Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(OC(C)(C)C)[O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)[CH:4]=1.C(=O)(OC(C)(C)C)OC1N(C2C=CC=CN=2)N=C(C2C=CC(C3C=CC=CC=3)=CC=2)C=1>>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:5]4[CH:4]=[C:3]([OH:2])[N:7]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=5)[N:6]=4)=[CH:19][CH:18]=3)=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccc4c(c3)OCO4)cc2)nn1-c1ccccn1
Agent: CC(C)(C)OC(=O)Oc1cc(-c2ccc(-c3ccccc3)cc2)nn1-c1ccccn1
Product: Oc1cc(-c2ccc(-c3ccc4c(c3)OCO4)cc2)nn1-c1ccccn1
Yield: 70 %

Procedure:
The title compound was prepared in the same manner as in Example D-1, except that an equimolar amount of Compound 28 of Example C-2 was used in place of Compound 27 of Example C-1.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:5][C:4]=1[CH3:13])=[O:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:13][C:4]1[CH:5]=[C:6]([CH2:8][CH2:9][C:10]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[O:12])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: CN1CCNCC1
Reactant: Cc1cc(CCC(=O)O)[nH]c1C=O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(CCC(=O)N2CCN(C)CC2)[nH]c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 3-(5-formyl-4-methyl-1H-pyrrol-2-yl)-propionic acid (271.8 mg, 1.5 mmol) in DMF (4mL) was added HOBt (243.2 mg, 1.8 mmol), EDC (345.1 mg, 1.8 mmol) and then 1-methylpiperazine (0.2 mL, 1.8 mmol). The mixture was stirred at room temperature under nitrogen for overnight. The reaction was poured into sat. sodium bicarbonate (50 mL) and extracted with ethyl acetate. The combined organic layer was dried, concentrated and column chromatographed (MeOH/DCM) to give 325.2 mg (82%) of 3-methyl-5-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([OH:21])[C:18](O)=[O:19])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.S(Cl)(Cl)=O.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1.CCN(CC)CC>C(Cl)Cl>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:16][CH:17]([OH:21])[C:18]([NH:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH3:26])[CH:29]=3)=[O:19])[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: O=C(O)C(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Reactant: COc1cccc(N)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)C(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)c1
Temperature: 0 °C
Yield: 47.5 %

Procedure:
3-(3,6-Dibromo-9H-carbazol-9-yl)-2-hydroxypropanoic acid (0.025 g, 0.061 mmol) was suspended in anhydrous CH2Cl2 and cooled to 0° C. Thionyl chloride (0.005 mL, 0.073 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 h. m-Anisidine (0.008 mL, 0.073 mmol) and Et3N (0.010 mL, 0.073 mmol) were added and the reaction was allowed to warm to ambient temperature over 2.5 h. Upon completion, the solution was partitioned between EtOAc and H2O. The aqueous layer was washed 3× with EtOAc, and the combined organics were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by chromatography (SiO2, 0-30% EtOAc/Hexane) to afford the desired product (15 mg, 48%).
Reaction SMILES: C([N:4](CC)C(C)C)(C)C.[CH3:10][C:11](=[N:13][OH:14])C.[F:15][C:16]1[C:21](C#N)=C(F)[C:19]([F:25])=[C:18]([C:26]#[N:27])[C:17]=1[F:28].[Cl-].[NH4+]>CC#N>[NH2:4][C:11]1[C:10]2[C:19]([F:25])=[C:18]([C:26]#[N:27])[C:17]([F:28])=[C:16]([F:15])[C:21]=2[O:14][N:13]=1
Reactant: N#Cc1c(F)c(F)c(C#N)c(F)c1F
Reactant: CC(C)=NO
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Product: N#Cc1c(F)c(F)c2onc(N)c2c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of N,N-diisopropylethylamine (19.2 g, 110 mmol) in CH3CN (100 mL) was added acetone oxime (8 g, 110 mmol). After stirring for 30 min, a solution of tetrafluoroterephthalonitrile (20 g, 100 mmol) in CH3CN (50 mL) was added; and the mixture was stirred overnight. Saturated aqueous ammonium chloride (100 mL) was added and the solvents were removed in vacuo. The residue was partitioned between EtOAc and brine. The layers were separated and the organic phase was washed once with brine, dried (MgSO4), filtered and concentrated. This crude solid was suspended in EtOH (150 mL) and concentrated HCl (50 mL) and water (100 mL) were added. This was refluxed for 3 h. After cooling to room temperature, the solvents were removed in vacuo. The residue was treated with saturated aqueous sodium bicarbonate (200 mL), and the product was extracted by washing the aqueous layer three times with EtOAc. This organic solution was washed once with brine, dried (MgSO4), filtered and concentrated to give a yellow solid. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes to 40% EtOAc/hexanes (9.2 g, 43%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:30][O:31][CH:32]2[CH2:34][CH2:33]2)[C:8]([NH:10][C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-:27])=[O:26])=[C:15]([CH2:18][N+:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[S:35](=[O:39])(=[O:38])([OH:37])[OH:36]>O>[S:35]([O-:39])([OH:38])(=[O:37])=[O:36].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:30][O:31][CH:32]2[CH2:34][CH2:33]2)[C:8]([NH:10][C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([OH:27])=[O:26])=[C:15]([CH2:18][N+:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)cs1
Solvent: O
Product: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(C[n+]4ccccc4)CS[C@H]23)cs1
Product: O=S(=O)([O-])O

