Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.Cl.[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:33])[CH2:30][CH2:31][NH:32][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:21]([F:22])([F:23])[F:24])=[CH:20][CH:19]=1)[CH3:27]
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2C(F)(F)F)cc1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 4-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.536 g (10 mmol) of β-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel and the title compound eluted with ethyl acetate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[CH:22]=[C:21]([O:23][C:24]3[CH:25]=[N:26][C:27]([N+:30]([O-])=O)=[CH:28][CH:29]=3)[CH:20]=[CH:19][N:18]=2)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.C1COCC1.[Zn]>[NH2:30][C:27]1[N:26]=[CH:25][C:24]([O:23][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:14]([N:11]3[CH2:10][CH2:9][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:13][CH2:12]3)=[O:15])[CH:22]=2)=[CH:29][CH:28]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1)N1CCN(Cc2ccccc2)CC1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCN(Cc4ccccc4)CC3)c2)cn1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 66.4 %

Procedure:
To a stirring solution of 4-benzyl-N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide (0.574 g, 1.321 mmol) in MeOH/THF (1:1, 30 mL) at RT was sequentially added ammonium formate (0.833 g, 13.21 mmol) and zinc powder (0.864 g, 13.21 mmol). The resulting suspension was stirred briskly at RT. After 75 min, the reaction was filtered through diatomaceous earth, rinsing with THF. The combined filtrates were concentrated and purified by silica gel chromatography (0-10% MeOH/DCM) to afford N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-4-benzylpiperazine-1-carboxamide (0.355 g, 64%) as a brittle pink foam. 1H NMR (400 MHz, DMSO-d6): δ 9.13 (s, 1H), 8.05 (d, J=5.7 Hz, 1H), 7.75 (d, J=2.9 Hz, 1H), 7.30-7.29 (m, 5H), 7.24-7.23 (m, 2H), 6.52 (dd, J=5.7, 2.4 Hz, 1H), 6.49 (d, J=8.9 Hz, 1H), 5.99 (s, 2H), 3.46 (s, 2H), 3.40 (t, J=4.7 Hz, 4H), 2.31 (t, J=4.7 Hz, 4H); MS (ESI) m/z: 405.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])=[CH:6][C:7]1[N:11]([CH:12]2[CH2:14][CH2:13]2)[C:10]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[N:9][N:8]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH3:21])[CH2:6][C:7]1[N:11]([CH:12]2[CH2:14][CH2:13]2)[C:10]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[N:9][N:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)=Cc1nnc(-c2ccncc2)n1C1CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)Cc1nnc(-c2ccncc2)n1C1CC1

Procedure:
3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-acrylic acid ethyl ester (5.76 g, 19.3 mmol) was hydrogenated with 10% Pd/C (3.0 g) in EtOH (100 ml) o.n. The reaction mixture was filtered and concentrated. The residue was triturated with hex. to give the title compound in 3.1 g (53%) yield. 1H-NMR: 8.76 (d, 2H), 7.73 (d, 2H), 4.14(m, 2H), 3.35 (m, 3H), 2.88 (q, 1H), 1.39 (d, 3H), 1.25 (t, 3H), 1.18 (m, 2H) and 0.73 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH3:23])[C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH2:15][C:14]1[C:17]([O:22][CH3:23])=[CH:18][CH:19]=[C:20]([F:21])[C:13]=1[F:12]
Reactant: O=C(O)c1ccc(F)c(O)c1
Reactant: COc1ccc(F)c(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(F)c1COc1cc(C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A suspension of 4-fluoro-3-hydroxybenzoic acid (0.19 g), 2,3-difluoro-6-methoxybenzyl bromide (0.6 g) and potassium carbonate (0.5 g) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (6 mL). To the solution were added methanol (3 mL), water (3 mL) and lithium hydroxide-monohydrate (0.5 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid (15 mL), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was suspended in a mixed solvent (n-hexane/ethyl acetate=4/1) and collected by filtration, and dried under reduced pressure to give 4-fluoro-3-(2,3-difluoro-6-methoxybenzyloxy)benzoic acid (0.31 g). This material was dissolved in 1,4-dioxane (4 mL). To the solution were added triethylamine (0.41 mL) and diphenylphosphoryl azide (0.21 mL), and the mixture was stirred at room temperature for 1 hour. Then the mixture was heated for reflux for 4 hours. To the reaction mixture was added 1 mol/L aqueous sodium hydroxide solution (4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1−1/1) to give crude product. To the crude product was added methylene chloride, and the insoluble material was removed by filtration.
Reaction SMILES: C([O:4][CH2:5][CH:6]1[O:11][C:10]2=[CH:12][S:13][CH:14]=[C:9]2[O:8][CH2:7]1)(=O)C.[OH-].[Na+]>O>[O:8]1[CH2:7][CH:6]([CH2:5][OH:4])[O:11][C:10]2=[CH:12][S:13][CH:14]=[C:9]12
Reactant: CC(=O)OCC1COc2cscc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCC1COc2cscc2O1
Temperature: 25 °C
Yield: 89 %

