Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][N:8]=[C:9]([C:25](OCC)([O:28]CC)[CH2:26][Br:27])[C:10]([NH:12][CH:13]1[C:23](=[O:24])[N:15]2[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11].O>C(C(C)=O)C(C)C>[CH3:6][O:7][N:8]=[C:9]([C:25](=[O:28])[CH2:26][Br:27])[C:10]([NH:12][CH:13]1[C:23](=[O:24])[N:15]2[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
70% Perchloric acid (0.54 ml) was added to a solution of 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 1 g) in methyl isobutyl ketone (4 ml) under ice-cooling, and stirred at the same temperature for 20 minutes. Water (4 ml) was added to the resultant mixture and stirred for 5 minutes. The precipiates were collected by filtration, washed with water and dried over phosphorus pentachloride in vacuo to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (shyn isomer, 502 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18]I>CN(C)C=O.O>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH3:18])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 39 g (14.3 mmol) of tert-butyl (6-bromopyrid-2-yl)carbamate in 400 ml of dimethylformamide are added portionwise 6.9 g (17.2 mmol) of 60% sodium hydride in oil. After stirring for 20 minutes at room temperature, 17.8 ml (28.6 mmol) of methyl iodide are added dropwise. The reaction medium is stirred at room temperature for 18 hours, taken up in water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated.
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[O:12][CH2:13][CH2:14]O)C=CC=CC=1.C(N(CC)CC)C.S(Cl)(C)(=O)=O.[Na].[NH:32]1[CH:36]=[CH:35][N:34]=[CH:33]1>C1COCC1.CO.[Pd]>[N:32]1([CH2:14][CH2:13][O:12][C:11]2[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][CH:16]=2)[CH:36]=[CH:35][N:34]=[CH:33]1
Reactant: c1c[nH]cn1
Reactant: OCCOc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Agent: CS(=O)(=O)Cl
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: Oc1cccc(OCCn2ccnc2)c1

Procedure:
A solution of 12.2 g (0.05 mole) 2-[3-(phenylmethoxy)phenoxy]ethanol and 5.6 g (0.555 mole) of triethylamine in 100 ml of THF was cooled to 0° C. with stirring and treated dropwise with 6.4 g (0.055 mole) of mesyl chloride over a 20-min period. The mixture was stirred at 10° C. or less for 1 hr, then filtered. The filtrate was combined with a slurry of 0.10 mole of imidazole sodium salt in 50 ml of THF and the mixture was heated at reflux for 8 hr. The 50 ml of THF and the mixture was heated at reflux for 8 hr. The cooled reaction mixture was filtered and the filtrate was partitioned between ethyl acetate/ether and water. The organic layer was concentrated to give 14.7 g (100%) of crude intermediate. This syrup (13.0 g) was dissolved in 100 ml of methanol and hydrogenated at 40° C. and 45 psi H2 using 1 g of 10% Pd/C catalyst. This mixture was filtered, and the filtrate was concentrated to give 9.0 g (100%) of crude, crystalline product. A portion was recrystallized from toluene/methyl isobutyl ketone to give the title compound as white crystals, mp 125.0° C.-127.0° C.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:13]3[CH:23]=[C:22]([F:24])[C:21]([O:25][CH3:26])=[CH:20][C:14]=3[S:15][C:16]=2[N:17]([CH3:19])[CH3:18])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H-].[Na+].[OH:29][CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C=O)C>[N:32]1([CH2:31][CH2:30][O:29][C:4]2[CH:5]=[CH:6][C:7]([C:10]([C:12]3[C:13]4[CH:23]=[C:22]([F:24])[C:21]([O:25][CH3:26])=[CH:20][C:14]=4[S:15][C:16]=3[N:17]([CH3:19])[CH3:18])=[O:11])=[CH:8][CH:9]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COc1cc2sc(N(C)C)c(C(=O)c3ccc([N+](=O)[O-])cc3)c2cc1F
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2sc(N(C)C)c(C(=O)c3ccc(OCCN4CCCC4)cc3)c2cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 220.5 %

