Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:14][CH2:15][CH3:16])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:17])[CH:5]=1.Cl.[N:19]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[ClH:1].[NH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([N:19]2[CH2:20][CH2:21][N:22]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([N:10]([CH2:14][CH2:15][CH3:16])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:17])[CH:5]=3)[CH2:23][CH2:24]2)=[N:26]1
Reactant: CCCN(C(C)=O)c1ccc(CCCl)cc1C
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: Cl
Product: CCCN(C(C)=O)c1ccc(CCN2CCN(c3n[nH]c4ccccc34)CC2)cc1C
Yield: 20 %

Procedure:
N-[4-(2-Chloro-ethyl)-2-methyl-phenyl]-N-propyl-acetamide (0.090 g, 0.355 mmole) was reacted with 3-piperazin-1-yl-1H-indazole hydrochloride (0.127 g, 0.532 mmol) according to the method outlined in Example 501. The titled product was precipitated as its hydrochloride salt from dioxane/HCl(gas) treatment (0.030 g, 0.071 mmol). Yield=20%. 100% purity at 254 nm; LCMS (APCI): 437.3 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.50 (s, 1H), 7.79 (d, J=8.55 Hz, 1H), 7.37 (d, J=8.55 Hz, 1H), 7.32–7.26 (m, 2H), 7.21–7.12 (m, 2H), 6.99 (t, J=7.48 Hz, 1H), 3.97 (bd, J=8.70 Hz, 2H), 3.87–3.77 (m, 1H), 3.65 (bd, J=7.25 Hz, 2H), 3.39 (bs, DMSO-H2O), 3.31–3.21 (m, 6H), 3.10–2.92 (m, 3H), 2.14 (s, 3H), 1.58 (s, 3H), 1.39 (sextet, J=7.38 Hz, 2H), 0.79 (t, 7.38 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:34]=[N:33][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:32])[N:14]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:15]4[CH:20]([C:21]=3[OH:22])[CH:19]3[CH2:23][CH:16]4[CH2:17][CH2:18]3)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C([O-])=O.[NH4+].C(OCC)(=O)C>CO.[Pd]>[O:11]=[S:9]1(=[O:10])[C:4]2[CH:3]=[CH:2][CH:34]=[N:33][C:5]=2[NH:6][C:7]([C:12]2[C:13](=[O:32])[N:14]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[C@@H:15]3[C@H:20]([C:21]=2[OH:22])[C@@H:19]2[CH2:23][C@H:16]3[CH2:17][CH2:18]2)=[N:8]1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(Br)cnc3N2)=C(O)C2C3CCC(C3)C2N1Cc1ccc(F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1C(C2=NS(=O)(=O)c3cccnc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
5-(7-Bromo-1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 62, 0.07 g, 0.128 mmol) was dissolved in methanol (8 mL). Ammonium formate (0.2 g, 3.17 mmol) followed by 10% palladium on carbon (wet, 0.1 g) were added. The mixture stirred at 50° C. for 3 h. The mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was dissolved in water (5 mL) and ethyl acetate (50 mL). The mixture was shaken and the layers were separated. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to a clear oil. Flash column chromatography (Merck silica gel 60, 40-63 μm; 20 to 40% ethyl acetate in hexanes) afforded the desired product, (1R,2S,7R,8S)-5-(1,1-dioxo-1,4-dihydro-1λ6-pyrido[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.0441 g, 0.094 mmol, 74%), as a white, brittle foam. 1H NMR (400 MHz, DMSO-d6) δ: 1.11-1.61 (6H, m), 2.51 (1H, s), 2.63 (1H, s), 2.99 (1H, d, J=9.4 Hz), 3.54 (1H, d, J=9.4 Hz), 4.41 (1H, d, J=15.7 Hz), 4.95 (1H, d, J=15.4 Hz), 7.14 (2H, t, J=8.6 Hz), 7.33 (2H, dd, J1=8.6 Hz, J2=5.4 Hz), 7.51 (1H, dd, J1=7.8 Hz, J2=4.5 Hz), 8.34 (1H, d, J=7.6 Hz), 8.68 (1H, dd, J1=4.6 Hz, J2=1.7 Hz). LC-MS (ESI) calcd for C23H21FN4O4S 468.13, found 469.4 [M+H+].
