Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].N#N>O.C(Cl)Cl>[C:17](=[O:18])([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[O:19][CH2:20][CH3:21]
Reactant: CCOC(=O)Cl
Reactant: O=Cc1ccc(O)cc1
Agent: N#N
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Oc1ccc(C=O)cc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a 250 mL dry round bottom flask were added 4-hydroxybenzaldehyde (6.11 g, 50.0 mmol), anhydrous CH2Cl2 (150 mL). The solution was cooled in an ice-water bath, then pyridine (4.86 mL, 60.0 mmol) was added. To the resulting solution, ethyl chloroformate (4.78 mL, 50.0 mmol) was added slowly under stirring and N2. The mixture was stirred and warmed to room temperature, then stirred at room temperature overnight. To the reaction mixture, water (100 mL) was added and the CH2Cl2 layer was separated. The aqueous layer was extracted continually with CH2Cl2 (100 mL×2). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give ethyl 4-formylphenyl carbonate (8.92 g) as colorless oil. Yield: 92%. 1H NMR (CDCl3, 300 MHz): δ=10.07 (s, 1H), 8.00 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 4.42 (q, J=7.2 Hz, 2H), 1.47 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz): δ=191.0, 155.7, 152.9, 134.2, 131.4, 121.9, 65.4, 14.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:12][N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[O:33][C:34]=3[CH3:35])=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A mixture of ethyl 3-[3-benzyloxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (380 mg), 1 N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (3 ml), and ethanol (3 ml) was stirred at room temperature for one hour, and then diluted with 1 N hydrochloric acid (5 ml) to give colorless crystals, which were collected by filtration. This was recrystallized from ethyl acetate-hexane, to yield 3-[3-benzyloxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (300 mg, yield: 83%). Melting point: 108–109° C.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:25])[C:19]3C=CC=CC=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+]>C(O)C>[C:18]([N:15]1[CH2:16][CH2:17][CH:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH2:1])[N:11]=2)[CH2:13][CH2:14]1)(=[O:25])[CH3:19]
Reactant: Nc1nc(C2CCN(C(=O)c3ccccc3)CC2)c2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1CCC(c2nc(N)nc3ccccc23)CC1
Yield: 66.8 %

Procedure:
A mixture of 2-amino-4-(1-benzoyl-4-piperidinyl)quinazoline (24 g, 0.072 mol) obtained in Example 8 (3), ethanol (250 ml) and 6N sodium hydroxide aqueous solution (250 ml) was refluxed for about 7 hours under a nitrogen atmosphere. Thereafter ethanol was removed from the reaction mixture in vacuo. The residue was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride aqueous solution, and then dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from isopropyl alcohol to give 13.0 g of the titled compound.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:23]=[C:22]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=4)[N:21]=3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[ClH:37]>O1CCOCC1>[ClH:37].[ClH:37].[CH3:36][O:35][C:32]1[CH:31]=[CH:30][C:29]([C:22]2[N:21]=[C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:7][NH:6][CH2:5]4)[CH:19]=3)[N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH:23]=2)=[CH:34][CH:33]=1
Reactant: COc1ccc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C(=O)OC(C)(C)C)C4)c3)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-(cyanomethyl)-3-(4-(7-(4-methoxyphenyl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (1.60 g, 3.30 mmol) was suspended in 20 mL of 1,4-dioxane and then HCl (41.2 mL, 165 mmol) (4 M in dioxane) was added in one portion. The reaction was stirred at ambient temperature overnight, then concentrated under reduced pressure to afford the crude material, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[C:32]([NH:31][C:27]1[CH:26]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:12]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:20][CH2:21]2)[CH:30]=[CH:29][CH:28]=1)(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCC3)CC2)c1

