Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C:27](OCC)(=[O:29])[CH3:28]>>[C:27]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:3]=1[C:19](=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:29])[CH3:28]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc([N+](=O)[O-])cc21
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2ccc([N+](=O)[O-])cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-2-benzoyl-1-(ethoxycarbonyl)-6-nitroindole (step 2). tlc: Rf=0.2 (50% ethyl acetate in hexanes)
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:54]=[S:55]1(=[O:65])[CH2:60][CH2:59][N:58]([CH2:61][CH2:62][CH2:63]O)[CH2:57][CH2:56]1.C(Cl)[Cl:67]>>[ClH:67].[Br:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:63][CH2:62][CH2:61][N:58]4[CH2:57][CH2:56][S:55](=[O:65])(=[O:54])[CH2:60][CH2:59]4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: ClCCl
Reactant: O=S1(=O)CCN(CCCO)CC1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
Diethyl azodicarboxylate (220 μl, 1.4 mmol) was added dropwise to a mixture of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (170 mg, 0.46 mmol), (prepared as described for the starting material in Example 48), triphenylphosphine (367 mg, 1.4 mmol) and 3-(1,1-dioxothiomorpholino)-1-propanol (135 mg, 0.7 mmol) in methylene chloride (4 ml) under nitrogen. The mixture was stirred for 1 hour at ambient temperature and further triphenylphosphine (61 mg, 0.23 mmol), 3-(1,1-dioxothiomorpholino)-1-propanol (30 mg, 0.23 mmol) and diethyl azodicarboxylate (37 μl, 0.23 mmol) were added. The mixture was stirred for 1 hour at ambient temperature and the mixture was purified by pouring it on to a column of silica and eluting with methylene chloride/methanol (95/5). The purified product was dissolved in methylene chloride/methanol, 2.2M ethereal hydrogen chloride (1 ml) was added and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline hydrochloride (138 mg, 47%).
Reaction SMILES: C([O:8][C:9]1[CH:37]=[C:36]([O:38]CC2C=CC=CC=2)[CH:35]=[CH:34][C:10]=1[C:11]([NH:13][C@H:14]([C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21])[CH2:15][CH2:16][C:17](=[O:19])[NH2:18])=[O:12])C1C=CC=CC=1>[H][H].[C].[Pd]>[OH:8][C:9]1[CH:37]=[C:36]([OH:38])[CH:35]=[CH:34][C:10]=1[C:11]([NH:13][C@H:14]([C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21])[CH2:15][CH2:16][C:17](=[O:19])[NH2:18])=[O:12]
Reactant: NC(=O)CC[C@H](NC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1)C(=O)N1CCN(c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Product: NC(=O)CC[C@H](NC(=O)c1ccc(O)cc1O)C(=O)N1CCN(c2ccccc2)CC1
Yield: 66.1 %

Procedure:
10% Palladium-carbon (120 mg) was added to an ethanolic solution (20 ml) of 1-(2,4-dibenzyloxybenzoyl-L-glutaminyl)-4-phenylpiperazine (364 mg) and catalytic reduction was carried out for 6 hours at room temperature and under atmospheric pressure in hydrogen stream. Thereafter, treatments were effected in the same manner as in Example 5 (ii) to obtain powdery 1-(2,4-dihydroxybenzoyl-L-glutaminyl)-4-phenylpiperazine (169 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([OH:12])=O.[CH:13]([NH:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:15])[CH3:14].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:16]([CH:13]([CH3:15])[CH3:14])[NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:12]
Reactant: O=C(O)CSc1ccccc1Br
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br

Procedure:
A solution of (2-bromo-phenylsulfanyl)-acetic acid (694 mg, 2.81 mmol) and benzoic acid N′-isopropyl-hydrazide (500 mg, 2.81 mmol) in DMF (10 mL) was treated with triethylamine (1.17 ml, 8.43 mmol), HOBT (455 mg, 3.37 mmol) and EDCI (645 mg, 3.37 mmol) at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was successively washed with 1N HCl, aqueous saturated sodium bicarbonate, and brine, then dried over sodium sulfate, filtered and concentrated. Pure product was obtained by crystallization from ethyl acetate (611 mg, 54%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1)[CH:11]=[CH:10]2
Reactant: O[C@@H]1CCNC1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@@H](O)C3)ccc12
Yield: 17.4 %

