Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=3)[CH:16]=[C:15]4[CH:34]=O)[C:9]([CH3:36])=[C:8]([F:37])[CH:7]=2)[CH2:3][CH2:2]1.[OH:39][CH2:40][C@H:41]1[CH2:46][NH:45][CH2:44][CH2:43][N:42]1C(OC(C)(C)C)=O>>[CH:1]1([NH:4][C:5](=[O:38])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=3)[CH:16]=[C:15]4[CH2:34][N:45]3[CH2:44][CH2:43][NH:42][C@@H:41]([CH2:40][OH:39])[CH2:46]3)[C:9]([CH3:36])=[C:8]([F:37])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)cc(C=O)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(S(C)(=O)=O)cc3)cc(CN3CCN[C@@H](CO)C3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 112 step i) and (R)-2-(hydroxymethyl)-piperazine-1-carboxylic acid, tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([CH2:23][N:13]2[CH:14]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[CH:11][C:12]2=[O:15])=[CH:21][CH:22]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: COc1ccc(-c2ccc(=O)[nH]c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)nc3)c2)cc1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
5-(4-Methoxyphenyl)pyridine-2(1H)-one (4.20 mmol, 0.85 g), 2-chloro-5-(chloromethyl)pyridine (1.5 eq, 6.30 mmol, 1.02 g), K2CO3 (2 eq, 8.40 mmol, 1.17 g) in THF (10 mL) were heated at 70° C. for 2 hours. Then, the reaction was cooled to room temperature. The suspension was filtered off and the filtrate was evaporated under reduced pressure. The residue was puridied by short open column chromatography CH2Cl2/MeOH(NH3)sat. 1% yielding 1-((6-chloropyridin-3-yl)methyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one as white solid (1.04 g, 75%)
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([OH:20])=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])[CH3:3].[NH2:21][C@@H:22]([CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)=[O:24]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]([NH:21][C@@H:22]([CH2:40][O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:23]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:30][CH:31]=3)=[O:24])=[O:20])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(N2CCN(CC(=O)O)CC2)cc1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CC(=O)c1ccc(N2CCN(CC(=O)N[C@@H](COCc3ccccc3)C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)CC2)cc1
Yield: 20.4 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(4-acetylphenyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 229, (S)-2-(2-(4-(4-acetylphenyl)piperazin-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (10.2 mg, 20.4%). 1H-NMR (400 MHz, DMSO-D6): σ 10.23 (s, 1H), 8.04 (d, 1H), 7.81 (d, 2H), 7.60 (d, 2H), 7.23 (m, 7H), 7.01 (m, 6H), 4.71 (m, 1H), 4.52 (s, 2H), 3.74 (m, 1H), 3.33 (m, 5H), 3.07 (s, 2H), 2.61 (m, 4H), 2.46 (s, 3H). MS (EI) for C36H37FN4O5: 625.6 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O1CCCC1.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>O>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])=[CH:3][CH:4]=1)(=[O:9])=[O:10]
Reactant: C=C(C)C(=O)Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)C(=O)Nc1ccc(S(N)(=O)=O)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a 1 l three-necked flask equipped with a stirring machine, a condenser and a dropping funnel, there were introduced 170.2 g (1.0 mole) of p-aminobenzenesulfonamide and 700 ml of tetrahydrofuran, and the mixture was stirred while cooling it in an ice-water bath. 52.3 g (0.5 mole) of methacrylic acid chloride was dropwise added to the mixture through the dropping funnel over about one hour. After the dropwise addition, the flask was removed from the ice-water bath and the content thereof was stirred at room temperature for 30 minutes and further stirred for additional one hour while heating it to 60° C. in an oil bath. After completion of the reaction, the reaction mixture was poured into 3 l of water while stirring. The stirring was continued for 30 minutes and then the mixture was filtered to give white solid of N-(p-aminosulfonylphenyl) methacrylamide. The white solid thus obtained was purified by recrystallization from ethanol-acetone mixed solvent (yield 39.3 g).
