Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12].OS(O)(=O)=O.[CH2:19](O)[CH3:20]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/c1ccc(Cl)cc1Cl

Procedure:
To a stirred solution of (2E)-3-(2,4-Dichlorophenyl)acrylic acid (10 g, 46 mmol) in ethanol (60 ml) was added conc. H2SO4 (2.5 ml). The mixture was heated to reflux and for 48 H, then allowed to cool, concentrated in vacuo, dissolved in ethyl acetate, washed three times with 4N NaOH, dried over sodium sulfate and concentrated in vacuo to afford ethyl (2E)-3-(2,4-dichlorophenyl)acrylate (10.7 g) as pale brown crystals. 1H NMR δ (ppm)(CDCl3): 8.00 (1 H, d, J=16.1 Hz), 7.55 (1 H, d, J=8.5 Hz), 7.44 (1 H, d, J=1.9 Hz), 7.26 (1 H, dd, J=2.0, 8.4 Hz), 6.41 (1 H, d, J=16.1 Hz), 4.28 (2 H, q, J=7.1 Hz), 1.34 (3 H, t, J=7.1 Hz).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][NH:12][CH:13]=[C:9]3[C:8](=[O:14])[N:7]([CH3:15])[C:6]2=[O:16])[CH2:3][CH2:2]1.[Br:17]N1C(=O)CCC1=O.O>ClCCCl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:17][C:13]1[NH:12][N:11]=[C:10]2[C:9]=1[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5]2[CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c(=O)c2c[nH]nc2n(CC2CC2)c1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClCCCl
Product: Cn1c(=O)c2c(Br)[nH]nc2n(CC2CC2)c1=O
Yield: 82.2 %

Procedure:
7-(Cyclopropylmethyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (6.0 g), N-bromosuccinimide (7.8 g), and 100 mg of AIBN was taken up in 50 mL of 1,2-dichloroethane. The heterogeneous mixture was brought to reflux overnight. Water (100 mL) was added to the solution and separated. The organic layer was dried over sodium sulfate, filtered and removed under reduced pressure to give a yellow solid. The compound was flashed through a plug of silica gel, gave 6.7 g of white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([C:17]([OH:19])=O)[CH2:12][CH:11]1[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:26]C=2C=1.CN1CCOCC1.C(Cl)CCl>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1([C:17](=[O:19])[NH2:26])[CH2:12][CH:11]1[CH2:13][CH:14]([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isobutyl-cyclopropanecarboxylic acid (5.2 g, 19.2 mmol) in dry THF (190 mL) was added HOBt (2.85 g, 21.1 mmol), NMM (2.32 mL, 21.1 mmol) and EDC (4.0 g, 21.1 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours and quenched with concentrated ammonium hydroxide (16 mL). The reaction mixture was stirred at room temperature overnight. Excess of solvent was removed in vacuo and the residue was dissolved in EtOAc (200 mL). The organic layer was washed with 1N HCl, aqueous NaHCO3, brine and dried over Na2SO4. Evaporation of excess of solvent gave 3.5 g (69%) of (1-carbamoyl-2-isobutyl-cyclopropylmethyl)-carbamic acid tert-butyl ester as a colorless oil: 1H NMR (300 MHz, CD3OD) & 0.61 (dd, J=4.2, 6.5 Hz, 1H), 0.94 (d, J=5.0 Hz, 3H), 0.96 (d, J=5.0 Hz, 3H), 1.20 (m, 1H), 1.29 (dd, J=3.9, 8.7 Hz, 1H), 1.44 (s, 9H), 1.51 (m, 2H), 1.65 (m, 1H), 3.20 (d, J=15.2 Hz, 1H), 3.54 (d, J=15.2 Hz, 1H); 13C (75 MHz, CD3OD) δ 21.5, 23.2, 23.6, 27.4, 29.3, 30.3, 30.4, 39.3, 41.8, 80.9, 159.3, 179.9; MS (APCI) m/z271 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].CC1C=C(C)[N:8]([C:12](N)=[NH:13])N=1.C(N(C(C)C)CC)(C)C.[NH2:24][CH2:25][CH2:26][NH:27][C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=2)[C:31]([C:42]([NH2:44])=[O:43])=[CH:30][N:29]=1.C1COCC1>C(OCC)(=O)C.O>[N+:1]([O-:4])([OH:3])=[O:2].[NH:24]([CH2:25][CH2:26][NH:27][C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[CH:36]=2)[C:31]([C:42]([NH2:44])=[O:43])=[CH:30][N:29]=1)[C:12]([NH2:13])=[NH:8]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: Cc1cccc(Nc2nc(NCCN)ncc2C(N)=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(Nc2nc(NCCNC(=N)N)ncc2C(N)=O)c1
Temperature: 60 °C