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[C:8]1([C:14]2[O:18][N:17]=[C:16]([CH2:19][NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[CH:23][C:22]=3[NH2:31])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>C(#N)C>[CH2:1]([O:3][CH2:4][C:5]1[N:20]([CH2:19][C:16]2[CH:15]=[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:18][N:17]=2)[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=1)[CH3:2]
Reactant: Nc1cnc2ccccc2c1NCc1cc(-c2ccccc2)on1
Reactant: CCOCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOCc1nc2cnc3ccccc3c2n1Cc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A solution of ethoxyacetyl chloride (0.87 g, 7.1 mmol) in acetonitrile (10 mL) was added to a solution of N4-[(5-phenylisoxazol-3-yl)methyl]quinoline-3,4-diamine (2.05 g, 6.48 mmol) in acetonitrile (100 mL), and the solution was stirred at room temperature overnight. The volatiles were removed under reduced pressure, and the residue was dissolved in 3:1 ethanol:water (100 mL). Solid sodium hydroxide (389 mg, 9.72 mmol) was added, and the solution was heated at reflux overnight. The ethanol was removed under reduced pressure, and the resultant aqueous solution was adjusted to pH 5 with the additional of dilute hydrochloric acid. The acidic solution was extracted several times with dichloromethane, and the combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (eluting with 4% to 6% methanol in dichloromethane to provide 0.650 g of 2-(ethoxymethyl)-1-[(5-phenylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:23][CH2:24][CH:25]([OH:27])[CH3:26]>O1CCCC1>[OH:27][CH:25]([CH3:26])[CH2:24][NH:23][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: CC(O)CN
Reactant: O=C(O)c1cccnc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)CNC(=O)c1cccnc1
Temperature: -4 °C
Reaction time: 2 h

Procedure:
To 4.29 g (0.039 mol) of nicotinic acid suspended in 120 mL of dry tetrahydrofuran, 4.04 g (0.039 mol) of freshly distilled triethylamine was added in one portion. The resultant clear solution was cooled to -4° C. in an ice bath under argon. Ethyl chloroformate (4.33 g, 0.039 mol) in 25 mL of tetrahydrofuran was added at such a rate that the temperature of the solution did not exceed 0° C. Then, 3 g (0.039 mol) of 1-amino-2-propanol were added directly to the cold reaction mixture. The reaction mixture was allowed to come to room temperature and stirred for 2 hours. The precipitate was removed by filtration and the filtrate was evaporated in vacuo. The oily residue was washed several times with anhydrous ether and allowed to stand. The title compound was obtained as a white, hygroscopic, low-melting, waxy solid melting at 40° C. (6.11 g, 85%) and having the formula ##STR115##
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[C:11]([O:14][CH2:15][CH3:16])(=[O:13])C.CCCCCC>>[Cl:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([NH:1][C:11]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1c(N)cccc1Cl
Solvent: CCCCCC
Product: CCOC(=O)Nc1cccc(Cl)c1C#N

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 (Method B) from 2-amino-6-chlorobenzonitrile. m.p.: 144.5-145.1 (ethyl acetate/hexane) 1H-NMR (CDCl3) δ: 8.21 (1H, d, J=8 Hz), 7.49 (1H, t, J=8 Hz), 7.16 (1H, d, J=8 Hz), 7.17 (1H, br s), 4.27 (2H, q, J=7 Hz), 1.35 (3H, t, J=7 Hz)
