Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[OH:34])[N:17]=2)[CH2:12]1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37].ClC([O-])=O>C1COCC1>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:34])[C:27]=1[C:18]1[N:17]=[C:16]([N:13]2[CH2:14][CH2:15][C@@H:11]([NH:10][C:36](=[O:37])[O:38][CH2:39][CH3:40])[CH2:12]2)[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[N:19]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3c(O)cccc3F)nc2c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N[C@@H]1CCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1
Temperature: -40 °C
Yield: 93.2 %

Procedure:
At RT, diisopropyl ethylamine (130 μL, 0.74 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (125 mg, 0.37 mmol) in THF (10 mL), and the reaction was cooled to −40° C. Ethyl chloroformate (33 μL in 0.33 mL THF, 0.34 mmol) was added dropwise over a period of 10 minutes. After addition of the chloroformate was complete, the reaction mixture was warmed to RT, quenched with H2O, and extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-10% EtOAc in a 1:1 mixture of hexanes and CH2Cl2 to give (R)-ethyl 1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 10) (130 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J=8.6 Hz, 1H), 7.58-7.57 (m, 2H), 7.38-7.29 (m, 2H), 6.76 (d, J=8.3 Hz, 1H), 6.72-6.67 (m, 1H), 4.25-4.21 (m, 1H), 4.16-4.13 (m, 2H), 4.07-3.97 (m, 3H), 3.84-3.82 (m, 1H), 2.52 (s, 3H), 2.24-2.16 (m, 1H), 2.04-2.00 (m, 1H), 1.16 (t, J=7.1 Hz, 3H) ppm. LC/MS: m/z 411.3 (M+H)+ at 2.24 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[OH:19][CH:20]([CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1[CH:31]=O)=[O:24].N1CCCCC1>C(O)C>[OH:19][CH:20]([CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1/[CH:31]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[CH:17]=[CH:16][CH:15]=2)=[O:24]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(/C=C2\C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)[nH]1
Yield: 60 %

Procedure:
4-(3-Chloro-4-fluoro-phenyl)-1,3-dihydro-indol-2-one (78.3 mg, 0.3 mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolid-1-yl-propyl)-amide (excess) and piperidine in ethanol to give 75 mg (60%) of the titled compound as a yellow solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[N+]=[N-])=[CH:7][CH:6]=1)([OH:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C1COCC1>[C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1)([OH:3])=[O:2]
Reactant: [N-]=[N+]=NCCCCc1ccc(CC(=O)O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCCCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
Azide 7 (1.7 g, 7.2 mmol) and triphenylphosphine (1.9 g, 7.2 mmol) were dissolved in a 10% solution of water in THF (66 mL) and stirred overnight at 25° C. Then more triphenylphosphine (0.8 g, 3 mmol) was added and the heating was continued at 60° C. (oil bath) for 6 h. The solvent was removed under reduced pressure and the residue was treated with 2M HCl (100 mL) and extracted with ethyl acetate (2×50 mL). The water fraction was collected and ammonium hydroxide was added until the pH reached approximately 13. The mixture was extracted with ethyl acetate (2×100 mL) then the organic fraction was washed with brine, water and dried with sodium sulfate. Ethyl acetate was removed under reduced pressure to give 0.8 g (53%) of amine 8.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>O1CCOCC1>[S:20]1[CH:24]=[CH:23][C:22]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)=[CH:21]1
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Solvent: C1COCCO1
Product: O=C(O)c1csc(COc2ccc(-c3ccsc3)cc2)n1