Procedure:
A 508 mg portion of 3,5-dimethylpyrazole-1-carboxamidine nitrate and 876 μl of diisopropylethylamine were added to a mixture of 328 mg of 2-(2-aminoethylamino)-4-(3-methylanilino)pyrimidine-5-carboxamide and THF, followed by stirring at 60° C. for one week. Water and ethyl acetate were added to the reaction mixture, and the water layer was concentrated under a reduced pressure. The resulting residue was washed with a mixed solution of methanol and ethyl acetate and then recrystallized from a mixed solvent of methanol and water to obtain 200 mg of 2-[(2-guanidinoethyl)amino]-4-(3-methylanilino)pyrimidine-5-carboxamide nitrate as colorless crystals.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]([CH2:34][CH3:35])[C:23]3[C:28]([C:29]=2[C:30]#[N:31])=[CH:27][CH:26]=[C:25]([O:32][CH3:33])[CH:24]=3)=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[C:30]([C:29]1[C:28]2[C:23](=[CH:24][C:25]([O:32][CH3:33])=[CH:26][CH:27]=2)[N:22]([CH2:34][CH3:35])[C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][NH:11][CH:8]=[O:10])=[CH:16][CH:17]=1)#[N:31]
Reactant: O=CO
Reactant: CCn1c(-c2ccc(OCCN)cc2)c(C#N)c2ccc(OC)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCn1c(-c2ccc(OCCNC=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 86 %

Procedure:
Acetic anhydride (700 μL) and 98% formic acid (280 μL) are heated at 65° C. for 1 h. This is cooled to 0° C. 2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, is taken up in THF (400 μL), and added to the mixed anhydride. This is stirred at 0° C. for 45 minutes. The mixture is then portioned between EtOAc and aqueous NaHCO3. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CH2Cl2/acetone) yields N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]-ethyl}formamide (28 mg, 86%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:12]([C:13](Cl)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)[N:4]=1.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>>[F:1][C:2]([F:21])([F:20])[C:3]1[C:12]([C:13]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)[N:4]=1
Reactant: CC(C)c1ccc2nc(C(F)(F)F)c(C(=O)Cl)c(O)c2c1
Reactant: Nc1nccs1
Product: CC(C)c1ccc2nc(C(F)(F)F)c(C(=O)Nc3nccs3)c(O)c2c1

Procedure:
Using the procedure of Step F of Example 1, the product of Step F and 10 g of 2-amino-thiazole were reacted to obtain after crystallization from isopropanol 9.64 g of 2-trifluoromethyl-6-isopropyl-4-hydroxy-N-(2-thiazolyl)-3-quinolinecarboxamide melting at 262° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=O)=[CH:7][CH:6]=1.[CH3:21][C:22]1([CH3:31])[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][C:24](=O)[CH2:23]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[C:24]2[CH2:25][C:26]([CH3:29])([CH3:28])[CH2:27][C:22]([CH3:31])([CH3:21])[CH2:23]2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
To a stirred suspension of zinc powder (1.67 g, 25.45 mmol) in THF (60 mL) was slowly added TiCl4 (1.40 mL, 12.72 mmol) via syringe at room temperature under a nitrogen atmosphere. The mixture was heated at reflux for 2 h. A solution of methyl {4-[(4-hydroxyphenyl)carbonyl]phenyl}acetate (152) (0.86 g, 3.18 mmol) and 3,3,5,5-tetramethyl cyclohexanone (1.50 g, 9.55 mmol) in THF (20 mL) was added to the mixture. The reaction mixture was heated at reflux with stirring under a nitrogen atmosphere for 1.5 h. The reaction mixture was allowed to cool to room temperature. To the reaction mixture was slowly added 10% aqueous K2CO3 (60 mL). The reaction mixture was filtered through a pad of Celite and the pad washed with EtOAc (150 mL). The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with EtOAc (50 mL). The combined organic phase washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 20% EtOAc:hexanes to give light brown oil, which upon adding hexanes solidified. The solid was triturated with hot hexanes to afford 0.90 g (72%) of 153 as a white solid. mp 154-155° C. 1H NMR (400 MHz, CDCl3): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.27 (s, 2H), 1.95 (s, 2H), 1.96 (s, 2H), 3.58 (s, 2H), 3.68 (s, 3H), 4.56 (br s, 1H), 6.72 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.1 Hz, 2H). LCMS (ESI): m/z 393 (M+H)+, 391 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@@H:10]2[O:15][CH2:14][C@H:13]3[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[ClH:28]>CC(O)C>[ClH:28].[F:9][C:8]1[C:3]([C:1]#[N:2])=[C:4]([CH3:27])[C:5]([C@@H:10]2[O:15][CH2:14][C@H:13]3[CH2:16][NH:17][CH2:18][CH2:19][N:12]3[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Cc1c([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO2)ccc(F)c1C#N
Agent: Cl
Solvent: CC(C)O
Product: Cc1c([C@H]2CN3CCNC[C@@H]3CO2)ccc(F)c1C#N
Temperature: 50 °C
Reaction time: 8 h

