Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10](=[O:17])[N:9]3[CH2:18][CH2:19][NH:20][C:8]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:23]I.O>CN(C)C=O>[CH3:23][N:20]1[C:8]2[N:9]([C:10](=[O:17])[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:18][CH2:19]1
Reactant: CI
Reactant: O=c1c2cccnc2c(-c2ccccc2)c2n1CCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCn2c1c(-c1ccccc1)c1ncccc1c2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 2,3-dihydro-10-phenyl-imidazo-[1,2-g][1,6]naphthyridin-5(1H)-one (2.63 g) in N,N-dimethylformamide (100 ml), and add the solution to a stirred suspension of dimethylformamide (25 ml) and sodium hydride (as a 60% dispersion in mineral oil). Use 0.25 g of the dispersion, and stir the resulting mixture for 1 hour at 25° C. Add methyl iodide (8.5 g), and stir for 15 hours, again at 25° C. Pour the mixture over ice and water (500 g), and extract with dichloromethane. Combine extracts, wash them with water and brine, dry them over magnesium or sodium sulfate, and concentrate them. Crystallize the residue from chloroform-acetone to obtain 2,3-dihydro-1-methyl-10-phenylimidazo[1,2-g]-[1,6]naphthyridin-5(1H)-one, mp 237°-240° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14][N:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[N:5]1)(=O)C.C[O-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[F:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16]3)=[N:5][NH:4]2)=[CH:8][CH:9]=1
Reactant: CC(=O)n1nc(CN2CCc3ccccc3C2)c2ccc(F)cc21
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Fc1ccc2c(CN3CCc4ccccc4C3)n[nH]c2c1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
2-(1-Acetyl-6-fluoro-1H-indazol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (300 mg, 0.93 mmol) in CH2Cl2 /MeOH (1:1, 10 mL) was treated with sodium methoxide (2 mg) and stirred for 15 min at 20° C. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (MgSO4), concentrated and purified by flash chromatography (50% EtOAc in hexane) to give the title compound as a colourless oil. Conversion to the hydrogen oxalate salt in MeOH/Et2O gave colourless crystals (202 mg, 59%); mp 200°-201° C. (from MeOH/Et2O); 1H NMR (360 MHz, d6 -DMSO) d 7.93 (dd, J=8.8, 5.3 Hz, 1H, indazole), 7.30 (dd, J=9.7, 2.8 Hz, 1H, indazole), 7.15-6.97 (m, 5H, aromatic), 4.25 (s, 2H, Ar--CH2N), 3.88 (s, 2H, Ar--CH2N), 3.00 (bs, 2H, tetrahydroisoquinoline), 2.89 (bs, 2H, tetrahydroisoquinoline); MS (CI+) m/e 282 (M+H+); Anal. calcd for C17H16FN3. (COOH)2. H2O: C, 65.35; H, 5.33; N, 12.71. Found: C, 65.40; H, 5.24; N, 12.49.
Reaction SMILES: [CH2:1]([N:4]([CH2:21][CH2:22][CH3:23])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].Cl.Cl.[NH2:26][C@@H:27]([CH2:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[C:44]([F:49])[CH:43]=1)[C@H:28]([OH:40])[CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH3:39])[CH:33]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C)C=O.O>[F:48][C:46]1[CH:47]=[C:42]([CH:43]=[C:44]([F:49])[CH:45]=1)[CH2:41][C@H:27]([NH:26][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:21][CH2:22][CH3:23])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:8]=1)[C@H:28]([OH:40])[CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][CH3:39])[CH:33]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2ncco2)c1
Reaction time: 8 h
Yield: 23.3 %