Procedure:
To a solution of 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (750 mg) in water (50 ml) was added concentrated sulfuric acid (0.0679 ml). The solution was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylic acid hydrogen sulfate (863 mg).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([NH:12][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=1)([CH3:15])[CH3:14])=[O:11])[CH2:2]2.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>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>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([NH:12][C:13]([C:16]1[CH:17]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=1)([CH3:15])[CH3:14])=[O:11])[CH2:2]2
Reactant: CC(C)(NC(=O)NC1CN2CCC1CC2)c1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(NC(=O)NC1CN2CCC1CC2)c1cccc(-c2ccccc2)c1
Yield: 19.2 %

Procedure:
Using general procedure E, 1-(1-azabicyclo[2.2.2]oct-3-yl)-3-[2-(3-bromophenyl)propan-2-yl]urea (111 mg, 0.301 mmol), phenylboronic acid (78.8 mg, 0.606 mmol) and tetrakis(triphenylphosphine)palladium(0) gave the title compound as an off-white solid (21 mg, 11%). 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.52-7.40 (m, 8H), 4.89 (s, 1H), 4.28 (d, J=7.3 Hz, 1H), 3.75-3.59 (m, 1H), 3.15 (ddd, J=1.9, 9.3, 13.9 Hz, 1H), 2.46 (m, 4H), 2.05 (dd, J=3.5, 14.0 Hz, 1H), 1.68 (d, J=4.7 Hz, 6H), 1.66-0.76 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 157.4, 146.9, 142.5, 141.1, 129.7, 129.1, 127.8, 127.4, 126.7, 124.8, 124.7, 57.1, 55.1, 30.7, 30.1, 26.1, 26.0, 20.2 ppm. Purity: 100% UPLCMS (210 nm); retention time 0.78 min; (M+1) 364.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([O:27][CH:28]([F:30])[F:29])[C:11]([N:18]3[CH2:22][CH2:21][C@@H:20]([C:23]([NH2:26])([CH3:25])[CH3:24])[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:31]2[CH2:33][CH2:32]2)[C:7]=1[S:34](C)(=O)=O)=[O:5])[CH3:2].O.[SH-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([O:27][CH:28]([F:29])[F:30])[C:11]([N:18]3[CH2:22][CH2:21][C@@H:20]([C:23]([NH2:26])([CH3:25])[CH3:24])[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:31]2[CH2:33][CH2:32]2)[C:7]=1[SH:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(S(C)(=O)=O)n(C2CC2)c2c(OC(F)F)c(N3CC[C@@H](C(C)(C)N)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(S)n(C2CC2)c2c(OC(F)F)c(N3CC[C@@H](C(C)(C)N)C3)c(F)cc2c1=O

