Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[C:28]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:26][CH:25]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccc(F)cc4)C3)nc(N)n2)cc1F
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@H](C(=O)Nc3ccc(F)cc3)C2)n1
Temperature: 150 °C
Yield: 21.6 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(4-fluorophenyl)-3-piperidinecarboxamide (90 mg, 0.207 mmol), 3 mL of EtOH, Hunig's base (0.11 mL, 0.621 mmol), and hydrazine anhydrous (0.026 mL, 0.829 mmol) were added, and the yellow mixture was heated at 150° C. for 150 minutes in microwave. The solution turned black. LCMS showed mainly product with 10% of remaining starting material. The black solids were filtered, and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (20 mg) as a light yellow solid. LC-MS (ES) m/z=447 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.50 (m, 1H), 1.85 (m, 2H), 2.07 (m, 1H), 3.17 (m, 2H), 4.52 (m, 1H), 4.74 (m, 1H), 4.98 (m, 1H), 6.94-7.08 (m, 1H), 7.16 (m, 2H), 7.39 (s, 1H), 7.56-7.69 (m, 2H), 7.73 (s, 1H), 7.82-8.04 (m, 1H), 10.13 (m, 1H), 11.86-12.16 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[C:12](O)([CH3:20])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.O=S(Cl)[Cl:32]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[C:12]([Cl:32])([CH3:20])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C)(O)C(F)(F)C3
Solvent: c1ccncc1
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C)(Cl)C(F)(F)C3
Temperature: 50 °C

Procedure:
Into a glass vial containing the product from step (a) (231 mg, 0.710 mmol) dissolved in SOCl2 (2 ml), pyridine (1 μL, 0.0071 mmol) was added. The stirred reaction mixture was heated to 50° C. for 30 minutes. The volatiles were evaporated in vacuo and the residue diluted with water (50 ml). The aqueous mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the sub-title compound as a dark yellow oil (214 mg) that was used without further purification. MS: ESI (positive): 344 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)[CH:3]=1.[NH3:24]>CO>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:24])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cc(C)cc(C(C)C)n1
Solvent: CO
Product: Cc1cc(Nc2cc(Cl)nnc2C(N)=O)nc(C(C)C)c1
Temperature: 45 °C
Yield: 100 %

Procedure:
To a solution of ethyl 6-chloro-4-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazine-3-carboxylate (115 mg, 343 μmol) in methanol (1 mL) was added ammonia in methanol (7 N, 4.91 mL, 34.3 mmol) and then the mixture heated at 45° C. for 20 h. The mixture was concentrated in vacuo to give 6-chloro-4-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazine-3-carboxamide (105 mg, 343 μmol, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H), 9.25 (s, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 6.87 (s, 1H), 6.77 (s, 1H), 3.01 (m, 1H), 2.31 (s, 3H), 1.28 (d, J=6.6 Hz, 6H); MS (EI/CI) m/z: 305.9 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][CH2:41][CH:40]([OH:44])[CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][CH2:41][CH:40]([OH:44])[CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: OC1CCCNC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCCC(O)C3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperidin-3-ol according to conditions described in general procedure C. Mp: 93-95° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.24-1.26 (m, 2 H), 1.58-1.60 (m, 7 H), 1.75-1.85 (m, 1 H), 2.68-2.80 (m, 2 H), 3.27-3.36 (m, 6 H), 4.80 (d, J=4.0 Hz, 1 H), 6.14 (d, J=5.5 Hz, 1 H), 6.95 (d, J=12.8 Hz, 1 H), 7.14 (d, J=9.1 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.61 (m, 3 H), 7.82-7.84 (m, 1H), 7.97 (d, J=7.3 Hz, 1H), 8.22 (d, J=5.4 Hz, 1H), 10.44 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH:17]C(=O)C)=[CH:16][C:11]=3[N:10]=[C:9]2[C:21]([CH3:25])([CH3:24])[CH2:22][CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CCO>[CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:21]([CH3:24])([CH3:25])[CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(C)(C)c1nc2cc(NC(C)=O)ccc2n1CC1CCCCC1
Agent: Cl
Solvent: CCO
Product: CCC(C)(C)c1nc2cc(N)ccc2n1CC1CCCCC1

