Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1)[CH3:2].Cl[CH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([C:3]1[N:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:19][CH2:20][CH2:21][NH:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:12][CH2:13]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1)[CH3:2]
Reactant: Fc1ccc(NCCCCl)cc1
Reactant: CCc1nc2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1C1CCN(CCCNc2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 37 %

Procedure:
To a stirred solution of 2-ethyl-1-piperidin-4-yl-1H-benzimidazole (0.6 g) and (3-chloropropyl)-(4-fluorophenyl)amine (0.4 g) in DMF (7 ml) was added K2CO3 (1.1 g) and KI (0.1 g). The mixture was heated at 100° C. for 2 h, and then allowed to cool to rt. Water (50 ml) was added and the mixture extracted with ethyl acetate (80 ml), and the organic layer separated and washed with water. This was further dried and concentrated in vacuo. The oil was purified by flash chromatography (95:5 DCM:MeOH), and the solid recrystallised from ether to yield 0.3 g of the title compound as colourless crystals. Mp. 121-124° C.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[NH2:19][N:20]1[C:24]([N:25]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[N:26]2)=[N:23][N:22]=[C:21]1[SH:32].C(=O)(O)[O-].[Na+]>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[CH:9]1[S:14][CH2:15][C:6]([CH2:5][S:32][C:21]1[N:20]([NH2:19])[C:24]([N:25]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[N:26]3)=[N:23][N:22]=1)=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1cc(C)n(-c2nnc(S)n2N)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C)n(-c2nnc(SCC3=C(C(=O)O)N4C(=O)C(N)C4SC3)n2N)n1

Procedure:
A 1.36 g. portion of 7-aminocephalosporanic acid, 1.05 g. of 4-amino-5-(3,5-dimethyl-1-pyrazolyl)-4H-1,2,4-triazole-3-thiol and 0.84 g. of sodium bicarbonate are reacted by the procedure of Example 1, giving the desired product, I.R. 5.60μ (β-lactam carbonyl).
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[C:16]([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)[O:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1ON=C(C(C2C=CC=CC=2)C(O)=O)C=1)CCCCCCCCCCC.[F:55][C:56]1[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:57]=1[NH2:58]>>[F:55][C:56]1[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:57]=1[NH:58][C:19](=[O:21])[CH:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[O:15][N:14]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:17]=1
Reactant: Nc1ccc(F)cc1F
Reactant: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)on1
Agent: CCCCCCCCCCCCc1cc(C(C(=O)O)c2ccccc2)no1
Product: CCCCCCCCCCCCc1cc(C(C(=O)Nc2ccc(F)cc2F)c2ccccc2)on1

Procedure:
In a manner similar to Example 128, a mixture of 3-dodecyl-α-phenyl-5-isoxazole acetic acid and 5-dodecyl-α-phenyl-3-isoxazole acetic acid was condensed with 2,4-difluoroaniline to give, after chromatography, pure title compound; mp 68°-70° C.
Reaction SMILES: [OH-].[K+].[SH:3][CH2:4][CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][O:8][C:6]1=[O:7].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.C(OCC)(=O)C>[CH2:20]([S:3][CH2:4][CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][O:8][C:6]1=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C1OCC(c2ccc([N+](=O)[O-])cc2)C1CS
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1OCC(c2ccc([N+](=O)[O-])cc2)C1CSCc1ccccc1
Reaction time: 4 h
Yield: 63.6 %

Procedure:
To a solution of 71 mg of potassium hydroxide in 6 ml of ethanol were added 253 mg of α-mercaptomethyl-β-(p-nitrophenyl)-γ-butyrolactone and 239 mg of benzyl bromide and the resulting mixture was kept at room temperature for 4 hours. After completion of the reaction, the reaction mixture was diluted with 60 ml of ethyl acetate, washed with water and saturated saline, dried over magnesium sulfate and the solvent was distilled off. The resulting crude product was purified by a silica gel column chromatography to give 218 mg (yield 50%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:3]=[CH:4][C:5]=1[CH3:15])=[O:14]
Reactant: Cc1ccc(Br)cc1NC(=O)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cc1ccc(C#C[Si](C)(C)C)cc1NC(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h
Yield: 67.6 %

