Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([S:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[N:1]1([C:22]([C:21]2[CH:20]=[CH:19][C:18]([S:17][CH:15]3[CH2:16][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:14]3)=[CH:26][CH:25]=2)=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC(Sc2ccc(C(=O)O)cc2)C1
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Sc2ccc(C(=O)N3CCCC3)cc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.6 %

Procedure:
Pyrrolidine (0.60 g, 8.4 mmol) was added to a solution of 59B (2.0 g, 6.5 mmol) and DCM (25 mL). The mixture was cooled to 0° C. and then DIPEA and TBTU were added in the given order. The mixture was stirred at 0° C. for 20 min and then at RT for 1.5 h. The solution was washed with aqueous Na2CO3 (1M) and then the organic solution was evaporated. The product was purified by silica-gel chromatography using 1-5% methanol in DCM. There was obtained 2.3 g (98%) of 59C as an oil. 1H NMR (500 MHz, CDCl3): δ 1.42 (s, 9H), 1.89 (m, 4H), 3.41 (m, 2H), 3.62 (m, 2H), 3.86 (m, 2H), 4.04 (m, 1H), 4.34 (m, 2H), 7.19 (d, 2H), 7.45 (d, 2H), MS (APCI+) m/z 363 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1(O)[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1.O=S(Cl)Cl>N1C=CC=CC=1>[O:14]1[C:10]2([CH2:15][CH2:16][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: OC1(c2ccccn2)CCC2(CC1)OCCO2
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C1=C(c2ccccn2)CCC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
The ketal (2 g, 8.5 mmol) obtained from step A, Example 7 was dissolved in pyridine (40 mL) and the solution was cooled in an ice bath. To it was added SOCl2 (3.1 mL, 42.5 mmol). The solution was allowed to warm to room temperature and stirring was continued overnight. The reaction was quenched by addition of ice and then water. The resulting solution was extracted with EtOAc three times. The combined EtOAc layer was dried over MgSO4 and concentrated. Flash chromatography on silica gel eluting with 0 to 55% EtOAc/hexanes provided 1.54 g of the title compound. MS calculated (M+H)+ 218. found 218.
Reaction SMILES: C(=O)(O)[O-].[Na+].C([O:8][CH2:9][C:10]([CH3:17])=[CH:11][CH2:12][O:13][C:14](=[O:16])[CH3:15])=O.O.Cl>CO.C(OCC)(=O)C>[C:14]([O:13][CH2:12][CH:11]=[C:10]([CH3:17])[CH2:9][OH:8])(=[O:16])[CH3:15]
Reactant: CC(=O)OCC=C(C)COC=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)OCC=C(C)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
Sodium bicarbonate (0.40 g, 4.75 mmol, 10 mol %) was added to a solution of 4-acetoxy-2-methyl-2-buten-1-ol formate (8.18 g, 47.5 mmol) in methanol (40 ml). The mixture was stirred at room temperature for 2 hours. After completion of the reaction, most of the methanol was evaporated under reduced pressure. The resulting reaction mixture was poured into a mixture of ice-cooled water (20 ml) and ethyl acetate (100 ml). The pH of the aqueous layer was adjusted to 5 to 6 with 1N hydrochloric acid, and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (50 ml) twice. The ethyl acetate layers were combined and dried over anhydrous sodium sulfate. Evaporation of the ethyl acetate gave 4-acetoxy-2-methyl-2-buten-1-ol (6.69 g, 46.4 mmol; Yield: 97.7%) as an oil.
Reaction SMILES: [CH3:1][CH:2]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH3:3].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)Cl>[CH3:3][CH:2]([S:4]([CH:5]1[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:9][CH2:10]1)=[O:26])[CH3:1]
Reactant: CC(C)SC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)S(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
tert-Butyl 4-(propan-2-ylsulfanyl)piperidine-1-carboxylate (prepared in an analogous manner to Intermediate 245, 0.160 g, 0.62 mmol) was dissolved in DCM (3 mL) and cooled to 0 C. m-Chloroperbenzoic acid (0.138 g, 0.62 mmol) was added, the mixture was warmed to room temperature and stirred for 17 h. Further m-chloroperbenzoic acid (0.040 g, 0.18 mmol) was added and the mixture was stirred at room temperature for 3 h. The mixture was then diluted with DCM (10 mL) and washed with saturated aq. sodium thiosulfate (10 mL). The organic layer was separated and purified by FCC, eluting with 50-100% EtOAc in heptane followed by 10% MeOH in EtOAc to afford the title compound as a colourless oil (0.124 g, 73%). Method C HPLC-MS: MH+ requires m/z=276 Found: m/z=298 (M+Na), Rt=1.14 min (100%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:19]=[N:20][C:21]4[CH:27]=[C:26]([C:28]5[CH:33]=[C:32]([O:34]C)[CH:31]=[CH:30][C:29]=5[Cl:36])[CH:25]=[C:24]([CH3:37])[C:22]=4[N:23]=3)=[CH:13][N:12]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.[ClH:42].C(OCC)C>C(Cl)Cl.CO>[ClH:36].[N:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[N:19]=[N:20][C:21]4[CH:27]=[C:26]([C:28]5[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:29]=5[Cl:36])[CH:25]=[C:24]([CH3:37])[C:22]=4[N:23]=3)=[CH:13][N:12]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1.[ClH:42]
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(C(=O)NCCN5CCCC5)nc4)nnc3c2)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(Nc3ccc(C(=O)NCCN4CCCC4)nc3)nc12
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5-[7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-pyridine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (0.085 g, 0.164 mmol, 1 equiv) was diluted with 20 mL DCM and chilled to 0° C. using an ice bath. A 1.0 M solution of BBr3 in DCM (1 mL, 0.984 mmol, 6.0 equiv) was then added in one portion resulting in a dark reaction mixture. The reaction was allowed to come to ambient temperature and stirred for 6 hours, then quenched by carefully pouring onto a saturated solution of sodium bicarbonate followed by sonication for 5 minutes. The resulting solids were filtered off, dried, and dissolved in DCM (10 mL) and MeOH (20 mL) mixture and treated with 2.0 M solution of HCl in diethyl ether (0.16 mL, 0.317 mmol, 2 equiv). The solvents were evaporated leaving desired product as HCl salt in a form of a yellow solid (0.084 g, 95% yield). MS (ESI+): m/z=504.1, LC retention time: 2.23 min. 1H NMR (DMSO-d6): δ 1.86-1.88 (m, 2H), 1.99-2.02 (m, 2H), 2.70 (s, 3H), 3.01-3.05 (m, 2H), 3.33-3.37 (m, 2H), 6.90 (dd, J=8.7 Hz, J=2.9 Hz, 1H), 6.97 (d, J=2.9 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.92-7.93 (m, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.22 (d, J=1.5 Hz, 1H), 8.51 (dd, J=8.6 Hz, J=2.5 Hz, 1H), 9.06 (t, J=5.9 Hz, 1H), 9.43 (d, J=2.4 Hz, 1H), 10.17 (bs, 1H), 11.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Ba:12].Cl.[OH2:14]>>[NH2:7][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[CH2:5][C:6]([O-:11])=[O:14].[NH2:7][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[CH2:5][C:6]([O-:11])=[O:14].[Ba+2:12]
Reactant: O
Reactant: [Ba]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Agent: Cl
Product: Nc1ccc(Cl)cc1CC(=O)[O-]
Product: [Ba+2]
Temperature: 0 °C
Reaction time: 15 h