Reaction SMILES: [NH:1]1[C:5]([C@@H:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)=[CH:10][CH:9]=2)[CH3:7])=[CH:4][N:3]=[N:2]1.CC[O:26]C(C)=O>>[F:22][C:20]([F:23])([F:21])[C:18]1[N:19]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C@H:6]([C:5]3[N:1]([OH:26])[N:2]=[N:3][CH:4]=3)[CH3:7])=[CH:9][CH:10]=2)[S:16][CH:17]=1
Reactant: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1cnn[nH]1
Reactant: CCOC(C)=O
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1cnnn1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of N-{4-[(1R)-1-(1H-1,2,3-triazol-5-yl)ethyl]phenyl}-4-(trifluoromethyl)-1,3-thiazol-2-amine (0.06 g, 0.18 mmol) in EtOAc (10 ml) m-CPBA (43 mg, 0.25 mmol) was added and the resulting mixture stirred at room temperature overnight. EtOAc (10 ml) was added and the organic layer was washed with water (2×10 ml) and dried over anhydrous Na2SO4 to give, after solvent evaporation, a crude which, by purification by flash chromatography (EtOAc/CH3OH 7:3) afforded the pure 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1H-1,2,3-triazol-1-ol (9) (0.025 g, 0.072 mmol) as a transparent oil (40%). [α]D=−19 (c=1; CH3OH); 1H-NMR (CD3OD): δ 9.40 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.35 (d, 2H, J=7 Hz), 7.15 (s, 1H), 7.40 (s, 1H), 3.70 (q, 1H, J=7 Hz), 1.55 (d, 3H, J=7 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[C:1]([O:5][C:6]([C:8]1[C:9]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:25])[CH3:26])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(OS(=O)(=O)C(F)(F)F)nc3ccc(Cl)cc23)c1
Reactant: C1CCNCC1
Product: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(N3CCCCC3)nc3ccc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 79 step A from 6-chloro-4-(3-isopropyl-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 78 step C, 250 mg, 0.47 mmol) and piperidine (0.093 ml, 0.94 mmol). Yellow solid (140 mg, 64%). LC-MS (ESI): 465 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:30])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:27](=[O:28])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH3:30])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1ccccc1/C=C/C(=O)O
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)/C=C/c3ccccc3C)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and (E)-3-o-tolyl-acrylic acid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1.C([BH3-])#N.[Na+]>CO>[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH:6][CH2:15][C:11]1[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](C)NCc1cccnc1
Temperature: 25 °C

Procedure:
Part A: To a solution of D-alanine methyl ester hydrochloride (6.0 grams) in methanol (25 mL) is added 1.1 equivalents of 3-Pyridinecarboxaldehyde. The solution is stirred at room temperature for several hours and then the solvent removed by rotary evaporation. The resulting imine is redissolved in acetic acid (10 mL) and methanol (2 mL), and sodium cyanoborohydride (1.5 equivalents) is added in several portions over 10 minutes. The mixture is then stirred for 16 hours and then concentrated by rotary evaporation. The resulting residue is partitioned between ethyl acetate and aqueous sodium carbonate (10%). The organic layer is dried over magnesium sulfate, filtered and concentrated to yield the desired N-3-picolyl-D-alanine methyl ester.
