Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.BrC1C=C(O)C=CC=1.[CH3:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[C:38]3[C:29](=[C:30]4[C:35](=[CH:36][CH:37]=3)[N:34]=[CH:33][CH:32]=[CH:31]4)[C:28](=[O:39])[C:27]2=[O:40])=[CH:23][CH:22]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[OH:39][C:28]1([C:8]2[C:7]([OH:10])=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[C:29]2=[C:30]3[C:35](=[CH:36][CH:37]=[C:38]2[N:26]([CH2:25][C:24]2[CH:41]=[CH:42][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:27]1=[O:40])[N:34]=[CH:33][CH:32]=[CH:31]3
Reactant: Oc1ccc2c(c1)OCC2
Reactant: COc1ccc(CN2C(=O)C(=O)c3c2ccc2ncccc32)cc1
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: COc1ccc(CN2C(=O)C(O)(c3cc4c(cc3O)OCC4)c3c2ccc2ncccc32)cc1

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 2,3-dihydrobenzofuran-6-ol to replace 3-bromophenol, and 3-(4-methoxybenzyl)-1H-pyrrolo[3,2-f]quinoline-1,2(3H)-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 1-hydroxy-1-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one was obtained (58%) as a colorless solid: MS (ES+) m/z 455.0 (M+1).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]2[CH:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.5 %

Procedure:
To a cooled and stirred solution of 3-{4-[4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide (0.71 g) in dichloromethane (12 ml) was added TFA (12 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.51 g, 49%). MS (ISP) 526.2 [(M+H)+]; mp 258° C.
Reaction SMILES: [OH-].[Na+].C(N(CC)C(=O)[S:7][C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]([Br:15])[CH:9]=1)C>CO>[Br:14][C:12]1[CH:13]=[C:8]([SH:7])[CH:9]=[C:10]([Br:15])[CH:11]=1
Reactant: CCN(CC)C(=O)Sc1cc(Br)cc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Sc1cc(Br)cc(Br)c1
Temperature: 20 °C
Yield: 76.5 %

Procedure:
Sodium hydroxide (1.96 g, 49 mmol) was added to a solution of S-(3,5-dibromophenyl) diethylthiocarbamate (12 g, 32.7 mmol) (Preparation 47) in methanol (33 ml) and the mixture was heated at reflux for 15 hours. The mixture was cooled to 20° C. and concentrated under reduced pressure. The residue was partitioned between dichloromethane (90 ml) and water (250 ml) and the aqueous layer was further extracted with dichloromethane (90 ml). The combined organic layers were washed with a solution of sodium hydroxide (1N, 100 ml). The combined aqueous layers were cooled to 0° C. and the pH was adjusted to 2 by the addition of concentrated hydrochloric acid, giving a white suspension. This suspension was extracted with dichloromethane (2×250 ml) and the combined extracts were washed with brine (25 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave the title compound as a yellow solid (6.7 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=O)[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([F:26])[CH:15]=3)[CH:9]([OH:27])[C:8]=2[C:7]([O:28][CH2:29][CH3:30])=[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=12)[CH3:2].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]([F:26])[CH:15]=3)[C:9](=[O:27])[C:8]=2[C:7]([O:28][CH2:29][CH3:30])=[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2O)cc1F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1F
Temperature: 0 °C

Procedure:
Ethyl {4-[4,9-bis(ethyloxy)-1-hydroxy-3-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetate (approx. 51.6 mmol) was dissolved in CH2Cl2 (50 ml) and cooled to 0° C. and TFA (50 ml) added. Triethylsilane (12.3 ml, 77 mmol) was added in one portion to give a brown solution. The solution was concentrated in vacuo to give a tan solid. This was recrystallised from hot isopropanol (550 ml), cooled, filtered, washed with isopropanol, and dried in a vacuum oven to give the title compound as off white crystals (20.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>C(#N)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[C:6]#[N:7]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(COc2ccc(C#N)cc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
To a stirred solution of 4-hydroxy-3-methoxybenzonitrile (2.43 g, 16.29 mmol) in acetonitrile (75 mL) was added cesium carbonate (6.68 g, 20.50 mmol) and p-methoxybenzyl chloride (2.81 g, 17.92 mmol). The reaction mixture was heated to reflux and stirred. After 1 h, the mixture was allowed to cool to room temperature and was filtered. The filtrate was concentrated to provide 4.56 g (>100%) 3-methoxy-4-((4-methoxybenzyl)oxy)benzonitrile as an off-white solid. The crude material was used without purification in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13]=[C:14]([CH3:16])[CH3:15].S(=O)(=O)(O)O>ClCCl>[C:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)([CH3:16])([CH3:15])[CH3:13]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc(C(=O)O)cc1
Reaction time: 2 h
Yield: 47.9 %