Procedure:
A solution of 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoic acid (133 mg, 0.42 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (171 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol), and N-methylmorpholine (148 μL, 1.3 mmol) was stirred in dimethylformamide (2 mL) for 15 min. EDC (130 mg, 0.75 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was diluted with water, and extracted with ethyl acetate (3×25 mL). The organic layer was washed with 1 M hydrochloric acid (25 mL), saturated sodium bicarbonate (25 mL), saturated sodium chloride, dried (sodium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provided N1-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-5-(1,3-oxazol-2-yl)-N3,N3-dipropylisophthalamide (62 mg): mp 65–67° C.; 1H NMR (500 MHz, CDCl3) δ 8.21 (br s, 1H), 8.15 (s, 2H), 7.69 (s, 1H), 7.60 (s, 1H), 7.25 (t, J=8 Hz, 1H), 7.19–7.17 (m, 3H), 7.10 (d, J=8 Hz, 1H), 6.96 (d, J=8 Hz, 2H), 6.60 (t, J=8 Hz, 1H), 4.27 (d, J=8 Hz, 1H), 3.88–3.80 (m, 3H), 3.53 (br s, 2H), 3.44 (br s, 2H), 3.09–3.01 (m, 4H), 2.85–2.82 (m, 2H), 2.62 (t, J=8 Hz, 2H), 1.74 (br s, 2H), 1.45 (br s, 2H), 1.21 (t, J=8 Hz, 3H), 1.03 (t, J=7 Hz, 3H), 0.66 (t, J=7 Hz, 3H); APCI MS m/z 633 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[CH:44][C:43]=2[OH:52])=[CH:38][N:37]=1>CS(C)=O>[Cl:1][C:2]1[C:3]([O:52][C:43]2[CH:44]=[CH:45][C:46]([C:48]([F:49])([F:50])[F:51])=[CH:47][C:42]=2[C:39]2[CH:40]=[CH:41][N:36]=[N:37][CH:38]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: Oc1ccc(C(F)(F)F)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3-c3ccnnc3)cc2F)c(OC)c1
Yield: 84.8 %

Procedure:
5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 247, 378.0 g, 0.761 moles) was dissolved in dimethylsulphoxide (1.9 L). Potassium carbonate (117.8 g, 0.8524 moles) was added and stirred to give a suspension to which was added 2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 712, 182.8 g, 0.761 moles) in one portion. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate (2.7 L) and aqueous sodium hydroxide solution (2.5 L of 1 molar). The organic phase was washed with water (2×2 L) and then saturated aqueous sodium chloride solution (250 mL). The solution was concentrated in vacuo to give the crude title product. The crude product was purified by column chromatography on silica gel (2 Kg) eluting with ethyl acetate/heptane (3:1). The cleanest fractions were combined and the solvents removed in vacuo to give the title compound as a dark red foam, (440 g). This material was dried in vacuo at 45° C. for 48 hours to give the title compound as a red solid (400 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:9]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:25][CH:26]=[CH:27][N:28]=4)=[CH:20][C:19]=3[CH2:29][CH:30]=[O:31])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[O:4][N:3]=1.NS(O)(=O)=[O:40].[O-]Cl=O.[Na+].ClCl>C1COCC1.O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([N:8]([CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[C:19]([CH2:29][C:30]([OH:40])=[O:31])=[CH:20][C:21]([C:24]3[O:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)(=[O:11])=[O:10])[O:4][N:3]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CC=O
Reactant: NS(=O)(=O)O
Agent: ClCl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncco2)cc1CC(=O)O
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To the title compound of Step (B) (300 mg, 0.57 mmol) and H2NSO3H (111 mg, 1.14 mmol) in 11.4 ml THF at 0° C., an ice cooled solution of NaClO2 (103 mg, 1.14 mmol) in 11.4 ml H2O was added. The mixture was stirred at 0° C. for 2 min. 60 ml CH2 Cl2 was added. The organic layer was separated and washed with H2O and brine, dried and concentrated to afford the title compound of this step, which was relatively pure and was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([C@H:14]2[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][N:15]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:10]=[CH:11][C:12]=1[F:13].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>O1CCCC1>[F:6][C:7]1[CH:8]=[C:9]([C@H:14]2[CH2:19][C@@H:18]([O:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:16][N:15]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C[C@@H]1c1ccc(F)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C[C@@H]1c1ccc(F)c(F)c1
Yield: 102.2 %