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[CH:4]=[CH:3]1.[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].C(OCC)(=O)C>N1C=CC=CC=1>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2ccc(N)cc21
Reactant: CC(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
To a solution of 1-methyl-1H-indol-6-amine (45 mg, 0.31 mmol) in pyridine (2 mL) at room temperature was added isobutyryl chloride (35 μL, 0.34 mmol). The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic layer was washed three times with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 24.3 mg (36%) of the title compound (LCMS RT=5.73 min, MH+ 217.2)
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3cncn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cncc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 95.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-imidazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (46 mg, 0.0767 mmol) prepared in Example 49c, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL), dichloromethane (1.0 mL), to yield the title compound (33 mg, 96%) as a colorless solid.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:44][C:45]1[C:49]([CH3:50])=[N:48][O:47][N:46]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]3[C:49]([CH3:50])=[N:48][O:47][N:46]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: Cc1nonc1CBr
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: Cc1nonc1Cn1nnc2c(N3CC4(COC4)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-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole and isolated as white solid. MS(m/e): 371.3 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:20]1[CH2:21][C:16]2[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])=[N:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(C)=O)C3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
To a stirred solution of (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 7) (60 mg, 0.16 mmol) in DCM (1.5 mL) was added triethylamine (42 uL, 0.31 mmol) and acetyl chloride (71 uL, 0.31 mmol). The reaction mixture was stirred overnight at room temperature, concentrated in vacuo, then diluted with water and ethyl acetate. The organic layer was concentrated and purified by prep HPLC (low pH) to give an off-white solid (5.7 mg, 0.013 mmol, 9% yield).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]#[N:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:20]([O:24][C:25]([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C(#N)C>[C:20]([O:24][C:25]([NH:27][CH:28]1[CH2:32][CH2:31][N:30]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]#[N:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:29]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: N#Cc1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2c(F)cc3c(=O)c(C#N)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.2 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carbonitrile (5.04 g) and 3-(tertbutyloxycarbonylamino)pyrrolidine (3.96 g) were combined in acetonitrile (48 ml). The mixture was heated to reflux at which point all the solids dissolved. After refluxing for 15-20 minutes a precipitate formed. Stirring was continued at reflux overnight (22 hours). Triethylamine (6 ml) was then added and refluxing continued another seven hours before cooling to room temperature. The solid was collected by filtration and then washed with acetonitrile (15 ml) followed by a solution of triethylamine (5 ml) in acetonitrile (5 ml). The solid was dried under vacuum at 50° C. to give 7-[3-(tert-butyloxycarbonylamino)pyrrolidin-1-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carbonitrile (7.65 g, 93%), mp 249°-250° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[CH:26]=3)[C:15]=2[CH3:40])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:23][CH2:24][C:25]3[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=3)[O:31][CH2:32][C:33]([OH:35])=[O:34])[C:15]=2[CH3:40])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OCc3cccc(OCC(=O)OC(C)(C)C)c3)c3ccccn23)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)c2c(C)c(OCc3cccc(OCC(=O)O)c3)c3ccccn23)ccc1N
Yield: 88.3 %

Procedure:
The solution of 0.87 g (1.60 mmol) of methyl 2-amino-5-[(1-{[3-(2-tert-butoxy-2-oxoethoxy)benzyl]oxy}-2-methylindolizin-3-yl)carbonyl]benzoate in 3.0 ml of trifluoroacetic acid and 16 ml of dichloromethane at ambient temperature is stirred for 4 hours at ambient temperature. The reaction medium is poured into a saturated aqueous solution of sodium bicarbonate and the mixture is washed with ethyl acetate. The aqueous phase is acidified with a saturated aqueous solution of potassium hydrogen sulphate and then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. 0.69 g (88%) of a green solid is obtained.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+:4].C(O)(=O)/[C:6](=[C:8](\[CH:10]=[O:11])/Br)/Br.[OH2:14]>C(O)C>[CH:10](/[O-:11])=[C:8](\[N+:1]([O-:3])=[O:2])/[CH:6]=[O:14].[OH2:2].[Na+:4]
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C/C(=C\[O-])[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of sodium nitrite (714 g, 10.2 mol) in 700 ml of water at 50° C.±5° C. was added over a period of 3 hours a solution of mucobromic acid (48) (700 g, 2.7 mol) in 700 ml of warm ethanol. The reaction was stirred for 15 minutes, cooled to 0° C., and 700 ml of ethanol was added. The resulting orange precipitate was collected by vacuum filtration and dried in vacuo to yield sodium nitromalondialdehyde monohydrate (305 g, 1.9 mol) which was used in the next step without further purification. Glycine ethyl ester (300 g, 2.9 mol) and nitromalondialdehyde monohydrate (305 g, 1.9 mol) were placed in a 12 l round bottom flask and slurried with a mechanical stirrer in 560 ml of methanol and 280 ml of water. Sodium hydroxide (800 g, 20 mol) dissolved in 1.6 l water was added to the solution at a rate which maintained the temperature at 50° C. The reaction was cooled to 0° C. with an ice bath and neutralized to pH. 0 with 1.7 l HCl (conc.) while maintaining the temperature below 10° C. A black precipitate was removed by filtration through Celite and the product was extracted with 20 liters of ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo to provide 4-nitropyrrole-2-carboxylic acid (140 g, 0.9 mol) as a brown solid which was used without further purification. To a solution of 4-nitropyrrole-2-carboxylic acid (140 g, 0.9 mol) dissolved in 180 ml of methanol was added 8 ml of concentrated sulfuric acid. The solution was refluxed for 15 hours, cooled to 0° C. and 90 ml of water was added. The solution was then allowed to stand at −20° C. for 2 days. The resulting light brown crystals were collected by vacuum filtration to yield pure methyl-4-nitropyrrole-2-carboxylate (49) (10 g, 0.62 mol) in 23% overall yield. 1H NMR (DMSO-d6) δ 14.2 (br s, 1H), 7.74 (d, 1H, J=1.6 Hz), 7.35 (d, 1H, J=1.7 Hz), 3.73 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:36](Cl)(=[O:40])[CH:37]([CH3:39])[CH3:38]>>[CH3:38][CH:37]([CH3:39])[C:36]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:40]
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Reactant: CC(C)C(=O)Cl
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)C(C)C)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available isobutyryl chloride (Aldrich) via the parallel synthesis described above. MS−base peak at m/z=548 by positive ion CI.
Reaction SMILES: C(O[CH:5]1[CH2:10][O:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:7][N:6]1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:22])(=O)C.[CH2:34]([SH:38])[CH2:35][CH2:36][CH3:37].B(F)(F)F.CCOCC>ClCCl>[CH2:34]([S:38][CH:5]1[CH2:10][O:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:7][N:6]1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=1)=[O:22])[CH2:35][CH2:36][CH3:37]
Reactant: CC(=O)OC1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: CCCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCSC1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) mixture of 3.0 g 5,6-dihydro-5-acetyloxy-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoro-methyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide (prepared in D above) and 2.0 ml butanethiol in 50 ml dichloromethane was added 1.0 ml borontrifluoride etherate. The cooling bath was removed and the mixture was stirred for 1 h. The mixture was then quenched with saturated sodium bicarbonate and the phases were separated. The organic phase was washed with 1 M sodium hydroxide and saturated sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum to give 5-(butylthio)-5,6-dihydro-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1(O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[Cl-].[Cl-].[Ca+2]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH2:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC1(O)CCc2ccc(F)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1=CCc2ccc(F)cc21