Reaction SMILES: [F:1][CH2:2][C:3]1([NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.O1CCOCC1.[ClH:38]>C1COCC1>[ClH:38].[F:1][CH2:2][C:3]1([NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)[CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(CF)(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1(CF)CCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 578 mg (1.29 mmol) of tert-butyl 3-(fluoromethyl)-3-[({[3-(trifluoromethyl)benzoyl]amino}acetyl)amino]pyrrolidine-1-carboxylate in 5 mL of THF was added 2 mL of 4 N HCl dioxane solution. The reaction mixture was stirred at room temperature for 1 h and evaporated to give the yellow solid, N-(2-{[3-(fluoromethyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide HCl salt: MS (m/e): 347 (M+1)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]2[C:5]=1[C:6](=[O:15])[C:7](=[O:14])[NH:8]2.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(OCC)C>CN(C)C=O>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]2[C:5]=1[C:6](=[O:15])[C:7](=[O:14])[N:8]2[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCBr
Reactant: O=C1Nc2c(Cl)ccc(Cl)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCN1C(=O)C(=O)c2c(Cl)ccc(Cl)c21
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a mixture of sodium hydride (0.17 g, 6.94 mmol, 60% dispersion in mineral oil) in anhydrous N,N-dimethylformamide (5.00 mL) was added a solution of 4,7-dichloro-1H-indole-2,3-dione (1.00 g, 4.60 mmol) in N,N-dimethylformamide (5.00 mL) at 0° C. The brown reaction mixture was stirred for 0.5 h followed by the addition of a solution of 1-bromopentane (0.84 g, 5.55 mmol) in anhydrous N,N-dimethylformamide (5.00 mL). The reaction mixture was stirred at ambient temperature for 16 h and poured into wet ethyl ether (30.0 mL). After the organic layer was separated, it was washed with water (2×20.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The gummy residue was dried under vacuum and the solid was triturated with ether to give the title compound (0.98 g, 98%): MS (ES+) m/z 286.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.Cl.[F:34][CH2:35][CH2:36][NH2:37]>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[NH:37][CH2:36][CH2:35][F:34])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NCCF
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC(=O)NCCF
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-tert-Butoxycarbonylamino-propionic acid (2.16 g, 11.4 mmol)) was dissolved in dichloromethane (80 ml) and cooled to 0° C. in an ice bath. [3-(Dimethylamino)propyl]ethylcarbodiimide hydrochloride (2.84 g, 14.8 mmol), hydroxybenzatriazole (1.54 g, 11.4 mmol) and triethylamine (7.9 ml, 57 mmol) were added and the reaction mixture stirred for 15 minutes. 2-fluoroethylamine hydrochloride (1.134 g, 11.4 mmol) was added in a single portion and then left to stir for 2 hours. The reaction mixture was partitioned between dichloromethane and water. The organic phase was dried over magnesium sulphate and evaporated. The crude product was purified by chromatography on silica using 2:3 iso-hexane:ethylacetate as eluant to afford the product.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:12][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].[Cl:42][C:43]1[CH:48]=[CH:47][C:46](F)=[CH:45][CH:44]=1>CN(C)C=O>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([O:1][CH2:2][C:3]2[N:4]([CH2:12][CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:16]3)[C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:45][CH:44]=1
Reactant: OCc1cc2ccccc2n1CCCC1CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: Fc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2cc3ccccc3n2CCCC2CCCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere 2-hydroxymethyl-1-[3-(1-tritylpiperidin-3-yl)propyl]-1H-indole (2.89 g, 5,61 mmol) was dissolved in about 11.2 ml of N,N-dimethylformamide. The resulting solution was then placed in an ice bath and sodium hydride (0.247 g of a 60% suspension in mineral oil, 6.18 mmol) was added and the resulting mixture was stirred at room temperature for about 60 minutes. To the reaction mixture 1-chloro-4-fluorobenzene (0.658 ml, 0.807 g, 6.18 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then heated to 80° C. and maintained at this temperature for about eight hours. The reaction mixture was then cooled to room temperature and stirred at this temperature overnight. Another half equivalence of sodium hydride was added and the reaction mixture was stirred at room temperature overnight again. Another half equivalence of 1-chloro-4-fluorobenzene was added and the reaction mixture was heated to 80° C.