Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O[C:17]1(O[Si](C)(C)C)[CH2:19][CH2:18]1)C.[BH3-]C#N.[Na+].[OH-].[Na+]>O.C(O)(=O)C.CO.C1COCC1>[CH:17]1([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:19][CH2:18]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(C2CC2)CC1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (75.0 g), THF (500 mL), methanol (500 mL), [(1-ethoxycyclopropyl)oxy]trimethylsilane (161 mL), NaBH3CN (38.0 g), and acetic acid (37 mL) was heated at 60° C. for 5 h. The mixture was cooled to room temperature, treated with water (30 mL) and stirred for 5 min. The mixture was then treated with 1 N NaOH (130 mL) and was further stirred for 15 min. The mixture was concentrated, and the remaining aqueous solution was extracted with CH2Cl2 (500 mL). The organic layer was washed with 1 N NaOH (500 mL). The combined aqueous layers were extracted with CH2Cl2 (150 mL). The combined organic layers were washed with brine (400 mL), dried (Na2SO4), and concentrated to yield the title compound as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[CH2:3]1.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]([NH:12][CH2:13][C:14]([NH2:16])=[O:15])=[O:10])[C:4](=[O:11])[CH2:3]1
Reactant: NCC(N)=O
Reactant: O=C(O)CN1CC(O)CC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: NC(=O)CNC(=O)CN1CC(O)CC1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 51.8 %

Procedure:
To an ice-cold mixture of 4-hydroxy-2-oxo-1-pyrrolidineacetic acid (1 g) and glycinamide (700 mg) in dimethylformamide (20 ml), dicyclohexylcarbodiimide (1.3 g) was added at once. Stirring was continued for 5 hours at room temperature, then the solvent was removed under vacuum. The residue was suspended in water (20 ml) and stirred for 30 minutes at room temperature. The insoluble material was filtered off and the filtrate evaporated to dryness. The residue was triturated with 2-propanol to yield the title compound (700 mg).
Reaction SMILES: [CH3:1][S:2][CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].[C:9](OC(=O)C)(=[O:11])[CH3:10].Cl>[OH-].[Na+]>[CH3:1][S:2][CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH:5][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CSC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CSC[C@H](NC(C)=O)C(=O)O
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A solution of 13.5 g (100 mmole) of S-methyl-L-cysteine dissolved in 210 ml of 1 N sodium hydroxide solution was ice cooled and 10.4 ml (110 mmole) of acetic anhydride was added thereto dropwise. After 2.0 hours at room temperature, the mixture was acidified to pH 1.0 with 6 N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 15.9 g (89.6% yield) of S-methyl-N-acetyl-L-cysteine as an oil.
Reaction SMILES: C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].O1CCCC1.[CH3:23][C:24]([CH3:36])([C:32](OC)=[O:33])[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[C:28]([O:27][C:25](=[O:26])[C:24]([CH3:36])([CH3:23])[CH2:32][OH:33])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)C(C)(C)C(=O)OC(C)(C)C
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)CO
Temperature: 25 °C
Yield: 82.9 %

Procedure:
1M lithium tri-tert-butoxy-aluminohydride/tetrahydrofuran solution (14 ml) was added dropwise to a solution of tert-butyl methyl 2,2-dimethyl-malonate (1.12 g) in tetrahydrofuran (30 ml) under nitrogen atmosphere over 15 minutes and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, a saturated ammonium chloride aq. solution and ethyl acetate were added and the organic layer was separated, washed with water and a saturated brine, dried over magnesium sulfate and concentrated in vacuo to give the titled compound (800 mg). MS (m/z): 175 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[NH:4][C:5]1[CH:22]=[CH:21][C:8]2[C:9](=[O:20])[C:10]3[CH:17]=[C:16]([O:18]C)[CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=1.Br>C(O)(=O)C>[NH2:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[NH:4][C:5]1[CH:22]=[CH:21][C:8]2[C:9](=[O:20])[C:10]3[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:11]=3[CH2:12][CH2:13][C:7]=2[CH:6]=1
Reactant: COc1ccc2c(c1)C(=O)c1ccc(Nc3ccc(F)cc3N)cc1CC2
Agent: Br
Solvent: CC(=O)O
Product: Nc1cc(F)ccc1Nc1ccc2c(c1)CCc1ccc(O)cc1C2=O
Temperature: 0 °C

