period of 10 minutes. The product-containing fractions were combined and the volatiles were evaporated using a GeneVac™ to give the title compound (0.178 g, 31.6%). 1H NMR (400 MHz, CD3OD) δ ppm 2.27 (s, 3H), 3.88 (s, 3H), 4.51 (s, 2H), 5.30 (s, 2H), 7.37 (d, J=1.26 Hz, 1H), 7.52 (s, 1H), 7.65 (s, 1H), 7.88 (s, 1H), 7.94-8.02 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C18H17F3N6O, 391.15. found 391.13.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:13][C@@H:12]2[C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:24][C:25]1[S:29][C:28]([CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[N:27][N:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:34]([O:33][C:32](=[O:38])[N:31]([C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:13][C@@H:12]2[C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:18][N:19]=2)[N:5]=[C:6]([CH3:8])[N:7]=1)[CH2:30][C:28]1[S:29][C:25]([CH3:24])=[N:26][N:27]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1nnc(CNC(=O)OC(C)(C)C)s1
Reactant: Cc1nc(Cl)cc(OC[C@H]2C[C@@H]2c2ccc(C(C)(C)O)cn2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(OC[C@H]2C[C@@H]2c2ccc(C(C)(C)O)cn2)cc(N(Cc2nnc(C)s2)C(=O)OC(C)(C)C)n1
Temperature: 85 °C
Yield: 99.2 %

Procedure:
The mixture of 8-3 (60 mg, 0.18 mmol), 8-4 (50 mg, 0.22 mmol), Cs2CO3 (88 mg, 0.27 mmol), Pd(OAc)2 (8.1 mg, 0.036 mmol), BINAP (25 mg, 0.040 mmol) in toluene (2.0 mL) was heated at 85° C. for overnight. Then the reaction mixture was diluted with EtOAc (20 mL), filtered and concentrated in vacuo to give crude product (94 mg) which was used for next step without further purification. LRMS (ES) calculated M+H for C26H34N6O4S: 527.24. Found: 527.2.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH3:15][N:16]=[C:17]=[O:18].C(OCC)(=O)C.O>C(Cl)Cl>[CH3:15][NH:16][C:17](=[O:18])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccc(NC(=O)NC)cc1
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-aminocinnamate (150 mg) in methylene chloride were added methyl isocyanate (0.06 ml) under nitrogen atmosphere at ambient temperature, and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into the mixture of ethyl acetate and water. The organic layer was washed with water twice, dried over magnesium sulfate, and concentrated in vacuo. The residue was crystallized from diisopropyl ether to give ethyl 4-(3-methylureido)cinnamate (136 mg).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:13])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2]>CO>[CH2:1]([C:3]1[N:4]=[C:5]([CH:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[OH:13])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2]
Reactant: CCc1nc(C(=O)c2cccs2)c2sccc2n1
Solvent: CO
Product: CCc1nc(C(O)c2cccs2)c2sccc2n1
Reaction time: 1.5 h
Yield: 65.7 %

Procedure:
A solution of 2-ethylthieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (170 mg, 0.6 mmol) in MeOH (10 mL) at room temperature was treated with NaBH (26 mg, 0.7 mmol), stirred for 1.5 h, concentrated in vacuo, treated with water (10 mL), extracted with EtOAc (2×10 mL) and purified by chromatography [SiO2; EtOAc] to give the title compound (109 mg, 64 %) as a pale yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26](F)[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1>>[CH:8]1([NH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([NH:20][C:21](=[O:32])[C:22]3[CH:27]=[C:26]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)[CH:25]=[CH:24][C:23]=3[N+:29]([O-:31])=[O:30])[CH:19]=2)=[O:13])[CH2:10][CH2:9]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: OC1CCNCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 13 which is concerned with the preparation of starting materials 4-hydroxypiperidine was reacted with N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-fluoro-2-nitrobenzamide to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-(4-hydroxypiperidin-1-yl)-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.68 (m, 2H), 1.43 (m, 2H), 1.82 (m, 2H), 2.30 (s, 3H), 2.84 (m, 1H), 3.25 (m, 2H), 3.82 (m, 3H), 4.76 (d, 1H), 7.04 (m, 2H), 7.28 (d, 1H), 7.56 (d, 1H), 7.96 (s, 1H), 8.02 (d, 1H), 8.36 (s, 1H), 9.90 (s, 1H); Mass Spectrum: M+Na+ 461.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25](O)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Product: CN1CCN(C(=O)c2cnn(C)c2C(=O)Nc2ccn3nc(-c4cccc(F)c4)nc3c2)CC1
Yield: 47.9 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (60 mg, 158 μmol) and 1-methylpiperazine (52.6 μl, 473 μmol) as starting materials. The reaction affords 2-methyl-4-(4-methyl-piperazine-1-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(3-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (35 mg, 48%) as light grey solid. mp.: 224-227° C., MS: m/z=263.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C@H:12]1[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)[CH:7]=[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:5]2=[O:30].Cl.O1CCOCC1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1)[CH:7]=[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:5]2=[O:30]
Reactant: CCOC(=O)c1cn([C@H]2CCCN(C(=O)OC(C)(C)C)C2)c2ncc(Br)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)c1cn([C@H]2CCCNC2)c2ncc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-ethyl 6-bromo-1-(1-(tert-butoxycarbonyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 30, 10.847 g, 22.58 mmol) was taken up in dichloromethane (10 mL) and added HCl 4M in Dioxane (113 mL, 451.63 mmol) while stirring at RT for 1 h. The solvent was removed in vacuo and the residue was triturated with DCM, ether and EtOAc to give the desired product as a yellow solid. (S)-ethyl 6-bromo-4-oxo-1-(piperidin-3-yl)-1,4-dihydro-1,8-naphthyridine-3-carboxylate (8.50 g, 90%) was recovered as the HCl salt. MS (ES)(M+H)+: 381 for C16H18BrN3O3.[HCl].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:11]N(C=O)C.C(Cl)(=O)C(Cl)=O.CO>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(Cl)n1
Reaction time: 1 h
Yield: 100 %