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]1([C:3]2[C:2]([N:33]3[CH2:32][CH2:31][N:30]([C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:36])([F:37])[F:22])=[CH:29][CH:28]=4)[CH2:35][CH2:34]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(C(F)(F)F)cc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in DMF (8 mL), 1-(4-(trifluoromethyl)phenyl)piperazine (202 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv) were placed in a 20-mL sealed tube and stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 4×50 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate followed by filtration to remove solids. The resulting mixture was concentrated under vacuum, resulting in 177.4 mg (78%) of methyl 2-phenyl-3-(4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19][S:20]([CH2:22][C:23](=O)[CH3:24])=[O:21]>O1CCCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:23]([CH3:24])[CH2:22][S:20]([CH3:19])=[O:21])=[O:14])[CH3:2]
Reactant: CC(=O)CS(C)=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
To a 50 ml volume three-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (2.0 g), tetrahydrofuran (anhydrous) (5 ml), and 1-methylsulfinyl-2-propanone (7-1-1) (1.65 g) were added under a nitrogen atmosphere, and stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure at room temperature. The residue was subjected to silica gel column chromatography (ethyl acetate to chloroform) to give 0.48 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfinyl-2-propylidene)hydrazine ((4-19)-(1)-39).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[CH:47]=[N:48][CH:49]=[C:50]([Cl:55])[C:51]=1[N:52]([CH3:54])[CH3:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:47]=[N:48][CH:49]=[C:50]([Cl:55])[C:51]=3[N:52]([CH3:54])[CH3:53])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)c1c(Cl)cncc1CBr
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CN(C)c1c(Cl)cncc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-5-chloro-N,N-dimethylpyridin-4-amine hydrobromide and isolated as light-yellow gum. MS(m/e): 451.4 (MH+).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CS(O[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2)(=O)=O>C(O)C.C(OCC)(=O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][CH:18]=[CH:17]2
Reactant: CS(=O)(=O)OCCc1cccc2cc[nH]c12
Reactant: NCCO
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCNCCc1cccc2cc[nH]c12
Yield: 84.6 %

Procedure:
Add ethanolamine (5 mL, 82 mmol) to a solution of 7-(2-(methanesulfonyloxy)eth-1-yl)indole (0.79 g, 3.3 mmol) in ethanol (50 mL) and stir the reaction mixture at reflux overnight Dilute with ethyl acetate (150 mL), wash sequentially with water (3×50 mL) and saturated aqueous sodium chloride (2×50 mL), dry over sodium sulfate, filter, and concentrate under reduced pressure to provide 7-(2-(N-[2-hydroxyeth-1-yl]amino)eth-1-yl)indole as a light-brown solid (0.57 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[C:13]([CH3:20])[C:14]([F:19])=[C:15]([F:18])[CH:16]=3)[C:11](=[O:21])[C:10]([C:22]([O:24]CC)=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[C:13]([CH3:20])[C:14]([F:19])=[C:15]([F:18])[CH:16]=3)[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1
Yield: 94.9 %

Procedure:
Employing ethyl 1-(4-fluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.56 g), conc. hydrochloric acid (1.5 ml), and 90% acetic acid (6 ml), the procedure of Reference Example 10 is repeated to give 1-(4-fluorophenyl)-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.49 g), as white crystals, m.p. 255°-257° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])[S:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.Cl[C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([C:18]([NH:17][C:8]3[S:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[N:7]=3)=[O:19])[CH2:21][CH2:22]2)=[N:28][CH:29]=1)#[N:34]
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)C1CCNCC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#Cc1ccc(N2CCC(C(=O)Nc3nc(-c4ccco4)c(N4CCOCC4)s3)CC2)nc1
Reaction time: 8 h
Yield: 68 %

Procedure:
Compound 44 (181 mg, 0.50 mmol), 2-chloro-5-cyanopyridine (104 mg, 0.75 mmol) and potassium carbonate (207 mg, 1.50 mmol) were suspended in 1,4-dioxane (4 mL), followed by stirring overnight under heating and reflux. The insoluble was removed through filtration, the filtrate was distilled away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform:methanol=20:1) to afford the entitled Compound 45 (158 mg, 68%).