Procedure:
Compound 14 (1.6 g, 2.93 mmol) is dissolved in DMF (40 mL) under an atmosphere of argon. Sodium hydrosulfide hydrate crystals (Aldrich, 72.6% by titration, 330 mg, 5.88 mmol) are added to this solution. The resulting mixture is sparged slowly with argon for 30 min. The progress of the reaction is monitored by HPLC-MS, and judged to be complete (≧2% of 14 remains) after 5 h. Excess sodium hydrosulfide is quenched upon addition of aq. HCl (4.5 mL, 4 N). The resulting orange solution (pH ˜2) is sparged with argon (30 min) to remove the generated hydrogen sulfide. DMF is removed under reduced pressure to give orange oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)([OH:5])[CH3:4].[NH2:14][C:15]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=1)(C)[CH2:16][OH:17].[C:27](O[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(Cl)(Cl)Cl>[C:30]([O:29][C:27](=[O:28])[NH:1][CH2:2][C:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:13])[CH:7]=1)([OH:5])[CH3:4])([CH3:33])([CH3:32])[CH3:31].[C:38]([O:37][C:35](=[O:36])[NH:14][CH:15]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=1)[CH:16]([OH:17])[CH3:2])([CH3:39])([CH3:40])[CH3:41]
Reactant: CC(N)(CO)c1ccc(F)c(F)c1
Reactant: CC(O)(CN)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCC(C)(O)c1ccc(F)c(F)c1
Product: CC(O)C(NC(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a solution of 1-amino-2-(3,4-difluorophenyl)-propan-2-ol and 2-amino-2-(3,4-difluorophenyl)-propan-l-ol (1.2 g, 6.4 mmol) in CHCl3 (50 mL) at 0° C. was added a solution of di-tert-butyl dicarbonate (1.74 g, 7.9 mmol) in CHCl3 (10 mL) in one portion and the resulting solution was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel (2:1 hexane-EtOAc followed by EtOAc) to obtain [2-(3,4-difluorophenyl)-2-hydroxy-propyl]-carbamic acid-tert-butyl ester and [1-(3,4-Difluorophenyl)-2-hydroxy-propyl]-carbamic acid-tert-butyl ester as a white solid (1.1 g, 60.1%).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(OC)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methoxyphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 8) 80.0 mg (0.183 mmol) in 3 ml of EtOH and 2 ml of THF was added 40.0 mg (1.00 mmol, 1.0 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ7.90 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.3 Hz), 7.45 (2H, s), 7.24 (2H, d, J=8.6 Hz), 7.02-6.89 (3H, m), 5.98 (1H, t, J=4.4 Hz), 3.79 (3H, s), 2.31 (2H, d, J=4.7 Hz), 1.29 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:17][C:18]1[O:19][CH:20]=[CH:21][C:22]=1/[CH:23]=[CH:24]/[C:25](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[C:25](/[CH:24]=[CH:23]/[C:22]3[CH:21]=[CH:20][O:19][C:18]=3[CH3:17])=[N:1][C:2]=2[CH:14]=1
Reactant: Cc1occc1/C=C/C(=O)Cl
Reactant: COc1ccc(Nc2ccccn2)c(N)c1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: COc1ccc2c(c1)nc(/C=C/c1ccoc1C)n2-c1ccccn1
Yield: 16 %