Procedure:
Example 106 was prepared from 1-(4-chlorophenyl)cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 2H), 7.32–7.23 (m, 6H), 6.95 (d, 1H, J=7.6 Hz), 6.53 (br s, 1H), 3.29 (dd, 2H, J=6.0, 12.4 Hz), 2.93 (d, 2H, J=10.8 Hz), 2.86–2.79 (m, 2H), 2.48–2.41 (m, 3H), 2.37–2.30 (m, 4H), 2.07 (m, 1H), 1.98–1.61 (m, 11H), 1.01 (t, 3H, J=7.6 Hz); ESMS m/e: 496.3 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].II.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22]>C1COCC1>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCBr
Reactant: O=CCCCCCCCCCCCBr
Agent: II
Solvent: C1CCOC1
Product: CCCCCC(O)CCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-bromopentane (2.54 ml, 20.51 mmol) in THF (5 ml) was added dropwise to a stirred suspension of Mg metal (0.54 g, 22.23 mmol) and a catalytic amount of iodine in dry THF (15 ml) at 75° C., after which stirring was continued for another 30 minutes. The generated Grignard reagent was cooled to room temperature and added slowly to a stirred solution of 12-bromododecanal (4.5 g, 17.09 mmol) in THF (40 ml) at 0° C. The reaction was warmed to room temperature and stirring continued another 1.5 hours, then quenched with NH4Cl solution, and extracted with EtOAc (3×50 ml). The combined organic layers were washed with brine solution, dried on MgSO4 and concentrated. The crude compound was purified over silica gel column (8% EtOAc in hexane) to give 17-bromoheptadecan-6-ol as an off-white low melting solid (3.34 g, 58%).
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH:4]([CH3:14])[CH:5]([CH:11]([CH3:13])[CH3:12])[C:6]([O:8]CC)=[O:7].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]([Cl:15])=[CH:3][CH:4]([CH3:14])[CH:5]([CH:11]([CH3:12])[CH3:13])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C(C)C)C(C)C=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(C(=O)O)C(C)C=C(Cl)Cl
Yield: 82.1 %

Procedure:
A solution of 23.41 g (0.0925 mol) of ethyl 5,5-dichloro-3-methyl-2-isopropyl-4-pentenoate, 11.10 g (0.278 mol) of sodium hydroxide, 40 ml of water, and 40 ml of ethanol was refluxed for 3 days under N2, the solvent was concentrated on the rotary evaporator, the residue taken up in 300 ml of water and extracted 2× with ether. The aqueous layer was acidified with conc. HCl, then extracted 3× with 150 ml of ether. The combined ether extracts were washed with water, dried (MgSO4), and stripped to give 17.09 g (82% yield) of the desired acid.
Reaction SMILES: [OH:1][CH:2]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>CCOCC>[CH2:13]([N:12]([CH2:11][CH:2]([OH:1])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCNCC(O)CNCCCCCC
Reactant: O=C1CCC(=O)O1
Solvent: CCOCC
Product: CCCCCCCCCCCCN(CC(O)CN(CCCCCC)C(=O)CCC(=O)O)C(=O)CCC(=O)O
Yield: 103.8 %

Procedure:
A reactor was charged with 20 g (0.053 mole) of 9-hydroxy-7,11-diaza-tricosane, 13 g (0.130 mole) of succinic anhydride and 300 ml of anhydrous ether, and the contents were refluxed for 5 hours. After completion of a reaction, insoluble succinic anhydride in an excess amount was removed by filtration, and an ether layer was washed with water. The ether was distilled off under reduced pressure, thereby obtaining 30 g (0.055 mole) of 4-dodecyl-8-hexyl-3,9-dioxo-6-hydroxy-4,8-diaza-1,11-undecanedicarboxylic acid as a viscous transparent liquid. After adjusted to pH 10 with sodium hydroxide, this compound gave a single peak in HPLC measurement [column: RP-18 (product of Merck Co.), eluent: methanol/water=80/20]. The 1 H-NMR data of the compound will be shown below.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]([CH:17]=[O:18])[NH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3]1=[O:21].[CH3:22][N:23]1C2=CNC(C3C=C(C=CC=3)C#N)=C2C(=O)N(C)C1=O>>[CH:17]([C:8]1[NH:9][C:10]([C:11]2[CH:16]=[C:15]([CH:14]=[CH:13][CH:12]=2)[C:22]#[N:23])=[C:6]2[C:5](=[O:19])[N:4]([CH3:20])[C:3](=[O:21])[N:2]([CH3:1])[C:7]=12)=[O:18]
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]cc2n(C)c1=O
Reactant: Cn1c(=O)c2c(-c3ccccc3)[nH]c(C=O)c2n(C)c1=O
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)[nH]c(C=O)c2n(C)c1=O