Procedure:
To a suspension of 5-chloro-1,3-dihydro-2H-indol-2-one x32 (30 g, 1 eq, 0.1754 mol) in water (240 ml), is added barium hydroxyde (75.15 g, 2.5 eq, 0.4385 mol) at room temperature. The resulting suspension is heated at reflux for 17 hours, cooled to 0° C. and a 6 N hydrochloric acid solution (113 ml) is added (until pH 8). The resulting solution is heated at reflux for 30 minutes, cooled to 70° C. in 2 hours and then to 50° C. for 15 hours. The resulting suspension is progressively cooled to 0° C. and the solid collected by filtration. Subsequent washing of the solid by water (2×90 ml) and drying in vacuum oven (70° C.) furnished barium bis[(2-amino-5-chlorophenyl)acetate] x33 as a colorless powder (yield: 73%).
Reaction SMILES: [CH2:1]([CH:9]1C[CH2:13][CH2:12][CH2:11][C:10]1=O)[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[C:16](=[O:19])([O-:18])[O-].[Na+].[Na+].C(OO)(=[O:24])C>C(Cl)CCl>[CH2:1]([CH:2]1[O:24][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH2:7]1)[CH:9]1[O:18][C:16](=[O:19])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(=O)OO
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCCC1CC1CCCCC1=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1CCCCC(CC2CCCCC(=O)O2)O1
Yield: 85.4 %