Procedure:
N-[1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-yl]acetamide (110.0 mg, 0.32 mmol) was dissolved in EtOH (3 mL) and 2N HCl (2 mL) in a Teflon-capped test tube. The vessel was irradiated by microvwave for 45 min. at 120° C. Upon evaporation of the solvent, the title compound was obtained as a grey white solid (117.8 mg, 100%). 1H NMR (400 MHz, CD3OD): δ 0.87 (t, J=7.52 Hz, 3H), 1.27 (m, 5H), 1.66 (m, 3H), 1.71 (s, 6H), 1.78 (m, 2H), 2.05 (q, J=7.42 Hz, 2H), 2.13 (m, 1H), 4.53 (d, J=7.62 Hz, 2H), 7.66 (dd, J=8.79, 1.56 Hz, 1H), 7.97 (d, J=1.76 Hz, 1H), 8.17 (d, J=8.79 Hz, 1H); MS (ESI) (M+H)+: 300.05.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:16][CH:15]([CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:36]1[C:44]2[C:39](=[C:40](B3OC(C)(C)C(C)(C)O3)[C:41]([F:45])=[CH:42][CH:43]=2)[CH:38]=[CH:37]1)(C(C)(C)C)(C)C>>[F:45][C:41]1[C:40]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:16][CH:15]([CH:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:39]2[C:44](=[CH:43][CH:42]=1)[NH:36][CH:37]=[CH:38]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)ccc2n1
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2nc(CN3CC(C4CCOCC4)C3)ccc2n1

Procedure:
Crude 4-(2-chloro-6-((3-(tetrahydro-2H-pyran-4-yl)azetidin-1-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (0.1 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 49 mg of 111 following reverse phase HPLC purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[BH4-].[Na+]>CO>[O:13]1[CH2:14][CH2:15][N:10]([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:11][CH2:12]1
Reactant: C1COCCN1
Reactant: O=Cc1cccc(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Oc1cccc(CN2CCOCC2)c1
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a solution of 0.2 mol of 3-hydroxybenzaldehyde in 100 ml of methanol, is added, at about 20° C., a solution of 0.4 mol of morpholine in 40 ml of methanol. To the mixture thus obtained is added portionwise, under stirring at the temperature of 20°-25° C. within about 90 minutes, 0.2 mol of sodium borohydride, then the reaction mixture is stirred 3 hours at room temperature and the solvent is evaporated under reduced pressure to dryness. The residue is taken up with ice and acidified with hydrochloric acid, the acid solution is washed twice with 40 ml of ethyl acetate and concentrated ammonium hydroxide is added thereto up to clearly basic reaction. The mixture is extracted 4 times with 80 ml of ethyl acetate and the solvent is evaporated off. The product thus obtained melts at 113°-116° C. Yield: 67%.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[C:18]([CH2:21][N:22]([CH3:24])[CH3:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].N1C[CH2:36][O:35][CH2:34]C1>>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[C:18]([CH2:21][N:22]2[CH2:24][CH2:36][O:35][CH2:34][CH2:23]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1CN(C)C
Reactant: C1COCCN1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1CN1CCOCC1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(morpholinomethyl)naphthalen-2-yl)acetic acid (134) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-methylnaphthalen-2-yl)acetic acid of Example 131, except using morpholine in the reductive amination step. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H33ClNO4: 482.2; Found: 482.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:6]=2[N:7]=1.[CH3:20][NH2:21]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1cc(F)cc(C2CCc3c(Cl)nc(Cl)nc32)c1
Reactant: CN
Solvent: CO
Product: CNc1nc(Cl)nc2c1CCC2c1cc(F)cc(F)c1
Yield: 30.6 %

Procedure:
A solution of 2,4-dichloro-7-(3,5-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 0.664 mmol) and methanamine (0.664 mL, 1.328 mmol) in MeOH (3 mL) was stirred at rt for 1 h. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to give 2-chloro-7-(3,5-difluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (60 mg, 0.203 mmol, 30.5% yield). LC-MS (M+H)+=296.1.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:9](=[O:20])[N:8]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.S(S([O-])=O)([O-])(=O)=[O:30].[Na+].[Na+]>C(O)(=O)C>[C:1]1([N:7]2[C:11](=[O:12])[C:10]([OH:30])([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:9](=[O:20])[N:8]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: Cc1ccc(C2C(=O)N(c3ccccc3)N(c3ccccc3)C2=O)cc1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(C2(O)C(=O)N(c3ccccc3)N(c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 384 h