Procedure:
(E)-3-(2-Methyl-3-furyl)acrylic acid (0.30 g, 2 mmol) was dissolved into thionyl chloride (5 ml) and the mixture was heated to reflux for 80 min. Volatiles were removed by evaporation to give crude (E)-3-(2-methyl-3-furyl)acryloyl chloride. The titled compound was prepared from 2-amino-4-methoxy-N-(2-pyridyl)aniline (0.43 g, 2 mmol) and (E)-3-(2-methyl-3-furyl)acryloyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). Recrystallization from a mixture of isopropyl ether (3 ml) and ethyl acetate (3 ml) to give 0.10 g (16%) of the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:16][CH:17]([CH2:19][C:20]([OH:22])=[O:21])[NH2:18].C1(C(CC(O)=O)[NH2:30])C=CC=CC=1>>[NH2:30][N:2]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][CH2:11][CH2:12][C:13]([NH:18][CH:17]([CH3:16])[CH2:19][C:20]([OH:22])=[O:21])=[O:15])=[CH:7][CH:8]=1
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: N#Cc1ccc(CCCCC(=O)O)cc1
Reactant: CC(N)CC(=O)O
Product: CC(CC(=O)O)NC(=O)CCC#Cc1ccc(C=NN)cc1

Procedure:
The title compound was prepared in the manner of Example 1 with the following modifications: Substituting 5-(p-cyanophenyl)-4-pentynoic acid for 5-(p-cyanophenyl)pentanoic acid and 3-methyl-beta-alanine for 3-phenyl-beta-alanine in procedure C of Example 1. The product was verified by C NMR (CD3OD) delta 15.5, 20.3, 34.5, 40.8, 42.0, 80.3, 92.2, 126.1, 127.8 131.2, 133.5, 166.7, 169.7, 172.5.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNc3ccccc3)ccc21
Yield: 92.2 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (57.5 mg, 0.140 mmol) was dissolved in acetonitrile (3 mL), and the solution was treated with aniline (0.051 mL, 0.56 mmol), acetic acid (0.160 mL, 2.80 mmol) and sodium triacetoxyborohydride (89 mg, 0.42 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-(phenylaminomethyl)indol-2-yl)isoindolinone (63.0 mg, yield 92%).
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28](/[CH:39]=[CH:40]/[C:41]2[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>>[F:54][C:51]([F:52])([F:53])[C:43]1[CH:42]=[C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)[CH:46]=[C:45]([C:47]([F:48])([F:50])[F:49])[CH:44]=1
Reactant: FC(F)(F)c1cc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc(C(F)(F)F)c1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Product: O=c1[nH]nc(CCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Yield: 49 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(E)-2-[3,5-bis(trifluoromethyl)phenyl]-ethenyl]pyridazine (Intermediate 71) in 49% yield.
Reaction SMILES: CON(C)[C:4](=[O:20])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C1COCC1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1.[BH4-].[Na+]>CCOCC.CO>[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH:4]([OH:20])[CH2:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:11][CH2:12]2)=[CH:30][CH:29]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(CCC(O)c2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 37 %

Procedure:
A solution of 1.30 g (4.5 mmol) of N-methoxy-N-methyl-3-(1-(t-butoxycarbonyl)piperidin-4-yl)propionamide (from EXAMPLE 188, Step A) in 25 (of THF at 0° C. was treated with 3.0 mL of 2.0 M (4-fluoro)phenylmagnesium bromide in ether and stirred cold for 1 h. The reaction was quenched with 100 mL of 0.5 N HCl and extracted with 150 mL of ether. The extract was washed with 50 mL of sat'd NaCl, dried and concentrated. The crude ketone in 10 mL of MeOH at 0° C. was treated with 110 mg (2.2 mmol) of NaBH4 and the resulting mixture was stirred cold for 30 min. The reaction was quenched with 5 mL of 1.0 N NAOH. The quenched mixture was partitioned between 100 mL of ether and 25 m of H2O and the layers were separated. The organic layer was dried; the aqueous layer was extracted with 100 mL of ether, the extract dried and the organic layers combined and concentrated. Flash chromatography on 40 g of silica gel using 3:2 v/v hexanes/ether as the eluant afforded 566 mg (37%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[N:4]([CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[N:8](C(=O)C(F)(F)F)[C@@H:7]([CH:25]2[CH2:27][CH2:26]2)[CH2:6]1.O1CCCC1.[OH-].[Li+].O>CO>[F:38][C:35]([F:36])([F:37])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:41])([F:42])[F:40])[CH:32]=1)[CH2:28][N:4]([C:3]([O:2][CH3:1])=[O:43])[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[NH:8][C@@H:7]([CH:25]2[CH2:27][CH2:26]2)[CH2:6]1
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)C(F)(F)F)c2ccc(C(F)(F)F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)Nc2ccc(C(F)(F)F)cc21
Reaction time: 2 h
Yield: 97.1 %