Procedure:
tert-butyl(3S,9aR)-3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1-17C) (158.8 g, 423.0 mmol) was suspended with 318 mL of 2-propanol. The resulting slurry was treated with HCl solution in 2-propanol (5.5 M, 1000 mL, 5499 mmol), and the mixture was heated to 50° C. for 2 hours. The mixture was concentrated to remove approximately 400 mL of 2-propanol, then was cooled to rt and agitated overnight. The mixture was filtered to collect the solid product and the wet cake was washed with 50 mL of 2-propanol. The filter cake was dried under vacuum for two days at 40° C. with nitrogen bleed to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C:12]1[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:14][CH:13]=1)=O)#[N:2].[OH:27]O.[OH-].[Na+]>C1COCC1.[Cl-].[Na+].O>[OH:27][C:1]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:9]=[C:10]([C:12]2[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[N:2]=1
Reactant: OO
Reactant: CCOP(=O)(Cc1ccc(C(=O)Nc2ccccc2C#N)cc1)OCC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOP(=O)(Cc1ccc(-c2nc(O)c3ccccc3n2)cc1)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Diethyl 4-[N-(2-cyanophenyl)carbamoyl]benzylphosphonate (11.2 g) was dissolved in 100 ml of THF and cooled with ice water. After adding 50 ml of a 30% hydrogen peroxide aqueous solution containing 1.2 g of sodium hydroxide dropwise, the reaction mixture was stirred at room temperature for 16 hours. Saturated brine (50 ml) was added, and the reaction mixture was extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 150 ml of ethanol and 20 ml of a 2N sodium hydroxide solution and stirred at room temperature for 6 hours. Saturated brine (150 ml) was added, and the reaction mixture was extracted with chloroform. The chloroform layer was dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was recrystallized with methylene chloride-diethyl ether to give 5.9 g of diethyl 4-(4-hydroxyquinazolin-2-yl)benzylphosphonate as colorless crystals.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].[OH-].[Na+].[C:8]([O:12][C:13]([O:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:14])([CH3:11])([CH3:10])[CH3:9]>O.O1CCOCC1>[C:13]([NH:5][CH2:4][CH2:3][Br:2])([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14].[C:19]([O:18][C:16]([O:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: NCCBr
Agent: Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCCBr
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
N-BOC-bromoethylamine was prepared as follows. 2-Bromoethylamine hydrobromide (6.15 g, 30 mmol) was dissolved in a mixture of 30 mL each water and dioxane and the solution was chilled in an ice bath to 0-5° C. Separately, a solution of 3.27 g (15 mmol) di-tert-butyl-dicarbonate in 35 mL dioxane was prepared. Finally a solution of 1 N sodium hydroxide (30 mL), was prepared. Dropwise addition of the di-tert-butyl-dicarbonate and the 1 N sodium hydroxide solutions to the stirred 2-bromoethylamine hydrobromide solution was begun at 0-5° C. The di-tert-butyl-dicarbonate addition took place over 30 min, and the 1N sodium hydroxide addition was complete after 15 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=3)[CH2:10][C@H:9]2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1.[CH3:24]I>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[N:15]([CH3:24])[N:14]=3)[CH2:10][C@H:9]2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(c2ccc(=O)[nH]n2)C[C@H]1c1ccc(Cl)cc1
Reactant: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CN(c2ccc(=O)n(C)n2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Methyl (3S,4R)-4-(4-chlorophenyl)-1-(6-oxo-1,6-dihydropyridazin-3-yl)pyrrolidine-3-carboxylate obtained in Step A of Preparation 22 was dissolved in DMF (5 ml). Cs2 CO3 (1.11 g, 3.41 mmol) was added, and methyl iodide (0.71 mL, 11.40 mmol) was added dropwise. The reaction mixture was stirred at 20-30° C. for 2 hours and concentrated in vacuo. The obtained residue was diluted with EtOAc, washed with water and purified by column chromatography (eluent: EtOAc/Hex=1/1) to give the title compound (0.55 g, 70%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(=O)(O)[O-].[Na+].[CH3:15][C@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1>CO>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:17]2[CH2:18][CH2:19][CH2:20][C@@H:16]2[CH3:15])[N:3]=1
Reactant: C[C@H]1CCCN1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CCCN1c1nc(Cl)cc(Cl)n1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Dissolve 2,4,6-trichloropyrimidine (23.5 g, 0.13 mol) in anhydrous MeOH (220 mL), and add solid sodium bicarbonate (28.3 g, 0.33 mol). Cool to 0° C. and add 2-(S)-methylpyrrolidine (12 g, 0.14 mol) dropwise. Let stir at room temperature for 16 h. Filter off the excess sodium bicarbonate, and evaporate under reduced pressure. Purify by SiO2 flash chromatography, using 50:1 hexanes:EtOAc, increasing to 30:1 hexanes:EtOAc, to provide the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12]>CO.[Pd]>[NH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=1[OH:12]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)c(F)c1O
Yield: 99.9 %

