Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=O)[CH3:18])[C:3]=1[O:20][CH2:21][CH3:22].[CH3:23][CH2:24][O:25][C:26]([CH:28](P(OCC)(OCC)=O)[F:29])=[O:27].C([Li])CCC>C1COCC1>[Cl:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:18])=[C:28](/[F:29])\[C:26]([O:25][CH2:24][CH3:23])=[O:27])[C:3]=1[O:20][CH2:21][CH3:22]
Reactant: CCOc1c(C(C)=O)cc2c(c1Cl)C(C)(C)CC=C2C(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Cl)c1OCC)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure F-1, 1-(4-chloro-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydronaphthalen-2-yl)-ethanone (Compound A-121, 0.23 g, 0.72 mmol) and triethyl 2-fluoro-2-phosphonoacetate (566 mg, 2.3 μmmol) were reacted with n-butyllithium (1.6 M in hexanes, 1.46 mL, 2.3 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% to 4% ethyl acetate in hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:21])([CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[C@@H:10](C)[C:11](O)=O.C([N:24](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)(C)C>[NH2:24][C@H:10]([CH3:11])[C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:21])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: C[C@@H](C(=O)O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: C[C@@H](N)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 70 °C
Yield: 41.2 %

Procedure:
A solution of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoic acid (50 mg, 0.17 mmol) (obtained in reference example 30) and triethylamine (0.35 mL, 0.25 mmol) in tert-butanol (3 mL) was treated with diphenylphosphoryl azide (0.44 mL, 0.20 mmol) and the reaction mixture was heated at reflux for 25 h. Removal of the volatiles under reduced pressure afforded a crude product that was partitioned between chloroform and saturated NaHCO3 aqueous solution. The organic phase was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to a brown oil that was dissolved in methanol (2 mL) and 1N aqueous KOH (1 mL) and then heated at 70° C. during 15 h. The volatiles were removed in vacuo and the aqueous residue was acidified to pH 1 by addition of 1N aqueous HCl and washed with CHCl3. The aqueous phase was basified with saturated Na2CO3, saturated with NaCl and extracted (3x) with CHCl3. The collected organic phases were dried over anhydrous Na2SO4, the drying agent was filtered and the filtrate was concentrated to afford the title product (18.8 mg) pure by TLC analysis. An analytical sample was obtained by chromatography on silica gel (CHCl3 : MeOH 5:1) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[C:6]([CH:11]=[O:12])=[CH:7]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1c[nH]c2cc(Br)ccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cn(Cc2ccccc2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-Bromo-1H-indole-3-carbaldehyde (1 eq.) from the previous step was dissolved in DMF (0.19 M). Sodium hydride was added (1.5 eq.) and the resulting solution was stirred at RT for 20 min. Benzyl bromide (1 eq.) was then added and the reaction solution was allowed to stir at RT for 24 h. The reaction mixture was subsequently quenched with water and extracted with EtOAc. The combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc 3:7 (v/v) Hex:EtOAc) afforded the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15]C3C=CC=C([N+]([O-])=O)C=3)[C:13]([CH2:25][CH2:26]O)=[N:12][C:11]=2[CH:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(OCCC1N(CC2C=CC([N+]([O-])=O)=CC=2)C(SC2C=C(Cl)C=C(Cl)C=2)=C(C(C)C)N=1)(=O)[NH2:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:25][C:26]#[N:32])=[N:12][C:11]=2[CH:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)c1nc(CCO)n(Cc2cccc([N+](=O)[O-])c2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1nc(CCOC(N)=O)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)c1nc(CC#N)n(C)c1Sc1cc(Cl)cc(Cl)c1
Yield: 83 %

Procedure:
2-(2-Carbamoyloxyethyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(m-nitrobenzyl)-1H-i-imidazole (128b) was obtained from (126b) by the same synthetic process as that for (128a) in Example 140 (yield 83%). mp 167-169° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]3[CH2:18][CH2:19][CH2:20][CH:14]3[CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CO.[Ni]>[CH2:13]1[N:12]([C:5]2[CH:6]=[CH:7][C:8]([NH2:9])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:17][CH2:16][N:15]2[CH2:18][CH2:19][CH2:20][CH:14]12
Reactant: COc1cc(N2CCN3CCCC3C2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: COc1cc(N2CCN3CCCC3C2)ccc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of the product of Example 47A (1.58 g, 5.68 mmol) in methanol (100 mL) was added Raney-Ni (158 mg) and the mixture was stirred at ambient temperature under hydrogen for 4 hours. The catalyst was filtered off and the filtrate was concentrated to give the title compound, which was used in the next step without further purification. MS: 248 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[C:10](=[O:11])[C:9]2[C:4](=[CH:5][C:6]([O:14]C)=[C:7]([Cl:13])[C:8]=2[Cl:12])[C:3]1=[O:16].Cl.N1C=CC=CC=1>>[CH3:1][C:2]1([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[C:10](=[O:11])[C:9]2[C:4](=[CH:5][C:6]([OH:14])=[C:7]([Cl:13])[C:8]=2[Cl:12])[C:3]1=[O:16]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1cccs1)C2=O
Agent: Cl
Solvent: c1ccncc1
Product: CC1(c2cccs2)C(=O)c2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 175 °C