Procedure:
A mixture of 2.0 g (5.34 mmol) of 2-dimethylamino-5-fluoro-6-methoxybenzo[b]thiophene-3-yl 4-nitrophenyl ketone (Part C) and 1.4 g (60% dispersion in mineral oil; 35.0 mmol; washed with hexanes) of NaH in 60 mL of DMF was treated with a solution of 3.75 mL (32.1 mmol) of 1-(2-hydroxyethyl)pyrrolidine in 10 mL of DMF in such rate to control the effervescence. After complete addition, the reaction was stirred at room temperature for 1 h and was quenched by the careful addition of 5 mL of MeOH. The mixture was diluted with 200 mL of EtOAc and was poured into 200 mL of H2O. The two layers were separated and the organic phase was washed with H2O (2×100 mL) and brine (100 mL). The organic phase was dried over K2CO3, filtered, and concentrated in vacuo to give 5.21 g of an amber oil. Purification by flash chromatography (SiO2; gradient of 2% then 5% MeOH in CH2Cl2) afforded 2.10 g (4.74 mmol; 89%) of the title compound as a bright yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[C:11](/[N:13]=[C:14](/[N:16](C)C)\[CH3:15])=O)=[N:8][C:4]=2[CH:3]=1.[NH2:29]N>C(O)(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[C:11]3[N:13]=[C:14]([CH3:15])[NH:16][N:29]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: C/C(=N\C(=O)c1ccccc1-c1nc2cc(Br)ccc2n1C(C)(C)C)N(C)C
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a round bottom flask is added 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-N-[1-dimethylamino-eth-(E)-ylidene]-benzamide (237 mg, 0.537 mmol) in glacial acetic acid (3 mL), followed by the addition of hydrazine (35% wt solution in water) (2 mL). The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with EtOAc, is washed with sat. NaHCO3, brine, dried under anhy. Na2SO4, filtered and concentrated. The residue is loaded to a silica gel column. The column is eluted with 0-3% 2M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford 5-bromo-1-tert-butyl-2-[2-(5-methyl-1H-1,2,4-triazol-3-yl)-phenyl]-1H-benzimidazole (78 mg, 35%) as a light brown solid. LCMS (ESMS): m/z 410.68, 412.71 (M++1)
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].N[CH2:34][C@H](O)C>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][C@H:16]([OH:17])[CH3:34])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: C[C@@H](O)CN
Reactant: Cc1ccc(C(=O)NCCO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Product: Cc1ccc(C(=O)NC[C@@H](C)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Yield: 58 %

Procedure:
The title compound was prepared by a procedure similar to the one described for (±) 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide using (R)-(−)-1-amino-2-propanol (0.98 mL, 12.45 mmol) as the amine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (2.70 g, 58%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 7.93 (dd, 1H, J=1.6 Hz), 7.69 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.56 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 3.94 (m, 1H), 3.39 (m, 2H), 2.18 (s, 3H), 2.13 (s, 3H), 1.9 (d, 3H, J=6.4 Hz); ES-HRMS m/z 478.1322 (M+H C23H23ClF2N3O4 requires 478.1340). Both (+) and (−) atropomers will be resolved and characterized.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]=[CH:8][N:7]([CH2:13][O:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])[C:6]=2[N:5]=[C:3]1[NH2:4].[C:20](Cl)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(Cl)Cl>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]=[CH:8][N:7]([CH2:13][O:14][CH:15]([CH2:18][O:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][O:17][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]=2[N:5]=[C:3]1[NH2:4]
Reactant: CCCCCCCC(=O)Cl
Reactant: Cn1c(N)nc2c(ncn2COC(CO)CO)c1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OCn1cnc2c(=O)n(C)c(N)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
1-Methyl-9-(1,3-dihydroxy-2-propoxymethyl) guanine (340 mg, 1.26 mmol) was suspended in dry DMF and dry pyridine (approximately 20 ml total) and evaporated to dryness. This process was repeated twice, the final time concentrating the suspension down to 10 ml. This suspension was cooled to 0°, under N2, and a solution of octanoyl chloride (822 mg, 5.05 mmol) in dry DMF (1 ml) was added. This reaction was stirred overnight at room temperature. Methylene chloride was then added and the mixture was extracted with saturated aqueous NaHCO3 solution. The organic phase was then washed three times with H2O, dried over MgSO4, filtered and evaporated to dryness. The residual oil was dissolved in CH2Cl2 and applied to a column of silica gel, packed in CH2Cl2. Elution was first performed with CH2Cl2 followed by 1% MeOH in CH2Cl2 (200 ml), 2% MeOH in CH2Cl2 (200 ml), 3% MeOH in CH2Cl2 (100 ml) and finally 5% MeOH in CH2Cl2 (100 ml). Fractions containing the required product were pooled and evaporated to dryness to give 529 mg of product. It was recrystallized from ether/petroleum ether. The PMR spectrum was in accord with the structure.
Reaction SMILES: [C:1]1([C:11](Cl)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][N:19]1[C:24](=[O:25])[C:23]2[CH:26]=[CH:27][S:28][C:22]=2[N:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:20]1=[O:33]>ClCCCl>[CH3:18][N:19]1[C:24](=[O:25])[C:23]2[CH:26]=[C:27]([C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)=[O:12])[S:28][C:22]=2[N:21]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:20]1=[O:33]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2ccsc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(=O)c3cccc4ccccc34)sc21
Temperature: 25 °C