Procedure:
0.2 g (0.55 mmol) of 2-(2-amino-4-fluoroanilino)-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one is dissolved in 2 ml of glacial acetic acid, 2 ml of HBr (45%) are added and the mixture is refluxed for 6 h. The solution is hydrolyzed with 200 g of ice and the precipitate is filtered off. The product is obtained in the form of a white powder. C21H17FN2O2 (Mr=348.38)
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:8]2([C@@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:10]([C:38]3[CH:43]=[CH:42][C:41](Cl)=[C:40]([CH2:45][C:46]4[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH3:54])=[CH:48][CH:47]=4)[CH:39]=3)[O:9]2)[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:31]([O:30][C@@H:11]1[C@@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2([CH:6]([CH2:4][OH:3])[CH2:7]2)[O:9][C@H:10]1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH3:54])=[CH:48][CH:47]=2)[CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)C1CC12O[C@@H](c1ccc(Cl)c(Cc3ccc(OCC)cc3)c1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cccc([C@@H]3OC4(CC4CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)cc1
Reaction time: 4 h
Yield: 97.2 %

Procedure:
To a solution of (5S,6S,7R,8S)-6,7,8-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-4-oxa-spiro[2.5]octane-1-carboxylic acid ethyl ester (350 mg, 0.46 mmole) in dry tetrahydrofuran (5 mL), lithium aluminium hydride (36 mg, 9.3 mmole) was added at 0° C. and stirred for 4 hours. The excess lithium aluminium hydride was decomposed by adding saturated aqueous sodium sulfate and extracted with Ethyl acetate (3×15 mL). The crude product obtained after the removal of solvent furnished 300 mg mixture of {(5S,6S,7R,8S)-6,7,8-Tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-1-yl}-methanol and {(5S,6S,7R,8S)-6,7,8-Tris-benzyloxy-5-(3-[4-ethoxy-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-1-yl}-methanol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[OH:16])=[O:4].C(N(CC)CC)C.[CH3:24][O:25][CH2:26]Cl.O>CN(C=O)C>[OH:15][C:14]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([O:16][CH2:24][O:25][CH3:26])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COC(=O)c1c(O)cc2ccccc2c1O
Reactant: COCCl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCOc1c(C(=O)OC)c(O)cc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
To a solution of 1,3-dihydroxy-2-naphthoic acid methyl ester 109 mg (0.53 mmol) in DMF (2 mL) was added triethylamine (200 μL, 1.43 mmol) and chloromethyl methyl ether (MOMCl) (125 μL, 1.65 mmol). The mixture was stirred at ambient temperature for 16 hours, poured into water (10 mL) and extracted with diethyl ether (2×5 mL). The combined ether layers were washed with 1M HCl (1×3 mL), brine (1×5 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to an oil. The oil was purified on silica gel eluting with 20% ethyl acetate/hexanes to provide the titled compound (83 mg, 60%).
Reaction SMILES: [H-].[Na+].C(OCC)(=O)[CH2:4][C:5]([O:7]CC)=[O:6].Br[CH2:15][C:16]1[O:20][C:19]([CH3:21])=[N:18][C:17]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1>CN(C)C=O.O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:17]2[N:18]=[C:19]([CH3:21])[O:20][C:16]=2[CH2:15][CH2:4][C:5]([OH:7])=[O:6])=[CH:23][CH:24]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(CBr)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Reaction time: 0.17 h

Procedure:
60% Sodium hydride in oil (0.6 g) was added portionwise to a solution of diethyl malonate (4.8 g) in N,N-dimethylformamide (50 ml). The mixture was stirred for 10 minutes and a solution of 5-bromomethyl-4-(4-chlorophenyl)-2-methyloxazole (4.30 g) in N,N-dimethylformamide (20 ml) was added dropwise under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes, diluted with water and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off. The residue was dissolved in ethanol (30 ml), 2N sodium hydroxide (50 ml) was added, and the mixture was refluxed for 30 minutes, concentrated and washed with ethyl ether. The aqueous layer was acidified with hydrochloric acid and the precipitate was taken up with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was dissolved in pyridine (30 ml). The solution was refluxed with stirring for an hour and the pyridine was distilled off. To the residue was added water and the mixture was adjusted to pH 2 with hydrochloric acid. The resulting crystalline precipitate was collected by filtration to give 4-(4-chlorophenyl)-2-methyloxazole-5-propionic acid, yield 2.50 g (62.8%). Recrystallization from ethanol gave needles, yield 1.85 g (46.5%), m.p. 211°-212° C.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[F:28][C:13]1([F:12])[CH2:14][CH2:15][C:16]([CH2:26][NH:27][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:2]=2[F:1])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18]1
Reactant: O=C(O)c1cccc(F)c1F
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1cccc(F)c1F