Procedure:
The title compound was prepared in a similar manner to 1,3-dimethyl-2,4-dioxo-5-phenyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidine-7-carbaldehyde (Intermediate Na), starting from 3-(1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9.0 Step 4) and omitting step 1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CO>[F:24][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:22]=[C:21]([F:23])[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCc2cc(F)cc(F)c2)CC1
Agent: Cl
Solvent: CO
Product: Fc1cc(F)cc(CCCC2CCNCC2)c1
Yield: 70 %

Procedure:
A solution of 1-t-butoxycarbonyl-4-(3-(3,5-difluorophenyl)propyl)piperidine (from EXAMPLE 95, Step D) in 2.0 N HCl in MeOH was stirred at rt for 20 h. The solution was concentrated. Ether was added and the mixture was concentrated to remove excess HCl to afford 381 mg (70% yield from EXAMPLE 95, Step C) of the title compound: 1H NMR (500 MHz, CD3OD) δ 1.32-1.37 (4H), 1.64-1.68 (1H), 1.94 (d, J=14.2, 2H), 2.64 (t, J=7.3, 2H), 2.95 (t, J=13.1, 2H), 3 35 (d, J=12.6, 2H), 6.69-6.78 (m, 1H). 6.80 (d, J=8.2, 2H).
Reaction SMILES: [F:1][CH2:2][CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1>ClCCl.O=[Mn]=O>[F:1][CH2:2][CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[O:11])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC(CF)c1ccc(CO)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CF)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 81.5 %

Procedure:
dioxomanganese (4.455 g, 886.4 μL, 51.24 mmol) was added to a stirred solution of tert-butyl N-[2-fluoro-1-[4-(hydroxymethyl)phenyl]ethyl]carbamate (1.15 g, 4.270 mmol) in dichloromethane (100 mL) and the reaction allowed to stir at ambient temperature for 65 hours. The reaction mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated in vacuo to give tert-butyl N-[2-fluoro-1-(4-formylphenyl)ethyl]carbamate as a colourless oil (930 mg, 82%). 1H NMR (400.0 MHz, DMSO-d6) δ 1.37 (s, 9H), 4.43-4.46 (m, 1H), 4.54-4.58 (m, 1H), 4.95-5.05 (m, 1H), 7.60 (d, 2H), 7.81 (d, 1H), 7.90 (d, 2H) and 10.00 (s, 1H) ppm; LC/MS m/z 212.0 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH:12](OC)(OC)OC.S(=O)(=O)(O)O>CO>[CH3:12][O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=1)[OH:11]
Reactant: COC(OC)OC
Reactant: O=C(O)c1cc(I)ccc1O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(I)ccc1O