Procedure:
A stirred mixture of 2-methyl-2-(2-thienyl)-4,5-dichloro-6-methoxyindan-1,3-dione (3.81 g., 0.0112 mole) and pyridine hydrochloride (36 g.) is heated at 175°C. for one half hour, then poured into crushed ice-water (500 ml.) to give 2-methyl-2-(2-thienyl)-4,5-dichloro-6-hydroxyindan-1,3-dione.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[C:1]1([C@H:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2=Nc3ccccc3OC2)cc1
Solvent: Cc1ccccc1
Product: c1ccc([C@@H]2COc3ccccc3N2)cc1
Temperature: 40 °C
Reaction time: 22 h
Yield: 100.1 %

Procedure:
To an argon-purged pressure-resistant glass vessel (100 mL) equipped with a magnetic stir bar, RuCl[(R)-daipena][(R)-segphos] (3.3 mg, 3.1 μmol) and KO(t-Bu) (17.1 mg, 0.152 mmol) were added, and the vessel was purged with argon again. To this vessel, a toluene (1.2 mL) solution containing 3-phenyl-2H-1,4-benzoxazine (128.7 mg, 0.615 mmol) and being degassed by the freeze-pump-thaw technique in advance was added by pressure transfer using a cannula. An operation in which hydrogen was introduced into the pressure-resistant vessel up to 0.8 MPa and then released was repeated 10 times to completely substitute the inside with hydrogen. Then, hydrogen was introduced up to 2.0 MPa, and the vessel was stirred in a water bath at 40° C. for 22 hours. After hydrogen was released, the solution was concentrated under reduced pressure, and the residue was purified through a silica gel short path column (hexane:ethyl acetate=1:1) to obtain (R)-3,4-dihydro-3-phenyl-2H-1,4-benzoxazine (130.1 mg, 990). A result of an analysis was conducted by high performance liquid chromatography (column: CHIRALCEL OD-H, mobile phase: hexane:IPA=70:30, 0.7 mL/min) showed that the optical purity of this product was 98% ee.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[O:11][CH2:10][CH2:9][O:8]1
Reactant: Cc1ccsc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccsc1C1OCCO1

Procedure:
3-Methyl-2-thiophenecarboxaldehyde (12 g), 1,2-ethanediol (20 ml) and a trace of toluene-p-sulphonic acid were heated at reflux in toluene (250 ml) under Dean and Stark conditions for 4 h. The reaction mixture was cooled and washed with 5% aqueous sodium carbonate solution and water. The toluene solution was evaporated to give an oil which was distilled to give the title compound as a pale yellow oil (14.5 g) b.p. 95°/0.1 mm.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][CH:13]=2)=[O:11])[CH2:5][CH2:4]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide hydrochloride (example A160) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@H:26]4[CH2:30][N:29]([C@@H](C5C=CC(OC)=CC=5)C)[C:28](=[O:41])[CH2:27]4)[CH3:25])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[CH:1]1([N:4]2[C:8]3[C:9]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:41])[CH2:27]4)[CH3:25])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(OC)c(OC)c4)cc4ncn(C5CC5)c34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 60 °C
Reaction time: 1.75 h

Procedure:
(R)-4-((R)-1-(3-cyclopropyl-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.38 (80 mg, 0.14 mmol) was dissolved in TFA (2 mL) and heated to 60° C. with stirring. After 1.75 h, the temperature was increased to 65° C. After an additional 4.25 h, the temperature was decreased to 55° C. After an additional 18 h, the red solution was concentrated in vacuo and diluted with EtOAc (15 mL) and saturated aqueous NaHCO3 (15 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×15 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (0% to 10% MeOH in DCM) provided (R)-4-((R)-1-(3-cyclopropyl-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.04
Reaction SMILES: C[S-].[Na+].[F:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13]C)=[CH:7][C:6]=1[F:15]>CN(C=O)C>[F:4][C:5]1[C:6]([F:15])=[CH:7][C:8]([OH:13])=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(F)c(F)cc1OC
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(F)cc1O
Temperature: 100 °C