Procedure:
Methanesulfonyl chloride (1.0 g, 3.2 mmol) was added to a mixture of (±)-1,1-dimethylethyl (2R,4S)-2-(3,4-difluorophenyl)-4-hydroxypiperidine-1-carboxylate (1.00 g, 3.0 mmol) (obtained by conducting reagent preparation 28 in the presence of di-tert-butyl dicarbonate) and triethylamine (0.70 g, 7.0 mmol), in tetrahydrofuran (25 mL) at 0° C., and the resulting mixture was at room temperature for two hours. The reaction mixture was then quenched with a cold mixture of water and ethyl acetate. The organic portion was separated, washed with 5% sodium hydroxide, 0.5M hydrochloric acid, water then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (5% to 75% ethyl acetate in hexanes gradient) to give (±)-1,1-dimethylethyl (2R,4S)-2-(3,4-difluorophenyl)-4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (1.2 g, 88% yield). MS (EI) for C17H23F2NO5S: 392 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[C:9]([NH2:17])([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:10].O>C(Cl)Cl>[CH3:10][C:9](/[N:17]=[CH:7]/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:11]
Reactant: O=Cc1ccccn1
Reactant: CC(C)(C)CC(C)(C)N
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)CC(C)(C)/N=C/c1ccccn1
Yield: 94.1 %

Procedure:
In air, to a solution of 2-pyridinecarboxaldehyde (0.338 g, 0.300 mL, 3.15 mmol, 1.01 equiv) in CH2Cl2 (10 mL) was added tert-octylamine (0.402 g, 0.500 mL, 3.11 mmol, 1.00 equiv). After heating at reflux for 1.5 h with azeotropic removal of water using a Dean-Stark trap, the reaction mixture was concentrated under reduced pressure. The residue was purified by bulb-to-bulb distillation (250 mTorr, 140° C.) to give the title compound as a colorless oil (0.639 g, 94% yield).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:10](Cl)=[O:11])[S:8][CH:9]=1)(=[O:4])=[O:3].[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]([NH2:25])=[O:24])[C:18](=[O:26])[CH2:17]2>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]([NH2:25])=[O:24])[C:18](=[O:26])[CH:17]2[C:10](=[O:11])[C:7]1[S:8][CH:9]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1csc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1
Yield: 49 %

Procedure:
The title compound was prepared according to the procedure of Example 32. The reaction of 10 ml of thionyl chloride with 1.39 g (6.7 mmoles) of 4-methylsulfonyl-2-thiophenecarboxylic acid (prepared according to Arndt, F., et al., Chem. Ber. 94:1757 (1961)) gave 1.54 g of the crude acid chloride as a solid. The entire amount of 4-methylsulfonyl-2-thiophenecarbonyl chloride was coupled to 1.28 g (6.1 mmoles) of 5-chloro-2-oxindole-1-carboxamide in the presence of 2.24 g (18.3 mmoles) 4-(N,N-dimethyl-amino)pyridine. Acidic workup gave 2.28 g of crude product as an orange solid. Recrystallization from 2-butanone gave two crops of slightly impure yellow crystalline solid which had a combined mass of 2.18 g. Further purification by recrystallization provided 1.19 g (2.98 mmoles, 49% yield) of pure 5-chloro-3-(4-methylsulfonyl-2-thenoyl)-2-oxindole-1-carboxamide as a yellow crystalline solid, m.p. 228-30° C. (acetic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[Cl:21][C:22]1[C:30]2[N:29]=[C:28]([CH3:31])[NH:27][C:26]=2[CH:25]=[CH:24][C:23]=1[O:32][C:33]1[CH:38]=[C:37](Cl)[N:36]=[CH:35][N:34]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Cl:21][C:22]1[C:30]2[N:29]=[C:28]([CH3:31])[NH:27][C:26]=2[CH:25]=[CH:24][C:23]=1[O:32][C:33]1[N:34]=[CH:35][N:36]=[C:37]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:38]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1nc2c(Cl)c(Oc3cc(Cl)ncn3)ccc2[nH]1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc5[nH]c(C)nc5c4Cl)ncn3)CC1)C(=O)N2