Procedure:
Prepared according to the method of example 27, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (0.05 g) and (3R)-3-pyrrolidinol (0.052 g) to afford the title compound (0.01 g).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-bromo-hexane (150 μL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-hexyl-1H-pyrazole (118 mg, 56%) as a clear oil.
Reaction SMILES: C(O[C:6](=[O:19])[NH:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:11]=2[N:12]=1)(C)(C)C.[CH2:20]([NH2:26])C1OC=CC=1.[O:27]1[CH2:32][CH2:31]O[CH2:29][CH2:28]1>>[O:27]1[CH:32]=[CH:31][CH:29]=[C:28]1[N:26]([CH3:20])[C:6]([NH:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:11]=2[N:12]=1)=[O:19]
Reactant: COc1cccc2sc(NC(=O)OC(C)(C)C)nc12
Reactant: NCc1ccco1
Reactant: C1COCCO1
Product: COc1cccc2sc(NC(=O)N(C)c3ccco3)nc12
Temperature: 100 °C
Yield: 92 %

Procedure:
To a solution of (4-Methoxy-benzothiazol-2-yl)-carbamic acid tert-butyl ester (80 mg, 0.29 mmol) in dioxane (2 ml) was addded furfurylamine (55 mg, 0.57 mmol) and the mixture heated to 100° C. for 20 h. The reaction mixture was then evaporated to dryness and the residue recrystallised from ether/nHexane to afford the title compound as a beige solid (80 mg, 92% yield), MS: m/e=303 (M+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7]([NH2:11])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[BrH:14].BrBr>C(O)(=O)C>[NH2:11][C:7]1[C:6]([C:12]#[N:13])=[CH:5][C:4]([C:1](=[O:3])[CH2:2][Br:14])=[C:9]([CH3:10])[N:8]=1
Reactant: Br
Reactant: CC(=O)c1cc(C#N)c(N)nc1C
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1nc(N)c(C#N)cc1C(=O)CBr
Temperature: 45 °C
Reaction time: 5 h

Procedure:
2.7 g (15.4 mmol) of 5-acetyl-2-amino-3-cyano-6-methyl-pyridine are suspended in 110 ml of glacial acetic acid, and 1.9 ml (16.2 mmol) of 48% strength HBr are added. Then 5.2 g (32.4 mmol) of bromine are added, and the mixture is stirred at 45° C. for five hours. After cooling, the mixture is filtered with suction and the filter cake is stirred with NaHCO3 solution, filtered with suction and dried. Recrystallization from ethanol is used for purification.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH:6]([C:8]1[O:9][C:10]2[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:11]=2[CH:12]=1)=O>CCO>[OH:3]/[N:2]=[CH:6]\[C:8]1[O:9][C:10]2[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:11]=2[CH:12]=1
Reactant: NO
Reactant: COC(=O)c1ccc2cc(C=O)oc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1ccc2cc(/C=N\O)oc2c1
Reaction time: 8 h

Procedure:
Hydroxylamine hydrochloride (153 mg, 2.2 mmol) is free based for 5 min in 2N NaOH (1.1 ml, 2.2 mmol) and added drop-wise to a solution of methyl 2-formyl-1-benzofuran-6-carboxylate (408 mg, 2.0 mmol) in EtOH (6 ml). The reaction is stirred overnight and the volatiles are removed in vacuo. The residue is suspended in water (5 ml) and the slurry is filtered. The cake is dried overnight to afford 399 mg (91%) of E/Z-methyl 2-[(hydroxyimino)methyl]-1-benzofuran-6-carboxylate as a light brown solid. HRMS (FAB) calcd for C11H9NO4+H: 220.0610, found 220.0602 (M+H)+.
Reaction SMILES: [C:1]([NH:3][C:4](=[NH:18])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15]([NH2:17])=[NH:16])[S:12][CH:13]=1)#[N:2].[ClH:19].C[OH:21]>C(Cl)(Cl)Cl>[OH2:21].[ClH:19].[ClH:19].[C:1]([NH:3][C:4](=[NH:18])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([NH:14][C:15]([NH2:17])=[NH:16])[S:12][CH:13]=1)(=[O:21])[NH2:2]
Reactant: N#CNC(=N)CCCCc1csc(NC(=N)N)n1
Reactant: CO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: N=C(N)Nc1nc(CCCCC(=N)NC(N)=O)cs1
Product: O