Yield: 21.4 %

Procedure:
The crude (6-Fluoro-1-hydroxy-indan-1-yl)-acetic acid ethyl ester (Compound G in FIG. 7; 3.55 g), p-toluene sulfonic acid.H2O (PTSA; 5.67 g, 29.8 mmol), and CaCl2 (4.13 g, 37.2 mmol) in toluene (66 mL) were refluxed overnight. The solution was filtered and the solid residue washed with benzene. The combined organics were washed with water, NaHCO3, water, dried (MgSO4), filtered, and concentrated in vacuo. Purification using flash chromatography (13:1 hexane/EtOAc) afforded the title compound (Compound H in FIG. 7) as an orange solid (0.703 g). 1H NMR (CDCl3) δ 7.25 (m, 2H), 7.06 (m, 1H), 6.25 (d, J=2.3 Hz, 1H), 4.24 (q, J=7.0 Hz, 2H), 3.32 (s, 2H), 3.03 (s, 2H), 1.33 (t, J=7.1 Hz, 3H); ESI-CID 221 (M-H+).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:21][CH:20]=2)[O:13][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH2:1]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:32]3[CH2:33][CH2:34][CH2:35][CH:31]3[CH3:30])=[CH:21][CH:20]=2)[O:13][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCCN1
Reactant: COC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1oc(-c2ccc(OCCCN3CCCC3C)cc2)nc1CNCc1ccccc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 4-[(benzylamino)methyl]-2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole-5-carboxylate i94 (0.11 g, 0.27 mmol, 1 eq), 2-methylpyrrolidine (30 μl, 0.32 mmol, 1.2 eq) and potassium carbonate (0.15 g, 1.06 mmol, 4 eq) in acetonitrile (5 ml) is stirred at 110° C. overnight. The mixture is then poured into ethyl acetate (50 ml) and washed with water. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. Two successive purifications over silicagel (eluent: dichloromethane, methanol, ammonia 90/10/1) and one purification by preparative liquid chromatography (gradient: acetonitrile/water/trifluoroacetic acid 95:5:01 to 5:95:01) yield 6 mg of methyl 4-[(benzylamino)methyl]-2-{4-[3-(2-methyl-1-pyrrolidinyl)propoxy]phenyl}-1,3-oxazole-5-carboxylate 99.
Reaction SMILES: Cl[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:10]=2)[N:7]=1.[OH-:23].[Na+]>O1CCOCC1.O>[C:11]1([C:8]2[N:6]3[NH:7][C:2](=[O:23])[C:3]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:5]3=[N:10][N:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [OH-]
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]n2c(-c3ccccc3)nnc2cc1-c1ccccc1
Yield: 92.3 %

Procedure:
To a solution of 6-chloro-3,7-diphenyl-1,2,4-triazolo[4,3-b]pyridazine (from Example 2, Step c) (1.02 g, 3.34 mmol) in 1,4-dioxane (60 ml) and water (12 ml) was added 4 M aqueous NaOH (4.17 ml, 16.7 mmol), and the solution was heated at reflux for 7.5 h whilst stirring magnetically. The mixture was then concentrated in vacuo and the aqueous residue was partitioned between water (200 ml) and diethyl ether (100 ml). The aqueous layer was then acidified with 5 M aqueous HCl until the pH was ca. 3. The resulting precipitated solid was collected by filtration, washed with water, then hexane, and dried at 60° C. under vacuum to give 0.8885 g (92%) of the title compound as a white solid. 1H NMR (360 MHz, d6-DMSO) δ 7.47-7.63 (6H, m), 7.71 (2H, dd, J=8.0, J=1.8 Hz), 8.31 (1H, s), 8.46 (2H, m), 12.80 (1H, br s); MS (ES+) m/e 289 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([O:36][C:37]([N:39]1[CH:43]=[CH:42][CH:41]=[C:40]1B(O)O)=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([C:25]3[CH:30]=[CH:29][C:28]([C:40]4[N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH:43]=[CH:42][CH:41]=4)=[CH:27][CH:26]=3)[C:16]3[C:21]([C:22]=2[CH:23]=[O:24])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(I)cc2)CC1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccc(-c3cccn3C(=O)OC(C)(C)C)cc2)CC1
Yield: 56 %

Procedure:
4-[3-Formyl-1-(4-iodophenyl)-1H-indol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester is reacted with 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid as described in Example 66 to afford 4-{1-[4-(tert-butoxylcarbonyl-1H-pyrrol-2-yl)-phenyl]-3-formyl-1H-indol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester as a beige solid (56% yield). ESI/MS 571 (M+1), 515 [M−C(CH3)3]; NMR (CDCl3) 10.28 (1H, s); 8.27 (1H, d, J=6 Hz); 7.59 (2H, d); 7.41 (6H, m); 6.32 (2H, m); 3.36 (8H, m); 1.46 (9H, s); 1.44 (9H, s).