Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([OH:20])=O)=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH:1]1([CH2:6][C@H:7]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[O:20])=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1
Product: CN1CCN(C(=O)CSc2cnc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)s2)CC1

Procedure:
The title compound was prepared from (R)-{2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-5-ylsulfanyl}-acetic acid and 1-methylpiperazine as described in Example 12. 1H-NMR (CD3OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.50 (s, 1H), 4.83-4.15 (broad m, 2H), 3.96 (t, 1H), 3.72 (s, 2H), 3.60-3.45 (broad m, 3H), 3.12-3.00 (broad m, 3H), 3.10 (s, 3H), 2.92 (s, 3H), 2.25-2.17 m, 1H), 1.90-1.75 (m, 3H), 1.70-1.60 (m, 3H), 1.51 (m, 2H), 1.18 (m, 2H); HPLC-MS: m/z: 551 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Si:10]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: O=c1cc(CO)cc[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc[nH]c(=O)c1
Reaction time: 16 h

Procedure:
4-Hydroxymethyl-1H-pyridin-2-one from Step 1 (1.3 g, 10.5 mmol) was dissolved in DMF. t-Butyl dimethylsilyl chloride (12.6 mmol, 1.9 g) and imidazole (12.6 mmol, 858 mg) were added and the reaction was stirred for 16 hours. The reaction mixture was diluted with EtOAc and washed with H2O (2x) and brine. The organic layer was dried (MgSO4), filtered and concentrated to yield a yellow oil Flash chromatography (EtOAC) yielded 4-(tert-butyldimethylsilyloxy-methyl)-1H-pyridin-2-one as an off white solid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[N-:6]([C:9]#[N:10])[C:7]#[N:8].[Na+].CN1CCCC1=O>CC(O)CC>[NH2:8][C:7]([NH:6][C:9]#[N:10])=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: N#C[N-]C#N
Reactant: N#CCC#N
Agent: [Na+]
Solvent: CCC(C)O
Solvent: CN1CCCC1=O
Product: N#CNC(N)=C(C#N)C#N
Temperature: 145 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a 250 ml flask is charged 6.6 gm (0.1 mole) of malononitrile, 8.9 gm (0.1 mole) of sodium dicyanamide and 40 ml of N-methylpyrrolidone. The stirred mixture is heated to 145° C. and held for one hour, then cooled to about room temperature. Then 150 ml of 2-butanol is added and the stirred mixture is cooled in an ice bath. The solids are filtered, washed with 2-butanol and dried. There is obtained 10.7 gm of 1-amino-1-cyanamido-2,2-dicyanoethylene, sodium salt, 82.5% pure, or a 57.0% yield.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[C:14]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([NH2:24])[CH2:19]3)[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])[C:12]2=[O:34])[CH:5]=1.[Li+].[OH-]>C1COCC1.O>[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:14]2[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]#[N:33])[C:12](=[O:34])[N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:35])=[O:2])[C:16](=[O:17])[CH:15]=2)[CH2:19]1
Reactant: COC(=O)c1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)n(Cc2cccc(C(=O)O)c2)c1=O