Procedure:
To a solution of N-(5-bromo-2-methylphenyl)-2,2,2-trifluoroacetamide (15 g, 54 mmol) in THF (300 mL) was added Pd(PPh3)2Cl2 (3.79 g, 5.4 mmol), CuI (513 mg, 2.7 mmol) and TEA (23 mL, 162 mmol). The solution was heated to 60° C. A solution of trimethylsilylacetylene (11.5 mL, 81 mmol) in THF (200 mL) was added dropwise through an addition funnel over about 60 min. After 16 h, the reaction was concentrated onto silica gel and purified by column chromatography to give the desired product (10.92 g, 67%). 1H NMR (400 MHz, d6-DMSO) δ 10.97 (s, 1H), 7.35-7.30 (m, 3H), 2.18 (S, 3H), 0.21 (s, 9H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C@H:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)=[O:21])=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([C@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:23]2)=[O:21])=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc(F)cc1)[C@H]1CCCNC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
4-Fluorobenzoyl chloride (53 mL, 0.45 mmol) was added at 0° C. to a solution of (S)-piperidine-3-carboxylic acid (4-fluoro-phenyl)-amide hydrochloride (0.116 g, 0.45 mmol) and triethylamine (131 mL, 0.94 mmol) in dichloromethane (3 mL), under nitrogen atmosphere. The reaction mixture was kept under stirring at R.T. for 2.5 h, the solvent was evaporated and the residue was diluted with water and ethyl acetate. The phases were separated and the organic layer was washed with HCl 1N (10 mL), with Na2CO3 2M (aq.) (10 mL) and with brine (10 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to give 0.127 g of (S)-1-(4-fluoro-benzoyl)-piperidine-3-carboxylic acid (4-fluoro-phenyl)-amide as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:32]([O:34]C(C)(C)C)=[O:33])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(C(O)=O)=NC(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)=NC=1O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10]([C:32]([OH:34])=[O:33])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3cccc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C(O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: O=C(O)c1nc(CC2(c3cccc(C(F)(F)F)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(Benzyloxy)-6-hydroxy-2-((1-(3-(trifluoromethyl)phenyl)cyclopentyl)methyl)pyrimidine-4-carboxylic acid (475) was synthesized as a white solid from tert-butyl 5-(benzyloxy)-6-hydroxy-2-((1-(3-(trifluoromethyl)phenyl)cyclopentyl)methyl)pyrimidine-4-carboxylate (474) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (244).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]([C:14]#[N:15])=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N>C(O)C.CO.[Ni]>[NH2:15][CH2:14][C:7]1[NH:8][C:9](=[O:13])[C:10]2[C:5]([C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2
Reactant: COc1ccc2c(=O)[nH]c(C#N)c(-c3ccccc3)c2c1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: CO
Product: COc1ccc2c(=O)[nH]c(CN)c(-c3ccccc3)c2c1
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a solution of 6-methoxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonitrile (200 mg) in 40 mL ethanol were added Raney Ni and 4 mL of 2 M ammonia in methanol. The reaction was shaken under 50 psi H2 pressure overnight. The reaction was filtered and concentrated to give 178 mg of 3-(aminomethyl)-6-methoxy-4-phenylisoquinolin-1(2H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25]CC4C=CC=CC=4)[CH:20]=3)[C:10]=2[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:5][CH:4]=1>[Pd].C(OCC)(=O)C>[OH:25][C:21]1[CH:20]=[C:19]([CH2:18][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:10]2[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c2ccccc2n1Cc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)c2ccccc2n1Cc1cccc(O)c1
Reaction time: 48 h
Yield: 89 %

