Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3]1=[O:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:24][C:25]([NH2:27])=[S:26])[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[N:21][C:20]([CH3:23])=[N:19]1>C(O)C.CCOC(C)=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:24][C:25]2[S:26][C:7]3[CH2:6][CH2:5][CH2:4][C:3](=[O:9])[C:2]=3[N:27]=2)[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[N:21][C:20]([CH3:23])=[N:19]1
Reactant: O=C1CCCC(Br)C1=O
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)n1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc3c(s2)CCCC3=O)ccc1-n1cnc(C)n1
Yield: 43.5 %

Procedure:
A mixture of 3-bromocyclohexane-1,2dione (158 mg, 0.827 mmol, from preparation AAE) and 1-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (109 mg, 0.414 mmol, from step 4 of preparation F) was heated in ethanol (1.4 mL) at 80° C. for 12 h. The crude reaction was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo. The crude product was purified using preparatory TLC (80% acetone/hexanes) to afford 2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-6,7-dihydrobenzo[d]thiazol-4(5H)-one (64 mg, 44% yield) as a yellow solid. LC-MS (M+H)+ 356.3. 1H NMR (400 MHz, chloroform-d) δ ppm 8.55 (s, 1 H) 7.68 (d, J=8.56 Hz, 1 H) 7.31 (d, J=2.27 Hz, 1 H) 6.96 (dd, J=8.56, 2.52 Hz, 1 H) 3.95 (s, 3H) 3.00 (t, J=6.04 Hz, 2 H) 2.59-2.68 (m, 2 H) 2.45-2.52 (m, 3H) 2.20-2.31 (m, 2H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([CH:14]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[F:43][C:40]1[CH:39]=[CH:38][C:37]([CH:14]([C:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH:10]=2)[C:15]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH2:21][CH2:22]2)=[O:16])=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(C(C(=O)N2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CC=C(C(C(=O)N2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
0.49 g of 1-t-Butoxycarbonyl-4-{1-(4-fluorophenyl)-2-[4-(4-naphthalen-1-yl-butyl)piperazin-1-yl]-2-oxoethyl}-3,6-dihydro-2H-pyridine was dissolved in 5 ml of methanol, and 20 ml of 4M hydrogen chloride/1,4-dioxane solution was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, the mixture was washed with 1M aqueous sodium hydroxide solution and a saturated aqueous sodium solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 5 ml of acetonitrile, and 340 μl of 37% formalin, 200 μl of acetic acid and 90 mg of sodium cyanoborohydride were added, followed by stirring at room temperature for an hour. The reaction solution was diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=2:1) to give 0.25 g of 4-{1-(4-fluorophenyl)-2-[4-(4-naphthalen-1-yl-butyl)piperazin-1-yl]-2-oxoethyl}-1-methyl-3,6-dihydro-2H-pyridine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1.[CH2:23]([N:25]1[C:30](=[O:31])[N:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:28](=[O:39])[C:27]([C:40](O)=[O:41])=[N:26]1)[CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:40]([C:27]2[C:28](=[O:39])[N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:30](=[O:31])[N:25]([CH2:23][CH3:24])[N:26]=2)=[O:41])=[N:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)nc3)c2cc1OC
Reactant: CCn1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: CCn1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cn2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 5-(6,7-dimethoxyquinolin-4-yloxy)-pyridin-2-ylamine and 2-ethyl-4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid using the procedure for example 1. mp=200-202° C.; LCMS m/z=585 (M+1); 1H NMR (CDCl3) δ: 11.13 (s, 1H), 8.52 (d, 1H, J=5 Hz), 8.48 (d, 1H, J=8.5 Hz), 8.27 (d, 1H, J=2.6 Hz), 7.60 (dd, 1H, J=2, 9 Hz), 7.52 (s, 1H), 7.43 (s, 1H), 7.28-7.26 (m, 3H), 6.47 (d, 1H, J=4.3 Hz), 4.33 (q, 2H, J=8.5 Hz), 4.05 (d, 6H), 1.51 (t, 3H, J=8 Hz).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][CH2:12][O:10][C:8]1[CH:9]=[C:4]([C:2]([CH3:1])=[O:3])[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(C(C)=O)c1
Temperature: 23 °C
Yield: 97.6 %