Procedure:
A mixture of 1,2-diphenyl-4-(4-methylphenyl)-3,5-pyrazolidinedione (1.10 g; 3.2 =mol), 35% H2O2 (0.47 ml; 5.5 mmol), and acetic acid (40 ml) was stirred 16 days at room temperature. Sodium metabisulfite (1.0 g) was added and excess acetic acid evaporated off. The residue was dissolved in hot ethyl acetate (25 ml) and benzene (25 ml) and filtered. After cooling to room temperature, the mixture was filtered and the residue recrystallized from 50% aqueous ethanol (20 ml) to give 0.58 g (53%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:51][C@@H:52]([CH2:66][C:67]3[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=3)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=3)=[O:16])[CH:12]=2)[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCn1ncc2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCn1ncc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 40 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To a mixture of 1-butyl-1H-indazole-6-carboxylic acid (0.2 g) in methylene chloride (20 mL) was added triethylamine (0.182 g), HOBT (126 g), and HATU (0.348 g). The mixture was stirred at 40° C. for 10 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.35 g) was added. The mixture was stirred at 40° C. for 3 h then poured into methylene chloride (50 mL), washed with water then brine, dried over anhydrous magnesium sulfate and concentrated under vacuum. Column chromatography on silica gel (100 mL) using 5% methanol in methylene chloride as eluent to give 0.2 g of the title compound: MS (ESI+) for C31H36F2N4O2 m/z 534.9 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([N:12]([CH3:14])[CH3:13])[N:6]=1)(=O)C.Cl.[CH3:16][C:17]([N:21]([CH3:23])[CH3:22])([CH3:20])[CH2:18]Cl>>[CH3:16][C:17]([N:21]([CH3:23])[CH3:22])([CH3:20])[CH2:18][NH:4][C:5]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([N:12]([CH3:13])[CH3:14])[N:6]=1
Reactant: CC(=O)Nc1nc(C)cc(N(C)C)n1
Reactant: CN(C)C(C)(C)CCl
Agent: Cl
Product: Cc1cc(N(C)C)nc(NCC(C)(C)N(C)C)n1

Procedure:
Following the procedure of Example 1 part A using 2-acetamido-4-methyl-6-dimethylaminopyrimidine and 2-methyl-2-dimethylaminopropyl chloride hydrochloride, there is obtained 2-(2-methyl-2-dimethylaminopropylamino)-4-methyl-6-dimethylaminopyrimidine.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]#[N:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15]>C1COCC1>[C:10]([CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:12]([O:13][CH2:14][CH3:15])=[O:16])#[N:11]
Reactant: CCOC(=O)OCC
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)c1ccccc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a solution of sodium hydride (24.5 g, 1.02 mol) in THF was added benzyl cyanide (50.0 g, 0.426 mol) at −10° C. The reaction mixture was stirred for 15 min at the same temperature. Diethyl carbonate (60.5 g, 0.512 mol) was added to the reaction mixture and the reaction mixture was allowed to come to room temperature and heated to 40° C. (Caution: Reaction will start suddenly and exothermic). The heating path was removed immediately once the reaction was started and the reaction mixture was cooled under ice/acetone. The solution was allowed to come to room temperature and stirred for 1 h. The reaction mass was cooled to 0° C. and quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (250 mL×3). The combined organic layer was washed with water (200 mL), brine solution (200 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give ethyl 2-cyano-2-phenylacetate as crude compound as crude compound (71.0 g). The crude compound was taken to the next step without further purification. LC-MS (M+H)+=190.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.45 (5H, m), 5.65 (1H, s), 4.18 (2H, m), 1.18 (3H, t, J=7.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:20]2[CH:25]=[C:24]([O:26]CC3C=CC=CC=3)[CH:23]=[CH:22][C:21]=2[CH3:34])[N:4]=[C:5]2[C:14]3[CH:13]=[C:12]([O:15][CH3:16])[C:11]([O:17][CH3:18])=[CH:10][C:9]=3[NH:8][C:7](=[O:19])[C:6]=12.CO.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:2]1[N:3]([C:20]2[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=2[CH3:34])[N:4]=[C:5]2[C:14]3[CH:13]=[C:12]([O:15][CH3:16])[C:11]([O:17][CH3:18])=[CH:10][C:9]=3[NH:8][C:7](=[O:19])[C:6]=12
Reactant: [H][H]
Reactant: COc1cc2[nH]c(=O)c3c(N)n(-c4cc(OCc5ccccc5)ccc4C)nc3c2cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2[nH]c(=O)c3c(N)n(-c4cc(O)ccc4C)nc3c2cc1OC
Yield: 62.3 %

Procedure:
A mixture of 3-amino-7,8-dimethoxy-2-(5-benzyloxy-2-methylphenyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (50 mg), 10% palladium/active carbon (50% water, 25 mg), methanol (20 ml) and ethyl acetate (20 ml) was stirred under the hydrogen atmosphere for 1 day. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was solidified by adding ethyl acetate-hexane. The solid was collected by filtration, washed with ethyl acetate-hexane, and then dried to obtain the target compound (25 mg).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[C:36]([F:39])([F:38])[F:37])[CH:25]=1.[OH-].[Na+].C(N(CC)CC)C>CN(C=O)C>[CH:1]1([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:9][C:10]3[C:15]=2[CH:14]=[CH:13][N:12]([CH2:23][C:24]2[O:28][N:27]=[C:26]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=4[C:36]([F:39])([F:37])[F:38])[CH:25]=2)[CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc(-c2[nH]c3cnccc3c2C2CCCCC2)cc1
Reactant: Fc1ccc(-c2cc(CCl)on2)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2cc(Cn3ccc4c(C5CCCCC5)c(-c5ccccc5)nc-4c3)on2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 26.2 %

