Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[C:26]([C:28]1[CH:29]=[CH:30][C:31]([F:37])=[C:32](B(O)O)[CH:33]=1)#[N:27].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([F:37])=[C:32]([C:2]2[N:6]([S:7]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=2)[CH:33]=1)#[N:27]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cc(C#N)ccc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (5-cyano-2-fluorophenyl)boronic acid (198 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (57.8 mg), the title compound was obtained as a pale-yellow oil (yield 28.9 mg, 6%).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][C:12]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=O)=[CH:9][CH:8]=1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[O:11][C:12]3[C:13](=[CH:17][CH:18]=[C:19]([CH3:21])[CH:20]=3)[C:14](=[O:16])[C:22]=2[CH:23]=1
Reactant: Cc1ccc(C(=O)O)c(Oc2ccc(Br)cc2)c1
Agent: O=S(=O)(O)O
Product: Cc1ccc2c(=O)c3cc(Br)ccc3oc2c1
Temperature: 80 °C

Procedure:
Sulfuric acid (5 ml, 93 mmol) was added to 2-(4-bromophenoxy)-4-methylbenzoic acid (200 mg, 0.62 mmol) at rt. The reaction mixture was heated to 80° C. for 30 min. LCMS showed complete reaction. The reaction mixture was cooled to rt and poured over ice water. The gray suspension was filtered, and the gray solid was washed with water. The residue was dissolved in EtOAc, and washed w/Sat. NaCl. After concentration in vacuo, the brown solid was used without further purification. MS m/z=291.1 [M+H]+. Calc'd for C14H9BrO2: 289.1.
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:12]([O:14][C:15]([C@@:17]12[CH2:32][C@H:31]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]([NH3+:33])[C:22](=[O:34])[N:21]1[CH2:35][C@H:36]([O:38][C:39](=[O:49])[C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)[CH2:37][C@H:20]1[C:19](=[O:50])[NH:18]2)=[O:16])[CH3:13].[CH3:51][C:52]1[O:56][N:55]=[C:54]([C:57](O)=[O:58])[CH:53]=1.C(N(C(C)C)CC)(C)C.CC1CCCO1>CCOC(C)=O.CN1C(=O)CCC1>[CH3:51][C:52]1[O:56][N:55]=[C:54]([C:57]([NH:33][C@@H:23]2[C:22](=[O:34])[N:21]3[CH2:35][C@H:36]([O:38][C:39](=[O:49])[C:40]4[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=4)[CH2:37][C@H:20]3[C:19](=[O:50])[NH:18][C@:17]3([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:32][C@H:31]3[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:58])[CH:53]=1
Reactant: Cc1cc(C(=O)O)no1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H]([NH3+])C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H]([NH3+])C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)c1cc(C)on1)C(=O)N1C[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C[C@H]1C(=O)N2
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS,Z)-14a-(ethoxycarbonyl)-2-(4-nitrobenzoyloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-aminium 4-methylbenzenesulfonate (1.53 kg), 5-methylisoxazole-3-carboxylic acid (327 g), and NMP (4.74 kg) at 5° C. was added diisopropylethylamine (996 g). Propanephosphonic acid anhydride (817 g) was charged as a solution in EtOAc (817 g) and NMP (3.16 kg) to the reaction mixture. The reaction was allowed to proceed for 30 min at 5° C., then warmed to 20° C. and aged for an additional hour. The reaction solution was diluted with IPAc (10.5 kg) and 2-methyltetrahydrofuran (10.5 kg). The diluted reaction solution was washed with water (23.7 kg), a 1.0 M aqueous solution of H3PO4 (2×7.5 kg), water (7.9 kg), a 5% aqueous solution of NaHCO3 (7.5 kg), and then a 10% aqueous solution of NaCl (2×7.5 kg). The organic solution was concentrated under reduced pressure, diluted with THF (12 kg), and then filtered. Concentration of the organic solution to a volume of 5 L was followed by co-distillation with THF (30 kg) to a final volume of 5 L. The solution was diluted with THF (2.5 kg). The assay yield was determined on the product-containing solution to be 96.5% (1.35 kg).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I.O>[O:18]([C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc2c(Br)cccn2n1