Procedure:
To a mixture comprising 20.8 g of 2,2'-methylenebiscyclohexanone and 50 g of powdered anhydrous sodium carbonate, 100 ml of ethylene dichloride was added with stirring. To the resulting solution, a mixture comprising 47.5 g of 40% peracetic acid and 50 ml of ethylene dichloride was added dropwise at 20°-25° C. over a period of about 2 hours. Following stirring for another 3 hours, the reaction mixture was washed first with water, then with a saturated Mohr's salt solution to decompose unreacted peracetic acid, and extracted with ether. The extract was washed with 2% aqueous sodium carbonate once, then washed with saturated aqueous sodium chloride, and the organic phase was dried over anhydrous magnesium sulfate. Concentration of the dried product gave 20.5 g of crude 6,6'-methylenebis-(6-hexanolide). Recrystallizing the crude product from isopropyl ether gave 19.0 g (yield: 79%) of a white crystal of 6,6'-methylenebis-(6-hexanolide) melting at 108°-109° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[CH3:20])[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH2:25])=[O:24]>>[C:23]([C@@H:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[CH3:20])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:26][CH:27]([CH3:29])[CH3:28])(=[O:24])[NH2:25]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: CC1CCCN1c1ccc(C(=O)O)nc1OCC1CC1
Product: CC(C)C[C@H](NC(=O)c1ccc(N2CCCC2C)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(2-methyl-pyrrolidin-1-yl)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (LC/MS): 389.2 [M+H]+.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Se]Cl)C=CC=CC=1.O>C(OCC)(=O)C>[CH2:1]([CH:8]1[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCC(Cc2ccccc2)CCC1
Agent: Cl[Se]c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1C=CCC(Cc2ccccc2)CCC1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
1.2 g of 5-benzyl-1-cyclooctanone prepared in Example 1 was dissolved in 50 ml of ethyl acetate. To the solution was added 1.25 g of phenylselenenylchloride. The reaction solution was stirred at room temperature for forty minutes. To the reaction solution was added 10 ml of water, followed by stirring for three minutes. The organic layer was separated. To the organic layer were added 20 ml of tetrahydrofliran and 1.4 ml of 30% hydrogen peroxide. The reaction solution was stirred at room temperature for two and a half hours. Then, the organic layer was washed with water and a saturated sodium bicarbonate aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated. The crude product was subject to column chromatography on silica gel, and the eluate with ethyl acetate-hexane (1:10) was collected, to afford 0.71 g of the titled compound as colorless liquid.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:1][CH:2]([C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:19])[CH3:18]
Reactant: OC(CCCc1ccccc1)c1ccoc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(CCCc1ccccc1)c1ccoc1

Procedure:
A solution of 3-(1-hydroxy-4-phenylbutyl)-furan (0.167 g., 0.772 mmol), acetic anhydride (1 ml, excess) and pyridine (3 to 4 drops, excess), was stirred at room temperature until no starting material remained (as monitored by TLC). The reaction mixture was then partitioned between ethyl ether and a 5% ammonium chloride solution. The organic portion was washed repeatedly with saturated sodium bicarbonate solution, aqueous cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give 3-(1-acetoxy-4-phenylbutyl)furan.
Reaction SMILES: [CH3:1][N:2]1[C:9]([CH3:10])=[C:8]([N+:11]([O-:13])=[O:12])[C:6](=[O:7])[N:5]([CH3:14])[C:3]1=[O:4].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].C(OCC)C>CN(C)C=O>[CH3:1][N:2]1[C:9]([CH:10]=[CH:17][N:18]([CH3:20])[CH3:19])=[C:8]([N+:11]([O-:13])=[O:12])[C:6](=[O:7])[N:5]([CH3:14])[C:3]1=[O:4]
Reactant: COC(OC)N(C)C
Reactant: Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)C=Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Step 1 intermediate, 1,3,6-Trimethyl-5-nitrouracil (0.60 g, 3.012 mmol) in dry N,N-dimethylformamide (5.0 mL) was added N,N-dimethylformamide dimethyl acetal (0.53 g, 4.447 mmol) and the reaction mixture was stirred at room temperature for 2 h. After this time, diethyl ether was added to the reaction mixture and the precipitate was collected by filtration and washed with diethyl ether to give 0.45 g of the product as brownish solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 2.98 (s, 6H), 3.16 (s, 3H), 3.40 (s, 3H), 4.78 (d, J=12.6 Hz, 1H), 7.05 (d, J=12.6 Hz, 1H); APCI-MS (m/z) 255.11 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3].[O:31]=[C:32]1[CH:36]([CH2:37]OS(C)(=O)=O)[CH2:35][CH2:34][N:33]1[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[O:31]=[C:32]1[CH:36]([CH2:37][N:25]2[CH:26]=[C:22]([C:9]3[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:11]4[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:30])[N:6]([CH2:27][CH2:28][CH3:29])[C:7]=4[N:8]=3)[CH:23]=[N:24]2)[CH2:35][CH2:34][N:33]1[C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:51])([F:50])[F:52])[CH:44]=1
Reactant: CS(=O)(=O)OCC1CCN(c2cccc(C(F)(F)F)c2)C1=O
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC4CCN(c5cccc(C(F)(F)F)c5)C4=O)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 77.5 °C
Yield: 64.5 %