Procedure:
cis-(3,5-Bis-trifluoromethyl-benzyl)-(2-cyclopropyl-1-trifluoroacetyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid methyl ester (Example 47) (900 mg, 1.41 mmol) was dissolved in 20 mL of methanol and 60 mL of tetrahydrofuran before adding lithium hydroxide (1.6 mL of 1.0M aqueous solution, 1.6 mmol) to the solution. After 2 h at room temperature, 100 mL of water was added and the mixture extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with 50 mL of brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title product (740 mg) as a colorless solid which was used without further purification. MS m/z 542 (M+2)+; 1H NMR (CDCl3) δ 0.2 (m, 2H), 0.55 (m, 2H), 0.8 (m, 1H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25].N1C=CC=[CH:37][CH:36]=1.Cl>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([O:22][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:25])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:36][CH3:37]
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Reactant: CCCCCCCCOC(=O)Cl
Reactant: c1ccncc1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCOc1ccc(-c2ncc(OC(=O)OCCCCCCCC)cn2)cc1
Reaction time: 8 h

Procedure:
(1.7 g) was hydrogenated in the presence of Pd-C and potassium carbonate in 1,4-dioxane at normal pressure to yield 2-(4-octyloxyphenyl)-5-hydroxypyrimidine (F). (F) (1.0 g) was dissolved in 50 ml of carbon tetrachloride. 0.8 ml of octyl chlorocarboxylate and 5 ml of pyridine were added, and the mixture was stirred for a while and then allowed to stand overnight. 1N hydrochloric acid was added thereto, and the carbon tetrachloride layer was taken and concentrated. The resulting residue was purified by repeated recrystallization from methanol to obtain 2-(4-decyloxyphenyl)-5-octyloxycarbonyloxypyrimidine (A).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[CH2:19][NH:18]/[C:17](=[N:20]\[C:21]([C:23]2[C:28]([NH2:29])=[N:27][C:26]([NH2:30])=[C:25]([Cl:31])[N:24]=2)=[O:22])/[NH:16]1)C1C=CC=CC=1.I[Si](C)(C)C.CO>C(Cl)Cl>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]1[CH2:19][NH:18]/[C:17](=[N:20]\[C:21]([C:23]2[C:28]([NH2:29])=[N:27][C:26]([NH2:30])=[C:25]([Cl:31])[N:24]=2)=[O:22])/[NH:16]1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCCNC(=O)OCc3ccccc3)N2)nc1Cl
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CO
Product: NCCCC[C@H]1CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a suspension of (4-{(S)-2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-imidazolidin-4-yl}-butyl)-carbamic acid benzyl ester (Ex. 5) (0.110 g, 0.239 mmol) in dry DCM (20 ml) is added iodotrimethylsilane (0.130 ml, 0.956 mmol). The reaction mixture is stirred at room temperature for 3.5 hours. MeOH is added to the suspension yielding a solution. Purification by catch and release resin (SCX-2) eluting with MeOH and 7 M NH3 in MeOH yields the title compound as a brown oil; [M+H]+ 327.1