Procedure:
A solution of 2,3-difluoro-6-nitrophenol (500 mg) in methanol (7 ml) was hydrogenated over 5% Pd/C (60 mg) for 6 hours. The reaction mixture was filtered under nitrogen stream and the filtrate was evaporated under reduced pressure to give 414 mg of crude 2-amino-5,6-difluorophenol.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Cl:13][CH:14]([C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]>CN(C)C=O>[Cl:13][CH:14]([CH:19]([OH:28])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(Cl)C(=O)c1ccc(OC)cc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CN(C)C=O
Product: COC(=O)C(Cl)C(O)c1ccc(OC)cc1

Procedure:
In a test tube with an outer diameter of 15 mm, 0.25 g of a baker's yeast (Saccharomyces cerevisiae, manufactured by Oriental Kobo Kogyo K K ) was suspended in 3 ml of a McIlvaine buffer containing 0.54 g of glucose dissolved therein, and then 6 μl of dimethylformamide containing 6 mg of methyl 2-chloro-3-oxo-3-(p-methoxyphenyl)propionate was charged, followed by shaking reaction at 30° C. for 24 hours. When the reaction mixture was extracted with 2 ml of ethyl acetate and the amount of methyl 2-chloro-3-hydroxy-3-(p-methoxyphenyl)propionate formed was quantitated, it was found that 0.6 mg of the product was formed.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[C:15]([CH:54]=[CH:55][CH:56]=3)[CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]([N:23]([CH2:30][CH2:31][N:32]([CH2:40][CH2:41][C:42]3[C:47]4[O:48][CH2:49][C:50](=[O:52])[NH:51][C:46]=4[C:45]([OH:53])=[CH:44][CH:43]=3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Si:66](Cl)([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[O:1]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[C:15]([CH:54]=[CH:55][CH:56]=3)[CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]([N:23]([CH2:30][CH2:31][N:32]([CH2:40][CH2:41][C:42]3[C:47]4[O:48][CH2:49][C:50](=[O:52])[NH:51][C:46]=4[C:45]([O:53][Si:66]([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67])=[CH:44][CH:43]=3)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:36])[CH3:37])[CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22])[CH2:8][CH2:7]2)[CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CNCCO3)c1)C1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N(CCc1ccc(O[Si](C)(C)C(C)(C)C)c2c1OCC(=O)N2)CCN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CNCCO3)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-(3-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)phenethoxy)-N-cyclohexylpropanamido)ethyl(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethyl)carbamate [Examples 81-175, step h] (0.97 g) was dissolved in NMP (10 mL) and treated with Hunig's base (1.0 mL) followed by tert-butyldimethylsilyl chloride (0.45 g). The resulting mixture was stirred at room temperature for 3 hours. The solution was poured into saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined extracts were washed three times with water, once with brine, then dried (MgSO4) and concentrated onto flash silica (20 mL) in-vacuo. The resulting powder was purified by flash chromatography on silica eluted with triethylamine:methanol:dichloromethane (1:5:94) to afford the subtitled compound as a white foam. Yield 0.81 g.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]([C:8](=[NH:10])[NH2:9])[N:6]=O)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([NH2:6])[C:8](=[NH:9])[NH2:10])[CH3:2]
Reactant: CCOC(=O)C(N=O)C(=N)N
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(N)C(=N)N