Procedure:
Ethyl 4-hydroxybenzoate (16.6 g), isobutene (25 g), and 95% sulfuric acid (0.5 ml) were stirred in dichloromethane (300 ml) overnight at 0° C. The reaction mixture was washed with 20% sodium carbonate aqueous solution, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was dissolved in ethanol (32 ml) and the solution, with potassium hydroxide (7.5 g) and water (6 ml) added thereto, was refluxed with stirring for 2 hours. The reaction mixture was neutralized with hydrochloric acid and then extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The resulting solid was recrystallized from ethyl acetate to yield 9.3 g of the aimed compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[NH:12][C:13](=[O:18])[N:14]([CH3:17])[C:15](=[O:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21]CCl>>[ClH:21].[CH2:1]([N:8]1[CH2:20][CH2:19][C:11]2[NH:12][C:13](=[O:18])[N:14]([CH3:17])[C:15](=[O:16])[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCl
Agent: Cn1c(=O)[nH]c2c(c1=O)CN(Cc1ccccc1)CC2
Product: Cl

Procedure:
14.3 g of 6-benzyl-3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione were dissolved in 300 ml of dichloromethane, and 6-benzyl-3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione hydrochloride was precipitated with a solution of hydrochloric acid in ether, while cooling with ice. The product was purified by recrystallization from isopropanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([NH:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([S:24]([C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[CH3:16])(=[O:26])=[O:25])[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)c(C)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N2CC3CCN(C(=O)OC(C)(C)C)CC32)c(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
3,8-Diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (240 mg, 1.1 mmol), 2,4-dimethyl-benzenesulfonyl chloride (278 mg, 1.4 mmol) and di-isopropylethylamine (0.4 mL, 2.3 mmol) were dissolved into DCM (5.0 mL) and stirred at room temperature for 18 h. The reaction mixture was diluted with DCM (25 mL) and washed with 1N NaOH (10 mL) and water (2×20 mL). The organic layers were combined, dried, filtered and concentrated to yield the title compound (300 mg, 97%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:14]>ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccnc1Br
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A mixture of 2-bromo-3-methyl-pyridine (1000 mg, 5.81 mmol) and 3-chloroperoxybenzoic acid (2150 mg, 8.72 mmol) in dichloromethane (8 mL) was stirred overnight at room temperature. The reaction mixture was diluted with DCM (50 mL) and washed with saturated aqueous sodium thiosulfite (10 mL) followed by saturated aqueous sodium bicarbonate (10 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (4 g, Silica, 0-10% methanol in DCM). Desired fractions were combined and evaporated in vacuo to afford the title compound as white solid (851 mg, 78%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=3)[C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=[N:41]C=2C=1.N.CO>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH2:41])=[O:29])=[CH:23][CH:22]=3)[C:11]3[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CO
Product: NC(=O)Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Temperature: 85 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a solution of 2-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)methyl)phenyl)acetic acid (0.040 g, 0.090 mmol) in DMF (2 mL) was added EDC (0.034 g, 0.18 mmol), HOBT (0.024 g, 0.18 mmol) and ammonia in methanol (0.13 mL, 0.90 mmol). The mixture was sealed and stirred at 85° C. for 16 h. The mixture was diluted with ethyl acetate and then washed with water. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/ethyl acetate) to afford the title compound (0.025 g, 62%) as a white solid. MW=441.93. 1H NMR (DMSO-d6, 500 MHz) δ 8.30-8.26 (m, 2H), 7.69-7.64 (m, 1H), 7.61-7.56 (m, 1H), 7.40 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 6.82 (s, 1H), 4.52 (s, 2H), 3.77-3.71 (m, 2H), 3.32 (s, 2H), 3.21 (t, J=6.5 Hz, 2H), 2.40-2.38 (m, 2H); APCI MS m/z 442 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:18])[C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@H:20]([C@H:22]1[CH2:26][N:25]([C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH3:28])[C:24](=[O:37])[CH2:23]1)[CH3:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:18][C@@H:20]([C@H:22]2[CH2:26][N:25]([C@@H:27]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[CH3:28])[C:24](=[O:37])[CH2:23]2)[CH3:21])[C:12]2[S:16][CH:15]=[N:14][C:13]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cc(OCc2ccccc2)cc2ncsc12
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(OCc4ccccc4)cc4ncsc34)CC2=O)cc1
Temperature: 40 °C
Reaction time: 17 h