Procedure:
5-Iodosalicylic acid (Aldrich Chemical Company, Milwaukee, Wis.) is converted to the methyl ester by reaction with methanol, trimethyl orthoformate and sulfuric acid. The 5-iodosalicylic acid methyl ester thus obtained is reacted with (trimethylsilyl)acetylene (Aldrich Chemical Company, Milwaukee, Wis.) in the presence of palladium. The trimethylsilyl group is removed and two equivalents of the resultant 5-acetylenylsalicylic acid methyl ester is reacted with 4,4'-dibromobiphenyl (Aldrich Chemical Company, Milwaukee, Wis.) in the presence of palladium as above. The resultant alkynyl analogue of Chrysamine G, 4,4'-bis(3-methoxycarbonyl-4-hydroxyphenylacetylenyl)-biphenyl is prepared by hydrolysis of the ester as described above.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[CH3:31])[NH:27][N:26]=[CH:25]2>>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][C:30]=3[CH3:31])[NH:27][N:26]=[CH:25]4)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: Cc1cc2[nH]ncc2cc1N
Product: Cc1cc2[nH]ncc2cc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 13) and 5-amino-6-methylindazole (Bionet), the title compound was obtained as an off-white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N(C(C)C)CC)(C)C.[NH:22](C(OC(C)(C)C)=O)[CH2:23][C:24]([O:26]N1C(=O)CCC1=O)=[O:25]>ClCCl>[NH2:22][CH2:23][CH:24]([OH:26])=[O:25].[ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH-:10])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: [NH-]Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Nitrobenzylamine hydrochloride (1 g; 5.3 mmol) and diisopropylethylamine (1.8 ml; 10.6 mmol) were dissolved in 70 ml of dichloromethane at RT. BOC-Gly-OSu (1.44 g; 5.3 mmol) was added and the solution was stirred at RT overnight. After evaporating the solvent in a rotary evaporator, the residue was taken up in 50 ml of ethyl acetate and extracted in each case 2× with 5% KHSO4, 5% NaHCO3 and distilled water. The organic phase was dried over Na2SO4, the solvent was evaporated and toluene was then added and evaporated in a rotary evaporator. The resultant oil was dissolved, without further work-up, directly in 15 ml of 4M HCl/dioxane and stirred at RT. After a short time, the product starts to precipitate. After 1 h, the solvent was evaporated, the solid was suspended in 100 ml of ethyl acetate, filtered off and washed with petroleum ether. The white solid was dried under vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]#[CH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22]/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]>>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:24]=[CH:23][CH2:22][N:11]([CH2:12][C:13]#[CH:14])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: C#CCNS(=O)(=O)c1ccc(C)cc1
Reactant: Clc1ccccc1/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCN(CC=Cc1ccccc1Cl)S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To an oven-dried, 100 mL three-necked round-bottomed flask equipped with a stir bar, two septa and a nitrogen inlet adaptor was added 4-methyl-N-(prop-2-yn-1-yl) benzenesulfonamide (S17) (1.0 g, 4.8 mmol) and potassium carbonate (2.69 g, 19.2 mmol). The flask was evacuated and refilled with nitrogen three times, then MeCN (60 mL) was added. (E)-1-(3-Bromoprop-1-en-1-yl)-2-chlorobenzene (S14) (1.66 g, 7.2 mmol) was added dropwise via syringe, turning the solution dark yellow. The mixture was heated at reflux and stirred overnight. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:9). The solvent was removed in vacuo, and the reaction residue was taken up in sat'd NaHCO3 solution (70 mL) and extracted with ether (3×50 mL). The combined organic layers were washed with brine (70 mL), dried over Na2SO4, gravity filtered, and concentrated under reduced pressure. The reaction residue was purified by silica gel flash chromatography, eluting with AcOEt/n-hexane 1:9, to provide 1.35 g of the title compound as a light yellow solid in a 78% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:12][CH:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)NN=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH:11]2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(C2=NNC(c3cccs3)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc(C2CC2c2cccs2)c1
Temperature: 250 °C
Yield: 81.2 %

Procedure:
To a 250 ml round bottom flask equipped with nitrogen inlet, thermometer, and reflux condenser was charged 5.0 g (0.0205 moles) of 3-(3-hydroxyphenyl)-5-(2-thienyl)-2-pyrazoline, and 5.0 g of powdered sodium hydroxide. The two solids were mixed thoroughly, then heated slowly to 250° C., under a rapid stream of nitrogen. The reaction mixture was heated continuously at 250° C. for a total of 2 hours, then cooled to ambient temperature. The resulting residue was the dissolved in 200 mls of water, then acidified to pH 2 with 1 N aqueous hydrochloric acid. The acidic solution was extracted with 3×100 mls of ethyl ether, and the ether extract was washed with 2×100 mls of water, and 100 mls of saturated aqueous sodium chloride solution. The ether extract was the dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure with a rotary evaporator at 45° C. The resulting crude product was chromatographed on silica gel with a 15% ethyl acetate, 85% hexane mobile phase. The pure fractions were combined and concentrated under reduced pressure on a rotary evaporator to afford 3.6 g of the title compound 1-(3-hydroxyphenyl)-2-(2-thienyl)cyclopropane as a pale yellow liquid. 84% yield
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:37][C:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[C:42]([C:47]4[C:52]([F:53])=[CH:51][C:50]([CH2:54][O:55][CH3:56])=[CH:49][C:48]=4[F:57])[N:41]=3)=[O:39])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C@@H:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:16]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.C1COCC1.[OH-].[Na+]>CO>[Si:22]([O:21][C@@H:17]1[C@@H:18]([CH3:20])[CH2:19][N:14]([C:13]2[C:12]([NH:37][C:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[C:42]([C:47]4[C:52]([F:53])=[CH:51][C:50]([CH2:54][O:55][CH3:56])=[CH:49][C:48]=4[F:57])[N:41]=3)=[O:39])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15][C@H:16]1[NH:29][C:30](=[O:31])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])([C:25]([CH3:28])([CH3:26])[CH3:27])([CH3:24])[CH3:23]
Reactant: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C3)CCC4O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the amide intermediate prepared as described above THF (5 mL), MeOH (5 mL) and 1.0 M aq. NaOH (5 mL, 5 mmol) were added. The mixture was stirred at room temperature for 20 min. The volatile organic solvents were removed under reduced pressure. The residue was extracted with EtOAc (2 times). The combined organic phases were then washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give an alcohol intermediate, tert-butyl ((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[O:17][CH2:18][C:19]2([N:37]=1)[C:28]1([CH2:31][O:30][CH2:29]1)[CH2:27][O:26][C:25]1[C:20]2=[CH:21][C:22]([C:32]#[C:33][CH2:34][O:35][CH3:36])=[CH:23][CH:24]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CCO>[CH3:36][O:35][CH2:34][CH2:33][CH2:32][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[O:26][CH2:27][C:28]1([CH2:31][O:30][CH2:29]1)[C:19]12[CH2:18][O:17][C:16]([N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:37]1
Reactant: COCC#Cc1ccc2c(c1)C1(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1)C1(COC1)CO2
Agent: [Pd]
Solvent: CCO
Product: COCCCc1ccc2c(c1)C1(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1)C1(COC1)CO2
Reaction time: 13 h
Yield: 99.9 %

Procedure:
A mixture of di-tert-butyl[6′-(3-methoxyprop-1-yn-1-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (34.7 mg, 0.067 mmol) and 10% palladium on carbon (7 mg) in EtOH (1.4 mL) was stirred for 13 hours under a hydrogen atmosphere (4.5 kgf/cm2). The mixture was filtered off, and the filtrate was evaporated to give crude di-tert-butyl [6′-(3-methoxypropyl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (34.7 mg).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]=[CH:13][C:14]([F:17])([F:16])[F:15])(=O)=O)=CC=1.[F:19][C:20]([F:30])([F:29])[CH2:21][CH2:22][S:23]([CH2:26][C:27]#[N:28])(=[O:25])=[O:24].[H-].[Na+].Cl>O1CCCC1>[F:15][C:14]([F:17])([F:16])[CH:13]=[CH:12][CH2:11][CH:26]([S:23]([CH2:22][CH2:21][C:20]([F:19])([F:29])[F:30])(=[O:24])=[O:25])[C:27]#[N:28]
Reactant: Cc1ccc(S(=O)(=O)OCC=CC(F)(F)F)cc1
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CC=CC(F)(F)F)S(=O)(=O)CCC(F)(F)F
Reaction time: 24 h
Yield: 51.5 %

Procedure:
To a solution of 1.7 g of 4,4,4-Trifluoro-2-butenyl p-toluenesulfonate and 1.2 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 30 ml of tetrahydrofuran, 0.2 g of sodium hydride (60% in oil) was added at room temperature, and stirred at the same temperature for 1 day. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.95 g of 6,6,6-trifluoro-2-(3,3,3-trifluoropropylsulfonyl)-4-hexenenitrile (hereinafter referred to as the present compound (19)).