Procedure:
A solution of 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2; 78 mg, 0.2 mmol) in dioxane (2 mL) was degassed with nitrogen and then added to a reaction vial containing thiophene-3-boronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). The solution was sonicated and degassed and a solution of potassium carbonate (1.5 M, 0.4 mL) was added, followed by bis(tri-cyclo-hexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 7 mg, 0.01 mmol) was added. The mixture was degassed and then heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was evaporated in the Genevac to give 2-(4-thiophen-3-yl-phenoxymethyl)-thiazole-4-carboxylic acid. Mass spectrum MH+=318.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:52][C:53]1[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[CH3:52][C:53]1[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][C:54]=1[NH:60][CH:61]1[CH2:66][CH2:65][N:64]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:63][CH2:62]1
Reactant: Cc1ccc(C)c(NC2CCNCC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(C)c(NC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.097 g, 0.00040 mol) in DMF (1 mL) was added DIPEA (0.233 g, 0.00180 mol), HOBt (0.053 g, 0.00040 mol) and EDCI.HCl (0.138 g, 0.00072 mol) at ambient temperature. After 2 minutes (2,5-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00036 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.12 g (77%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2,5-dimethyl-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 432.23 (M+1)+, 96.91%, 1H NMR (DMSO-d6): δ 8.1 (s, 1H), 7.8 (d, 2H), 7.5 (t, 2H), 7.4 (t, 1H), 7.1 (s, 1H), 6.8 (d, 1H), 6.5 (s, 1H), 6.3 (d, 1H), 4.4 (d, 2H), 4.2 (bs, 2H), 3.9 (d, 1H), 3.6 (bs, 1H), 3.2 (t, 1H), 2.8 (t, 1H), 2.2 (s, 3H), 2.0 (s, 3H), 1.9 (d, 1H), 1.5 (d, 1H), 1.3 (d, 1H).
Reaction SMILES: [Cl-].[Cl:2]C(=[N+](C)C)Cl.C(Cl)(Cl)=O.[CH:12]1([NH:18][S:19](=[O:22])(=O)[OH:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCCl>[CH:12]1([NH:18][S:19]([Cl:2])(=[O:22])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=S(=O)(O)NC1CCCCC1
Reactant: C[N+](C)=C(Cl)Cl
Agent: O=C(Cl)Cl
Agent: [Cl-]
Solvent: ClCCCl
Product: O=S(=O)(Cl)NC1CCCCC1
Yield: 68 %

Procedure:
15 parts of dichloromethylenedimethylammonium chloride, suspended in 540 parts of 1,2-dichloroethane, are saturated with 40 parts of phosgene at 35° C, whilst stirring. 89.6 parts of cyclohexylsulfamic acid are now added and a further 550 parts of phosgene are then introduced in the course of 15 hours at 83° C, whilst stirring. After removing excess phosgene, and the solvent, under reduced pressure, 67.2 parts (68% of theory) of cyclohexylsulfamic acid chloride of boiling point 100°-114° C/0.01 mm Hg and melting point 43°-47° C are obtained by distillation of the residue.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[BrH:13]>>[BrH:13].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2
Agent: Br
Product: Oc1ccc2c(c1)CCNC2

