Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[C:21]4[C:27]([C:28](=[O:44])[C:29]5[C:34]([F:35])=[CH:33][CH:32]=[C:31]([NH:36][S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])[C:30]=5[F:43])=[CH:26][NH:25][C:22]4=[N:23][CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:43][C:30]1[C:29]([C:28]([C:27]2[C:21]3[C:22](=[N:23][CH:24]=[C:19]([C:17]4[CH:16]=[N:15][N:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:18]=4)[CH:20]=3)[NH:25][CH:26]=2)=[O:44])=[C:34]([F:35])[CH:33]=[CH:32][C:31]=1[NH:36][S:37]([CH2:40][CH2:41][CH3:42])(=[O:38])=[O:39]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cc23)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnn(C5CCNCC5)c4)cc23)c1F
Yield: 16.1 %

Procedure:
In a reaction flask, 4-(4-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (P-1001, 42.0 mg, 0.067 mmol) is dissolved in 9.0 mL of dichloromethane and 1.0 mL of trifluoroacetic acid and the reaction is stirred at room temperature for 2 hours. Aqueous saturated sodium bicarbonate is added and the mixture is extracted with ethyl acetate. The aqueous layer is frozen and lyophilized and the residue is suspended in tetrahydrofuran and sonicated. The mixture is filtered twice and the filtrate is concentrated under vacuum. The resulting material is purified by reverse phase HPLC, eluting with acetonitrile/water with 0.1% formic acid, 5-47.5% acetonitrile over 40 minutes. Appropriate fractions are combined and dried by lyophilization to provide the desired compound as a white solid (P-1002, 5.7 mg). MS (ESI) [M+H+]+=529.0.
Reaction SMILES: [NH:1]([C:8]([NH:10][C:11]1[CH:31]=[CH:30][C:14]2[N:15]([C@@H:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][C:20]([O:22]C)=[O:21])[CH:16]=[N:17][C:13]=2[CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.Cl>O1CCCC1>[NH:1]([C:8]([NH:10][C:11]1[CH:31]=[CH:30][C:14]2[N:15]([C@@H:18]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[N:17][C:13]=2[CH:12]=1)=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@H](c1ccccc1)n1cnc2cc(NC(=O)Nc3ccccc3)ccc21
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(O)C[C@H](c1ccccc1)n1cnc2cc(NC(=O)Nc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 110 h

Procedure:
A solution of methyl (3R)-3-{5-[(anilinocarbonyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (204 mg, 492 μmol) in a mixture of tetrahydrofuran (2 mL), acetonitrile (20 mL) and hydrochloric acid (50 mL of a 5N solution) was stirred at room temperature for 110 hours. The solution was evaporated in vacuo to afford the title compound, [LCMS (Method C, Mobile Phase I) RT=2.25 min, MH+ 401.34].
Reaction SMILES: [CH3:1][O:2][CH2:3][S:4][C:5]1[N:6]([C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15]CC)=O)[CH:7]=[CH:8][N:9]=1.[C:21]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH3:22].[Li]>>[C:25]([O:24][C:21](=[O:23])[CH2:22][C:13]([C:12]1[CH:18]=[CH:19][CH:20]=[C:10]([N:6]2[CH:7]=[CH:8][N:9]=[C:5]2[S:4][CH2:3][O:2][CH3:1])[CH:11]=1)=[O:15])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)c1cccc(-n2ccnc2SCOC)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: COCSc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1