Procedure:
To a Parr shaker bottle purged with Argon was added palladium on carbon (Degussa type) (500 mg), ethyl acetate (10 mL), ethyl 3-(4-methoxyphenyl)-1-{[3-(phenylmethoxy)phenyl]methyl}indole-2-carboxylate (Example 45, 5 g crude material, 7.0 mmol, in 120 mL methanol and 40 mL ethyl acetate). The mixture was hydrogenated at 55 psi for 48 h. The mixture was then filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified with silica gel flash chromatography using hexane/ethyl acetate (3/1 to 2/1) to give ethyl 1-[(3-hydroxyphenyl)methyl]-3-(4-methoxyphenyl)indole-2-carboxylate as a light yellow oil (2.5 g, 89%): MS (M+) calcd for C25H23NO4 401.1, found 401.0; 1H NMR (CDCl3) δ 7.60 (dd, J=8.1 Hz, 1H), 7.30-7.45 (m, 4H), 7.13-7.21 (m, 2H), 6.98 (d, J=8.1 Hz, 2H), 6.64-6.78 (m, 2H), 6.52 (s, 1H), 5.77 (s, 2H), 4.14 (q, J=7.0 Hz, 2H), 1.04 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][C:8]=2[F:17])=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].Br[C:22]1[N:27]=[C:26]([CH:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:29][OH:30])[CH:25]=[CH:24][CH:23]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:17][C:8]1[CH:9]=[C:10]([C:13]([OH:16])([CH3:15])[CH3:14])[CH:11]=[CH:12][C:7]=1[C:5]1[S:6][C:2]([NH:1][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([CH:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH2:29][OH:30])[N:27]=2)=[C:3]([C:18]([NH2:20])=[O:19])[N:4]=1
Reactant: OCC(c1cccc(Br)n1)N1CCOCC1
Reactant: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(N)s2)c(F)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(Nc3cccc(C(CO)N4CCOCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1, Step 2 using 5-amino-2-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (115 mg, 0.39 mmol), 2-(6-bromopyridin-2-yl)-2-morpholin-4-ylethanol (Enantiomer B) (Example 3, Step 1, chiral separation) (112 mg, 0.39 mmol), Pd2(dba)3 (36 mg, 0.039 mmol), X-PHOS (93 mg, 0.20 mmol), potassium carbonate (54 mg, 0.39 mmol), and tert-amyl alcohol (0.8 ml) as starting materials. 1H NMR (500 MHz, d6-DMSO) δ 11.25 (s, 1H), 8.29 (t, 1H), 7.86 (s, 1H), 7.70 (m, III), 7.65 (s, 1H), 7.42 (m, 2H), 7.10 (d, 1H), 6.92 (d, 1H), 5.24 (s, 1H), 4.47 (t, 1H), 4.00 (m, 2H), 3.65 (t, 1H), 3.54 (m, 4H), 2.51 (m, 4H), 1.44 (s, 6H). LRMS (APCI) calc'd for C24H29FN5O4S [M+H]+ 502.2, found 502.0.
Reaction SMILES: Cl.[S:2]1[CH2:6][C@@H:5]([C:7]([N:9]2[CH2:13][CH2:12][S:11][CH2:10]2)=[O:8])[NH:4][CH2:3]1.Cl.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:15]([N:4]1[C@H:5]([C:7]([N:9]2[CH2:13][CH2:12][S:11][CH2:10]2)=[O:8])[CH2:6][S:2][CH2:3]1)(=[O:22])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1
Reactant: O=C([C@@H]1CSCN1)N1CCSC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C([C@@H]1CSCN1C(=O)c1ccncc1)N1CCSC1
Yield: 74.6 %

Procedure:
To a solution of 0.48 g of 3-[(R)-(-)-thiazolidine-4-carbonyl]thiazolidine hydrochloride and 0.36 g of isonicotinoylchloride hydrochloride in 10 ml of dichloromethane was added 1.6 ml of triethylamine with stirring under cooling. The reaction mixture was stirred for 24 hours at room temperature, and then washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/acetonitrile=1/1) to obtain 0.46 g of 3-[(R)-(-)-3-isonicotinoylthiazolidine-4-carbonyl]thiazolidine (yield: 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([F:14])[CH:7]=1.[C:19](Cl)(Cl)=[O:20].CCO>C1(C)C=CC=CC=1>[F:14][C:8]1[CH:7]=[C:6]([N:5]2[CH2:4][C:3]3[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:1][C:19]2=[O:20])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1ccc(NCc2ccccc2N)cc1F
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(N2Cc3ccccc3NC2=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.9 %

Procedure:
To a stirred suspension of crude N-(2-aminobenzyl)-3-fluoro-4-methoxyaniline (246 mg, 1 mmol) in 10 mL toluene at 0° C. under a drying tube was added phosgene solution (20% in toluene, 683 μL, 1.30 mmol). The cooling bath was removed and the reaction allowed to warm to room temperature over 30 minutes. The solution was then warmed to reflux. After 1 hour, the reaction was concentrated to dryness and the residue dissolved in a minimum of hot 95% EtOH. A precipitate formed which was isolated by filtration with 95% EtOH and dried to give a tan solid (65 mg, 24%). 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 1H), 7.14 (m, 1H), 7.08 (m, 2H), 7.01 (m, 2H), 6.81 (d, 1H), 4.80 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([CH2:21][OH:22])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([CH2:21][O:22][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(COc2ccccc2C=O)C1
Temperature: 120 °C
Reaction time: 168 h
Yield: 34.5 %

Procedure:
A mixture of 2-fluoro-benzaldehyde (0.85 mL; 8.06 mmol; 1 eq.), 3-hydroxymethyl-azetidine-1-carboxylic acid tert-butyl ester (1.66 g; 8.86 mmol; 1.1 eq.) and K2CO3 (2.23 g; 16.11 mmol; 2 eq.) in DMF (20 mL) was stirred at 120° C. for 7 days. The reaction mixture was diluted with sat. aq. NaHCO3 and extracted with DCM (2×). The combined organic layer was washed with brine (2×), dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (heptane/EA, 95/5 to 60/40) afforded the title compound (810 mg, 35%) as a white solid. HPLC (max plot) 96.2%; Rt 4.15 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:13][C@H:12]2[CH2:36][NH:37][S:38]([N:41]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)=[O:44])[CH3:42])(=[O:40])=[O:39])=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1>ClCCl.CO.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([SH:16])[CH2:13][C@H:12]2[CH2:36][NH:37][S:38]([N:41]([C:43]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=2)=[O:44])[CH3:42])(=[O:39])=[O:40])=[O:10])=[CH:55][CH:56]=1
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CNS(=O)(=O)N(C)C(=O)OCc2ccc(OC)cc2)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(COC(=O)N2C[C@@H](S)C[C@H]2CNS(=O)(=O)N(C)C(=O)OCc2ccc(OC)cc2)cc1
Yield: 83.2 %

Procedure:
To a solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-tritylthio-2-(N-p-methoxybenzyloxycarbonyl-N-methylaminosulfonyl)aminomethylpyrrolidine (1.5 g: 1.88 mmole) in a mixture of dichloromethane (4 ml) and methanol (10 ml), a solution of pyridine (381 μl: 2.5 eq.) and silver nitrate (640 mg: 2 eq.) in water (6 ml) is added with stirring under ice cooling. The mixture is stirred at the same temperature for 30 minutes. The reaction mixture is diluted with dichloromethane, washed with water, dried over magnesium sulfate, and concentrated in vacuo to about 5 ml. The residue is dissolved in methanol (10 ml) and hydrogen sulfide is bubbled through it. The mixture freed from solid by filtering is concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene:ethyl acetate=2:1) to give (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-mercapto-2-(N-p-methoxybenzyloxycarbonyl-N-methylaminosulfonyl)aminomethylpyrrolidine (866 mg). Yield: 83%. NMR δ(CDCl3) ppm: 1.6 to 1.8(m, 1H), 2.3 to 2.6(m, 1H), 2.9 to 3.4(m, 5H), 3.3(s, 3H), 3.8(s, 6H), 3.8 to 4.2(m, 1H), 6.3 to 6.6(m, 1H), 6.88(d, J=8.6 Hz, 2H), 7.2 to 7.4(m, 2H). IR ν (CHCl3) cm-1 : 1690.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:6]([N+:15]([O-:17])=[O:16])=[CH:7][C:8]=1[S:9](=[O:14])(=[O:13])[N:10]([CH3:12])[CH3:11])[NH2:5].[OH:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.[OH-].[K+]>CS(C)=O>[CH3:11][N:10]([CH3:12])[S:9]([C:8]1[CH:7]=[C:6]([N+:15]([O-:17])=[O:16])[C:4]([NH2:5])=[CH:3][C:2]=1[N:22]1[CH:23]=[CH:24][C:19](=[O:18])[CH:20]=[CH:21]1)(=[O:14])=[O:13]
Reactant: CN(C)S(=O)(=O)c1cc([N+](=O)[O-])c(N)cc1Cl
Reactant: Oc1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)c1cc([N+](=O)[O-])c(N)cc1-n1ccc(=O)cc1
Temperature: 130 °C
Yield: 46.2 %