Reactant: Oc1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1nc2c(Oc3ccccc3)cccn2n1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (see example 66b, 500 mg, 2.35 mmol), phenol (442 mg, 4.69 mmol), copper(I) iodide (44.7 mg, 235 μmol), picolinic acid (57.8 mg, 469 μmol) and potassium phosphate tribasic (1.49 g, 7.04 mmol) in DMSO (10 mL) was heated to 120° C. After 12 hours further phenol (442 mg, 4.69 mmol), copper(I) iodide (44.7 mg, 235 μmol), picolinic acid (57.8 mg, 469 μmol) and potassium phosphate tribasic (1.49 g, 7.04 mmol) were added and stirred at 120° C. for another 18 hours. Water was added to the reaction mixture and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was evaporated. The crude material was purified by prep. HPLC. The title compound was obtained as off-white solid (200 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:21]([O-])=O)=[CH:4][C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=2[F:20])=[C:6]([OH:8])[CH:7]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:34][O:35][CH3:36].Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:34][O:35][CH3:36])[C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=2[F:20])=[CH:4][C:3]=1[NH2:21]
Reactant: COCCl
Reactant: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(Cl)c(N)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)-4-nitrophenol (0.52 g) and N,N-diisopropylethylamine (0.52 mL) in methylene chloride (5 mL) was added (chloromethyl)methyl ether (0.17 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (7.5 mL). To the solution were added methanol (7.5 mL) and nickel(II) bromide (17 mg). To the mixture was added sodium borohydride (0.17 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−1/1) to give the title compound (0.4 g).
Reaction SMILES: IC.[NH:3]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[N:6][N:5]=[N:4]1.[C:35](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:35][N:6]1[C:7]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=4)=[O:23])=[CH:19][CH:20]=3)[CH:11]=[CH:10][N:9]=2)=[N:3][N:4]=[N:5]1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1ccc(Oc2ccnc(-c3nnn[nH]3)c2)cc1)Nc1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1cc(Oc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Iodomethane (0.21 mL, 3.40 mmol, 1.5 equiv) is added to a cold (0° C.) mixture of 1-{4-[2-(1H-tetrazol-5yl)-pyridin-4-yloxy]-phenyl}-3-(3-trifluoromethyl-phenyl)-urea (Example 122) (1.0 g, 2.27 mmol) and potassium carbonate (0.94 g, 6.80 mmol, 3.0 equiv) in DMF abs. (5.8 mL), under an argon atmosphere. The reaction mixture is stirred at 0° C. for 2 h, allowed to warm to rt and stirred for additional 20 h. The resulting brown suspension is filtered and concentrated in vacuo. MeOH (10 mL) and DMF (0.5 mL) are added to the residue and the resulting suspension is filtered. The white solid is washed with MeOH and dried in vacuo to afford the title compound as a white solid. The filtrate is concentrated in vacuo and the residue is purified by MPLC (CH3CN/H2O/TFA) to afford additional title compound as a beige solid: ES-MS: 455.9 [M+H]+; single peak at tR=9.15 min (System 2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([NH:17][C:18]([N:20]3[CH2:23][CH:22]([CH2:24][NH:25]C(=O)OC(C)(C)C)[CH2:21]3)=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:25][CH2:24][CH:22]1[CH2:21][N:20]([C:18]([NH:17][C:10]2[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:13]=[CH:12][C:11]=2[N+:14]([O-:16])=[O:15])=[O:19])[CH2:23]1
Reactant: CC(C)(C)OC(=O)NCC1CN(C(=O)Nc2cc(-c3ccc(F)cc3)ccc2[N+](=O)[O-])C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1CN(C(=O)Nc2cc(-c3ccc(F)cc3)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
To a solution of tert-butyl (1-(4′-fluoro-4-nitrobiphenyl-3-ylcarbamoyl)azetidin-3-yl)methylcarbamate (2.0 g, 4.5 mmol) in DCM (60 mL) was added TFA (8 mL, 104 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was then concentrated under reduced pressure. The residue was basified with a saturated aqueous solution of NaHCO3 and extracted with a 15% MeOH in DCM. The organic layer was dried over Na2SO4 and concentrated to afford 3-(aminomethyl)-N-(4′-fluoro-4-nitro-[1,1′-biphenyl]-3-yl)azetidine-1-carboxamide (1.6 g, 100% yield) as yellow syrup which is used in the next step as such without any further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20](F)[N:19]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1)[CH3:2].[NH:25]1[CH2:31][CH:30]([OH:32])[CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[N:19]=[C:20]([N:25]5[CH2:31][CH:30]([OH:32])[CH2:29][NH:28][CH2:27][CH2:26]5)[CH:21]=[CH:22][CH:23]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1)[CH3:2]
Reactant: OC1CNCCNC1
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)c1
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCNCC(O)C3)n2)c1
Yield: 12 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 6-(5-ethylpyridin-3-yl)-1-(6-fluoropyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine and 1,4-diazepan-6-ol, 106 was obtained as an off-white solid (49.4 mg, 12%). MS (ESI) m/z: 416.1 [M+H]+
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1)=[O:23])([O-])=O>C(O)C.[Fe]>[NH2:4][C:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:21][C:22]([N:24]1[CH2:25][CH2:26][CH:27]([OH:30])[CH2:28][CH2:29]1)=[O:23]
Reactant: O=C(Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-])N1CCC(O)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1c(CC(=O)N2CCC(O)CC2)cccc1Oc1ccccc1F
Yield: 100.7 %

Procedure:
A mixture of iron powder (2.7 g.), ammonium chloride (0.3 g.), ethanol (20 ml.) and water (10 ml.) and a solution of 1-[2-{2-nitro-3-(2-fluorophenoxy)phenyl}acetyl]-4-hydroxypiperidine (2.7 g.) in ethanol (5 ml.) were treated in a similar manner to that of Example 1-(1) to give oily 1-[2-{2-amino-3-(2-fluorophenoxy)phenyl}acetyl]-4-hydroxypiperidine (2.5 g.). Thus obtained compound was dissolved in ethanol containing hydrochloric acid and evaporated under reduced pressure. The residue was crystallized with a mixture of ethanol and ethyl acetate to give white needles of the captioned compound (2 g.). mp 160° to 161° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][OH:11].C(N(CC)CC)C.CS(C)=O.N1C=CC=CC=1.S(=O)(=O)=O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: OCc1cc(F)c(F)cc1Br
Agent: O=S(=O)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=Cc1cc(F)c(F)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
A solution of (2-bromo-4,5-difluoro-phenyl)-methanol (1.23 g, 5.50 mmol), triethylamine (1.39 g, 13.75 mmol) and dimethyl sulfoxide (1.72 g, 22.00 mmol) in dichloromethane (25 mL) was cooled to 0° C. Then, sulfur trioxide-pyridine (1.32 g, 8.25 mmol) was added portionwise. After one hour stirring at 0° C., a second batch of triethylamine (1.39 g, 13.75 mmol), dimethyl sulfoxide (1.72 g, 22.00 mmol) and sulfur trioxide-pyridine (1.32 g, 8.25 mmol) were added to the above reaction mixture. After another 30 minutes at 0° C., the reaction solution was diluted with dichloromethane (50 mL), and then washed with saturated sodium bicarbonate and saturated sodium thiosulfate. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (RediSep® Flash column, 230-400 mesh, 10-30% ethyl acetate in hexane) afforded 2-bromo-4,5-difluoro-benzaldehyde (0.47 g, 39%). 1H NMR (300 MHz, CDCl3) δ 10.23 (s, 1 H), 7.77 (m, 1 H), 7.52 (m, 1 H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.CSC.B>O1CCCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: O=Cc1ccc(I)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a suspension of 4-iodobenzoic acid (14.88 g) in dry tetrahydrofuran (75 ml) was added borane dimethyl sulphide (6.12 ml ) dropwise under a nitrogen atmosphere. The reaction mixture was heated under reflux for 1 hr, after which time the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was dissolved indichloromethane (20 ml) and added to a suspension of the pyridinium chlorochromate (14.23 g) in dichloromethane (100 ml). The resulting mixture was heated under reflux for 1 hr and allowed to cool to room temperature. The resulting mixture was diluted with diethyl ether (250 ml) and filtered through a plug of arbocel. The filtrate was evaporated under reduced pressure, and the crude product was purified by column chromatography over silica gel eluting with dichloromethane to afford the title compound as a white solid (11.33 g).
Reaction SMILES: ClCC(O)CO.CN.CO.Cl.[CH3:12][NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17].[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>CO.C(N(CC)CC)C>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([N:13]([CH3:12])[CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[O:24]
Reactant: CNCC(O)CO
Reactant: O=C=NCCCl
Agent: CN
Agent: Cl
Agent: OCC(O)CCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(CC(O)CO)C(=O)NCCCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
A mixture of 3.3 g of 3-chloro-1,2-dihydroxy-n-propane and 20 ml of 30% methylamine-methanol solution is allowed to stand at room temperature for 3 days. The reaction mixture is condensed to dryness under reduced pressure, whereby 4.2 g of N-methyl-2,3-dihydroxy-n-propylamine hydrochloride are obtained as a crude product. 4.2 g of said crude product and 3 g of triethylamine are dissolved in 30 ml of methanol. To the solution, 3.2 g of 2-chloroethyl isocyanate are added dropwise to the solution at 0° to 5° C. The solution is stirred at room temperature for 2 hours. Then, the reaction solution is condensed under reduced pressure and the residue thus obtained is purified by silica gel chromatography (Solvent: chloroform-ethyl acetate-methanol(3:1:1)). 3.5 g of 1-(2-chloroethyl)-3-methyl-3-(2,3-dihydroxy-n-propyl)urea are obtained as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][C@H:3]1[CH:16]([CH3:18])[CH3:17].[NH:19]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:20][C:21](O)=[O:22].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:27]([O:26][C:24]([NH:19][CH2:20][C:21]([NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:4][C@H:3]1[CH:16]([CH3:18])[CH3:17])=[O:22])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
Tert-butyl(1R,3S,4S)-4-amino-3-isopropylcyclohexylcarbamate (780 mg) dissolved in DMF (10 mL) and cooled to 0° C. prior to the addition of N-Cbz-Gly-OH (1.14 g), 4-methylmorpholine (1.2 mL), and BOP (2.42 g). The reaction was stirred for 12 h at rt and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford tert-butyl (1R,3S,4S)-4-(2-benzyloxycarbonylaminoacetamido)-3-isopropylcyclohexylcarbamate (790 mg). MS found: (M+H)+=448.4.
Reaction SMILES: COC([C@@H]1CC2C=C3OC[C@@H](C4C=CC(OCC5C=CC(Cl)=C(Cl)C=5)=CC=4)OC3=CC=2CN1C(OC(C)(C)C)=O)=O.[C:42]([O:46][C:47]([N:49]1[C@H:58]([C:59]([OH:61])=O)[CH2:57][C:56]2[CH:55]=[C:54]3[O:62][CH2:63][C@@H:64]([C:66]4[CH:71]=[CH:70][C:69]([O:72][CH2:73][C:74]5[CH:79]=[CH:78][C:77]([Cl:80])=[C:76]([Cl:81])[CH:75]=5)=[CH:68][CH:67]=4)[O:65][C:53]3=[CH:52][C:51]=2[CH2:50]1)=[O:48])([CH3:45])([CH3:44])[CH3:43].[CH3:82][O:83][C:84](=[O:102])[C@@H:85]([NH2:101])[CH2:86][C:87]1[CH:92]=[CH:91][C:90]([C:93]2[CH:98]=[CH:97][C:96]([C:99]#[N:100])=[CH:95][CH:94]=2)=[CH:89][CH:88]=1>>[C:42]([O:46][C:47]([N:49]1[C@H:58]([C:59](=[O:61])[NH:101][C@H:85]([C:84]([O:83][CH3:82])=[O:102])[CH2:86][C:87]2[CH:88]=[CH:89][C:90]([C:93]3[CH:98]=[CH:97][C:96]([C:99]#[N:100])=[CH:95][CH:94]=3)=[CH:91][CH:92]=2)[CH2:57][C:56]2[CH:55]=[C:54]3[O:62][CH2:63][C@@H:64]([C:66]4[CH:71]=[CH:70][C:69]([O:72][CH2:73][C:74]5[CH:79]=[CH:78][C:77]([Cl:80])=[C:76]([Cl:81])[CH:75]=5)=[CH:68][CH:67]=4)[O:65][C:53]3=[CH:52][C:51]=2[CH2:50]1)=[O:48])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: COC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 76.7 %