Procedure:
A mixture of 1,3-dipropyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.100 g, 0.23 mmol), methanesulfonic acid 2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl ester (0.10 g, 0.32 mmol), K2CO3 (0.045 g, 0.32 mmol) and DMF (1 ml) was heated at 75-80° C. for 16 hrs. Reaction mixture was cooled to 20-25° C. and diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate, washed with saturated brine solution. The organic layer was dried over Na2SO4 and evaporated to obtain crude product (0.2 g). The crude product was purified by preparative TLC to obtain pure 8-{1-[2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.10 g, 65%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[S:9]1[C:13](B(O)O)=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2.[CH3:21][C:22]1([CH3:30])[CH2:27][CH:26]([NH2:28])[CH2:25][CH:24]([CH3:29])[NH:23]1>>[S:9]1[C:13]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:28][CH:26]3[CH2:25][CH:24]([CH3:29])[NH:23][C:22]([CH3:30])([CH3:21])[CH2:27]3)[N:7]=2)=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]1=2
Reactant: Clc1ccnc(Cl)n1
Reactant: CC1CC(N)CC(C)(C)N1
Reactant: OB(O)c1cc2ccccc2s1
Product: CC1CC(Nc2nccc(-c3cc4ccccc4s3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Method A, starting from 2,4-dichloro-pyrimidine, benzo[b]thiophen-2-boronic acid and 2,2,6-trimethyl-piperidin-4-ylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[CH2:13][C:12]([C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([CH3:22])[CH:15]=3)=[N:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:27][NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30].C(O)(=O)C.O>CCO>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[CH2:13][C:12]([C:14]3[CH:21]=[CH:20][C:17](/[CH:18]=[N:27]/[NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])=[C:16]([CH3:22])[CH:15]=3)=[N:11][CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=O
Reactant: NNC(=O)NCC(F)(F)F
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1/C=N/NC(=O)NCC(F)(F)F
Temperature: 70 °C
Yield: 73 %

Procedure:
A mixture of 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,4-dihydropyrrol-5-yl]-2-methyl-benzaldehyde (i.e. the product of Step 5, 200 mg), 1-amino-3-(2,2,2-trifluoroethyl)urea (145 mg) and acetic acid (0.1 mL) in EtOH (5 mL) was heated at 70° C. for 4 h. Water was added, the reaction cooled to room temperature and the solid was collected by filtration. Recrystallization from diisopropylether yielded the title compound (198 mg, 73%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:39][CH2:38][N:13]2[C:14]3[C:19]([C:20]([C:21]4[C:22](=[O:37])O[C:24](=[O:36])[C:25]=4[C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[CH:27]=4)=[C:12]2[CH2:11]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:41][OH:42].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:39][CH2:38][N:13]2[C:14]3[C:19]([C:20]([C:21]4[C:22](=[O:37])[N:41]([OH:42])[C:24](=[O:36])[C:25]=4[C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[CH:27]=4)=[C:12]2[CH2:11]1)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: NO
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CNC(=O)OC(C)(C)C)C4)C(=O)OC2=O)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CNC(=O)OC(C)(C)C)C4)C(=O)N(O)C2=O)c2ccccc21
Temperature: 100 °C
Yield: 46.2 %