Procedure:
1-Naphthoyl chloride (1.25 ml) was added under nitrogen to a stirred slurry of aluminium chloride (1.1 g) in 1,2-dichloroethane (10 ml). A solution of 3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidin-2,4(1H,3H)-dione (2.0 g) in 1,2-dichloroethane (10 ml) was added dropwise and the resultant mixture was heated under reflux for 24 h and then allowed to cool to ambient temperature. The reaction mixture was quenched by the careful addition of water (2 ml) and was then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed thrice with dilute hydrochloric acid, twice with saturated sodium hydrogen carbonate solution, and once with brine, then dried over magnesium sulfate and concentrated in vacuo. Purification by chromatography on silica gel eluting with toluene:ethyl acetate (9:1) gave the title compound (0.78 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[C:8]([CH3:13])[C:6]=2[N:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][OH:12])=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(CO)sc2c(N3CCOCC3)nc(Cl)nc12
Reaction time: 2 h

Procedure:
To a suspension of 2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (400 mg, 1.34 mmol) in methanol at 0° C. was added sodium borohydride. After stirring for 2 hours, the mixture was quenched with 50:50 H2O:NaHCO3(sat. aq). The methanol was removed under reduced pressure to give a suspension which was filtered and washed with H2O followed by ether to give (2-Chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH2:19][C:20]([F:23])([F:22])[F:21].C1C(=O)N([Br:31])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])=[CH:4][C:5]([C:8]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:31]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC(F)(F)F)c2)CCCC1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C1(c2cc(Br)c(N)c(OCC(F)(F)F)c2)CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (1.2 g, 4.0 mmol) in dry CCl4 (60 mL), NBS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude reaction mixture was purified by column chromatography to give ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclopentanecarboxylate (920 mg) as a yellow solid.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:3].[B-](F)(F)(F)F.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[N:33]=[N:34][N:35]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45](O)=[O:46])=[CH:39][CH:38]=3)[CH:36]=2)=[N:24]1.CCN(C(C)C)C(C)C.CNC>CN(C=O)C.C1COCC1>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[N:33]=[N:34][N:35]([C:37]3[CH:38]=[CH:39][C:40]([CH2:43][CH2:44][C:45]([N:2]([CH3:3])[CH3:1])=[O:46])=[CH:41][CH:42]=3)[CH:36]=2)=[N:24]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)CCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
TBTU (188 mg; 0.58 mmol; 1.3 eq.) was added to a cooled (0° C.) solution of 3-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}propanoic acid (150 mg; 0.45 mmol; 1.0 eq.) and DIEA (176 μl; 1.03 mmol; 2.3 eq.) in DMF (3 mL). After 10 min, dimethylamine (270 μl of a 2.00 M in THF; 0.54 mmol; 1.20 eq.) was added and the reaction mixture was stirred overnight at RT. The resulting solid was filtered off and purified by preparative HPLC to afford the title compound as a brown solid. 1H NMR (300 Mz, DMSO-d6) δ: 13.34 (brs, 1H), 9.26 (s, 1H), 8.36 (d, J=8.1 Hz, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.62-7.59 (m, 1H), 7.50 (d, J=8.5 Hz, 2H), 7.46-7.41 (m, 1H), 7.28-7.23 (m, 1H), 2.96 (s, 3H), 2.93-2.88 (m, 2H), 2.83 (s, 3H), 2.70-2.65 (m, 2H). HPLC (Condition A): Rt 3.23 min (purity 92.2%). MS (ESI+): 361.3, MS (ESI−): 359.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:22])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH3:23][NH2:24].O>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]2[CH2:12][C:11](=[O:22])[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:24]2[CH3:23])=[CH:15][CH:16]=1
Reactant: COc1ccc(C=CC(=O)C=Cc2ccc(OC)cc2)cc1
Reactant: CN
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2CC(=O)CC(c3ccc(OC)cc3)N2C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.9 %