Procedure:
In a 25 mL round bottom flask equipped with a reflux condenser 0.64 g (0.0030 mol) of (2,3-dihydrothieno[3,4-b][1,4]dioxin-2-yl)methyl acetate was combined with 50% NaOH in water. The reaction was refluxed overnight and then cooled to room temperature. It was then poured into an Erlenmeyer flask filled with 100 mL water. The mixture was acidified then extracted with DCM. The solvent was removed under reduced pressure and column chromatography (7:3 hexanes/ethyl acetate) was performed to give 0.46 g (90%) of product. The structure was confirmed by LC-MS and 1H/13C NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6]([NH2:8])=O)[CH2:5][CH2:4]1.C([N+](CC)(CC)S(NC(=O)OC)(=O)=O)C.ClCCl.[Cl-].[OH:28][NH3+:29]>O1CCCC1.C(N(CC)CC)C.O>[OH:28][NH:29][C:6]([C:3]1([O:2][CH3:1])[CH2:5][CH2:4]1)=[NH:8]
Reactant: COC1(C(N)=O)CC1
Reactant: [NH3+]O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC1(C(=N)NO)CC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
100 mg (1.03 mmol) of 1-methoxycyclopropanecarboxamide [L. N. Owen, H. M. Babatunde Somade, J. Chem. Soc. 1947, 1030-1034] in tetrahydrofuran (22.7 ml) was admixed with 1.51 g (6.08 mmol) of methyl N-(triethylammoniumsulphonyl)carbamate (Burgess reagent) and then stirred at 60° C. for 1.5 h. The reaction mixture was admixed with dichloromethane and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure (637 mg of crude product). 100 mg of the crude product were initially charged in ethanol (1.2 ml), admixed with 107 mg (1.55 mmol) of hydroxylammonium chloride and 0.17 ml (125 mg, 1.24 mg) of triethylamine and then stirred under reflux overnight. The reaction solution was concentrated under reduced pressure, and the residue was admixed with saturated aqueous sodium chloride solution and then extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was subsequently stirred with ethyl acetate, the insoluble salts were filtered off and the filtrate was concentrated under reduced pressure. Yield: 32.3 mg (23% of theory)
Reaction SMILES: [CH3:1][N:2]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:3][CH:4]([OH:26])[CH2:5][O:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.[CH3:51][N:52]=[C:53]=[O:54]>C1C=CC=CC=1>[CH3:1][N:2]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:3][CH:4]([O:26][C:53](=[O:54])[NH:52][CH3:51])[CH2:5][O:6][C:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCCCCCCCCCCCCCCCCN(C)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN=C=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(C)CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)NC
Yield: 80 %

Procedure:
A solution of 3-(N-methyl octadecylamino) 1-trityloxypropan-2-ol 6b (6 10-3M), pyridine (1 ml) and methylisocyanate (1.2 ml) in dry benzene (45 ml), was heated at 40° C. for three days. After elimination of the solvent, the residue was purified by column chromatography with CH2Cl2 as eluent, to give 7b.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:33])(=O)=O.[N-:44]=[N+:45]=[N-:46].[Na+]>CN(C)C=O.O>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:32]([N:8]2[CH2:9][C@@H:10]([S:12][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:11][C@H:7]2[CH2:6][N:44]=[N+:45]=[N-:46])=[O:33])=[CH:41][CH:40]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COS(C)(=O)=O)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CN=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol methanesulfonate (27.81 g) in dimethylformamide (120 ml), a solution (12 ml) of sodium azide (3.50 g: 53.8 mmole) in water is added. The mixture is stirred at 80° C. for 8 hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is successively washed with water and brine and concentrated. The residue is purified by silica gel column chromatography to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-2-azidomethyl-4-tritylthiopyrrolidine (17.27 g: 30.64 mmole). Total yield of Steps 4 and 5: 74%. NMR δ(CDCl3) ppm: 3.84(s, 3H), 4.82 to 5.15(m, 2H). IR ν (CHCl3) cm-1 : 2105, 1685.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([Cl:12])[C:3]=1[Cl:13].[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Cl:12][C:4]1[C:3]([Cl:13])=[C:2]([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)Nc1ccc(Br)c(Cl)c1Cl
Product: CC(=O)Nc1ccc(-c2ccncc2)c(Cl)c1Cl