Procedure:
To a solution of carbamimidoyl-nitroso-acetic acid ethyl ester (5.5 g, 31.4 mmol) in ethanol/5M HCl (1:1 ratio, 250 ml) was added 10% Pd/C (1.3 g). The reaction mixture was hydrogenated (H2(g)) at low pressure over 2 nights. The Pd/C was filtered through Celite® (filter material) and the filtrate reduced in vacuo to give the title compound as a white solid. This was taken through to the next step as crude.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25](S(C)(=O)=O)[N:24]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([O:14][C:25]2[N:26]=[C:27]([O:29][CH3:30])[CH:28]=[C:23]([O:22][CH3:21])[N:24]=2)[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(O)c1cccc(OC)c1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)c1cccc(OC)c1
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
8 g (230 mmol) Methyl 2-(3-methoxyphenyl)glycolate was dissolved in 100 ml dimethylformamide and treated with 2.8 g (20.4 mmol) potassium carbonate. After 20 minutes stirring, 8.8 g (40.7 mmol) 4,6-dimethoxy-2-methylsulphonylpyrimidine was added and the mixture heated for 1 hour at 90° C. The reaction mixture was then poured into 100 ml water and extracted with 100 ml ethyl acetate. The combined ethyl acetate phase was washed with water, dried over magnesium sulphate and evaporated. The residue was recrystallised from diisopropyl ether.
Reaction SMILES: [OH-].[Li+].[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[C@H:9]([NH:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:8][C@@H:7]1[CH3:36])(=[O:5])[CH3:4]>CO>[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[C@H:9]([NH:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:8][C@@H:7]1[CH3:36])(=[O:5])[CH3:4]
Reactant: CCOC(=O)CCc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(CCC(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
Lithium hydroxide (1N in water, 2 mL, 2.000 mmol) was added to a solution of ethyl 3-{4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}propanoate (for a preparation see Intermediate 101) (39.7 mg, 0.085 mmol) in methanol (5 mL). The reaction mixture was stirred at room temperature for 12 h then most of the solvent was removed in vacuo. The residue was partitioned between AcOEt (30 mL), water (20 mL) and glacial acetic acid (0.5 mL). The layers were separated and the organic layer was washed with brine (20 mL). The combined aqueous phases were extracted with AcOEt (20 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give 3-{4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}propanoic acid (35.8 mg, 0.082 mmol, 96%) as a white solid.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.N12CCN(CC1)CC2>C1C=CC=CC=1>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:14]2[C:15](=[O:16])[C:6]3([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]3)[NH:7][C:8]32[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:25])=[CH:19][CH:18]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: Cc1ccc(NC(=O)N2C(=O)C3(CCCCC3)NC23CCCCC3)cc1

Procedure:
3.33 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 2.19 parts of p-tolylisocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 150 parts of dry benzene were heated at reflux for 24 hours. The solvent was evaporated in vacuo to yield a solid material which was recrystallised from ethanol to give 4.2 parts of 14-p-tolylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one as colourless crystals of melting point 136° to 138°C. This material gave the following elemental analysis by weight: