Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH2:12].CCN(CC)CC>C(Cl)(Cl)Cl>[CH2:1]([NH:8][CH2:12][C:11]([O:13][S:14]([C:17]([F:20])([F:18])[F:19])(=[O:16])=[O:15])=[CH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CBr)OS(=O)(=O)C(F)(F)F
Reactant: NCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=C(CNCc1ccccc1)OS(=O)(=O)C(F)(F)F
Yield: 55 %

Procedure:
Sources of Starting Materials as illustrated in FIG. 10, SCHEME B: α,β-Unsaturated amides with exocyclic double bonds: Reaction conditions: (a) TfOH, CHCl3, RT; (b) BnNH2, CHCl3, reflux; (c) 10 mol % Pd(PPh3)4, Bu3N, CO (1 atm), CH3CN, 65° C. Typical experimental procedure for the preparation of 700—described for the case in which n=1, X=Br, and R=Bn: Triflic acid (2.32 mL, 26.23 mmol) was added dropwise under N2 over 10 min to a stirred solution of propargyl bromide (2.0 mL, 26.23 mmol) in CHCl3 (30 mL) at 0° C. The ice bath was removed and the dark solution was stirred at RT for 60 min, followed by the addition of pyridine (5 mL). The solution was washed with water (50 mL) and dil. hydrochloric acid (2×50 mL). The organic phase was dried and the solvent evaporated. The residue was purified by Kugelrohr distillation to yield 1-bromo-2-[(trifluoromethanesulfonyl]oxylprop-2-ene as a colorless liquid. A solution of benzylamine (81 mL, 0.74 mmol) in CHCl3 (4 mL) was added dropwise to a mixture of 1-bromo-2-[(trifluoromethanesulfonyl)oxy]prop-2-ene (0.37 mmol) and Et3N (0.1 mL, 0.74 mmol) in CHCl3 (4 mL) at 1° C. The solution was then heated at reflux for 15 h. The mixture was washed with water (10 mL), the organic extracts were dried and the solvent was evaporated. The residue was purified by flash chromatography (hexanes-EtOAc, 9:1) to yield N-benzyl-2-[(trifluoromethanesulfonyl)oxy]-2-propenylamine as a pale yellow solid. Yield: 55%. Next, for the case in which n=1 and R=Bn: Carbon monoxide was bubbled through a solution of N-benzyl-2-[(trifluoromethanesulfonyl)oxy]-2-propenylamine (0.36 mmol), Pd(PPh3)4 (0.041 g, 0.036 mmol), tri-n-butylamine (0.17 mL, 0.72 mmol) in acetonitrile (15 mL) for 25 min. The reaction was then heated to 65° C. for 5 h. The solution was then allowed to cool to room temperature upon which ether (15 mL) was added and the solution filtered through a pad of kenite. The pad was subsequently thoroughly rinsed with ether (3×10 mL). The solvent was then removed in vaccuo and the residue taken up in dichloromethane. Flash chromatography (hexanes:ethyl acetate; 19:1) twice yielded 1-benzyl-3-methyleneazetidinone as a white amorphous solid. Yield: 73%.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[S:6]1[CH:7]=[CH:8][C:4]([CH2:3][NH:2][C:16](=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5]1
Reactant: NCc1ccsc1
Reactant: CCCCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NCc1ccsc1
Yield: 88.8 %

Procedure:
Using the same reaction conditions as those of Example 4, 3-(aminomethyl)thiophene hydrochloride (4 mmol), triethylamine (4.4 mmol) and octanoyl chloride (40 mmol) were reacted to give N-(3-thienylmethyl)octanamide (0.85 g, 89%). M.p. 71°-72° C. (Found: C, 65.0; H, 8.4; N. 5.7; S, 13.2. Calculated for C13H21NOS: C, 65.3; H, 8.8; N, 5.9; S, 13.4%); EI m/e Intensity (%): 239 (19, M+), 97 (63, C4H3S.CH2+); δH(CDCl3) 7.03-7.33 (3H, m), 5.60 (1H, br,s), 4.44 (2H, d), 2.19 (2H, t), 1.61 (2H, m), 1.28 (8H, m), 0.87 (3H, t); δC(CDCl3): 14.2, 22.7, 25.8, 29.1, 29.3, 31.8, 36.9, 38.8, 122.3, 126.5, 127.1, 140.0, 173.1 ppm.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>C1COCC1.CO>[OH:2][CH2:1][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(C=O)cc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(-c2ccccc2)c2ccc(CO)cc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 7-formyl-4-phenylquinoline-2-carbonitrile (516 mg, 2.0 mmol) in THF (6 mL) and MeOH (2 mL) was added at 0° C. sodium borohydride (91 mg, 2.4 mmol). The mixture was stirred 1 h at 0° C., quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The compound was used as such for the next step. MS (+ESI): 262 (M+H)+.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH3:13][C@H:14]1[O:18][C:17](=[O:19])[NH:16][CH2:15]1>>[CH3:13][C@H:14]1[O:18][C:17](=[O:19])[N:16]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)[CH2:15]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C[C@@H]1CNC(=O)O1
Product: C[C@@H]1CN(c2ccc(C(=O)O)cc2)C(=O)O1

Procedure:
By reaction and treatment in the same manner as in Preparation Example 40 and using ethyl 4-iodobenzoate and (R)-5-methyloxazolidin-2-one, the title compound (2 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH3:8])[NH:4][N:3]=1.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[O:12]>C(Cl)Cl>[CH3:8][S:7][C:5]1[NH:4][N:3]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:11]([O:10][CH3:9])=[O:12])(=[O:21])=[O:20])=[O:24])[N:6]=1
Reactant: CSc1nc(N)n[nH]1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1n[nH]c(SC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5.0 grams (0.0385 mole) 3-amino-5-methylthio-1H-1,2,4-triazole (Aldrich Chemicals) and 75 ml of dry methylene chloride stirring in a 200 ml RB single neck flask, 10.5 grams of 2-(methoxycarbonyl)benzenesulfonylisocyanate was added at ambient temperature; a clear solution gradually formed. After stirring overnight at room temperature, the white solid which precipitated was filtered and washed with methylene chloride, yield 11.7 grams, m.p.147°-153°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:12])=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[N+:18]([O-])([O-:20])=[O:19].[K+]>>[Cl:1][C:2]1[C:11]([N+:18]([O-:20])=[O:19])=[C:10]2[C:5]([C:6]([CH3:12])=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cncc2cc(Cl)ccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cncc2c([N+](=O)[O-])c(Cl)ccc12
Reaction time: 1 h

Procedure:
A mixture of 17.7 g. (0.1 mole) of 7-chloro-4-methylisoquinoline and 100 ml. of concentrated sulfuric acid is treated with 10 g. (0.1 mole) of potassium nitrate dissolved in 150 ml. of concentrated sulfuric acid. The mixture is stirred for one hour, quenched on ice, made alkaline with ammonium hydroxide and filtered to yield 7-chloro-4-methyl-8-nitroisoquinoline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:20]([CH3:25])=[N:21][NH:22][C:23]=2[CH3:24])=[CH:8][CH:7]=1.[H-].[K+].Br[CH2:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>O1CCCC1.CS(C)=O>[CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:20]([CH3:25])=[N:21][N:22]([CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:23]=2[CH3:24])=[CH:10][CH:11]=1
Reactant: BrCC1CCOCC1
Reactant: COC(=O)/C=C/c1ccc([C@@H]2CCCN2CCc2c(C)n[nH]c2C)cc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC(=O)/C=C/c1ccc([C@@H]2CCCN2CCc2c(C)nn(CC3CCOCC3)c2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.6 %

Procedure:
To an ice cold mixture of (E)-3-(4-{(S)-1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester (0.85 g, 2.4 mmol) and potassium hydride (115 mg, 2.88 mmol) in 4.0 mL tetrahydrofuran:dimethyl sulfoxide (9:1 v/v) was added 4-bromomethyltetrahydropyran (945 mg, 5.28 mmol). The mixture was slowly warmed to room temperature and stirred under nitrogen for 16 h. It was then quenched with aqueous ammonium chloride and added with ethyl acetate. The layers were separated and the organic layer was washed with more aqueous ammonium chloride. The aqueous layers were then washed with more ethyl acetate and the combined organic extracts were dried over magnesium sulfate and concentrated to a yellow oil. The oil was then purified via silica gel column chromatography (100:0 to 0:100 heptane:ethyl acetate) to give (E)-3-[4-((S)-1-{2-[3,5-dimethyl-1-(tetrahydro-pyran-4-ylmethyl)-1H-pyrazol-4-yl]-ethyl}-pyrrolidin-2-yl)-phenyl]-acrylic acid methyl ester (160 mg, 0.35 mmol, 14% yield) as a yellow oil. LC/MS (m/z): 452.5 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.[NH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CC(N(C)C)=O>[CH3:13][O:12][C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]1[N:6]=[CH:7][C:2]([NH:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: COC(=O)/C=C/c1cnc(Cl)cn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cn1
Temperature: 92.5 °C
Reaction time: 6 h
Yield: 60.7 %

Procedure:
A mixture of methyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (10.00 g), tert-butyl (3R)-3-amino-1-pyrrolidinecarboxylate (14.01 g) and potassium phosphate (21.30 g) in DMA (25 mL) was stirred at 90-95° C. for 6 hours under nitrogen atmosphere. After addition of water, the reaction mixture was extracted with AcOEt. Water was added to the organic layer and the mixture was adjusted to pH 8 with 1N HCl aq., washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel (chromatorex NH) (hexane-AcOEt 60:40 v/v) to give tert-butyl (3R)-3-({5-[(1E)-3-methoxy-3-oxo-1-propen-1-yl]-2-pyrazinyl}amino)-1-pyrrolidinecarboxylate as a solid (10.64 g).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:27]([NH:31][CH2:32][C:33]1[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:46])[CH:34]=1)[CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH2:27]([N:31]([CH2:32][C:33]1[CH:45]=[CH:44][C:36]([O:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:35]([CH3:46])[CH:34]=1)[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:3]=1)[CH2:28][CH2:29][CH3:30]
Reactant: FC(F)(F)c1ccc(-c2cncc(Br)n2)cc1
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cncc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 18.7 %

Procedure:
A mixture of 2-bromo-6-[4-(trifluoromethyl)phenyl]pyrazine (0.5 g, 1.6 mmol), N,N-diisopropylethylamine (0.29 mL, 1.6 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.5 g, 1.8 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The reaction mixture was then allowed to come to room temperature, and the residue dissolved in CH2Cl2 (130 mL), the organic extract was washed water (30 mL) passed through a hydrophobic frit and concentrated in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting 1:19–1:4 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (0.15 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[CH:6]=[C:5]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3.[N+:26]([O-])([OH:28])=[O:27]>>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:18])[CH2:10][C:11]3([O:17][C:7]=2[C:6]([N+:26]([O-:28])=[O:27])=[C:5]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)COc1cc(OC)c2c(c1)OC1(CCCCC1)CC2=O
Product: CCOC(=O)COc1cc(OC)c2c(c1[N+](=O)[O-])OC1(CCCCC1)CC2=O
Yield: 74.2 %

Procedure:
Ethyl 2-{(5-methoxy-3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,1'-cyclohexan]-7-yl) oxy}acetate prepared in Preparation 49) (1.3 g, 3.92 mmol) is added by portions to fuming nitric acid (d=1.50, 10 ml) at -60° C. with stirring. After one hour stirring at -60° to -40° C., the reaction mixture is poured into ice-cold water. The mixture is extracted with diethyl ether. The ether layer is separated, washed with water and then aqueous sodium bicarbonate, dried and concentrated. The residue is washed with diethyl ether. Recrystallization from a mixture of ethyl acetate and hexane gives the title compounds as a crystalline solid (1.05 g, yield 74.2%, m.p.=142°-143° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][OH:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH:21]=[O:22].CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]=[O:11].[CH3:25][N:26]([CH3:28])[CH:27]=[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH3:12])[CH:21]=[O:22]
Reactant: COC(OC)N(C)C
Reactant: COc1ccccc1CCO
Agent: COc1ccccc1CC=O
Product: COc1ccccc1C(C=O)=CN(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
(2-Methoxyphenyl)acetaldehyde is prepared by oxidation of 2-(2-methoxyphenyl)ethanol according to the procedure disclosed in J. Org. Chem., 49:1720, 1999. A mixture of (2-methoxyphenyl)acetaldehyde (3.8 g, 25.3 mmol) and dimethylformamide dimethyl acetal (4.52 g, 37.9 mmol) is stirred at room temperature for 1 hour. Excess of the acetal is removed under reduced pressure to leave 4.68 g of 3-dimethylamino-2-(2-methoxyphenyl)propenal (90%).
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([NH2:12])=[CH:7][C:6]=1[O:13][CH3:14].C[Li].[CH3:19]COCC.Cl>C1COCC1>[NH2:12][C:8]1[C:9]([Cl:11])=[CH:10][C:5]([C:4](=[O:15])[CH3:19])=[C:6]([O:13][CH3:14])[CH:7]=1
Reactant: CCOCC
Reactant: COc1cc(N)c(Cl)cc1C(=O)N(C)OC
Agent: Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: COc1cc(N)c(Cl)cc1C(C)=O
Temperature: 0 °C
Yield: 75 %

Procedure:
N-Methoxy-N-methyl-4-amino-5-chloro-2-methoxybenzamide (24.4 g, 100 mmol) was dissolved in THF (400 mL) and the solution was cooled to -400° C. Methyl-lithium in ether (143 mL, 4.4 g, 200 mmol) ) was added and the mixture was allowed to warm to 0° C. Aqueous hydrochloric acid was added and the mixture was extracted into ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and evaporated to leave a solid. Crystallization from ethyl acetate-hexane gave 4'-amino-5'-chloro-2'-methoxyacetophenone (15.0 g, 75 mmol), m.p. 114°-116° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]([CH2:10][C:11]#[CH:12])[C:8](=[O:13])[CH2:7][CH2:6]1)=O.[NH3:14]>CO>[O:13]=[C:8]1[N:9]([CH2:10][C:11]#[CH:12])[CH:5]([C:3]([NH2:14])=[O:2])[CH2:6][CH2:7]1
Reactant: C#CCN1C(=O)CCC1C(=O)OC
Reactant: N
Solvent: CO
Product: C#CCN1C(=O)CCC1C(N)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An ice water chilled solution of 5-methoxycarbonyl-1-(2-propynyl)-2-pyrrolidinone (5.1 g) and sieve dried methanol (250 ml) was treated with anhydrous ammonia for ten minutes and was then allowed to stand overnight at ambient temperature. The solution was concentrated to afford an oil which crystallized (4.81 g). Recrystallization from 95% ethanol (20 ml) gave 3.07 g of almost colorless crystals, mp 145°-147° C.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+]>O1CCCC1>[CH3:6][NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18]
Reactant: COc1ccccc1CCNC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNCCc1ccccc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To N-(t-Butyloxycarbonyl)-2-(2-methoxyphenyl)-ethylamine (182.7 mmol, 45.9 g) in dry tetrahydrofuran (200 mL) at 0° C. was added, in portions, lithium aluminum hydride (219.2 mmol, 8.3 g) under N2. After stirring at 0° C. for 1 hour, the ice-bath was removed and then the reaction heated to reflux for 24 hours, cooled to room temperature then to 0° C.; the excess lithium aluminum hydride was destroyed very carefully with 20% potassium hydroxide solution (1.3 equivalent). After removing the salt by filtration, the filtrate was dried then evaporated to dryness to give product as a white solid (26.2 g, 87%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[C@@H:10]([NH:25][C@H:26]([C:28]([O:30]C(C)(C)C)=[O:29])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:35])[C@@H:10]([NH:25][C@H:26]([C:28]([OH:30])=[O:29])[CH3:27])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
To a solution of (S)-2-((S)-1-tert-butoxycarbonyl-ethylamino)-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester (1.12 g, 2.27 mmol) in DCM (5 mL) was added TFA (5 mL). After being stirred for 3 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (eluent: 10% MeOH in DCM) to give (S)-2-((S)-1-carboxy-ethylamino)-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester. MS: m/z (MH+) 438; HPLC retention time 0.73 min (HPLC condition C).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]2[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[CH:19][C:17]=2[N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc2nc(N3CC(NC(=O)OC(C)(C)C)C3)sc2c1
Yield: 74.9 %

Procedure:
The same operation as in Example (221a) was performed using 3-tert-butoxycarbonylaminoazetidine (199 mg, 1.15 mmol), ethyl 2-bromo-1,3-benzothiazole-6-carboxylate obtained in Example (225a) (300 mg, 1.05 mmol) and diisopropylethylamine (0.37 mL, 2.10 mmol), to obtain 297 mg of the title compound as a milk white solid (75%).
Reaction SMILES: [C:1]([NH:4][C:5](=[O:8])[CH2:6][SH:7])(=[O:3])[CH3:2].[C:9]([CH2:13][CH2:14][C:15](Cl)=[O:16])([O:11][CH3:12])=[O:10].C(N(CC)CC)C>ClCCl>[C:1]([NH:4][C:5](=[O:8])[CH2:6][S:7][C:15](=[O:16])[CH2:14][CH2:13][C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(=O)CS
Reactant: COC(=O)CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)SCC(=O)NC(C)=O
Reaction time: 1 h

Procedure:
The concentrated product of Step A. above was added to 100 ml. of dichloromethane and cooled to -5° C. under nitrogen. There was then added 8.3 g. (0.055 mole) of 3-carbomethoxypropionyl chloride in 20 ml. of dichloromethane, over from 5 to 10 minutes. Next, there was added 5.57 g. (0.055 mole) of triethylamine in 20 ml. of dichloromethance and the reaction mixture was aged for 1 hour at -5° C., then permitted to come to room temperature over 2 hours. The reaction mixture was then concentrated under vacuum after having been made slightly acidic with acetic acid. Ice water was then added to the reaction mixture, and the water was extracted with dichloromethane dried over magnesium sulfate and concentrated to an oil of 15.4 g. The oil was changed to a silica gel column and eluted with 25% ethylacetate/hexane to obtain 2.3 g. of final product having an m.p. of 111°-113° C.
Reaction SMILES: [N:1]1([C:6]([O:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([NH:15][C:16]3[N:24]=[C:23]4[C:19]([NH:20][C:21](=[O:33])[N:22]4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])=[C:18]([C:34]([O:36]CC)=O)[N:17]=3)[CH2:11][CH2:10]2)=[O:7])C=CN=C1.[NH2:39]C1C(C(OCC)=O)=NC(N[C@H]2CC[C@@H](O)CC2)=NC=1NC1C=CC=CC=1OC>ClCCl>[C:6](=[O:7])([O:8][C@H:9]1[CH2:10][CH2:11][C@@H:12]([NH:15][C:16]2[N:24]=[C:23]3[C:19]([NH:20][C:21](=[O:33])[N:22]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[C:18]([C:34](=[O:36])[NH2:39])[N:17]=2)[CH2:13][CH2:14]1)[NH2:1]
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@@H](OC(=O)n3ccnc3)CC2)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: CCOC(=O)c1nc(N[C@H]2CC[C@@H](O)CC2)nc(Nc2ccccc2OC)c1N
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CC[C@@H](OC(N)=O)CC3)nc21

Procedure:
Ethyl 2-(cis-4-(1H-imidazole-1-carbonyloxy)cyclohexylamino)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. Ethyl 5-amino-2-(cis-4-hydroxycyclohexylamino)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.272 g, 0.678 mmol) and 1,1′-1,1′-carbonyldiimidazole (1.09 g, 6.78 mmol) in dichloromethane (20 mL) were reacted according to General Procedure F and purified using biotage chromatography (60-100% ethyl acetate in hexanes) to afford the title compound and the free hydroxyl derivative (0.250 g, 71%). MS (ESI) m/z 522.4 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][C:19]([NH2:21])=[O:20])[CH:15]3[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:17][CH:9]2[CH2:10]4)[CH2:14]3)=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:27][O+](C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][C:19](=[NH:21])[O:20][CH3:27])[CH:9]3[CH2:17][CH:13]4[CH2:12][CH:11]([CH2:16][CH:15]2[CH2:14]4)[CH2:10]3)=[CH:4][CH:3]=1
Reactant: C[O+](C)C
Reactant: NC(=O)CC1(c2ccc(Cl)cc2)C2CC3CC(C2)CC1C3
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=N)CC1(c2ccc(Cl)cc2)C2CC3CC(C2)CC1C3
Reaction time: 18 h
Yield: 100.7 %

Procedure:
A solution of 6-1a (30 mg, 0.1 mmol) in 0.5 mL of anhydrous methylene chloride was treated with trimethyloxonium tetrafloroborate (30 mg, 0.2 mmol). The mixture was stirred under nitrogen for 18 h, then added to a separatory funnel containing 25 mL of methylene chloride and saturated aqueous sodium bicarbonate solution. The layers were mixed and separated and the organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to yield 32 mg of title compound, which was used without purification.