Procedure:
The title compound was prepared from N-[4-bromo-2,3-dichlorophenyl]acetamide and pyridin-4-ylboronic acid using a similar procedure to Description 3.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17](O)=[O:18])[C:15]=1[NH2:23]>>[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:16]2[C:15]=1[N:23]=[C:2]1[NH:3][C:4]3[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=3[N:6]1[C:17]2=[O:18]
Reactant: Cc1cc2nc(Cl)[nH]c2cc1C
Reactant: Cc1cccc(C(=O)O)c1N
Product: Cc1cc2[nH]c3nc4c(C)cccc4c(=O)n3c2cc1C

Procedure:
4,8,9-Trimethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-chloro-5,6-dimethylbenzimidazole and 3-methylanthranilic acid.
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][C:4]1[C:5]([O:16][CH3:17])=[CH:6][C:7]2[CH2:12][O:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]=2[CH:15]=1.O.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.CO.C(OCC)(=O)C>[CH3:17][O:16][C:5]1[C:4]([CH2:3][CH:2]=[O:1])=[CH:15][C:8]2[N:9]([CH3:14])[C:10](=[O:13])[O:11][CH2:12][C:7]=2[CH:6]=1
Reactant: COc1cc2c(cc1CC(O)CO)N(C)C(=O)OC2
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1CC=O)N(C)C(=O)OC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
280 mg of 7-(2,3-dihydroxypropyl)-6-methoxy-1-methyl-1,4-dihydrobenz[d][1,3]oxazin-2-one was dissolved in 4 ml of tetrahydrofuran and 4 ml of methanol. Thereafter, 8 ml of water containing 0.29 g of sodium metaperiodate was added to the reaction solution while cooling on ice, and the obtained mixture was then stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate and then washed with a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), so as to obtain 167 mg of (6-methoxy-1-methyl-2-oxo-1,4-dihydro-2H-benz[d][1,3]oxazin-7-yl)acetaldehyde.
Reaction SMILES: [BrH:1].[C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N>CS(C)=O>[Br:1][C:6]1[CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=[CH:4][C:5]=1[NH2:8]
Reactant: Br
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: N
Solvent: CS(C)=O
Product: Nc1ccc(-c2ccccc2)cc1Br
Temperature: 100 °C
Reaction time: 14 h

Procedure:
8.7 mL (76.8 mmol) of a 48% hydrogen bromide solution is added dropwise to a solution of 13.008 g (76.8 mmol) of biphenyl-4-ylamine in 60 mL of DMSO at ambient temperature and the mixture is stirred for 14 hours. Then it is heated to 100° C. for 1 hour, the mixture is then cooled and poured onto water. By the addition of ammonia solution, the reaction mixture is made alkaline and the precipitate formed is filtered off and washed with water. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane). Yield: 11.3 g (60% of theory); C12H10BrNO (M=248.19); calc.: molecular ion peak (M+H)+: 248/250 (Cl); found: molecular ion peak (M+H)+: 248/250 (Cl).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)(=O)=O.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:23]([F:37])([F:38])[C:24]1[CH:25]=[C:26]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH:8]=2)[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A solution of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (2, 1.10 g, 3.32 mmol) and (3,5-bis(trifluoromethyl)phenyl)boronic acid (1.42 g, 3.32 mmol), Pd(PPh3)4 (0.38 g, 0.33 mmol) and 2 M Na2CO3 (20 mL) in DME (50 mL) was heated at 80° C. for 6 h. The mixture cooled to ambient temperature, and the resulting solids were removed by filtration through a Celite pad. The filtrate was washed brine solution (4×50 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 40 g Redisep column, 0% to 80% EtOAc in hexanes) to provide tert-butyl 4-(3,5-bis(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (18) as a yellow oil (0.891 g, 68%): 1H NMR (300 MHz, DMSO-d6) δ 8.09-8.04 (m, 2H), 8.00-7.96 (m, 1H), 6.53-6.42 (m, 1H), 4.09-4.00 (m, 2H), 3.55 (t, J=5.7 Hz, 2H), 2.60-2.52 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)CCC>C(#N)C.[Pd](Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccs4)cc3CC[C@@H]12
Yield: 33.1 %