Procedure:
1 g of N-cyano-5-(2-guanidinothiazol-4-yl)pentanoamidine was suspended in a mixture of 20 ml of methanol and 30 ml of chloroform. Hydrogen chloride gas was passed through the suspension for 1.5 hour at -5° to 5° C. and the reaction solution was concentrated under reduced pressure. The oily residue was recrystallized from a mixture of methanol and ether containing a small amount of water to provide 1.1 g of N-carbamoyl-5-(2-guanidinothiazol-4-yl)pentanoamidine dihydrochloride monohydrate having a melting point of 148°-150° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].CCCCCCC.[S:16](=O)(=[O:19])([OH:18])[OH:17].C(C(CCCC)C([O-])=O)C.[K+:31]>C(OCC)(=O)C>[K+:31].[OH:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[S:16]([O-:19])(=[O:18])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: Oc1ccc(O)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])c1cc(O)ccc1O
Temperature: 12.5 °C
Reaction time: 0.21 h
Yield: 96.6 %

Procedure:
Hydroquinone (20 g, 0.1816 mol) and n-heptane (60 mL) was taken in a round bottom flask, after cooling the flask to about 10-15° C., sulfuric acid (36 N, 17.8 g) was added dropwise at the same temperature and stirring continued further for about 10-15 min. The temperature was slowly raised to 50-60° C. then stirred for 3-8 h. The reaction mass was then cooled to 25-35° C., n-heptane was decanted and ethyl acetate (200 mL) added to dissolve the solid formed. A solution of potassium 2-ethylhexanoate (36.4 g, 0.1996 mol) in ethyl acetate (200 mL) was added slowly. The reaction was further stirred for an hour. The precipitated crude solid was filtered, washed with ethyl acetate to give 40 g of 2,5-dihydroxybenzenesulfonic acid potassium salt.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][C:5]([Cl:20])=[CH:4][N:3]=1.ClC1C=C(O)C=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[OH:37]>>[Cl:20][C:5]1[CH:6]=[C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[O:9])[C:2]([O:37][C:31]2[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=2[Cl:29])=[N:3][CH:4]=1
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: O=C(c1cc(Cl)cnc1Cl)N1CCCc2ccccc21
Agent: Oc1cccc(Cl)c1
Product: O=C(c1cc(Cl)cnc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 25, Step 2, replacing (2-chloro-5-fluoro-pyridin-3-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanon with (2,5-dichloro-pyridin-3-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone and 3-chloro-phenol with 2,5-dichloro-phenol ([CAS RN 583-78-8]). MS (ISP): 433.2 [M+H]+.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Br:16])[CH:15]=1)[C:5]([O:7]CC)=O.[NH:18]([C:20]1[CH:25]=[C:24]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:23]=[CH:22][N:21]=1)N.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:43]>C(O)C.O1CCOCC1>[ClH:43].[Br:16][C:14]1[CH:15]=[C:10]([C:4]2[C:5](=[O:7])[N:18]([C:20]3[CH:25]=[C:24]([N:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)[N:23]=[CH:22][N:21]=3)[NH:2][CH:3]=2)[CH:11]=[N:12][CH:13]=1
Reactant: NNc1cc(N2CCCCC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)c1cncc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=c1c(-c2cncc(Br)c2)c[nH]n1-c1cc(N2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 100° C., 500 mg (1.7 mmol) of the compound from Example 11A, 323 mg (1.7 mmol) of the compound from Example 8A and 58 mg (0.3 mmol) of p-toluenesulfonic acid are stirred in 2 ml of ethanol for 16 h. After cooling to RT, 0.5 ml of a 4 N solution of hydrogen chloride in dioxane is added, and the mixture is stirred at RT for 30 min. The precipitate is filtered off, washed first with ethanol and then with diethyl ether and dried under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1Br.O(CC)[C:14]([S-:16])=S.[K+].[ClH:20]>CN(C=O)C>[Cl:20][C:14]1[S:16][C:7]2[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=S)[S-]