Procedure:
Prepared from ethyl 3-(2-methoxymethylsulfanyl-imidazol-1-yl)-benzoate [prepared by esterification of 3-(2-methoxymethylsulfanyl-imidazol-1-yl)-benzoic acid [CAS-No. 108035-46-7] with conc. H2SO4 in EtOH, followed by treatment with chloromethylmethyl ether and NaH in THF/DMF] by treatment with lithium tert.-butyl acetate according to general procedure H (method b). Obtained as an orange oil (1.82 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)I)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C(I)c2ccc(Cl)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-[(4-Chloro-phenyl)-iodo-methyl]-azetidine-1-carboxylic acid tert-butyl ester (58 g, 140 mmol) in dimethylsulphoxide (450 ml) is treated with sodium borohydride with cooling. The reaction mixture was stirred at room temperature for 20 hours, then quenched by the slow addition of water (1000 ml). The aqueous mixture is extracted into ethylacetate, and the ethylacetate phase washed with saturated brine, dried over magnesium sulphate and evaporated. The crude product is purified by flash chromatography using a biotage 75 column (eluant gradient isohexane:ethylacetate 9:1 to 85:15) to afford 3-(4-Chloro-benzyl)-azetidine-1-carboxylic acid tert-butyl ester. 1H NMR 400 MHz, CDCl3, δ 1.35 (9H), 2.70 (1H), 2.80 (2H), 3.55 (2H), 3.90 (2H), 6.97 (2H), 7.17 (2H).
Reaction SMILES: Cl.[C:2]([O:6][C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:25](O)=[O:26])[CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)=[O:16])[C@H:11]([CH2:13][CH3:14])[CH3:12])=[O:8])([CH3:5])([CH3:4])[CH3:3].Cl.[CH3:29][O:30][C:31](=[O:43])[C@H:32]([CH2:41][OH:42])[NH:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:29][O:30][C:31](=[O:43])[C@H:32]([CH2:41][OH:42])[NH:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:25](=[O:26])[C@H:18]([CH2:19][C:20]1[N:24]=[CH:23][NH:22][CH:21]=1)[NH:17][C:15](=[O:16])[C@H:10]([C@H:11]([CH2:13][CH3:14])[CH3:12])[NH:9][C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:8]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.1 g of t-butoxycarbonylisoleucylhistidine hydrochloride and 6.3 g of prolylserine methyl ester hydrochloride are dissolved in 100 ml of dimethylformamide. The solution is cooled to 0° C. To the solution is added 3.4 g of 1-hydroxybenzotriazole, 2.8 ml of N-methylmorpholine and 7.6 g of dicyclohexylcarbodiimide. The reaction mixture is stirred for two hours at 0° C. and then is allowed to stand at 4° C. for sixteen hours. Dicyclohexylurea is filtered from the reaction mixture and is washed with acetone. 300 ml of ethyl acetate is added to the solution. The solution is extracted three times with 300 ml saturated potassium bicarbonate and two times with 300 ml of brine. The product is extracted into 300 ml of 2 M potassium bisulfate. The acidic solution is neutralized with potassium carbonate. The slightly basic aqueous solution is extracted three times with 300 ml of methylene chloride. The methylene chloride solution, which contains the product, is dried over sodium sulfate, filtered and stripped of solvent under vacuum. The residue is dissolved in 100 ml of ethyl acetate. The solution is added to 1 liter of cold rapidly stirring Skellysolve B. The white precipitate was filtered and dried under vacuum at 55° C. to afford the product t-butoxycarbonylisoleucylhistidylprolylserine methyl ester.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[OH-].[Na+]>CO.C1COCC1>[CH2:24]([N:12]([S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:15])=[O:14])[C:5]1[C:6]([CH3:11])=[CH:7][C:8]([Br:10])=[CH:9][C:4]=1[C:3]([OH:31])=[O:2])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C)cc(Br)cc2C(=O)O)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 0.444 g (0.88 lmmol) of the product of Example 11 in 20 mL of MeOH/THF (1:1) was added 9.3 mL 1N NaOH and the mixture heated at reflux for 18 h. The mixture was cooled to room temperature and the organic removed in vacuo. The remaining solution was acidified with 10% HCl and extracted with EtOAc. The extract was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue provided 0.364 g (84%) of the desired carboxylic acid as a white solid after trturation with ether. CI Mass Spec: 490 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Br[CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[NH2:7][CH:4]1[CH2:3][CH2:2][N:1]([CH2:16][CH2:17][OH:18])[CH2:6][CH2:5]1
Reactant: OCCBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC1CCN(CCO)CC1
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of 0.5 g of tert-butyl 4-piperidinylcarbamate, 0.21 ml of 2-bromoethanol and 2.76 g of K2CO3 in 10 ml of acetonitrile was stirred for 5 hrs under reflux. The reaction mixture was cooled to a room temperature, filtered to remove solids, and concentrated. The concentrate was purified by silica gel column chromatography (mobile phase: 20 (v/v) % EA in hexane) to afford 0.58 g of the title compound (Yield: 94%). 1H NMR (CDCl3) δ 4.76 (d, 1H), 3.65 (t, 2H), 3.48 (m, 1H), 2.92 (m, 2H), 2.59 (t, 2H), 2.26 (m, 2H), 1.94 (m, 2H), 1.52 (m, 2H), 1.44 (s, 9H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]1)=[O:5])[CH3:2].F[B-](F)(F)F.[CH3:18][O+](C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]=[C:8]([O:12][CH3:18])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNC(=O)C1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCN=C(OC)C1
Temperature: 0 °C