Procedure:
From 2,3-difluorobenzoic acid and C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=385.0, tR (minutes, Method D)=0.71
Reaction SMILES: IC1C=CN=C(OC)C=1C1N(O)C(C2C=CC=CC=2)=C(C)N=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]([OH:53])[CH2:31][NH:32][C:33]2[CH:38]=[CH:37][NH:36][C:35](=[O:39])[C:34]=2[C:40]2[NH:41][C:42]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[C:43]([CH2:45]C)[N:44]=2)[CH:27]=[CH:28][CH:29]=1.Cl.C(O)(=O)C>[Cl-].[Ti+3].[Cl-].[Cl-]>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]([OH:53])[CH2:31][NH:32][C:33]2[CH:38]=[CH:37][NH:36][C:35](=[O:39])[C:34]=2[C:40]2[NH:41][C:42]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[C:43]([CH3:45])[N:44]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CCc1nc(-c2c(NCC(O)c3cccc(Cl)c3)cc[nH]c2=O)[nH]c1-c1ccccc1
Agent: [Ti+3]
Agent: COc1nccc(I)c1-c1nc(C)c(-c2ccccc2)n1O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2c(NCC(O)c3cccc(Cl)c3)cc[nH]c2=O)[nH]c1-c1ccccc1

Procedure:
2-(4-Iodo-2-methoxy-pyridin-3-yl)-4-methyl-5-phenyl-imidazol-1-ol (0.093 g, 0.228 mmol) was reacted as described for the synthesis of 4-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-3-(4-ethyl-5-phenyl-1H-imidazol-2-yl)-1H-pyridin-2-one except that the compound was first treated with titanium(III) chloride and then hydrochloric acid/acetic acid. The title material was obtained (0.013 g, 14%) as a brown solid. HPLC 90.4% (220 nm), LCMS (+ESI, M+H+) m/z 421; IR ν (cm−1): 3276, 2920, 1643; HRMS calcd for C23H22N4O2Cl=421.1431, found: 421.1409; 1H NMR (400 MHz, methanol-d4) δ (ppm): 2.54 (3H, g), 3.64 (1H, dd, J=13.5 and 7.1 Hz), 3.70 (1H, dd, J=13.5 and 5.1 Hz), 4.97 (1H, t, J=5.8 Hz), 6.25 (1H, d, J=7.5 Hz), 7.21-7.68 (1OH, m), 7.71 (1H, d, J=8.0 Hz).
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH2:21][OH:22])[CH:20]=[C:14]3[CH2:13]2)=O)=CC=1)([O-])=O>[Pd].CO>[N:18]1[N:15]2[CH2:16][CH2:17][NH:12][CH2:13][C:14]2=[CH:20][C:19]=1[CH2:21][OH:22]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCn2nc(CO)cc2C1
Agent: [Pd]
Solvent: CO
Product: OCc1cc2n(n1)CCNC2
Reaction time: 2 h