Reactant: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2sc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Amino-4-bromobenzotrifluoride (1.00 g, 4.17 mmol) and potassium ethyl xanthate (1.60 g, 10.0 mmol) were heated to 130° C. in DMF (5 mL) overnight. After cooling to rt, the reaction mixture was diluted with 1 M aqueous HCl (15 mL) and stirred at rt for an additional 30 min. The resulting solid was collected by filtration and washed with water (2×). The solid was dissolved in EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. This gave 0.895 g (91%) of the 2-mercapto intermediate as a yellow solid. LC-MS: RT=8.60 min., [M+H]+=236.2. The material was suspended in sulfuryl chloride (5 mL) and CH2Cl2(2 mL). After 2 h, water (20 mL) was added and stirring continued for an additional 30 min. The reaction mixture was extracted with EtOAc (3×), and the combined extracts were dried over Na2SO4, filtered, concentrated under reduced pressure. This gave 0.886 g (98%) of the title compound as an off-white solid. LC-MS: RT=10.12 min., compound does not ionize.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH:7]1([CH:12]([C:18](=O)[CH3:19])[C:13](OCC)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(N(CCCC)CCCC)CCC>[OH-].[Na+]>[CH3:19][C:18]1[C:12]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:13]([OH:14])[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=1
Reactant: CCOC(=O)C(C(C)=O)C1CCCC1
Reactant: Nc1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: Cc1nc2ncnn2c(O)c1C1CCCC1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A mixture of 3-amino-1,2,4-triazole (14 g), ethyl 2-cyclopentyl-3-oxobutanoate (0.17 mol, Ex. 1) and tributylamine (50 ml) was heated at 180° C. for 6 hours. The reaction mixture was cooled to about 70° C., and aqueous NaOH solution (21 g in 200 ml of H2O) was then added and the solution was stirred for another 30 min. Following phase separation and extraction with diethyl ether, the aqueous phase was acidified with conc. HCl solution. The precipitate gave 19 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:3]=1.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:4]2[CH:3]=[C:2]([C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]([F:25])([F:37])[F:38])=[CH:33][CH:32]=3)[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=2)=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)c1ccc(Nc2cc(Cl)nc(-c3ccccc3)n2)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
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: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2cc(-c3ccc(OC(F)(F)F)cc3)nc(-c3ccccc3)n2)cc1

Procedure:
The title compound was prepared by reacting (6-chloro-2-phenyl-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.15 g, 0.41 mmol) with 4-trifluoromethoxy-phenyl boronic acid (0.09 g, 4.3 mmol) in presence of (PPh3)4Pd (0.02 g, 0.017 mmol) and 2 M sodium carbonate (0.35 g in 1.5 mL H2O) in DMF at 80° C. for 12 hours. Followed by work up and column purification to yield the desired compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:20]([CH:22]=O)C.[C:24](Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH2:1]([C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([NH:20][CH2:22][CH3:24])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)O)c(Cc2ccccc2)c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)c1ccc(OC)cc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0 C solution of 2-benzyl-4-methoxybenzoic acid (5 g) in 250 mL CH2Cl2 were added a catalytic amount of DMF and a solution of oxalyl chloride (2 mL) in 40 mL CH2Cl2. The reaction was warmed to room temp and stirred overnight, then concentrated to dryness and azeotroped from toluene (2×). The residue was dissolved in 50 mL THF and added dropwise to a 0 C solution of ethylamine (10 mL, 70% aqueous solution) in 200 mL THF. The reaction was warmed to room temp and stirred for 2 h, then quenched with saturated aqueous KHSO4 solution and extracted with EtOAc (2×). The organic solutions were dried (Na2SO4) and concentrated, then triturated with hexanes to give 5.2 g of 2-benzyl-N-ethyl-4-methoxybenzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][CH:22]([O:28]C)[CH2:23][C:24](OC)=O.C(O)(=O)C.P(Cl)(Cl)(Cl)=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[C:9]=2/[CH:24]=[CH:23]/[C:22]([O:21][CH3:20])=[O:28])=[CH:4][CH:3]=1
Reactant: COC(=O)CC(OC)OC
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 9 h
Yield: 92.9 %