Procedure:
6-Chloropyridine-2-carboxylic acid (15.0 g, 0.11 mol) was dissolved in DCM (300 mL) and DMF (1.5 mL) and oxalyl chloride (27.4 g, 0.22 mol) was added dropwise over 10 min. The reaction mixture was stirred for 1 h, MeOH (50 mL) was added dropwise over 5 min and the reaction mixture was stirred for 1.5 h. The solvents were removed in vacuo and the residue azeotroped with DCM (2×150 mL) to give the crude title compound (16.5 g, 100%) as a green solid. LCMS (ES+): 154.5 [MH]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Br[CH:20]([CH2:28][CH3:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([F:17])([F:18])[F:1])[CH:20]([CH2:28][CH3:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:6][C:7]=1[C:13]([F:16])([F:14])[F:15])#[N:10]
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C(F)(F)F
Reactant: CCC(Br)C(=O)OC(C)(C)C
Product: CCC(C(=O)OC(C)(C)C)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in step B of example 1 using 4-[(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and tert-butyl 2-bromobutanoate: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.8 Hz, 1H), 7.14 (d, J=2.7 Hz, 1H), 7.00 (dd, J=8.8, 2.8 Hz, 1H), 4.05 (m, 3H), 2.12 (m, 1H), 1.93 (m, 1H), 1.41 (s, 9H), 1.02 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:26][CH:25]3[CH2:24][CH:23](O)[CH2:22][CH2:21]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.C(N(S(F)(F)[F:34])CC)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]34[CH2:26][CH:25]3[CH2:24][CH:23]([F:34])[CH2:22][CH2:21]4)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CCC(O)CC2C3)cc1F
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(C2CC2)c(OCC23CCC(F)CC2C3)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((4-hydroxybicyclo-[4.1.0]heptan-1-yl)methoxy)benzoate (0.13 g, 0.41 mmol) in chloroform (2 mL) was added diethylaminosulfur trifluoride (0.11 mL, 0.89 mmol). The reaction solution was stirred at ambient temperature for 16 h and quenched with slow addition of aqueous saturated sodium hydrogencarbonate. The reaction mixture was extracted with dichloromethane. The solvent was concentrated in vacuo to dryness. The residue (0.10 g) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.15 g, 1.30 mmol) was added. The reaction mixture was stirred for 2 h and the solvent was concentrated in vacuo to obtain the title compound as a gum (0.080 g, 95%). The residue was carried forward without any further purification in next reaction: MS (ES−) m/z 321.1 (M−1).
Reaction SMILES: C[N:2](C)[CH:3]=[O:4].[CH3:6][O:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10](Cl)=O>O>[OH:7][C:8]1[CH:16]=[CH:15][C:10]([C:9]2[C:8]([O:7][CH3:6])=[C:16]([CH:15]=[C:14]([O:17][CH3:18])[CH:13]=2)[C:3]([NH2:2])=[O:4])=[C:13]([CH3:14])[CH:9]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(OC)c(C(=O)Cl)c1
Solvent: O
Product: COc1cc(C(N)=O)c(OC)c(-c2ccc(O)cc2C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
4-Amino-3-metlhylphenol (304 mg, 2.47 mmols) was put into a 30-ml conical flask, purged with argon, and dissolved in 10 ml of dry dimethylformamide (DMF). Next, a DMF solution (2 ml) of 2,5-dimethoxybenzoyl chloride (708 mg, 3.53 mmols) was added, and stirred at room temperature for 12 hours. The resulting reaction mixture was poured into 75 ml of cold water, suction-filtered, extracted with methylene chloride, and washed with water. The methylene chloride layer was dried with sodium sulfate, and the methylene chloride was removed by evaporation under reduced pressure. Next, the residue was purified by column chromatography (silica gel eluted with methylene chloride) to obtain 302 mg of the intended product, 4-hydroxy-2-methylphenyl-2,5-dimethoxybenzamide (yield: 43%).
Reaction SMILES: C(O[CH:6]([N:10]([CH3:12])[CH3:11])[N:7]([CH3:9])[CH3:8])(C)(C)C.[CH3:13][O:14][CH2:15][C:16]#[N:17]>>[CH3:12][N:10]([CH3:11])[CH:6]([N:7]([CH3:8])[CH3:9])[CH:15]([O:14][CH3:13])[C:16]#[N:17]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COCC#N
Product: COC(C#N)C(N(C)C)N(C)C
Yield: 33.2 %