Procedure:
Commercially available 3-hydroxyacetophenone (25 g, 184 mmol) was stirred with ethyl iodide (17.8 mL, 220 mmol) and potassium carbonate (126.89 g, 918 mmol) in acetone (500 mL) at 55° C. for 16 h. Cooled to 23° C., filtered the solids off and the solvent was removed in vacuum. The residue was purified by silica gel column chromatography with heptane/ethyl acetate 4:1 to give the title compound as a light yellow liquid (29.5 g, 98%). MS (ISP) 165.2 [(M+H)+].
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl[CH:11](Cl)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CO.C(OCC)C>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:11]([S:9][C:6]2[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1
Reactant: Cc1ccc(S)cc1
Reactant: CCOC(=O)C(Cl)Cl
Agent: [Na]
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)C(Sc1ccc(C)cc1)Sc1ccc(C)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Sodium (3.54 g) is dissolved in methanol (140 cc) and a solution of 4-methylthiophenol (21.8 g) in methanol (25 cc) is added. The mixture is stirred for 1 hour at 20° C. and a solution of ethyl dichloroacetate (12.5 g) in methanol (30 cc) is then added. The mixture is allowed to cool, the white precipitate obtained is filtered off, and the filtrate is concentrated to dryness under reduced pressure (20 mmHg) at 40° C. The oil obtained is taken up in diethyl ether (250 cc) and washed four times with N sodium hydroxide solution (50 cc each time) and four times with distilled water (50 cc each time). The ethereal phase is dried over anhydrous sodium sulphate, filtered, treated with animal charcoal, filtered and concentrated to dryness under reduced pressure (20 mmHg) at 40° C. Ethyl 2,2-bis(4-methylthiophenoxy)acetate (18 g) is thus obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]5[C:30]6[C:25](=[CH:26][CH:27]=[C:28]([O:31]CC7C=CC=CC=7)[CH:29]=6)[N:24]=[CH:23][N:22]=5)[CH2:16][C:15]=4[CH:39]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1>FC(F)(F)C(O)=O>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]5[C:30]6[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=6)[N:24]=[CH:23][N:22]=5)[CH2:16][C:15]=4[CH:39]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccc(-c3ccc4c(c3)CN(c3ncnc5ccc(OCc6ccccc6)cc35)CCO4)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2ccc(-c3ccc4c(c3)CN(c3ncnc5ccc(O)cc35)CCO4)cc2[nH]1

Procedure:
A solution of 7-(2-methyl-1H-benzimidazol-6-yl)-4-{6-[(phenylmethyl)oxy]quinazolin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (example 1) (26 mg, 0.05 mmol) in trifluoroacetic acid (3.0 mL) was heated to 68° C. for 3.5 hours then concentrated and dried. This material was then carried forward into step 2 without further purification. A sample of material obtained in this manner was purified by preparative reverse phase HPLC to give 4-[7-(2-methyl-1H-benzimidazol-6-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]quinazolin-6-ol. 1H NMR (400 MHz, d6-DMSO): 10.1 (s, 1H), 8.44 (s, 1H), 7.73 (d, 1H), 7.70 (d, 1H), 7.65 (d, 1H), 7.55-7.51 (m, 2H), 7.48 (d, 0.5H), 7.46 (d, 0.5H), 7.40 (dd, 1H), 7.33 (d, 1H), 7.04 (d, 1H), 5.00 (s, 2H), 4.46 (t, 2H), 4.24 (t, 2H), 2.54 (s, 3H). MS (EI) for C25H22N5O2: 424 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1C=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 5-bromo-2-hydroxy-benzaldehyde (14 g, 69.6 mmol) (Aldrich) in N,N-dimethylformamide (300 mL) was added K2CO3 (29 g, 208.9 mmol) and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (20 g, 83.5 mmol) (Aldrich). The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled to room temperature and poured into water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, filtered and concentrated to give 5-bromo-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde as brown oil (Yield: 25 g, 100%).
Reaction SMILES: [C:1]([N:5]([C:19]([C:21]1[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=[O:20])[NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([C:14](OC)=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>CCOCC.C(Cl)Cl>[C:1]([N:5]([C:19]([C:21]1[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=[O:20])[NH:6][C:7](=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:31][CH2:30][C:29]([CH3:33])([CH3:32])[N:28]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)NN(C(=O)c2cccc(C)c2)C(C)(C)C)cc1
Reactant: CC(C)(N)CO
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cccc(C(=O)N(NC(=O)c2ccc(C3=NC(C)(C)CO3)cc2)C(C)(C)C)c1

Procedure:
1.2 g of N'-t-butyl-N-(4-carbomethoxybenzoyl)-N'-(3-toluoyl)hydrazine was heated in 2 ml of 2-amino-2-methyl-1-propanol at 90-100° C. for 5 hours. After cooling, the mixture was diluted with ether/methylene chloride and washed with 0.1 N HCl. The organic layer was evaporated to afford 1.0 g of the corresponding amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[C:20]3[C:15](=[C:16]([F:21])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([C:11]2[C:20]3[C:15](=[C:16]([F:21])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[C:22](=[O:24])[CH3:23])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1cccc2c(NCCc3ccc(Cl)cc3)ccnc12
Product: CC(=O)N(CCc1ccc(Cl)cc1)c1ccnc2c(F)cccc12

Procedure:
A mixture of 2.0 g of N-[2-(4-chlorophenyl)ethyl]-8-fluoro-4-quinolinamine and 5.0 mL of acetic anhydride was refluxed overnight. The mixture was then cooled, and solvents were removed by reducing pressure. The residue was washed with water and then dried. The resulting oil was passed over a silica gel column with ethyl acetate, and the front running spot was collected, producing 0.8 g of the title product as a thick oil.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:16]=3[C:15]=2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[C:27]([O:37][CH3:38])[CH:26]=2)=[CH:10][CH:9]=1)[NH2:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(Cl)Cl>[NH2:5][C@H:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:16]=3[C:15]=2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[C:27]([O:37][CH3:38])[CH:26]=2)=[CH:10][CH:9]=1)[CH2:3][OH:2]
Reactant: COC(=O)[C@@H](N)COc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(CN3CCCC3)c(OC)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(Cc2c(-c3ccc(OC[C@@H](N)CO)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Yield: 34.3 %