Procedure:
A solution of 400 mg of 3-[8-[(t-butoxyformamido)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 50 ml of dimethylformamide and 50 ml of water was treated with 2.5 g of hydroxylamine hydrochloride and 2.5 g of potassium carbonate and the solution obtained was heated to 100° C. The solvents were evaporated and the residue was dissolved in dichloromethane, washed with water and dried. The solvent was removed under reduced pressure and the residue was crystallized from ethyl acetate/petroleum ether to give 190 mg of 3-[8-[(t-butoxyformamido)methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-1-hydroxy-4-(1-methyl-3-indolyl)pyrrole-2,5-dione of melting point 238°-240° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([CH3:21])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15].[P:22](Cl)(Cl)(=[O:34])[O:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(Cl)[Cl:38]>>[Cl:38][C:25]1[CH:26]=[CH:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]=1[O:23][P:22](=[N:12][C@@H:13]([CH3:21])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])=[O:34]
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: ClCCl
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(C)COC(=O)[C@H](C)N=[P+]([O-])Oc1c(Cl)ccc2ccccc12

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates, the tosylate salt of (S)-isobutyl 2-aminopropanoate (2.5 g), naphthalen-1-yl phosphorodichloridate (2.06 g), TEA (2.19 mL) and DCM (50 mL) were combined to give (2S)-isobutyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)propanoate as a crude pale yellow thick oil. The crude compound was taken forward without further purification.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[N:30]([CH3:35])[N:31]=[C:32]([CH3:34])[CH:33]=1)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl.CN(C=O)C>[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[N:30]([CH3:35])[N:31]=[C:32]([CH3:34])[C:33]=1[F:21])([CH3:25])([CH3:24])[CH3:23]
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: Cc1cc(NC(=O)OC(C)(C)C)n(C)n1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nn(C)c(NC(=O)OC(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Selectfluor® [140681-55-6] (66 mmol) was added portionwise to a solution of (2,5-dimethyl-2H-pyrazol-3-yl)-carbamic acid tert-butyl ester [1246552-45-3] (32.7 mmol) in CH2Cl2 (800 mL) and DMF (800 mL) at 0° C. and then the reaction was warmed to rt. After 1 h, the mixture was quenched with H2O and extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound. ESI-MS: tR=0.83 min, [M+H]+ 230 (LC-MS 1).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([C@H:10]3[CH2:15][CH2:14][C@H:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=4[F:23])[CH2:12][CH2:11]3)[CH2:6][CH2:5]2)[O:3]C1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>O>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][CH2:11][C@H:10]([CH:7]2[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]2)[CH2:15][CH2:14]1
Reactant: Fc1cccc([C@H]2CC[C@H](C3CCC4(CC3)OCCO4)CC2)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C1CCC([C@H]2CC[C@H](c3cccc(F)c3F)CC2)CC1

Procedure:
First, 5.85 g of 4-[trans-4-(2,3-difluorophenyl)cyclohexyl]cyclohexanone ethylene ketal, 0.5 g of p-toluenesulfonic acid monohydrate, 35 ml of dioxane, and 105 ml of water were placed in a 200 ml flask. The mixture was stirred under reflux for 2 hours. The reaction mixture was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=9/1), distilled under reduced pressure, and recrystallized from hexane to obtain 2.2 g of 4-[trans-4-(2,3-difluorophenyl)cyclohexyl]cyclohexanone (Y: 55.8%). The compound thus obtained had a purity of 98.1% by GC and a b.p. of 165° C./0.5 mmHg.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([F:14])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([Cl:15])[CH:5]=1)(=O)[NH2:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[Cl:15][C:6]1[CH:5]=[C:4]([C:1]#[N:2])[CH:13]=[C:12]([F:14])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(F)cc(C(N)=O)cc1Cl
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: COC(=O)c1c(F)cc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a suspension of methyl 4-carbamoyl-2-chloro-6-fluorobenzoate (2.527 g, 10.9 mmoles) in 1,4-dioxane (25 mL) at room temperature was added pyridine (38.2 mmoles, 3.02 g), followed by trifluoroacetic anhydride (5.04 g, 24.0 mmoles). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (100 mL), extracted with EtOAc (3×100 mL). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-15% EtOAc/hexane) to afford methyl 2-chloro-4-cyano-6-fluorobenzoate as a white solid (1.953 g, yield: 84%). 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J=1.1 Hz 1H), 7.37 (dd, J=8.0, 1.2 Hz, 1H), 4.00 (s, 3H). LCMS (APCI+) 214.0 [M+H]+.