Procedure:
Methanol (150 ml) was added to the mixture of 2-hydroxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid 4-nitrobenzyl ester (Example 25) (2.38 g) and 10% Pd—C (50% wet, 1.19 g). The reaction mixture was stirred for 2 hours under a hydrogen atmosphere. The mixture was filtered and concentrated under reduced pressure. The residue was applied to silica-gel column chromatography, then the column was eluted with 50% methanol in chloroform. The titled compound was obtained as a white solid (1.08 g, 98%).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH3:13])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].[Cl-].[NH4+]>CN(C)C=O>[CH2:10]([O:9][C:6]1[C:7]([F:8])=[C:2]([O:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: Oc1ccccc1Cl
Reactant: CC#CCOc1ncnc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1ncnc(Oc2ccccc2Cl)c1F
Temperature: 60 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.1 g of 4-chloro-6-(2-butynyloxy)-5-fluoropyrimidine, 0.1 g of potassium carbonate, and 0.08 g of 2-chlorophenol, followed by stirring at 60° C. for 1 hour. The reaction mixture was left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.12 g of 4-(2-butynyloxy)-6-(2-chlorophenoxy)-5-fluoropyrimidine (the present compound (184)).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH3:13])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[CH:19][C:20]=1[Cl:21].[Cl-].[NH4+]>C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([C:4]2([OH:9])[C:3]([C:10]([O:12][CH3:13])=[O:11])=[C:2]([CH3:1])[CH2:7][CH:6]([CH3:8])[CH2:5]2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Clc1ccc([Mg]Br)cc1Cl
Reactant: COC(=O)C1=C(C)CC(C)CC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)CC(C)CC1(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of racemic methyl 2,4-dimethyl-6-oxocyclohex-1-enecarboxylate (Example 1-03, Step 4; 100 mg) in THF (5 mL) was treated with 3,4-dichlorophenylmagnesium bromide (0.5 M, 1.3 mL). The mixture was stirred at rt overnight and then treated with saturated aqueous ammonium chloride. The resulting mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under vacuum to provide methyl (4RS,6SR)-6-(3,4-dichlorophenyl)-6-hydroxy-2,4,-dimethylcyclohex-1-enecarboxylate (97 mg). Mass spectrum m/z 353.32 (M+Na+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.Cl[CH2:11][CH2:12][N:13]([CH2:21][CH2:22]Cl)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:13]1[CH2:21][CH2:22][C:7]([C:8]#[N:9])([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:11][CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: N#CCc1cccnc1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccnc2)CC1

Procedure:
Prepare by the method of example 30.2 using 3-pyridylacetonitrile (10 mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-butoxycarbonyl-ethanamine (11 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH:10]=[N:11][OH:12].[Cl:13]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([Cl:13])=[N:11][OH:12]
Reactant: ON=CCc1c(Cl)cccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)Cc1c(Cl)cccc1Cl
Reaction time: 1 h
Yield: 226.2 %

Procedure:
A solution of sodium hydroxide (0.672 g, 16.8 mmol) and hydroxylamine hydrochloride (1.17 g, 16.8 mmol) in water (11 mL) was added to a solution of (2,6-dichlorophenyl)acetaldehyde (2.78 g, 14.7 mmol) in ethanol (21 mL). The resulting solution was heated in an 83° C. oil bath overnight. The sample was concentrated and filtered. The resulting solid was dried with P2O5 in a vacuum oven at 45° C. under reduced pressure to provide the oxime as a mixture of isomers (2.21 g yield, 74%). A solution of (2,6-dichlorophenyl)acetaldehyde oxime (1.05 g, 4.82 mmol) in dimethylformamide (3.8 mL) was stirred as N-chlorosuccinimide (0.64 g, 4.82 mmol) was added and the resulting solution was allowed to stir for one hour. The solution was poured into water and extracted with ether. The organic layer was washed with brine, dried with magnesium sulfate, filtered and concentrated to yield the title compound (2.60 g, 77%). 1H NMR (DMSO-d6): 11.78 (s, 1H), 7.47 (d, J=8 Hz, 2H), 7.33 (t, J=8 Hz, 1H), 4.08 (s, 2H).
Reaction SMILES: C(OC([N:11]([CH2:16][CH2:17][N:18](C)[C:19]([CH:21]1[CH2:26][N:25]([C:27](=[O:39])[N:28]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][CH2:23][N:22]1[C:40](=[O:55])[N:41]([C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:20])[CH2:12][C:13](=[O:15])[NH2:14])=O)C1C=CC=CC=1>C(O)C.[Pd]>[Cl:54][C:50]1[CH:49]=[C:48]([N:41]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:40]([N:22]2[CH2:23][CH2:24][N:25]([C:27](=[O:39])[N:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:26][C@H:21]2[C:19]([NH:18][CH2:17][CH2:16][NH:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:20])=[O:55])[CH:53]=[CH:52][CH:51]=1
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)C(C(=O)N(C)CCN(CC(N)=O)C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2cccc(Cl)c2)[C@H](C(=O)NCCNCC(N)=O)C1
Reaction time: 0.42 h