Procedure:
360 g of 1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (Bredereck's reagent) (2068 mmol, 1.0 eq.) and 150 g of methoxyacetonitrile (2068 mmol, 1.0 eq.) were stirred for 18 h at 80° C. The reaction mixture was concentrated in vacuo. The residue was purified by vacuum distillation to yield 117 g (687 mmol, 33.0%) of the analytical pure target compound as a yellowish liquid.
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:9]=[C:8]1[CH3:22])[CH3:2].[NH3:27]>>[CH2:1]([C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[NH:5][CH:6]=[C:7]1[C:11](=[O:12])[N:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH2:27])=[O:18])=[CH:20][CH:21]=2)[N:9]=[C:8]1[CH3:22])[CH3:2]
Reactant: N
Reactant: CCc1ccccc1NC=C1C(=O)N(c2ccc(C(=O)O)cc2)N=C1C
Product: CCc1ccccc1NC=C1C(=O)N(c2ccc(C(N)=O)cc2)N=C1C

Procedure:
From the reaction of 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzoic acid and diluted ammonia solution, 4-(4-(2-ethylanilinomethylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzamide is obtained, Mp 225.2° C.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15]OS(C)(=O)=O)=[O:11])[CH2:5][CH2:4]1)[CH3:2].Cl.[Cl:22][C:23]1[C:24]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.Cl.ClC1C=C(N2CCNCC2)C=CC=1>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][N:36]2[CH2:37][CH2:38][N:33]([C:24]3[C:23]([Cl:22])=[CH:28][C:27]([C:29]([F:32])([F:31])[F:30])=[CH:26][N:25]=3)[CH2:34][CH2:35]2)=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2COS(C)(=O)=O)CC1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(Cl)c1
Agent: Cl
Agent: Clc1cccc(N2CCNCC2)c1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)CC1

Procedure:
Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester (Example 13d) for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein to obtain the title compound LC/MS m/z=473 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].F[C:22](F)(F)[C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.O>CN1C(=O)CCC1>[C:1]([C:5]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCc2[nH]c3ccc(C(C)(C)C)cc3c2C1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(CCn2c3c(c4cc(C(C)(C)C)ccc42)CN(C)CC3)cn1
Reaction time: 0.17 h
Yield: 10.1 %

Procedure:
To a solution of 8-tert-butyl-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200 mg, 0.82 mmol) in NMP (3.0 ml), powdered KOH (462 mg, 8.23 mmol) was added and stirred for 10 min at 25 deg C. After which 2-(trifluoromethyl)-5-vinylpyridine (286 mg, 1.65 mmol) was added slowly to the above solution and stirred for 14 h at 25 deg C. After completion of the reaction (monitored by LCMS), water (5 mL) was added to the crude and extracted with the ethylacetate. The organic layer was dried and concentrated. The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 30 mg of 8-tert-butyl-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole as TFA salt
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:5]=[N:6][CH:7]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[Cl:25][C:24]1[CH:23]=[N:22][C:21]2[NH:1][C:2]3[CH:7]=[N:6][CH:5]=[C:4]([CH:3]=3)[CH2:8][CH2:9][C:10]3[CH:11]=[C:12]([NH:18][C:19]=1[N:20]=2)[CH:13]=[CH:14][C:15]=3[O:16][CH3:17]
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)cc1CCc1cncc(N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 85.2 %

Procedure:
Into the reaction was added N-{3-[2-(5-aminopyridin-3-yl)ethyl]-4-methoxyphenyl}-2,5-dichloropyrimidin-4-amine (1.75 g, 4.48 mmol), 1,4-dioxane (29 mL), N,N-dimethylformamide (29 mL), palladium acetate (30 mg, 0.1 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (90 mg, 0.2 mmol), and cesium carbonate (2.92 g, 8.97 mmol). The mixture was degassed with N2 bubbling and then microwaved at 150° C. for 20 min. After concentration to remove the solvent, 20 mL of water was added to the residue. The formed precipitate was then collected by vacuum filtration and air dried overnight to give the desired product (1.35 g, 85%). LCMS for C18H17ClN5O (M+H)+: m/z=354.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O.O1CCOCC1>[CH2:20]([O:19][C:17]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of piperidine-4-carboxylic acid in a 1:1 mixture of H2O/dioxane (0.4 M), 5 eq of K2CO3 were added before dropwise introduction at 0° C. of 1.1 eq of benzyl chloroformate. The reaction was stirred at RT overnight. The reaction was first washed with Et2O. The aqueous phase was acidified to pH 2 with aqueous HCl (6N) before being extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the product (91%); MS (ES+) m/z 264 (M+H)+