Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][C:15]3[CH:14]=[N:13][C:12]4[NH:17][N:18]=[CH:19][C:11]=4[C:10]=3[C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24]N1C(=O)CCC1=O.O>ClCCl>[Br:24][C:19]1[C:11]2[C:10]3[C:9]4[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=4[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:16][C:15]=3[CH:14]=[N:13][C:12]=2[NH:17][N:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(C2Cc3cnc4[nH]ncc4c3-c3ccccc32)cc1
Solvent: ClCCl
Solvent: O
Product: Brc1n[nH]c2ncc3c(c12)-c1ccccc1C(c1ccccc1)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a solution of 7-phenyl-6,7-dihydro-3H-benzo[f]pyrazolo[3,4-c]isoquinoline (0.018 g, 0.060 mmol) in dichloromethane (2 mL) was added N-bromosuccinimide (0.011 g, 0.063 mmol). The reaction was stirred at room temperature for 16 hours followed by addition of water (2 mL) and dichloromethane (3 mL). The organic layer was separated, dried using Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using flash column chromatography (SiO2, 10% EtOAc in hexane) to give the pure desired product, 1-bromo-7-phenyl-6,7-dihydro-3H-benzo[f]pyrazolo[3,4-c]isoquinoline as a yellow solid (0.010 g, 44%). M.p.=176-178° C.; 1H NMR (DMSO-d6, 400 MHz) δ 9.36 (m, 1H), 8.63 (s, 1H), 8.49 (s, 1H), 7.56 (m, 2H), 7.30-7.15 (m, 6H), 4.73 (t, J=7.2 Hz, 1H), 3.42 (m, 2H); LCMS [M+H]: 377; Elemental analysis (%): C, 63.59; H, 4.10; N, 10.98. Calcd for C20H14BrN3: C, 63.85; H, 3.75; N, 11.17.
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([CH2:24][S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(CSc2ccccc2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cc(CSc2ccccc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.50 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise to a mixed solution of 3 mL of methanol and 3 mL of tetrahydrofuran containing 0.29 g of methyl 2-(benzamido)-4-((phenylthio)methyl)benzoate while ice-cooled and stirred at room temperature for 5 hours. 0.25 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise and stirred at the same temperature for 14 hours. The solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A solid substance was separated by filtration to obtain 0.28 g of 2-(benzamido)-4-((phenylthio)methyl)benzoic acid as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1)([CH3:14])[C:6](=[O:13])[NH:7]2.C(N(CC)CC)C.[CH3:30][C@H:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:32]1([C@@H:31]([NH:38][C:39]([C:18]2[CH:19]=[CH:20][C:15]([C:5]3([CH3:14])[C:4](=[O:22])[C:3]4[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=4[Cl:1])[NH:7][C:6]3=[O:13])=[CH:16][CH:17]=2)=[O:40])[CH3:30])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC1(c2ccc(O)cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Reactant: C[C@H](N=C=O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccc(C2(C)C(=O)Nc3cc(Cl)cc(Cl)c3C2=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.3 %

Procedure:
A solution of 5,7-dichloro-3-(4-hydroxy-phenyl)-3-methyl-1H-quinoline-2,4-dione (0.45 g, 1.30 mmol) and triethylamine (0.18 mL) in dichloromethane (15 mL ) was added (S)-methyl benzylisocyanate (0.15 g, 1.56 mmol) at 0° C. The reaction mixture was stirred for 20 hours at room temperature, and then poured into ice water (100 mL). The reaction mixture was extracted with dichloromethane (100 mL×3), washed with brine (100 mL×2), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by a flash column chromatography (n-hexane:EtOAc=7:1) to afford the unseparable diastereomeric 1:1 mixture (0.50 g, 80%) of the objective diastereomers: 1H NMR (500 MHz, DMSO-d6) δ 1.37 (d, J=7.0 Hz, 3H, CH3), 1.54 (s, 3H, CH3, one diastereomeric peaks), 1.64 (s, 3H, CH3, the other diastereomeric peaks), 4.65 (q, 1H, CH), 7.01-7.3 (m, 11H, ArH), 8.35 (br s, 1H, NH), 11.28 (br s, 1H, NH); m.p. 110-115° C. (diastereomeric 1:1 mixture); MS(EI) m/e 483 [M+−1], 335, 269, 120.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:5]=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(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>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:3]=[C:4]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:5]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccccc2)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Yield: 44.5 %