Procedure:
1,5-Bis(4-methoxyphenyl)-1, 4-pentadien-3-one (20e, 0.40 g, 1.4 mmol) was dissolved in dimethyl formamide (10 ml). Methylamine (51, 0.75 ml, 8.7 mmol, 40% in water) was added and the mixture stirred for 24 hr at room temperature. The mixture was poured into water (50 ml) and stirred for 2 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to afford a solid that was recrystallized from ethanol to give 0.30 g (68%) of a white solid: mp 141-143° C. [expected mp 129-130° C.]; 1H NMR δ 1.77, (s, 3H), 2.45 (d, 2H, J=14.5 Hz), 2.78 (t, 2H, J=12.9 Hz), 3.33 (d, 2H, J=11.9 Hz), 3.79 (s, 6H), 6.88 (d, 4H, J=8.5 Hz), 7.32 (d, 4H, J=8.5 Hz); 13C NMR: δ 40.6, 50.9, 55.3, 69.5, 114.1, 128.0, 135.3, 158.9, 207.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH:7]([CH2:14][C:15]([OH:17])=O)[CH2:6][CH2:5]2.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH:7]([CH2:14][C:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17])[CH2:6][CH2:5]2
Reactant: C1CCNC1
Reactant: Cc1cc2c(cc1C)C(=O)C(CC(=O)O)CC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C)C(=O)C(CC(=O)N1CCCC1)CC2
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-6,7-dimethyl-1-oxo-2-naphthalene-acetic acid (8.0 g), pyrrolidine (3.8 g) and benzotriazol-1-yloxy-tris(dimethyl-amino) phosphonium hexafluorophosphate (BOP Reagent,16.7 g) in dichloro-methane (80 ml) was added dropwise triethylamine (3.8 g) at 25° C., and the mixture was stirred for three hours. The mixture was concentrated under reduced pressure to remove the solvent, and to the residue were added water and toluene, and the insoluble materials were removed by filtration. The toluene layer was collected, washed successively with 1N aqueous sodium hydroxide solution, water and a saturated aqueous sodium chloride solution, an dried over anhydrous sodium sulfate. The resultant was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent; toluene-ethyl acetate=10:1), and the fractions containing the desired compound were combined, and concentrated under reduced pressure to give the desired compound (9.5 g) as an oily product.
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][C:9]=2[S:11][CH3:12])[CH2:5][CH2:4][C:3]=1[CH:18]=[O:19].C(N(CC)CC)C.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:28][SH:29]>N1C=CC=CC=1>[CH2:32]([O:31][C:27]([CH2:28][S:29][C:2]1[C:10]2[C:6](=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:8][C:9]=2[S:11][CH3:12])[CH2:5][CH2:4][C:3]=1[CH:18]=[O:19])=[O:30])[CH3:33]
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(C=O)=C2Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)CSC1=C(C=O)CCc2c(C(=O)OCC)sc(SC)c21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80.9 %

Procedure:
To a mixture of ethyl 4-chloro-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (3.00 g), triethylamine (1.44 g) and pyridine (25 ml), ethyl thioglycolate (1.37 g) was added at 0° C., followed by stirring at 0° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure; the residue was poured over water and extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid and water in that order and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:7 to 1:5, v/v) to yield ethyl 4-ethoxycarbonylmethylthio-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (3.07 g, 81.0%), which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 102-103° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([O:52][Si](CC)(CC)CC)[CH2:16][CH:15]1[O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][CH:51]=[C:25]23)[CH2:20][CH2:19]1>C(OCC)(=O)C>[OH:52][C@:14]1([CH3:13])[CH2:16][C@H:15]1[O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:45][C:4](=[O:7])[O:5][N:3]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][CH:51]=[C:25]23)[CH2:20][CH2:19]1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC3CC3(C)O[Si](CC)(CC)CC)CC2)c2ccnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](O[C@@H]3C[C@@]3(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.56 g), sodium hydrogen carbonate (0.84 g) and dimethyl sulfoxide (3.5 mL) was stirred at 50° C. for 30 min, 4′-({4-[trans-4-({2-methyl-2-[(triethylsilyl)oxy]cyclopropyl}oxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.44 g) was added, and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 1.5 mL), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.82 g, 20%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([C:26]([N:28]1[CH2:32][CH2:31][C@H:30]([F:33])[CH2:29]1)=[O:27])[C@H:9]([CH:11]1[CH2:16][CH2:15][CH:14]([N:17](CC2C=CC=CC=2)[CH3:18])[CH2:13][CH2:12]1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-]>[F:33][C@H:30]1[CH2:31][CH2:32][N:28]([C:26]([C@@H:8]([NH:7][C:6](=[O:34])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C@H:9]([CH:11]2[CH2:16][CH2:15][CH:14]([NH:17][CH3:18])[CH2:13][CH2:12]2)[CH3:10])=[O:27])[CH2:29]1
Reactant: C[C@@H](C1CCC(N(C)Cc2ccccc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC1CCC([C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N2CC[C@H](F)C2)CC1

Procedure:
To a solution of the material prepared in Step B (0.18 g, 0.37 mmol) in methanol (100 mL) was added palladium(II) hydroxide (0.10 g). The mixture was placed under 3 atm of hydrogen at ambient temperature for 6 h, then filtered through Celite. The solution was concentrated in vacuo, affording the title compound as a clear oil. This material was used without further purification. LC/MS 386.3 (M+1).