Procedure:
Five hundred mg of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was combined with 730 mg of 2-(tri-n-butylstannyl)thiophene and 100 mg of bis(triphenylphosphene) palladium chloride in 6 mL of acetonitrile in a screw capped sealable tube. The mixture was flushed with argon for 5 minutes, capped and heated at 90° for 20 h. Upon cooling, the mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by chromatography on a silica gel column, eluting with ethyl acetate, and the isolated product was recrystallized from ethyl acetate/hexane/chloroform to obtain 167 mg of the desired product. mp 193°-195°. FDMS 311.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][N:11]3[C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=4[CH:9]=[CH:10]3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cn1ncc2[nH]ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (298 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 30 minutes, after which a solution of 4-(4-chlorobenzoyl)benzyl bromide (712 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 1.5 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:2) to provide the title compound as white powder (505 mg, yield 57%).
Reaction SMILES: [NH2:1][N:2]1[C:7](SC)=[N:6][C:5](=[O:10])[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:3]1.[CH3:18][NH:19][CH3:20]>C(#N)C>[NH2:1][N:2]1[C:7]([N:19]([CH3:20])[CH3:18])=[N:6][C:5](=[O:10])[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:3]1
Reactant: CNC
Reactant: CSc1nc(=O)c(-c2ccc(F)cc2)nn1N
Solvent: CC#N
Product: CN(C)c1nc(=O)c(-c2ccc(F)cc2)nn1N
Yield: 53 %

Procedure:
2-Amino-3-methylthio-6-(p-fluorophenyl)-5-oxo-2,5-dihydro-1,2,4-triazine (1.0 g) was added to a mixture of an aqueous solution of 40% dimethylamine (5 ml) and acetonitrile (10 ml), and the resultant mixture was heated under reflux for 1 hour. After completion of the reaction, the resultant mixture was evaporated to dryness under reduced pressure to give a crude product. Recrystallization of the crude product from acetone gave 0.7 g of 2-amino-3-dimethylamino-6-(p-fluorophenyl)-5-oxo-2,5-dihydro-1,2,4-triazine in 53% yield. M.P., 212° C.
Reaction SMILES: [C:1]([C@H:5]([NH:27][CH2:28][C:29]([O:31]CC)=O)[C:6]([N:8]1[CH2:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:10][C@H:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:36])[CH3:35]>C1COCC1>[C:1]([C@H:5]([NH:27][CH2:28][C:29]([NH:36][CH2:34][CH3:35])=[O:31])[C:6]([N:8]1[CH2:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH:10][C@H:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN
Reactant: CCOC(=O)CN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CCNC(=O)CN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C(C)(C)C

Procedure:
A solution of ethyl({(1S)-1-tert-butyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}amino)acetate (30-1, 50 mg, 0.11 mmol) in a solution of ethylamine in THF (2 M, 2 mL) was heated in a sealable tube at 100° C. for 16 hours. The reaction mixture was concentrated and the residue purified by flash column chromatography (EtOAc) to give 2-({(1S)-1-tert-butyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}amino)-N-ethylacetamide (30-2) as a white solid. 1H NMR (500 MHz, CDCl3) showed a 1:1 mixture of rotamers; one rotamer: δ 7.43-7.22 (m, 5H), 7.11-6.96 (m, 3H), 6.89 (br m, 1H), 6.38 (br s, 1H), 5.94 (m, 1H), 4.92 (ddd, 1H, J=14.9, 4.4, 1.7 Hz), 4.87 (br d, 1H, J=15.3 Hz), 3.42 (d, 1H, J=16.8 Hz), 3.35 (m, 2H), 3.03 (s, 1H), 2.88 (d, 1H, J=16.8 Hz), 2.34 (br s, 1H), 1.18 (t, 3H, J=7.3 Hz), 1.06 (s, 9H). LRMS m/z (M+H) 456.5 found, 456.2 required.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=[CH:9]3)[CH:5]=[CH:4][N:3]=[CH:2]1.C([OH:24])C>>[OH2:24].[N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=[CH:9]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCO
Agent: c1ccc(-c2ncc3cc(-n4ccnc4)ccc3n2)cc1
Product: O
Reaction time: 0.08 h

Procedure:
3 g of 6-(1H-imidazol-1-yl)-2-phenylquinazoline are suspended in 80 mL of ethanol, the suspension is heated at reflux for 10 minutes, and then filtered while hot, the resulting solution is added at room temperature to 80 mL of water, with stirring, stirring is continued for a further 5 min and the mixture is then filtered and dried at 20° C., 10 mmHg, for 12 hours. 2.3 g (75%) of product are obtained in the form of a yellow powder. The crystals obtained are analysed. XRPD: Form C. Form C is similarly obtained by precipitating the product from methanol/H2O.