Procedure:
6-Methoxy-1,2,3,4-tetrahydroisoquinoline (2.89 g) was dissolved in 48% aqueous hydrogen bromide solution (70 ml) and the mixture was refluxed for 2 hours. The solvent was evaporated and to the obtained residue were added ethanol and diethyl ether. The mixture was filtrated and dried under reduced pressure to give the title compound (3.93 g).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[NH:24][C:23](=[O:26])[CH:22]=[N:21]4)[CH:10]=2)=[CH:5][CH:4]=1.[C:29]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[CH3:29][N:24]1[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:1])[F:28])=[CH:4][CH:5]=3)[N:14]=[CH:13][N:12]=2)[N:21]=[CH:22][C:23]1=[O:26]
Reactant: O=c1cnc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)cnc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 8-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-1H-quinoxalin-2-one, (Example 32(e)), (0.10 g, 0.26 mmol) and K2CO3 (0.043 g, 0.31 mmol, Aldrich) in DMF (1 mL) was added iodomethane (0.019 mL, 0.31 mmol, Aldrich). The mixture was stirred at room temperature for 20 h, diluted with water and extracted with 25% i-PrOH/CHCl3 (3×). After being concentrated in vacuum, the residue was purified by flash chromatography (0→2% 2M NH3 in MeOH/CH2Cl2) to afford the title compound as an off-white amorphous solid. Mp:158° C. MS (ESI, pos. ion) m/z: 399 (M+1).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].C(OCC)(=O)C>CCO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in EtOH (15 ml). The mixture was stirred at about 70EC for 4 h (it became clear and turned to a slurry), after which the starting material was not detected by HPLC. Then, 40 ml of ethyl acetate was dripped into the mixture and it was cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with ethyl acetate (10 ml) and dried at 50EC in a vacuum oven for 24 h to obtain fluvastatin sodium Form XXXVIII (1.78 g, 87.4%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:29][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:3]=1
Reactant: CCCCCCCCCCCCN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(dodecylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, n-dodecylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C1(SC)C=CC=CC=1.C([O:16][C:17]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][S:48][CH2:47][CH2:46]2)=[CH:38][C:18]=1[C:19]([NH:21][C:22]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:20])C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:16][C:17]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][N:45]2[CH2:46][CH2:47][S:48][CH2:49][CH2:50]2)=[CH:38][C:18]=1[C:19]([NH:21][C:22]1[CH:31]=[C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:20]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCSCC2)ccc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCSCC2)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
Thioanisole (3.2 mL) and trifluoroacetic acid (10 mL) were added to the obtained methyl 2-(2-(benzyloxy)-5-(2-(thiomorpholin-4-yl)ethoxy)benzamido)-4-phenylbenzoate (0.80 g), followed by stirring at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and chloroform were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 70-0% hexane/ethyl acetate to 100-95% chloroform/methanol] to obtain 0.54 g of methyl 2-(2-hydroxy-5-(2-(thiomorpholin-4-yl)ethoxy)benzamido)-4-phenylbenzoate as a brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].N1C=CN=C1.[C:16]1([Si:22](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][Si:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:23]([CH3:26])([CH3:24])[CH3:25])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC(=O)c1cccc(O)c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
To stirred solution of 50.4 g of 3-hydroxybenzoic acid in 200 ml of dry dimethylformamide at 0° C. was added 24.85 g of imidazole, followed by 100 g of diphenyl-(2-methylprop-2-yl)silyl chloride. The mixture was stirred at room temperature for 16 hours, and partitioned between ethyl acetate and cold water. The organic layer was washed with water, with an aqueous potassium hydrogen carbonate solution and with brine, was dried over anhydrous magnesium sulphate and evaporated to dryness. The resulting white solid was slurried in dry chloroform and filtered to afford 72 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5]C[O:3]1.[CH3:7][Mg]Cl.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15](C=C(C(OCC)=O)[N:19]=2)[N:16]=1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:5]=[C:6]([C:2]([OH:3])([CH3:1])[CH3:7])[N:19]=2)[N:16]=1
Reactant: CCOC(=O)c1cn2nc(Cl)ccc2n1
Reactant: C[Mg]Cl
Reactant: CC1CCCO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(O)c1cn2nc(Cl)ccc2n1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-methyltetrahydrofuran (0.45 mL, 4.43 mmol) in toluene (6.1 mL) was cooled to −20° C. and methylmagnesium chloride (14.8 ml, 44.3 mmol) was added dropwise over five minutes. The solution was stirred for 30 minutes at −20° C., warmed to 0° C. and stirred for 15 minutes, and then re-cooled to −20° C. Ethyl 6-chloroimidazo[1,2-B]pyridazine-2-carboxylate (1 g, 4.43 mmol) was added in portions and the resulting mixture was stirred at 0° C. for 30 minutes then poured into a flask containing 40 ml of cooled (0° C.) 1 N HCl, diluted with ethyl acetate (40 mL) and stirred for ten minutes. The resulting organic layer was washed with saturated aqueous sodium bicarbonate and sodium chloride. The aqueous later was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, concentrated, and purified via silica gel chromatography (0-15% methanol in dichloromethane) to afford the title compound as a white solid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=C(C(O)=O)[CH:10]=2)[NH:5][CH:4]=1)=O.Cl.[NH2:16]O.C([O-])(=O)C.[Na+].[C:23]([O:26][C:27](=[O:29])[CH3:28])(=O)C>C(O)(=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:28]([C:27]([O:26][CH3:23])=[O:29])[CH:10]=2)[NH:5][CH:4]=1)#[N:16]
Reactant: NO
Reactant: O=Cc1c[nH]c2ccc(C(=O)O)cc12
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]cc(C#N)c2c1
Reaction time: 12 h