Procedure:
5-(benzyloxy)benzo[d]thiazol-7-ol (420 mg, 1.63 mmol), (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (607 mg, 2.31 mmol), and PPh3 (615 mg, 2.35 mmol) were dissolved in THF (15 ml). DEAD (0.36 mL, 2.30 mmol) was added and the resulting mixture was heated to 40° C. After 17 h, additional (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (105 mg, 0.40 mmol), PPh3 (110 mg, 0.42 mmol) and DEAD (0.060 mL, 0.38 mmol) were added. The reaction mixture was stirred an additional 1.5 h and was then concentrated directly onto silica gel. Purification by silica gel chromatography (70 to 100% EtOAc in hexanes) provided (R)-4-((R)-1-(5-(benzyloxy)benzo[d]thiazol-7-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 4.03C. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H31N2O4S: 503.2; found 503.2.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:4]2[C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc(-c2cccc3c2oc2ccccc23)cc1
Temperature: 90 °C

Procedure:
A solution of dibenzofuran-4-boronic acid (1.0 g, 4.7 mmol) in ethanol (10 mL) was added to a stirred solution of 1-bromo-4-iodobenzene (1.33 g, 4.7 mmol) and tetrakis-(triphenylphosphine)-palladium(0) (271 mg, 5 mol %) in toluene (40 mL). 2 N sodium carbonate (4.7 mL, 9.4 mmol) was added and then the reaction was heated to 90° C. (oil bath temp.) for 2-3 h until complete (TLC control). The reaction mixture was cooled to room temperature and partitioned between water and diethyl ether. The phases were separated, the aqueous phase being further extracted with diethyl ether (2×20 mL). The combined organic extracts were washed with water and sat'd aq NaCl. The ethereal solution was dried over anhyd MgSO4, filtered and concentrated in vacuo to yield 4-(4-bromophenyl)-dibenzofuran as a yellow solid, which was used immediately without further purification.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:12]=1.CI>O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH3:1])[C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc(OC)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of lithium diisopropylamide (2.0M solution in tetrahydrofuran/ethylbenzene/heptane, 34.0 ml, 0.0667 mol) was added dropwise to a solution of methyl 4-methoxyphenylacetate (12.0 g, 0.0667 mol) in tetrahydrofuran (150 ml) at −70° C. under a nitrogen atmosphere and the mixture was stirred at −70° C. for 1 hour. A solution of methyl iodide (9.5 g, 0.0667 mol) in tetrahydrofuran (20 ml) was added dropwise and the mixture was stirred at −70° C. for a further 1 hour. The cooling bath was removed and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:hexane 1:9, to give methyl 2-(4-methoxyphenyl)propionate (8.8 g) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[C:12]([NH:16][C:17](=[O:31])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:19]=1)([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:27][CH2:26][N:25]([CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:17]([NH:16][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:31])[CH2:30][CH2:29]2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)ccc1N
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To a stirred solution, of. 4-amino-3-methylbenzoic acid (3.31 mmol, 0.50 g), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (3.45 mmol, 0.95 g) and triethylamine (14.35 mmol, 2.00 mL, 1.452 g) in dichloromethane (10 mL) was added 1-propanephosphonic acid cyclic anhydride (6.75 mmol, 4 mL, 4.30 g, 50% in ethyl acetate) dropwise. The mixture was allowed to stir for 1 hour. After this time ethyl acetate was added and the organic mixture was washed with saturated sodium hydrogen carbonate (×2), water (×2) and finally brine. The organic layer was dried with sodium sulfate and concentrated under vacuum to yield the title compound (0.60 g).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[CH:15]=[CH:16][C:6]=2[N:5]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH3:36])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)=[CH:19][CH:18]=2)[C:4](=[O:37])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.O>CN(C)C=O>[CH3:36][NH:23][C:20]1[CH:19]=[CH:18][C:17]([N:5]2[C:4](=[O:37])[CH2:3][C:2](=[O:1])[NH:8][C:7]3[C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=4[CH:15]=[CH:16][C:6]2=3)=[CH:22][CH:21]=1
Reactant: CN(c1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[4-(2,4-Dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide (50 mg, 0.096 mmol) was dissolved in dry dimethylformamide (2 mL). To the solution were added potassium carbonate (40 mg, 0.29 mmol), and then thiophenol (12 μL, 0.12 mmol). The mixture was stirred overnight at room temperature. To the reaction mixture was added cold water. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 5-(4-methylaminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione as a colorless amorphous form (32 mg, 0.095 mmol).
Reaction SMILES: [CH3:1][CH2:2]OCC.[CH2:6]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:7]1[O:9][CH2:8]1.C([Mg]Cl)=C.[Cl-].[NH4+]>C1COCC1.[Cu]I>[CH2:11]([O:10][CH2:6][C@H:7]([OH:9])[CH2:8][CH:1]=[CH2:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: CCOCC
Agent: [Cu]I
Agent: C=C[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CC[C@@H](O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Ether (100 ml) and copper(I) iodide (580 mg) were added to a solution of (R)-benzyl glycidyl ether (10.0 g) in THF (100 ml). The mixture was cooled to −78° C., and vinylmagnesium chloride (1.38 M, 53.0 ml) was added dropwise. The mixture was stirred overnight with gradual heating to room temperature. Ice was added to the reaction solution, and an ammonium chloride solution was further added. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with an ammonium chloride solution. The insoluble matter was removed by filtration through celite, and the solvent was evaporated under reduced pressure to obtain the title compound (12.5 g).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH3:17][C:18]1[N:22]=[C:21]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=O)[O:31]C3C=CC([N+]([O-])=O)=CC=3)[CH:26]=[CH:27][CH:28]=2)[O:20][N:19]=1.CN(C)C=O>C(#N)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:30]([NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:21]4[O:20][N:19]=[C:18]([CH3:17])[N:22]=4)[CH:24]=3)=[O:31])[C:7]=2[CH:8]=1)#[N:13]
Reactant: Cc1noc(-c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)n1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1noc(-c2cccc(NC(=O)N[C@@H]3c4cc(C#N)ccc4OC(C)(C)[C@H]3O)c2)n1