Procedure:
To 3-cyclohexyl-2-phenyl-1H-pyrrolo[2,3-c]pyridine (9 mg, 33 μmol) and 5-(chloromethyl)-3-(4-fluoro-2-(trifluoromethyl)phenyl)isoxazole (11 mg, 39 μmol) in DMF (326 μL) was added 10% aqueous NaOH (16 mL, 39 μmol). After stirring 12 h at room temperature, the reaction was neutralized with triethylamine and the crude purified by reverse phase HPLC to provide 4.5 mg (27%) of the title compound: 1H NMR (CD3OD, 300 MHz) δ 9.2 (s, 1H), 8.36 (s, 2H), 7.55-7.72 (m, 8H), 6.82 (s, 1H), 6.12 (s, 2H), 3.04 (m, 1H), 1.78-2.06 (m, 7H), 1.30-1.50 (m, 3H); LCMS found 520.3 (M++H, C30H26F4N3O requires 520.5).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[S:16][CH:17]=2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[OH:5][S:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)[S:16][CH:17]=2)=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(-c2nc(-c3ccc(O)cc3)cs2)cc1OC
Reactant: O=S(=O)(O)Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(-c3ccc(OS(=O)(=O)O)cc3)cs2)cc1OC
Temperature: 50 °C
Reaction time: 12 h

Procedure:
2 ml of chlorosulfonic acid was dropwise added to 40 ml of pyridine at room temperature. The mixture was stirred at 50° C. for 12 hours. Thereto was added 0.33 g of 4-(4-hydroxyphenyl-2-(3,4-dimethoxyphenyl)thiazole. The mixture was stirred at 50° C. for 6 hours and then at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure. The residue was mixed with water and the resulting crystals were collected by filtration. The resulting 4-(4-hydroxysulfonyloxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole pyridinium salt was suspended in 3 ml of methanol. Thereto was added 5 ml of a 0.1N aqueous potassium hydroxide solution. The mixture was stirred at room temperature overnight, The reaction mixture was concentrated. The residue was dissolved in water. The solution was treated with 0.5 g of an ion exchange resin (Dowex 50Wx8), The filtrate was concentrated to obtain 0.04 g of 4-(4-hydroxysulfonyloxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.C(N(CC)CC)C.ClC(OCC)=O.[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].Cl>CN(C)C=O>[F:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH:30][C:11]([C:4]1[C:3]2[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=2[NH:6][CH:5]=1)=[O:13]
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Reactant: Nc1ccccc1F
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1F)c1c[nH]c2c1C(=O)CCC2
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 64.9 %

Procedure:
To a solution of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (538 mg, 3 mmol) and triethylamine (0.88 mL, 6.3 mmol) in N,N-dimethylformamide (15 mL) at 0° C. was added ethyl chloroformate (0.57 mL, 6 mmol). After stirring at 0° C. for 45 minutes, 2-fluoroaniline (0.58 mL, 6 mmol) wad added. The mixture was stirred for an additional 45 minutes, then allowed to stir at ambient temperature for 14 hours. The mixture was poured into aqueous 1.2 N hydrochloric acid and extracted 2× with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. To the residue was added aqueous 1N sodium hydroxide (10 mL) and ethyl alcohol (2 mL) and the mixture heated at reflux for 4.5 hours. After cooling in an ice water bath, the mixture was acidified with aqueous hydrochloric acid, the precipitate collected, rinsed with water and dried. Recrystallization from ethyl alcohol afforded N-(2-fluorophenyl)-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 46) (530 mg). mp 238-240° C.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([C:29]4([C:32]5[CH:33]=[C:34]6[C:39](=[CH:40][CH:41]=5)[N:38]=[CH:37][CH:36]=[CH:35]6)[CH2:31][CH2:30]4)=[CH:27][N:28]=3)[CH:25]=2)[CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].CN.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:10][C:11]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([C:29]4([C:32]5[CH:33]=[C:34]6[C:39](=[CH:40][CH:41]=5)[N:38]=[CH:37][CH:36]=[CH:35]6)[CH2:31][CH2:30]4)=[CH:27][N:28]=3)[CH:25]=2)[CH:17]=[CH:16][C:12]=1[C:13]([NH:4][CH3:1])=[O:14]
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylethylamine (14 μL, 0.081 mmol) was added to a mixture of 2-chloro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid (0.027 mmol), methylamine (2M in THF, 0.2 mL, 0.4 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14 mg, 0.032 mmol) in N,N-dimethylformamide (0.5 mL). The mixture was stirred at RT for 2 h, and then purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=454.1/456.0.