Procedure:
Add 2-oxopiperidine-4-carboxylic acid ethyl ester (6.0 g, 35 mmol) to a solution of trimethyloxonium tetrafluoroborate (9.0 g, 59.6 mmol) in dichloromethane (78 mL) cooled to 0° C. Stir the reaction for 3 hours and pour into an ice cold solution of saturated aqueous sodium bicarbonate. Separate layers and extract the aqueous layer with additional dichloromethane. Combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to afford the title compound which was used without further purification (5.87 g, 90%). Mass spectrum (m/z): 186 (M+1).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=1[CH:16]=[N:17]O)(=O)C>CC(O)=O.[Zn]>[NH2:17][CH2:16][C:9]1[C:10]([Cl:15])=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=1[O:7][CH2:6][CH2:5][OH:4]
Reactant: CC(=O)OCCOc1cc(Cl)cc(Cl)c1C=NO
Agent: [Zn]
Solvent: CC(=O)O
Product: NCc1c(Cl)cc(Cl)cc1OCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 2-(3,5-dichloro-2-((hydroxyimino)methyl)phenoxy)ethyl acetate (1.15 mmol) in 2 mL AcOH was cooled to 0° C. and zinc dust (4.36 mmol) was added. The reaction mixture was stirred at RT for 1 h. It was filtered over a pad of celite and washed with EtOAc and MeOH. The filtrate was concentrated and redissolved in water (pH 4 with 2N HCl solution). It was washed once with EtOAc, the ageous phase was basified with 1M NaOH solution, extracted 3 times with EtOAc and DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:10]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:7][C:6]2[CH:8]=[CH:9][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:14]=1)[CH3:11]
Reactant: CSc1ccc(N)cc1
Reactant: CCOc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ccc(CNc2ccc(SC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To 5.0 mL (40.19 mmol) of 4-(methylthio)aniline dissloved in 25 mL dichloromethane was added 5.59 mL (40.19 mmol) 4-ethoxybenzaldehyde followed by 12.78 g (60.28 mmol) sodium triacetoxyborohydride. The mixture was stirred at overnight at room temperature, partitioned between EtOAc and brine, dried over MgSO4 and concentrated. Crystallization from dichloromethane/hexane, provided 7.87 g of (4-Ethoxy-benzyl)-(4-methylsulfanylphenyl)-amine, pure by 1H NMR.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]1([O:31][CH2:32][CH2:33][CH:34]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[CH:25]1([O:31][CH2:32][CH2:33][CH:34]=[C:1]([Br:5])[Br:2])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=CCCOC1CCCCC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=CCCOC1CCCCC1
Yield: 73.4 %

Procedure:
Subsequently, to a solution of carbon tetrabromide (36.5 g, 0.11 mol) in dichloromethane (120 ml) was added a solution of triphenylphosphine (57.7 g, 0.22 mol) in dichloromethane (120 ml) with stirring while ice-cooling under a nitrogen atmosphere, and the resulting mixture was stirred for 5 minutes. After stirring, to the reaction mixture was added a solution of the crude 3-cyclohexyloxypropionaldehyde (8.60 g) obtained above in dichloromethane (90 ml) with stirring while ice-cooling under a nitrogen atmosphere, and the resulting mixture was stirred at the same temperature for 25 minutes. After stirring, the reaction mixture was diluted with dichloromethane and washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (100:1-33:1) as the eluent to afford 4-cyclohexyloxy-1,1-dibromobut-1-ene (12.6 g, overall yield in two steps: 55%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[OH:13])([OH:3])=[O:2].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1F)([O-:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[O:13][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=1)([OH:3])=[O:2]
Reactant: COc1ccc(CC(=O)O)c(O)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CC(=O)O)c(Oc2cccc([N+](=O)[O-])c2)c1

Procedure:
A solution of 2-carboxymethyl-5-methoxyphenol (34.1 g, 0.187 mol), 2-nitrofluorobenzene (19.7 mL, 0.187 mol), and K2CO3 (65 g, 0.467 mol) in DMF (200 mL) was heated to 110° C. for 18 h. The solution was diluted with water (200 mL) and extracted with ethyl acetate. The ethyl acetate layer was concentrated to give the crude title compound which was used as is for the next step (57 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([N:15]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:16]1[CH2:21][C@@H:20]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]1)=[O:14].[ClH:41].CO>>[ClH:41].[ClH:41].[OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([N:15]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:16]1[CH2:21][C@@H:20]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:19][NH:18][CH2:17]1)=[O:14]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCO)[C@@H]1CNC[C@H](C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 41 h