Procedure:
A mixture of (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.65 g, 3.0 mmol, from Example 1, part B) and [3-[3-methyl(1,2,4-oxadiazol-5-yl)]phenyl]carbamic acid, 4-nitrophenyl ester (1.12 g, 3.3 mmol, title A compound) in acetonitrile (20 mL) and dimethyl-formamide (40 mL) was stirred at 80° C. for two hours. The reaction mixture was concentrated in vacuo and the residue, diluted with ethyl acetate, was washed with 10% citric acid and water. The organic layer was dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (Sorbisol C 60 flash silica gel, 400 mL) and eluted with Hexane/EtOAc (1:1). The solvent was removed in vacuo, to give a solid that was triturated in hexane and dried in vacuo to yield 1.10 g of the title compound, m.p. 157°-161 ° C. TLC, silica gel, EtOAc/Hexane(2:1), Rf =0.41. 1H-NMR (DMSO-d6) δ9.1 (s, 1H), 8.4 (s, 1H), 7.5 (m, 5H), 6.9 (d, J=9.4 Hz, 1H), 6.8 (d, J=8.2 Hz, 1H), 5.7 (d, J=5.9 Hz, 1H), 4.7 (t, J=8.8 Hz, 1H), 3.7 (dd, J =5.9 & 4.1Hz, 1H), 2.4 (s, 3H), 1.4 (s, 3H), 1.2 (s, 3H); 13C-NMR (DMSO-d6) δ174.9, 167.6, 156.3, 155.6, 141.4, 132.6, 132.5, 130.0, 125.9, 123.8, 122.1, 120.4, 119.1, 117.9. 116.6, 102.76, 80.4, 71.2, 49.5, 26.5, 18.9, 11.3; IR (KBr) 2980, 2228, 1670, 1574, 1553, 1489 cm-1. M.S. (M+H)+ at 420, M.W. 419; [α]D =-43.6° (c=0.77 DMSO).
Reaction SMILES: [N:1]1([CH2:7][CH:8]([NH2:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:16][C:17]1[N:32]=[CH:31][CH:30]=[CH:29][C:18]=1[C:19](NC1C=CC=CC=1C)=[O:20]>>[F:16][C:17]1[N:32]=[CH:31][CH:30]=[CH:29][C:18]=1[C:19]([NH:15][CH:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:20]
Reactant: NC(CN1CCOCC1)c1ccccc1
Reactant: Cc1ccccc1NC(=O)c1cccnc1F
Product: O=C(NC(CN1CCOCC1)c1ccccc1)c1cccnc1F
Yield: 87 %

Procedure:
2-Morpholin-4-yl-1-phenylethylamine (Array Biopharma, Inc., 0.33 g, 1.6 mmol) was converted to the desired compound (0.12 g, 87%) in a manner similar to the preparation of 2-fluoro-N-o-tolylnicotinamide (Step A of Example 8). HRMS(ESI+), 330.1618 (M+H)+ calc, 330.1620 (M+H)+ found.