Procedure:
(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester 8-methyl ester, (200 mg) hydrolyzed according to General Procedure B and the resulting (3R,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (172 mg) was coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (126 mg) according to General Procedure L to give (3R,8S)-8-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (191 mg). This intermediate (188 mg) was deprotected as described in General Procedure C to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(3R,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester hydrochloride (155 mg). LCMS (m/z): 749; 1H NMR (400 MHz, Methanol-d6): 8.54 (d, 1H), 7.95 (s, 1H), 7.87 (d, 1H), 7.81-7.72 (m, 2H), 7.63-51 (m, 4H), 7.50-7.47 (m, 2H), 7.38-7.32 (m, 3H), 7.01 (d, 2H), 6.99 (d, 2H), 5.07 (s, 2H) 5.04-5.03 (m, 1H), 4.34-4.31 (m, 1H), 4.12-4.08 (m, 1H), 4.01-3.96 (m, 3H), 3.75 (s, 3H), 3.74-3.63 (m, 4H), 3.11-2.97 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:21])[NH:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:6][N:5]=[C:4]([C:22]([OH:24])=O)[N:3]=1.Cl.[NH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][NH:26][C:22]([C:4]1[N:3]=[C:2]([OH:1])[C:7]([C:8](=[O:21])[NH:9][CH2:10][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:18]=[CH:19][CH:20]=2)=[CH:6][N:5]=1)=[O:24])[CH3:32]
Reactant: O=C(O)c1ncc(C(=O)NCc2cccc3ccccc23)c(O)n1
Reactant: CCOC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)CNC(=O)c1ncc(C(=O)NCc2cccc3ccccc23)c(O)n1
Temperature: 0 °C
Yield: 10.5 %

Procedure:
The mixture of step D product, 2-20-e, (2.5 g, 7.7 mmol), ethyl 2-aminoacetate hydrochloride (1.29 g, 9.3 mmol), TBTU (2.98 g, 9.3 mmol), DIPEA (2.0 g, 15.5 mmol) in DMSO (20 mL) and stirred at the ambient temperature overnight. Then the reaction mixture was added ice-water (40 mL), extracted with DCM (30 mL×2). The organic phase was concentrated to give a residue, which was purified by column chromatography with DCM:MeOH=150:1 to obtain 2-20 (330 mg, 11%). 1H NMR (300 MHz, DMSO-d6): δ 1.18-1.22 (t, J=6 Hz, 3H), 4.0-4.02 (d, J=6 Hz, 2H), 4.11-4.14 (q, J=6.0 Hz, 2H), 5.0-5.02 (d, J=6.0 Hz, 1H), 7.48-7.57 (m, 4H), 7.87 (m, 3H), 8.55 (br s, 1H), 9.48 (m, 1H), 9.87 (br s, 1H), 13.54 (br s, 1H). LC-MS: (M+H)+ 409.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][NH:13][C:12]2=[O:22])=[CH:7][CH:6]=1.[CH3:23][O:24][C:25](=[O:34])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>CN(C=O)C>[CH3:23][O:24][C:25](=[O:34])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:13]1[CH:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)[C:12]1=[O:22]
Reactant: COc1ccc(-n2c(-c3ccccc3)c[nH]c2=O)cc1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2ccc(OC)cc2)c1=O

Procedure:
The product is produced as described in example 1 from 2.4 g of NaH (80% suspension in mineral oil), 21.3 g of 1-(4-methoxyphenyl)-5-phenyl-4-imidazolin-2-one, 160 cc. of DMF 19 g of 8-bromocaprylic acid methyl ester and 2.4 g of NaJ. Eluant in chromatographic purification: hexane/ethyl acetate.