Procedure:
A solution of 89 mg (0.11 mmole) of 2-(2-(N-(benzyloxycarbonyl)-N-(carbamoylmethyl)amino)-N-(methyl)ethylaminocarbonyl)-4-(N,N-di-n-pentylcarbamoyl)-1-(N-(3-chlorophenyl)-N-phenylcarbamoyl)piperazine in 6 mL of ethanol was treated with 50 mg of 10% Pd/C, and the resulting suspension was stirred under an atmosphere of hydrogen for 25 min. The mixture was then filtered through Celite and the filtrate concentrated in vacuo. The residue was carried on in Step F below.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[N:29]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O[Na])(C)(C)C>O1CCOCC1>[C:38]([O:37][C:35]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([C:15]5[N:16]([C:20]6[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=6[F:27])[N:17]=[CH:18][N:19]=5)[S:8][C:7]=4[C:6]=3[N:28]=2)[CH2:31][CH2:30]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: CC(C)(C)O[Na]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 112 °C
Yield: 54 %

Procedure:
9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (208 mg×4, 2.0 mmol), tert-butyl piperazine-1-carboxylate (445 mg, 2.4 mmol), Pd(OAc) (45 mg, 0.20 mmol), Xphos (95 mg, 2.0 mmol), t-BuONa (460 mg, 4.0 mmol) and dioxane (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 112° C. for 7 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative TLC (DCM/EtOAc=10:1) to give 4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-piperazine-1-carboxylic acid tert-butyl ester (612 mg, yield: 54%). 1HNMR (DMSO-d6, 400 MHz): δ8.30 (s, 1H), 7.99-7.90 (m, 1H), 7.79-7.70 (m, 2H), 7.32 (s, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 6.78 (d, J=8.8 Hz, 1H), 4.19 (s, 4H), 4.04-4.02 (m, 4H), 3.44 (m, 1H), 3.12 (s, 1H), 1.57 (s, 9H) ESI-MS: m/z=567 [M+H+]
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])C(C(F)(F)F)=[CH:10][C:9]=1[NH:21][C:22](=[O:47])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH2:38][O:39]C3CCCCO3)[N:35]=[C:34]([CH3:46])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.[C:49](O)([C:51]([F:54])([F:53])[F:52])=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:49]([C:51]([F:54])([F:53])[F:52])=[CH:10][C:9]2[NH:21][C:22](=[O:47])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[C:34]([CH3:46])[N:35]=[C:36]([CH2:38][OH:39])[CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(COC4CCCCO4)c3)c2)cc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(C)nc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-ethoxy-2-(3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M301) (0.54 g, 0.80 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light red solid (240 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].Br[C:11]([CH3:16])([CH3:15])[C:12](Br)=[O:13]>ClC(Cl)C>[CH3:15][C:11]1([CH3:16])[C:12](=[O:13])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=2[O:8]1
Reactant: Cc1ccc(N)c(O)c1
Reactant: CC(C)(Br)C(=O)Br
Solvent: CC(Cl)Cl
Product: Cc1ccc2c(c1)OC(C)(C)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6-amino-m-cresol (10 g, 81.2 mmol) in dichloroethane (100 mL) was treated with 11.1 mL of 2-bromoisobutyryl bromide (89.3 mmol). The reaction was allowed to stir at room temperature for 3 hours, then refluxed overnight. The reaction was cooled to room temperature and filtered through celite. The filtrate and washings were combined and excess solvent removed to yield crude product which was then triturated with hexanes to give pure product as a white solid. MS (electrospray): mass calculated for C11H13NO2, 191.09; m/z found 192.2, [M+H]+.
Reaction SMILES: [Na].C([O-])(O)=O.[Na+].C([N:10]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[CH:12]=[N:11]1)(=O)C>CO>[NH:10]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[CH:12]=[N:11]1
Reactant: COC(=O)/C=C/c1cnn(C(C)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)/C=C/c1cn[nH]c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.6 %

Procedure:
Sodium hydrogenocarbonate, NaHCO3 (32 g, 1.15 equiv), was added to a suspension of protected compound, (E)-methyl 3-(1-acetyl-1H-pyrazol-4-yl)acrylate (65 g, 0.33 mol), in MeOH (600 mL). The mixture was stirred for 7 h at room temperature. The solids were then filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Hexane/EtOAc 8:1 to 1:2) to give the title compound as a solid (47 g, 92%).