Procedure:
A crude mixture of compound 24 (˜50 mg) was treated with LiOH in THF-water (10:1) to give the title compound 25. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.90 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.45 (d, J=7.3 Hz, 1H), 7.26-7.36 (m, 2H), 7.17 (d, J=8.1 Hz, 1H), 5.39 (s, 1H), 5.10-5.25 (ABq, J=36.9, 15.5 Hz, 2H), 5.03 (s, 2H), 3.31 (m, 2H), 2.95 (m, 1H), 2.81 (m, 1H), 2.64 (m, 1H), 2.07 (m, 1H), 1.82 (m, 1H), 1.51-1.68 (m, 2H). MS (ES) [m+H] calc'd for C25H26N5O4, 460.2; found 460.2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[O:9])[CH2:2]1.C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:32][N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]2[C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)=[O:9])[CH2:2]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(N[C@@H]1CCCNC1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC[C@@H](NC(=O)N2CCc3ccccc3C2c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N—((R)-piperidin-3-yl)-1-(4-(trifluoromethyl)phenyl)-3,4-dihydro-isoquinoline-2(1H)-carboxamide (30 mg, 74 μmol, example 24) in DCE (0.5 mL) was added formaldehyde (28 μL, 372 mol). The resulting mixture was stirred at RT for 1 h and then sodium triacetoxyborohydride (16 mg, 74 μmol) was added. The mixture was then stirred at RT for 4 h. Then, saturated NaHCO3 (0.4 mL) was added and the mixture was extracted with EtOAc (2×3 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel flash column chromatography (0%-10% MeOH (2M NH3)/EtOAc) to give the title compound as an off-white solid. MS (ESI, positive ion) m/z: 418 (M+H).
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.Cl.[NH2:49][C:50]1[N:51]=[C:52]([CH2:55][C:56]2[O:60][C:59]([C:61](=[O:63])[CH3:62])=[CH:58][CH:57]=2)[S:53][CH:54]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:61]([C:59]1[O:60][C:56]([CH2:55][C:52]2[S:53][CH:54]=[C:50]([NH:49][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[N:51]=2)=[CH:57][CH:58]=1)(=[O:63])[CH3:62]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(=O)c1ccc(Cc2nc(N)cs2)o1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1ccc(Cc2nc(NC(=O)c3ncoc3-c3ccccc3)cs2)o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-phenyl-1,3-oxazole-4-carboxylic acid (41 mg, 0.21 mmol) in CH2Cl2 (2.0 mL) was treated sequentially with DMAP (6 mg, 0.05 mmol), HOBt (30 mg, 0.22 mmol), EDC.HCl (89 mg, 0.46 mmol) and DIPEA (0.13 mL, 0.74 mmol) and the resulting mixture was stirred at rt for 15 min. This solution was then added to a solution of 1-[5-(4-amino-thiazol-2-ylmethyl)-furan-2-yl]-ethanone hydrochloride (41 mg, 0.19 mmol) in dry CH2Cl2 (0.5 mL) and the reaction mixture was stirred for 16 h at rt. CH2Cl2 (20 mL) was then added and the org. phase was washed with water (15 mL) and brine (15 mL). The org. phase was then dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept:EA) gave the title compound as a brown foam. TLC: rf (1:1 hept-EA)=0.30. LC-MS-conditions 02: tR=1.04 min, [M+H]+=394.37.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH2:12][C:13]([OH:15])=O)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:19])=O>>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]([CH2:12][C:13]([Cl:19])=[O:15])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(CC(=O)O)oc12
Reactant: O=C(Cl)C(=O)Cl
Product: COc1cccc2cc(CC(=O)Cl)oc12
Yield: 100 %

Procedure:
A solution of 15.0 g of 7-methoxy-3-benzofuranacetic acid in 86 ml of oxalyl chloride was stirred at 25° for 1 hour. Removal of the solvent gave 16.35 g (100%) of crude 7-methoxy-3-benzofuranacetic acid chloride. NMR spectrum (200 mHz in CDCl3): δ4.0 (s, 3H), 4.23 (s, 2H), 6.83 (d, J=7 Hz, 1H), 7.07 (d, J=7 Hz, 1H), 7.18 (d, J=8 Hz, 1H) and 7.68 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.O([C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1)S(C(F)(F)F)(=O)=O>CCOCC.C([O-])([O-])=O.[Na+].[Na+].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>[S:1]1[CH:5]=[CH:4][C:3]([C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=2)=[CH:2]1
Reactant: OB(O)c1ccsc1
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
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: CCOCC
Product: C1=C(c2ccsc2)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
3-Thiophene boronic acid (128 mg, 1.00 mmol), cyclohexenyl triflate (230.2 mg, 1.00 mmol) was dissolved in Et2O (4 mL) and 2M Na2CO3 (1 mL). The mixture was degassed and Pd(PPh3)4 (0.05 mmol) added. After stirring at room temperature for 4 h the mixture was filtered through celite, rinsed with Et2O, dried (Na2SO4) and subjected to column chromatography (silica, pentane) to yield 150 mg of a volatile liquid. GC-MS: M+=164.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:20])[NH:13]2
Reactant: Fc1cccc(-c2cccc3[nH]ccc23)c1F
Reactant: CCO
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To the suspension of 4-(2,3-difluoro-phenyl)-1H-indole (2.85 g, 12.4 mmol) in t-BuOH: ethanol: acetic acid (78.5 mL: 46.5 mL: 24.13 mL) was added pyridinium tribromide (11.93 g, 37.3 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added with acetic acid (60 mL). Zinc dust (4.1 g, 62.2 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), sat NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 2.32 g (76%) of 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one as an earth colored solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([Cl:16])[C:7]=1[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([Cl:16])[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: OC(c1ccccc1)c1c(Cl)nnc(-c2ccccc2)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1c(Cl)nnc(-c2ccccc2)c1Cl
Temperature: 115 °C
Yield: 75.9 %

Procedure:
A mixture of (3,5-dichloro-6-phenylpyridazin-4-yl)(phenyl)methanol (200 mg, 0.6 mmol), manganese dioxide (700 mg, 8 mmol) in dry toluene (20 mL) was heated at 115° C. for 3 h under Dean Stark conditions. The reaction mixture was cooled and filtered, and the residue was washed with CH2Cl2. The filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, gradient 10 to 20% ethyl acetate/isohexane) yielding (3,5-dichloro-6-phenylpyridazin-4-yl)(phenyl)methanone as a solid (150 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][C:18](=[O:23])N(OC)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH:18]=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)CCN1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCC(=O)N(CCC=O)CC1
Yield: 61.7 %

Procedure:
To a cooled (−78° C.) solution of 4-[2-(methoxy-methyl-carbamoyl)-ethyl]-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester 3 g (9 mmol) was added dropwise a solution of lithium aluminum hydride 9.1 ml (9 mmol, 1 M solution in THF). The mixture was quenched by addition of acetone and then AcOH. The reaction was allowed to reach RT after which time water and 10% aq. KHSO4 solution were added and the mixture repeatedly extracted with TBME. The combined organic was washed with brine, dried (MgSO4) and concentrated. Purification by flash column chromatography (EtOAc:MeOH 19:1) afforded the title compound 1.5 g (61%) as a colorless oil. MS: 271.5 (MH+).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][O:8][C:7]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[O:15][C:14]([CH3:24])([CH3:23])[CH2:13][CH2:12][C:11]=3[C:10]2=[O:25])[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][CH:5]1[CH2:9][O:8][C:7]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[O:15][C:14]([CH3:23])([CH3:24])[CH2:13][CH2:12][C:11]=3[C:10]2=[O:25])[O:6]1
Reactant: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(CN=[N+]=[N-])O1)C2=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(CN)O1)C2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4′-(azidomethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one (0.012 mg, 0.035 mmol) in THF (1.0 mL) is added triphenylphosphine (0.033 mg, 0.13 mmol). The mixture is stirred at room temperature for 3 hour followed by addition of water (50 μL). The reaction is then stirred for another 16 hour at room temperature and solvent is removed under reduce pressure to yield a reside of 4′-(aminomethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one as confirmed by LC/MS, which indicates the product, which has a molecular weight of 315 Da, is present in the crude residue along with triphenylphosphine oxide (a side product from the triphenylphosphine).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:29])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:10]=2)[CH:8]=1.[Cl:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](O)=[O:36].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>O1CCOCC1.C(Cl)Cl>[Cl:30][CH2:31][C:32]1[CH:33]=[C:34]([C:35]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([F:29])=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]4[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]4)[CH:10]=3)[CH:8]=2)=[O:36])[CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CN)ccc3F)c2)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CCl)c4)ccc3F)c2)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 48.9 %

Procedure:
To a solution of 1,1-dimethylethyl 4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.32 g, 0.80 mmol) in p-dioxane/DCM (4/4 mL) was added 3-(chloromethyl)benzoic acid (0.12 g, 0.88 mmol), EDC (0.23 g, 1.2 mmol), HOBt (0.011 g, 0.08 mmol), and Et3N (0.112 mL, 0.8 mmol). The mixture was stirred at room temperature for 50 min before was the reaction was quenched with H2O (3 mL). The organic layer was separated, dried over Na2SO4, filtered, concentrated and purified by CombiFlash chromatograph to afford the title compound 0.216 g (49%). LC-MS m/z 552 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])=O)[CH:5]=[CH:4][N:3]=1.[CH3:19][C:20]([S:23]([NH2:25])=[O:24])([CH3:22])[CH3:21].CO.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])=[N:25][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(F)cccc1C(=O)c1ccnc(Cl)c1
Reactant: CC(C)(C)S(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)S(=O)N=C(c1ccnc(Cl)c1)c1cccc(F)c1C#N
Yield: 47.8 %

Procedure:
Ti(OEt)4 (15 mL) was added to a solution of 2-(2-chloro-pyridine-4-carbonyl)-6-fluoro-benzonitrile (3.6 g, 13.81 mmol) and 2-methyl-propane-2-sulfinic acid amide (2.5 g, 20.72 mmol) in dry THF (100 mL) at room temperature. The resulting mixture was stirred to reflux for 40 hours and then treated with CH3OH (50 mL) and saturated sodium bicarbonate solution (10 mL). The resulting suspension was filtered through a pad of Celite® and the solids were washed with THF (50 mL) and CH3OH (20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography using a gradient of 25-50% EtOAc in hexane to afford the title compound (2.4 g, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]([C:15]([OH:17])=O)[C:13]=1[C:21]([OH:23])=O.Cl.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:14]2[C:13]=1[C:21](=[O:23])[N:25]([CH:26]1[CH2:32][CH2:31][C:30](=[O:33])[NH:29][C:27]1=[O:28])[C:15]2=[O:17]
Reactant: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)c(OC)c1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c(OC)c1
Yield: 67 %

Procedure:
A mixture of 3-(2,4-dimethoxyphenylamino)phthalic acid (0.75 g, 2.4 mmol) and rac-α-aminoglutarimide hydrochloride (0.40 g, 2.4 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 0.64 g of the product at 25:75 hexanes-ethyl acetate, in 67% yield: mp 208-210° C.; 1H NMR (DMSO-d6) δ 2.04-2.09 (m, 1H), 2.54-2.64 (m, 2H), 2.83-2.92 (m, 1H), 3.78 (s, 3H), 3.79 (s, 3H), 5.12 (dd, J=12.7 Hz, J=5.4 Hz, 1H), 6.57 (dd, J=8.6 Hz, J=2.6 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 7.15 (d, J=7.0 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.95 (s, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.1, 31.0, 48.7, 55.4, 55.7, 99.5, 104.7, 110.4, 112.2, 118.3, 120.1, 125.2, 132.1, 136.1, 144.2, 153.7, 157.9, 167.2, 168.9, 170.1, 172.8; Anal. calcd for C21H19N3O6.0.3H2O: C, 60.81; H, 4.76; N, 10.13. Found: C, 60.87; H, 4.64; N, 10.00.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[CH2:12][OH:13]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[CH:12]=[O:13]
Reactant: COc1ccc2[nH]nc(CO)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]nc(C=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of (5-methoxy-1H-indazol-3-yl)methanol (0.367 g, 2.06 mmol) in ethyl acetate (20 mL) was added with manganese dioxide (1.79 g, 20.6 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite, and then the filtrate was concentrated to obtain 5-methoxy-1H-indazole-3-carbaldehyde (0.254 g, 70%).
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][N:15]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[CH:21]3)=[N:16]2)[CH2:10]1)(OC(C)(C)C)=O.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>ClCCl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[N:16]1[N:15]([CH2:14][C@@H:11]2[CH2:12][CH2:13][C@H:9]([NH2:8])[CH2:10]2)[CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[CH:21]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Cn2cc3ccccc3n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](Cn2cc3ccccc3n2)C1

Procedure:
Deprotection of N1-BOC-(1S,3R)-3-(2H-indazol-2-ylmethyl)cyclopentan-1-amine (400 mg, 1.27 mmol), the more polar isomer from Step 1, Example 67, using TFA (3 ml) in dry dichloromethane (3 ml) as described in Example 1, Step 2 gave 273 mg of the amine as its TFA salt, which was used as such for the coupling reaction. Step 2: Coupling reaction of Step 1 intermediate (273 mg, 1.27 mmol) with Intermediate 17 (109 mg, 0.63 mmol) in the presence of potassium carbonate (175 mg, 1.27 mmol) and NaI (95 mg, 0.63 mmol) in THF (30 ml) as described in Example 1, Step 3 gave 90 mg of the product as a yellow semisolid; IR (neat) 3317, 3117, 3058, 2943, 2872, 2239, 1660, 1514, 1412, 1306, 1262, 1191, 1157, 1139, 1042, 1009 cm−1; 1H NMR (CDCl3, 300 MHz) δ 1.14–1.29 (m, 2H), 1.53–1.62 (m, 2H), 1.74–1.90 (m, 3H), 1.95–2.32 (m, 5H), 2.67–2.73 (m, 1H), 3.12–3.17 (m, 1H), 3.35 (s, 2H), 3.37–3.59 (m, 2H), 4.38–4.41 (m, 2H), 4.74 (m, 1H), 7.04–7.09 (m, 1H), 7.26–7.30 (m, 1H), 7.64–7.71 (m, 2H), 7.92 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:40][C@@H:39]2[C@@H:10]([CH2:11][C:12]3[N:13]([CH2:38]2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]=3[C:21]2[C:22](=[O:37])[O:23][C:24](=[O:36])[C:25]=2[C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]([CH3:35])[CH:27]=2)[CH2:9]1)=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:9]1[C@@H:10]2[CH2:11][C:12]3[N:13]([CH2:38][C@@H:39]2[CH2:40][NH:8]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=1[C:20]=3[C:21]1[C:22](=[O:37])[O:23][C:24](=[O:36])[C:25]=1[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([CH3:35])[CH:27]=1
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)C[C@@H]3CN(C(=O)OC(C)(C)C)C[C@@H]3C4)C(=O)OC2=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)C[C@@H]3CNC[C@@H]3C4)C(=O)OC2=O)c2ccccc21

Procedure:
A stirred solution of 5 g of cis-3-[2-(tertbutoxycarbonyl)-2,3,3a,4,11,11a-hexahydro-1H-pyrrolo[3',4':4,5]-pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione [prepared as described in Example 5(viii)] in 200 ml of dichloromethane was treated with 30 ml of trifluoroacetic acid. After 0.5 hour the solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel using dichloromethane/methanol/acetic acid/water (90:18:3:2) for the elution. Removal of the solvent gave 4.5 g of cis-3-[2,3,3a,4,11, 11a-hexahydro-1H-pyrrolo[3',4':4,5]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione trifluoroacetate of melting point 199°-201° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([I:18])=[C:14]([OH:19])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:22]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([I:18])=[C:14]([O:19][CH3:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2ccc(I)c(O)c12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(I)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To 748 mg (2 mmol) of 5-iodo-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 1.42 g (10 mmol) of iodomethane, 553 mg (4 mmol) of K2CO3 and 10 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent gave 790 mg (100% yield) of 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a pale brown oil.