Procedure:
100 mg (0.36 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 110 mg (0.37 mmol) 4-chloro-5-(6-chloropyrimidin-4-yloxy)-2-methyl-1H-benzo[d]-imidazole and 0.14 mL (0.81 mmol) DIPEA in 2.0 mL DMF were stirred for 3 h at RT and for 4 h at 40° C. The reaction mixture was mixed with water. The precipitate formed was suction filtered, washed and dried. The filtrate was again suction filtered, washed and dried.
Reaction SMILES: C([O:3][C:4]([C@@:6]12[CH2:24][C@H:23]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:14](=[O:33])[C@H:13]1[C@@H:9]([CH2:10][C@@H:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[N:38]=[C:37]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:36]=3)[CH2:12]1)[C:8](=[O:53])[NH:7]2)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[C:29]([O:28][C:26]([NH:25][N:15]1[C:14](=[O:33])[C@H:13]2[C@@H:9]([CH2:10][C@@H:11]([O:34][C:35]3[C:44]4[C:39](=[CH:40][C:41]([O:45][CH3:46])=[CH:42][CH:43]=4)[N:38]=[C:37]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:36]=3)[CH2:12]2)[C:8](=[O:53])[NH:7][C@@:6]2([C:4]([OH:5])=[O:3])[C@@H:23]([CH2:24]2)[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)[C@@H]1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCCN(NC(=O)OC(C)(C)C)C(=O)[C@@H]1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2
Agent: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5/C=C\CCCCCN(NC(=O)OC(C)(C)C)C(=O)[C@@H]4C3)cc(-c3ccccc3)nc2c1
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(O[C@@H]3C[C@H]4C(=O)N[C@]5(C(=O)O)C[C@H]5C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)[C@@H]4C3)cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 49 (27 mg, 0.037 mmol) in THF/MeOH/H2O 2:1:1 (5 mL) was added 1 M LiOH (300 μL, 0.300 mmol). The solution was stirred for 24 h at room temperature and finally for one hour at reflux. After acidification to pH 3-4 with 1 M HCl and evaporation the residue was purified by HPLC (MeOH/H2O 80:20 and MeOH/H2O 90:10) providing 50 (12 mg, 46%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:6]([CH:7]=O)=[C:5](Br)[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:20][SH:21].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:6]2[CH:7]=[C:20]([C:19]([O:23][CH2:24][CH3:25])=[O:22])[S:21][C:5]=2[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1
Reactant: CCOC(=O)CS
Reactant: COc1ccc(Cn2nc(Br)c(C=O)c2Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(Br)nn(Cc3ccc(OC)cc3)c2s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
3,5-Dibromo-1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde (1.3301 g, 3.56 mmol), ethyl thioglycolate (0.419 ml, 3.73 mmol), and sodium carbonate (0.761 g, 7.18 mmol) were dissolved in ethanol (35 ml) at 25° C. under Ar in a sealed heavy-walled reaction vessel. The reaction mixture was warmed to 80° C. and allowed to stir for 4 h. The reaction was stopped, cooled to room temperature, quenched by addition of saturated aqueous ammonium chloride (40 mL), and the mixture extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×20 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 120 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-25%). The title compound (1.2063 g, 3.05 mmol, 86% yield) was recovered as a white solid. LC-MS [M+1]=395.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:29]#[N:30])[CH:25]=4)[O:20][C:19]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42]C(=O)NC1(C2C=CC(C3C(=O)C4C(=CC(OC)=C(Br)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C>>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([O:42][CH3:38])=[C:24]([C:29]#[N:30])[CH:25]=4)[O:20][C:19]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(C#N)cc4c3=O)cc2)CCC1
Reactant: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1Br
Product: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1C#N
Yield: 77 %

Procedure:
Following the procedure used to prepare {1-[4-(6-cyano-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, {1-[4-(6-bromo-7-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (115 mg, 0.20 mmol) was reacted to give the title compound (81 mg, 77%). 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 7.45-7.14 (m, 9H), 7.00 (s, 1H), 5.05 (s, 1H), 4.05 (s, 3H), 2.60-2.39 (m, 4H), 2.16-2.00 (m, 1H), 1.92-1.77 (m, 1H), 1.56-1.14 (m, 9H).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([NH2:36])=[O:35]>COCCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=3)[C:34]([NH2:36])=[O:35])=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: NC(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(C(N)=O)c3)nn12
Yield: 14.9 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 3-Amino-benzamide (118 mg, 0.000870 mol) were dissolved in 2-Methoxyethanol (3.05 mL) and the reaction was microwaved on 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 23.30 mg of 3-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-benzamide as a lyophilized powder. (M+H)=360.11. 1H NMR (400 MHz, CDCl3) δ 9.39 (m, 1H), 8.60 (s, 1H), 8.17 (s, 1H), 7.86 (d, 1H, J=7.64 Hz), 7.63 (d, 1H, J=8.00 Hz), 7.57 (d, 1H, J=7.80 Hz), 7.50 (t, 1H, J=7.56 Hz), 7.36 (t, 1H, J=7.88 Hz), 7.19 (d, 1H, J=5.00 Hz), 7.13 (m, 3H), 3.83 (s, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18].Br.C1(NC2C=CC(N)=CC=2)C=CC=CC=1>C(#N)C>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:16]2[CH2:21][CH2:20][O:19][C:17]2=[O:18])=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1OCCC1Br
Reactant: Nc1ccc(Nc2ccccc2)cc1
Agent: Br
Solvent: CC#N
Product: O=C1OCCC1Nc1ccc(Nc2ccccc2)cc1

Procedure:
A mixture of 1.84 g (10 mmoles) of N1-phenyl-1,4-benzenediamine and 0.41 ml (5 mmoles) of α-bromo-γ-butyrolactone in 20 ml of acetonitrile is heated under reflux for 5 hours. After returning to 20° C., the precipitate which appears during the reaction (N1-phenyl-1,4-benzenediamine hydrobromide) is filtered and rinsed with 20 ml of acetonitrile. The filtrate is concentrated to dryness under vacuum and the residue is purified on a silica column (eluent: Heptane/AcOEt: 1/1 to 4/6). Beige powder. Melting point: 142.5-143° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:14]=[N:13][C:6]2[N:7]([CH3:12])[CH2:8][C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>C(#N)CC.O>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]2[CH2:41][CH2:42][N:43]([CH2:2][C:3]3[CH:14]=[N:13][C:6]4[N:7]([CH3:12])[CH2:8][C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:44][CH2:45]2)=[CH:36][CH:35]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: CN1CC(=O)Nc2cc(CO)cnc21
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN1CC(=O)Nc2cc(CN3CCC(c4ccc(Cl)cc4)CC3)cnc21
Temperature: 90 °C
Reaction time: 2 h
Yield: 11.1 %

Procedure:
7-(hydroxymethyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (85.0 mg, 0.44 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)piperidine hydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (18.1 mg, 11%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.49 (s, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.30-7.36 (m, 2H), 7.23-7.29 (m, 2H), 6.95 (d, J=2.0 Hz, 1H), 3.92 (s, 2H), 3.32 (s, 3H), 2.84-2.92 (m, 5H), 1.98 (t, J=10.7 Hz, 2H), 1.66-1.75 (m, 2H), 1.50-1.64 (m, 2H). [M+H] calc'd for C20H23ClN4O, 371. found, 371.