Procedure:
A mixture of 3-formylindole-5-carboxylic acid (3.47 g), hydroxylamine hydrochloride (1.97 g) and sodium acetate (2.41 g) in acetic acid (30 ml) was stirred for 12 hours, then acetic anhydride (15 ml) was added to the mixture and allowed to react under reflux for 5 hours. After cooling, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. Methanol was added to the residue and the mixture was reevaporated under reduced pressure. Thionyl chloride (8 ml) and small amounts of N,N-dimethylformamide was added to the residue obtained above in dichloromethane (20 ml). After being stirred for 2 hours at room temperature, the reaction mixture was evaporated under reduced pressure, and the residue was treated with methanol and concentrated under reduced pressure. The residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and chloroform. The fractions containing the objective compounds were combined and concentrated under reduced pressure to give methyl 3-cyanoindole-5-carboxylate (2.87 g).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]1([C:16]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=2[C:18](O)=[O:19])[CH2:15][CH2:14][CH2:13]1>>[CH:12]1([C:16]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:17]=2[C:18]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:19])[CH2:13][CH2:14][CH2:15]1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CCC1
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1ccc(C(F)(F)F)cc1C1CCC1

Procedure:
The title compound, light orange solid, MS: m/e=381.4 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-cyclobutyl-4-trifluoromethyl-benzoic acid (intermediate AP).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[F:26]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][C:18]=1[F:26]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-3-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H10ClFN4, 314. Found, 313, 315.
Reaction SMILES: [CH2:1]([NH:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC[O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O>[CH2:1]([N:8]1[C:19](=[O:18])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c[nH]n(Cc2ccccc2)c1=O

Procedure:
Benzyl hydrazine (324 mg, 2.65 mmol) in water (15 ml) containing potassium carbonate (368 mg, 2.65 mmol) was treated with diethyl ethoxymethylene malonate (575 μl, 2.65 mmol) and the whole refluxed for 3 hours. The reaction mixture was allowed to cool and then washed with ethyl acetate. The aqueous solution was then acidified (HCl) to pH 2 and extracted with ethyl acetate. The ethyl acetate extraction was dried (MgSO4) and evaporated to give the title product as an oily solid which solidified on hexane trituration 265 mg, 41%), recrystallised from aqueous ethanol, mp 79°-81° C. νmax (CHCl3) 1720, 1659, 1575 cm-1. δ(CDCl3) 1.37 (3H, t, J8 Hz, --OCH2CH3), 4.4 (2H, q, J8 Hz, OCH2CH3), 5.23 (2H, s, --CH2N), 7.44 (5H, m, phenyl protons), 7.73 (1H, s, C3 pyrazole proton), 8.50 (1H, bs, --NH proton). Found: M+, 246.0995; C13H14N2O3 requires M, 246.1003.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[C:34]([S:36]([CH3:38])=[O:37])[CH:33]=[C:32]([F:39])[C:31]=1[C:40]1[N:45]=[C:44]([C:46](O)=[O:47])[CH:43]=[CH:42][C:41]=1[F:49].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:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:46]([C:44]3[CH:43]=[CH:42][C:41]([F:49])=[C:40]([C:31]4[C:32]([F:39])=[CH:33][C:34]([S:36]([CH3:38])=[O:37])=[CH:35][C:30]=4[F:29])[N:45]=3)=[O:47])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CS(=O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
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: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(S(C)=O)cc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.1 %

Procedure:
A mixture of 3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (12.0 mg, 0.031 mmol), 6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxylic acid (11.6 mg, 0.037 mmol), HATU (29.2 mg, 0.077 mmol) in DMF (0.07 mL) and DIPEA (11.9 mg, 0.092 mmol) was stirred at room temperature for 16 h. The reaction mixture was filtered, concentrated under reduced pressure and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a colorless gum (3.0 mg, 14%). LCMS calc. for C33H37F3N5O6S (M+H)+: m/z=688.2. Found: 688.2.