Procedure:
A solution of ethyl 4-chloro-6-(2,4-dichlorophenyl)-2-phenylpyrimidine-5-carboxylate (30 mg, 0.07 mmol) and phenyl boronic acid (14 mg, 0.11 mmol) in toluene (3 mL) was degassed with argon for 15 minutes. To this solution was added Pd(PPh3)4 (9 mg, 0.007 mmol), Na2CO3 (23 mg, 0.22 mmol) and the reaction was heated to reflux for 3 days. The reaction was diluted with EtOAc (20 mL) and extracted with saturated NH4Cl solution (2×20 mL), brine (20 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The crude reaction product was purified by flash chromatography (silica gel, 20% EtOAc/hexane) to give ethyl 4-(2,4-dichlorophenyl)-2,6-diphenylpyrimidine-5-carboxylate (14 mg, 42%).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5]OCC(O)=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH:38]1([CH2:37][C@H:13]([NH:12][C:29](=[O:30])[CH2:28][N:16]([CH3:14])[NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC1CCCCC1
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CC1CCCCC1)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC
Yield: 44.6 %

Procedure:
According to the procedure described in the synthesis method of Compound II-130, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 32 mg (0.18 mmol) was coupled with (S)-2-amino-3-cyclohexyl-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-23) 66 mg (0.15 mmol) to obtain the title compound 20 mg (23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([OH:25])=O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[CH3:27][O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][NH:33][CH2:34]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([N:33]3[CH2:32][CH2:31][C:30]4[C:35](=[CH:36][CH:37]=[CH:38][C:29]=4[O:28][CH3:27])[CH2:34]3)=[O:25])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2nc(C(=O)O)c3ccccc3n2)cc(OC)c1OC
Reactant: COc1cccc2c1CCNC2
Agent: Cl
Product: COc1cccc2c1CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccccc13)C2
Yield: 36.3 %

Procedure:
Reaction of 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 90 (36.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.79 and 2.90 (2t, 2H), 3.56 and 4.08 (2t, 2H), 3.76-3.81 (m, 6H), 3.86 and 3.92 (2s, 6H), 4.50 and 4.99 (2s, 2H), 6.49-7.28 (m, 3H), 7.67-8.18 (m, 6H); MS (ESI) m/z 486 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[Cl:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([O:14][C:13]([Cl:12])([F:22])[F:23])=[CH:16][CH:17]=1)=[O:7]
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Reactant: O=C(O)c1ccc(F)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 1.2 using 3-bromo-4-fluorobenzoic acid and 4-(chlorodifluoromethoxy)aniline to afford an off-white solid. UPLC-MS (Condition 3) tR=1.25 min, m/z=394.0 [M+H]+, m/z=391.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.37 (d, J=9.17 Hz, 2H) 7.57 (t, J=8.68 Hz, 1H) 7.84-7.91 (m, 2H) 8.03 (ddd, J=8.62, 4.83, 2.32 Hz, 1H) 8.32 (dd, J=6.60, 2.20 Hz, 1H) 10.52 (s, 1H).
Reaction SMILES: O[Li].O.[CH3:4][C@H:5]1[C:13]2[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=2[C@H:7]([O:27]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:6]1.C1COCC1>O>[OH:27][C@H:7]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[C:13]=2[C@H:5]([CH3:4])[CH2:6]1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
LiOH—H2O (0.499 g, 11.9 mmol) was added to a 0° C. solution of tert-butyl 4-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro -5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (2.30 g, 4.76 mmol) in 2:1 THF:H2O (40 mL). The reaction mixture was warmed to room temperature and stirred for 1 hour. The THF was removed by rotary evaporation, saturated NaHCO3 was added, and the mixture was extracted with ethyl acetate. The combined extracts were washed (1×) with saturated NaHCO3, dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.59 g, 100.0% yield) as a yellow foam. HPLC after workup just product>98 area % pure. LC/MS (APCI+) m/z 335 [M+H]+. The tert-butyl 4-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H -cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate was prepared using an analogous method.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[OH:20][CH2:21][C:22]([NH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2)=[O:23]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=[C:28]2[C:27]3[C:31](=[CH:32][CH:33]=[C:25]([NH:24][C:22](=[O:23])[CH2:21][OH:20])[CH:26]=3)[NH:30][C:29]2=[O:34])=[CH:6][CH:7]=1
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Reactant: O=C(CO)Nc1ccc2c(c1)CC(=O)N2
Product: O=C(CO)Nc1ccc2c(c1)C(=Cc1[nH]c3c(c1-c1ccc(F)cc1)C(=O)NCC3)C(=O)N2
Yield: 47 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 2-hydroxy-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide as starting materials to give N-{3-[3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-2-hydroxy-acetamide (50 mg, 47.0%) as a red solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:7]=1>C1COCC1.CO.[Pt]>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[N:7]=1
Reactant: COC(=O)/C=C/c1cc(C)n(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2)n1
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(C)n(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of unsaturated ester 6 (0.31 g, 0.65 mmol) and 5% Pt/C (0.01 g) in THF (6 mL) and MeOH (12 mL), previously purged with nitrogen, was stirred under a hydrogen atmosphere (balloon) at RT overnight. The platinum was removed by filtration through Hyflo and the filtrate was evaporated to dryness to afford the saturated ester 7, 0.31 g (99%).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:18])[NH:6][N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([F:17])[CH:11]=2)[CH:9]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:23]O>>[F:17][C:12]1[CH:11]=[C:10]([C:8]2[CH:9]=[C:4]([C:1]([O:3][CH3:23])=[O:2])[C:5](=[O:18])[NH:6][N:7]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1ccc(-c2cc(C(=O)O)c(=O)[nH]n2)cc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(-c2ccc(C)c(F)c2)n[nH]c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To an ice-cold suspension of 4-carboxy-6-(3-fluoro-4-methylphenyl)-2H-pyridazin-3-one (5.50 g, 22.2 mmol) in methanol (100 mL) was added dropwise thionyl chloride (2.72 g, 24.4 mmol), and the mixture was stirred at 80° C. for 8 hours. The temperature of the reaction mixture was allowed to drop back to room temperature, and the solvent was distilled off under reduced pressure. Water was added to the ice-cold residue. The precipitate was collected by filtration, washed with water and dried to yield the title compound as pale yellow fine-needles (5.43 g, 92.7%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH:38]=[CH:39][CH2:40][NH2:41])[CH2:33][CH2:32]1.C(Cl)(Cl)Cl>N1C=CC=CC=1.CC=C(C)C>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:37][CH:38]=[CH:39][CH2:40][NH:41][C:18](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([OH:13])=[CH:22][CH:21]=2)[CH2:35][CH2:36]1
Reactant: NCC=CCN1CCN(c2cccc(Cl)c2Cl)CC1
Reactant: O=C(O)c1ccc(O)cc1
Agent: CC=C(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(NCC=CCN1CCN(c2cccc(Cl)c2Cl)CC1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
1,1′-carbonyldiimidazole (0.18 g, 1.1 mmol) was added to a solution of the 4-hydroxy benzoic acid (0.15 g, 1.1 mmol) in absolute pyridine and the mixture was stirred at room temperature under Argon for 1 h. After that time a solution of 4-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]-but-2-enylamine (0.33 g, 1.1 mmol) in 3 ml amylene-stabilized chloroform was added and the mixture was stirred overnight. All volatiles were removed in vacuo and the residue was purified by chromatography to give 0.23 g (51%) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:26]([BH3-])#N.[Na+]>CC#N.O>[CH2:1]([N:8]([CH2:9][CH2:10][CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCCC(c2ccccc2)c2ccccc2)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN(CCC(c1ccccc1)c1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-benzyl-3,3-diphenylpropylamine (1.29 g, 4.30 mmol) and 30% aq. formaldehyde (1.50 ml, 20 mmol) in CH3CN:H2O (2:1, v/v, 40 ml) was added sodium cyanoborohydride (563 mg, 8.96 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred for 90 min. The organic solvent was evaporated, and the residue diluted with water and extracted with CH2Cl2. The organic extracts were washed with brine, dried (Na2SO4) and the solvent evaporated in vacuo to afford the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH3:47])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCOCC4)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J28) (271 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (355 mg, 79%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:10][C:9]=1[NH:24]C(OC(C)(C)C)=O)(C)(C)C>Cl.O1CCOCC1>[CH3:23][S:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([NH2:24])[CH:10]=1)(=[O:21])=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccccc1-c1ccc(N)c(N)c1
Yield: 97.8 %

Procedure:
A solution of (3-tert-butoxycarbonylamino-2′-methanesulfonyl-biphenyl-4-yl)-carbamic acid tert-butyl ester (12.47 g, 0.0270 mol) in 4M HCl in dioxane (120 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, and the solution was washed with saturated sodium bicarbonate and water (pH=7). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to provide the title compound as a yellow oil (6.93 g, 98%).
Reaction SMILES: N1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](N)=[O:4].[C:9]1([Se:15]N2C(=O)C3=CC=CC=C3C2=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:7]1([CH2:6][CH:2]([Se:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:3]=[O:4])[CH:8]=[CH:7][CH:6]=[CH:2][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1[Se]c1ccccc1
Reactant: NC(=O)[C@@H]1CCCN1
Solvent: ClCCl
Product: O=CC(Cc1ccccc1)[Se]c1ccccc1
Reaction time: 0.5 h

Procedure:
General Procedure B for α-Selenenylation of Aldehyde (Table 9, Entries 11 and 12): To a vial containing an aldehyde (0.25 mmol), and 0.5 mL of anhydrous CH2Cl2 was added catalyst L-prolinamide I (0.005 mmol) at room temperature. The mixture was vigorously stirred for 0.5 h in the presence of 4 Å molecule sieves (40 mg). Then N-(phenylseleno)phthalimide (0.3 mmol) was added. After 0.5 h, the molecule sieves were removed by filtrating paper and then the filtrate was treated with water (5 mL), the solution was extracted with ethyl acetate (3×5 mL). The combined extracts were dried over MgSO4, filtered, and concentrated iii vacuo. The resulting residue was then purified by silica gel chromatography, eluting with EtOAc/Hexane (1/40) to provide a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([N:24]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH2:26][CH:25]3[CH3:34])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36]>Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([N:24]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH2:26][CH:25]3[CH3:34])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:35]([F:37])([F:38])[F:36]
Reactant: COCN(c1cc(Cl)cnc1C(=O)N1c2ccccc2OCC1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: CC1COc2ccccc2N1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of crude 4-chloro-N-[5-chloro-2-(3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide in 3 mL HCl (4M in dioxane) and water (1 mL) was refluxed for 2 h. Upon cooling to room temperature, the mixture was concentrated and the residue was purified via preparative TLC (50% EtOAc in hexane) to afford 11 mg of 4-chloro-N-[5-chloro-2-(3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide as an off white solid. MS m/z: 546.1(M+H).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][C:8](=[O:14])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:5]=32)[N:3]1[CH2:15][C:16]([O:18]C)=[O:17].[OH-].[Na+:21].Cl>CO.CC#N>[O:1]=[C:2]1[N:6]2[CH2:7][C:8](=[O:14])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:5]=32)[N:3]1[CH2:15][C:16]([O-:18])=[O:17].[Na+:21]
Reactant: COC(=O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: O=C([O-])Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl (2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl) acetate from Step C (367 mg, 1.40 mmol) in MeOH (40 mL) and CH3CN (5 mL) was added 1.0 N sodium hydroxide (2.82 mL, 2.82 mmol) and the reaction mixture was stirred at room temperature for 18 h. The mixture was neutralized with 1 N aqueous HCl and concentrated in vacuo to give the title compound. MS: m/z=248 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)[O:9][C:10](=O)[C:4]2=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1CCC(N=C=NC2CCCCC2)CC1>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][N:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:5](=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:10]2=[O:9])[C:6]1=[O:7]
Reactant: Nc1ccccc1
Reactant: CN1C(=O)C2=C(c3ccc(Br)cc3)OC(=O)C2=C1c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C2=C(c3ccc(Br)cc3)N(c3ccccc3)C(=O)C2=C1c1ccccc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 47.9 %

Procedure:
A mixture of furopyrrole 7 (300 mg, 0.79 mmol), aniline (146 mg, 1.57 mmol), DCC (323 mg, 1.57 mmol), trifluoroacetic acid (2-3 drops) and DCM was stirred at room temperature for 144 hours. The solvent was removed, and washing with methanol gave the pyrrolopyrrole 8 as a red solid (173 mg, 55%), m.p. 255-256° C. δH (CDCl3) 7.88-7.83 (2H, m, Ar—H), 7.49-7.43 (5H, m, Ar—H), 7.40-7.26 (5H, m, Ar—H), 7.12-7.07 (2H, m, Ar—H) and 3.35 (3H, s, NCH3)