Procedure:
tert-Butyl (3S,5R)-3-[[[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]carbonyl](2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (51 mg) was dissolved in 10% hydrogen chloride-methanol (4 ml), and the mixture was stirred at room temperature for 41 hr and concentrated to give the object product (44 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24](OC)=[CH:23][CH:22]=3)[N:13]=[C:12]2[CH3:29])[CH:5]=1.[F:31]C1C=CC(CBr)=CC=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:31])=[CH:23][CH:22]=3)[N:13]=[C:12]2[CH3:29])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(OC)cc3)c(Cl)c2=O)c1
Reactant: Fc1ccc(CBr)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of Intermediate 3 (120 mg, 0.39 mmol) in N,N-dimethylformamide (2 mL) was added 4-fluorobenzyl bromide (0.05 mL, 0.39 mmol), potassium carbonate (81 mg, 0.58 mmol) and 18-crown-6 (10 mg). The slurry was stirred at ambient temperature for two hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a colorless oil. (63 mg, 38% yield). MS (M+H): 417
Reaction SMILES: Cl.C([O:6][C:7]([NH:9][CH:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:11][C:12](=[CH2:23])[CH2:13][CH:14]([NH:20]C=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)(C)(C)C>CCOCC.C(Cl)Cl>[NH2:20][CH:14]([CH2:13][C:12](=[CH2:23])[CH2:11][CH:10]([NH:9][CH:7]=[O:6])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C=C(CC(NC=O)C(=O)OCC)CC(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C=C(CC(N)C(=O)OCC)CC(NC=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
100 ml of a solution of 2.6N hydrochloric acid in anhydrous ether were added to a solution of 6.4 g of the product of Step F in 200 ml of methylene chloride and after stirring at room temperature for one hour, nitrogen was bubbled therethrough The mixture was evaporated to dryness under reduced pressure at 30° C. and the residue was taken up in methylene chloride. The mixture was neutralized and evaporated to dryness to obtain 4.6 g of raw product. The latter was chromatographed over silica and eluted with a 9-1 ethyl acetate-ethanol mixture to obtain the desired product with an Rf=0.06.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([O:12]/[CH:13]=[CH:14]/B1OC(C)(C)C(C)(C)O1)[CH3:11]>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[C:7](/[CH:11]=[CH:10]/[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Clc1ccc(I)c(Cl)n1
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCO/C=C/c1ccc(Cl)nc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a degassed solution of 2,6-dichloro-3-iodopyridine (3.0 g, 11 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 g, 11 mmol) in 1,4-dioxane (20 mL) and water (1.0 mL) was added CS2CO3 (7.1 g, 22 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (357 mg, 0.54 mmol) under N2 protection. The resulting mixture was heated to 70° C. and stirred at this temperature overnight. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-20% EtOAc/DCM) to provide (E)-2,6-dichloro-3-(2-ethoxyvinyl)pyridine (1.96 mg, yield: 86%). MS (M+H)+: 218.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]3[O:44][CH2:43][CH2:42][C@H:18]4[S:19](=[O:41])(=[O:40])[C:20]([CH3:39])([CH3:38])[C:21]([N:23](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:22][C@:17]4([CH3:45])[C:15]=3[CH:16]=2)=[O:9])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].[CH2:52]([OH:55])[C:53]#[CH:54].C(O)(C(F)(F)F)=O>CN(C=O)C.C(Cl)Cl>[NH2:23][C:21]1[C:20]([CH3:38])([CH3:39])[S:19](=[O:41])(=[O:40])[C@@H:18]2[CH2:42][CH2:43][O:44][C:14]3[CH:13]=[CH:12][C:11]([NH:10][C:8]([C:5]4[CH:4]=[N:3][C:2]([O:55][CH2:52][C:53]#[CH:54])=[CH:7][N:6]=4)=[O:9])=[CH:16][C:15]=3[C@@:17]2([CH3:45])[N:22]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(NC(=O)c4cnc(Cl)cn4)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Reactant: C#CCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C#CCOc1cnc(C(=O)Nc2ccc3c(c2)[C@@]2(C)N=C(N)C(C)(C)S(=O)(=O)[C@@H]2CCO3)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of tert-butyl N-[(4aR,11bR)-10-[(5-chloropyrazine-2-carbonyl)amino]-3,3,11b-trimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (126 mg, 0.190 mmol) in DMF (2 mL) was added a mixture of potassium tert-butoxide (63.9 mg, 0.569 mmol) in propargyl alcohol (0.224 mL, 3.79 mmol). The reaction was stirred at ambient temperature for 1 h. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was concentrated. The crude residue was diluted with DCM (3 mL) and TFA (0.292 mL, 3.79 mmol) was added and the reaction was stirred at ambient temperature. After 1 h, the reaction mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, and concentrated. The crude product was purified by column chromatography, eluting with 20-80% (3:1 ethyl acetate/ethanol) in heptane, to provide N-((4aR,11bR)-2-amino-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-10-yl)-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamide (82 mg, 0.170 mmol, 89% yield) as an off-white powder. MS m/z=484.0 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:48])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40]C3CCCCO3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:40][CH2:39][C:38]1[N:34]([C:30]2[CH:29]=[C:28]([C:27]3[CH2:26][C:25](=[O:48])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([N:14]5[CH2:15][CH2:16][O:17][CH2:18][CH2:19]5)=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[N:35]=[N:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(N3CCOCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[5-morpholin-4-yl-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M1) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (51 mg).