Procedure:
First, a mixture containing 3.0 g of 3-chloro-4-dimethylsulfamoyl-6-nitroaniline, 1.39 g of 4-hydroxypyridine, 0.91 g of 86% potassium hydroxide, and 20 ml of dimethylsulfoxide was heated in an oil bath at 130° C. for 1.5 hours. The subsequent processes were conducted in the same way as in Reference Example 3 to give 1.675 g of 4-dimethylsulfamoyl-3-(4-oxo-4H-pyridin-1-yl)-6-nitroaniline.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:22][CH:23]=2)[CH2:32][CH2:31]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
A mixture of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (150 mg, 0.4 mmol), N-methyl-piperazine (123 mg, 1.2 mmol) and acetic acid (120 mg, 1.2 mmol) in methanol (50 mL) was stirred at room temperature for 60 min. Then the mixture was cooled to 0° C. Sodium triacetoxyborohydride (130 mg, 0.6 mmol) was added. After the addition, the mixture was stirred at room temperature for overnight. Methanol was removed under reduced pressure. The crude product was purified by pre-HPLC to give 8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (36 mg, yield 19%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.29 (s, 3H), 2.12-2.73 (br s, 8H), 3.47 (s, 2H), 4.30 (d, J=8.0 Hz, 1H), 4.74 (d, J=8.0 Hz, 1H), 7.08-7.10 (m, 2H), 7.18-7.21 (m, 6H), 7.23-7.25 (m, 2H), 7.55-7.57 (d, J=8.0 Hz, 1H), 7.62-7.64 (m, 1H). LC-MS (ESI) m/z: 452 (M+1)+.
Reaction SMILES: [C:1]1([CH:7]([NH:9][CH:10]2[C:14]3=[N:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:22](=[O:23])[N:13]3[CH2:12][CH2:11]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35])[CH2:25][CH3:26]>C(Cl)Cl>[O:23]=[C:22]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=[C:14]2[CH:10]([N:9]([CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH3:8])[C:34]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH2:24][CH2:25][CH3:26])=[O:35])[CH2:11][CH2:12][N:13]12
Reactant: CC(NC1CCn2c1nc1ccccc1c2=O)c1ccccc1
Reactant: CCCc1ccccc1N=C=O
Solvent: ClCCl
Product: CCCc1ccccc1NC(=O)N(C(C)c1ccccc1)C1CCn2c1nc1ccccc1c2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
To a solution of 3-(1-phenyl-ethylamino)-2,3-dihydro-1H-pyrrolo[2,1-b]quinazolin-9-one (50 mg, 0.163 mmol) in dry CH2Cl2 (1 mL), was added 2-n-propylphenyl isocyanate (26.3 mg, 0.163 mmol). The resulting reaction mixture was stirred at rt under nitrogen for 20 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified by FC (AcOEt/heptane: 7/3) to give the title compound as a white foam (45%). LC-MS (MeCN/H2O: 1/1): Rt=3.00 min. m/z=467 (M+1).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=2[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=1)=O.[NH2:23][C:24]1([CH3:37])[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:33]([O:32][C:30]([N:27]1[CH2:26][CH2:25][C:24]([NH:23][CH2:1][C:3]2[C:11]3[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=3[N:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:4]=2)([CH3:37])[CH2:29][CH2:28]1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)c1ccnc2c1c(C=O)cn2C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccnc2c1c(CNC1(C)CCN(C(=O)OC(C)(C)C)CC1)cn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
1-tert-Butyl 4-methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (71 mg, 0.233 mmol) was dissolved in DCM (5 mL) and tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (50 mg, 0.233 mmol) was added to the solution and allowed to stir for 2 h at room temperature. Then sodium triacetoxyborohydride (148 mg, 0.700 mmol) was added and the mixture was allowed to stir for 2 h at room temperature. The solution was quenched with water and extracted with DCM. The organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (70% EtOAc/Hexanes) gave 90 mg of 1-tert-butyl 4-methyl 3-((1-(tert-butoxycarbonyl)-4-methylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate. [M+H] found 403.