Procedure:
O-[4-[6-Hydroxy-3-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]benzo[b]thiophen-2-yl]phenyl]-L-serine methyl ester (25 mg, 0.045 mmol) in THF:CH2Cl2 (3:1, 4 mL) was treated with lithium aluminum hydride (12 mg) at ambient temperature under argon for 3 h. The reaction was quenched with water (0.5 mL) and sodium hydroxide solution (1.0 M, 1 mL) and stirred for 30 more min before dilution with water (50 mL) and extracting with ethyl acetate (50 mL×3). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography with Et3N:MeOH:EtOAc (10:20:70) afforded the product as a white solid (8 mg, 34%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:8][N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1
Reactant: O=Cc1cccs1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N(CC1CCCN(Cc2cccs2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (31 mg, 0.090 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 2-thiophene carboxaldehyde (12.5 μL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 28.45 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(Thiophen-2-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 8 as a colorless oil (25.2 mg, 82%). LRMS 343.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].Cl.[NH2:13][OH:14].C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:6]([NH:13][OH:14])=[NH:7])=[CH:8][C:9]=1[CH3:10]
Reactant: NO
Reactant: Cc1cc(C#N)cc(C)c1Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C(=N)NO)cc(C)c1Br
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-3,5-dimethyl-benzonitrile (1.50 g), hydroxylamine hydrochloride (0.90 g), triethylamine (1.8 mL) and ethanol (30 mL) is stirred at reflux temperature for 4 h. After cooling to room temperature, the mixture is concentrated, the residue is taken up in water, and the resulting mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 7:3→3:7) to give the title compound. LC (method 11): tR=0.73 min; Mass spectrum (ESI+): m/z=243/245 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:16]([C:26](=[O:29])[NH:27][CH3:28])[C:15]=3[CH:30]=2)=[C:9]([CH3:31])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1([NH2:41])[CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([C:4](=[O:5])[NH:41][C:38]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)[CH2:40][CH2:39]2)=[CH:7][CH:8]=[C:9]([CH3:31])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]2[O:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[C:16]([C:26]([NH:27][CH3:28])=[O:29])[C:15]=2[CH:30]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3c(C)ccc(C(=O)O)c3F)cc12
Reactant: NC1(c2ccccn2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3c(C)ccc(C(=O)NC4(c5ccccn5)CC4)c3F)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 2-fluoro-3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.1 g, 0.273 mmol, 1.0 eq) in DMF (5.0 ml), 1-(pyridin-2-yl)cyclopropanamine (0.038 g, 0.285 mmol, 1.2 eq), TBTU (0.130 g, 0.403 mmol, 1.7 eq) and DIPEA (0.154 g, 1.187 mmol, 5.0 eq) were added. Mixture was stirred at ambient temperature for 12 h under nitrogen atmosphere. DMF was concentrated and to this residue water was added and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate and ethyl acetate was evaporated. The crude was purified by preparative TLC eluted with hexane/EtOAc (5:5). The product was further purified by recrystallization with DCM and hexane. Yield: 0.045 g (39%). 1H NMR (400 MHz, DMSO-d6): δ 1.23-1.25 (m, 2H), 1.51-1.54 (m, 2H), 2.18 (s, 3H), 2.81-2.82 (d, 3H, J=4.0 Hz), 7.13-7.15 (t, 1H, J=3.78 Hz), 7.27-7.29 (d, 1H, J=8.00 Hz), 7.33-7.35 (d, 1H, J=4.26 Hz), 7.39-7.44 (m, 3H, J=5.26 Hz), 7.56-7.60 (t, 2H, J=7.56 Hz), 7.68-7.72 (m, 1H), 7.80-7.82 (d, 1H, J=8.44 Hz), 7.96-8.00 (m, 2H), 8.43-8.49 (m, 2H), 9.12 (s, 1H). LCMS: (ES+) m/z=538.0 (M+H). Method: Column: Chromolith SpeedRod C18 (4.6×30) mm, 5 micron Mphase A: 10% MeOH-90% H2O-0.1% TFA Mphase B: 90% MeOH-10% H2O-0.1% TFA Flow: 5 ml/min
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[C:21]([C:25](O)=[O:26])[NH:22]2)=[CH:18][CH:17]=1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:25]([C:21]3[NH:22][C:23]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[C:16]([OH:15])[CH:24]=4)=[O:26])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Solvent: CC#N
Product: O=C(c1cc2ccc(O)cc2[nH]1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 4-(4-fluorobenzyl)piperidine [J. Med. Chem., 35, 4903. (1992)] and 6-hydroxy-1H-indole-2-carboxylic acid in acetonitrile at room temperature. The reaction mixture is concentrated and the residue is purified by column chromatography using Kiesel gel 60 as adsorbent (Merck) and toluene:methanol 4:1 as eluent. Mp.: 180-182° C. (toluene)
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([NH:16][C:17]2[N:22]=[C:21]([NH:23][CH:24]3[CH2:26][CH2:25]3)[C:20]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]3[N:18]=2)[C:9]=1[Cl:32])[CH3:7])(=O)=O.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][C:34]1=[O:39]>>[Cl:32][C:9]1[C:8]([CH:6]([N:36]2[CH2:37][CH2:38][NH:33][C:34](=[O:39])[CH2:35]2)[CH3:7])=[CH:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH:24]2[CH2:25][CH2:26]2)[C:20]2=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]2[N:18]=1
Reactant: CC(OS(C)(=O)=O)c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Reactant: O=C1CNCCN1
Product: CC(c1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl)N1CCNC(=O)C1

Procedure:
This was similarly prepared as Example 678 from 1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)ethyl methanesulfonate and piperazin-2-one (22.74 mg).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[CH:24]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:29]([CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:30]2=[O:31])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: O=C=NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(C3CCCC3)c(=O)n(C3CCCC3)c12
Yield: 44.8 %

Procedure:
1,3-Dicyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (17 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.10 mmol) and cyclopentyl isocyanate (0.4 mmol) following general procedure C. LCMS: m/z 380 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.51 (s, 1H), 7.82 (d, 1H), 7.62 (t, 1H), 7.28 (d, 1H), 5.34 (m, 1H), 4.98 (m, 1H), 4.15 (s, 3H), 3.95 (m, 4H), 2.38 (m, 2H), 2.12 (m, 2H), 1.93-1.98 (m, 2H), 1.58-169 (m, 4H), and 1.38 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH:6](O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(Cl)([Cl:21])=O>C(Cl)Cl>[Cl:21][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]1[CH:14]=[CH:15][CH:16]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:4]=1
Reactant: OC(c1ccccc1)c1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1cccc(C(Cl)c2ccccc2)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
To a solution of 3-(trifluoromethyl)benzhydrol (5 mL, 20 mmol) in CH2Cl2 (10 mL) was added dropwise thionyl chloride (3 mL, 41 mmol) at rt. The reaction was stirred at 50° C. for 18 h, concentrated under vacuum, azeotroped with toluene and dried under vacuum to give the title compound (4.9 g, 89% yield) as oil, which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 235.0 (M-HCl).