Procedure:
1.01 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 0.92 g of methyl 3,3-dimethoxypropionate, 0.72 mL of 90 wt % aqueous acetic acid (containing 4 mmol of water) and 6 mL of glacial acetic acid were mixed, then, 0.33 g of phosphorus oxychloride was added dropwise into the mixture at an inner temperature of 25° C., the added mixture was stirred for 9 hours at the same temperature to cause a reaction. After completion of the reaction, 16 mL of water was added dropwise into the reaction liquid, and the precipitated crystals were filtrated. The crystals were washed with 20 vol % aqueous methanol, then, dried to obtain 1.25 g of methyl trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylate (yellow solid). Yield: 93%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24](Br)[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH3:38][CH2:39]OC(C)=O>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>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[O:27])=[C:24]([CH:38]=[CH2:39])[N:23]=[C:22]3[O:29][CH2:30][CH3:31])=[C:16]([F:32])[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1F
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1nc(OCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2F)c1C=O
Temperature: 90 °C

Procedure:
Intermediate (16a) (9.5 g, 18.9 mmol), tetrakis(triphenylphosphine)palladium(0) (1.0 g, 0.9 mmol), (2-ethenyl)tri-n-butyltin (11.0 mL, 37.8 mmol) were dissolved in DMF (70 mL, 900 mmol), and heated at 90° C. for 1.5 hours. The mixture was cooled to room temperature and 300 mL of EtOAc was added. The organic layer was washed using a 20% potassium fluoride solution (2×100 mL) and saturated aqueous NaCl. The resulting material was purified by silica gel chromatography (0-60% EtOAc:hexanes) to yield intermediate (16b) (7.7 g). MS m/z: [M+H+] calcd for C26H27FN2O4, 451.2; found 451.0. 1H-NMR (CDCl3): 8.17 (1H, s), 7.79 (1H, d), 7.48 (1H, t), 7.40 (1H, t), 7.28 (1H, s), 7.01(2H, m), 6.86 (1H, t), 6.67 (1H, m), 5.95 (1H, d), 5.41 (2H, s), 5.27 (1H, d), 4.48 (2H, q), 1.38 (3H, t), 1.25 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:16][C@H:10]3[CH2:11][N:12](C)[CH2:13][CH2:14][C@@H:9]3[CH2:8][C:7](=O)[C:6]=2[CH:18]=1.[BH4-].[Na+].CO>C(O)C.O.[OH-].[Na+]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:16][C@H:10]3[CH2:11][NH:12][CH2:13][CH2:14][C@@H:9]3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: CN1CC[C@@H]2CC(=O)c3cc(N)ccc3C[C@H]2C1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)C=C[C@H]1CCNC[C@@H]1C2
Reaction time: 1 h

Procedure:
The starting material can be produced as follows. A solution of 13.2 g of trans-8-amino-1,2,3,4,4a,5,11,11a-octahydro-2-methyl-6H-benzo[5,6]cyclohepta[1,2-c]pyridin-6-one in 132 ml of ethanol is mixed at 40° with a solution of 1.45 g of sodium borohydride in 4 ml of water and 0.1 ml of water and 0.1 ml of conc. caustic soda and the resulting mixture is stirred for 1 hour at 70°. After addition of 10 ml of methanol, the reaction mixture is boiled for 10 minutes and evaporated to dryness and the residue is dissolved in water and chloroform. After separation of the organic phase, the aqueous phase is extracted with chloroform and the combined organic extracts are washed with water, dried over potassium carbonate and evaporated. The crude product is employed as such in the next step.