Procedure:
Sodium thiomethoxide (0.4 g) was added to a solution of 1,2-difluoro-4,5-dimethoxybenzene (1.0 g) in DMF (10 ml) at RT, then heated at 100° C. for 4 h. A further 0.8 g of sodium thiomethoxide was added, the mixture heated for a further 2 h. The mixture was cooled, partitioned between ethylacetate/2M hydrochloric acid, the organics dried and evaporated under reduced pressure, yield 1.05 g
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:22]([O:26][C:27]([N:29]1[C:41]2[CH2:40][CH:39]([C:42]([S:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)(=[O:50])=[O:49])([C:44]([O:46][CH3:47])=[O:45])[CH3:43])[CH2:38][CH2:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[C:33](Br)[CH:34]=2)=[O:28])([CH3:25])([CH3:24])[CH3:23].[CH3:58][NH:59][CH3:60].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1COCC1.CCOC(C)=O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:22]([O:26][C:27]([N:29]1[C:41]2[CH2:40][CH:39]([C:42]([S:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)(=[O:50])=[O:49])([C:44]([O:46][CH3:47])=[O:45])[CH3:43])[CH2:38][CH2:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[C:33]([N:59]([CH3:60])[CH3:58])[CH:34]=2)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)C(C)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(Br)cc23)C1)S(=O)(=O)c1ccccc1
Reactant: CNC
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(N(C)C)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 80 °C
Yield: 24.2 %

Procedure:
Under argon a flask was charged with 24 mg of (0.03 mmol, 0.05 eq) tris(dibenzylidene-acetone) dipalladium, 16 mg (0.05 mmol, 0.1 eq) of 2(di-tertbutylphosphino)biphenyl and 85 mg (0.88 mmol, 1.7 eq) of sodium tert-butylate, evacuated and backfilled with argon. 300 mg (0.52 mmol) of (RS,SR)-2-(-1-benzenesulfonyl-1-methoxycarbonyl-ethyl)-6-bromo-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester in 15 ml of toluene were added, followed by a solution of 1.95 ml 2M (3.9 mmol, 7.5 eq) of dimethylamine in THF. The solution was heated to 80° C. overnight in a sealed tube. The mixture was diluted with EtOAc and a saturated solution of Na2CO3 was added. The inorganic layer was extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. Column chromatography yielded 68 mg (24%) of (RS,SR)-2-(-1-benzenesulfonyl-1-methoxycarbonyl-ethyl)-6-dimethylamino-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester as orange oil, MS: 541 (MH+).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.N[N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C@H:11]1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.S(=O)(=O)(O)O>C(O)C>[CH:20]1([C@H:11]2[N:10]3[C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])=[CH:4][C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([C:15]=43)[O:13][CH2:12]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)C(C)=O
Reactant: NN1c2ccccc2OC[C@H]1C1CCCCC1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cc2cccc3c2n1[C@H](C1CCCCC1)CO3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
Ethyl pyruvate (882 mg, 7.59 mmol) was added to a solution of (R)-4-amino-3-cyclohexyl-3,4-dihydro-2H-1,4-benzoxazine (1.47 g, 6.33 mmol) in ethanol (40 ml). The reaction mixture was stirred at room temperature for 15 min. To the reaction mixture, sulfuric acid (10% v/v in ethanol; 8.0 ml) was added. The reaction mixture was refluxed for 2 h. The mixture was cooled to room temperature and partitioned between ethyl acetate and sodium carbonate solution. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography eluting with 0-10% (v/v) ethyl acetate in heptane to afford ethyl (R)-3-cyclohexyl-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine-5-carboxylate (1.49 g, 4.76 mmol).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(Br)c1OCc1ccc(S(N)(=O)=O)cc1
Temperature: 80 °C
Yield: 92.1 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.743 mmol) in acetonitrile (10 mL) was added potassium carbonate (307 mg, 2.228 mmol) and 4-(bromomethyl)benzenesulfonamide (370 mg, 1.48 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 300 mg of 4-((6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)benzenesulfonamide crude product as a solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](OC)=[O:8])=[C:4]([NH:11][CH2:12][CH3:13])[CH:3]=1.[OH-].[Na+].Cl.C([N:19](CC)CC)C.[Cl-].[NH4+].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CO.O.CCOC(C)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([NH2:19])=[O:8])=[C:4]([NH:11][CH2:12][CH3:13])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: CCNc1cc(Br)sc1C(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCNc1cc(Br)sc1C(N)=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 41.8 %

Procedure:
To a solution of methyl 5-bromo-3-(ethylamino)thiophene-2-carboxylate (2.46 g, 9.31 mmol) in MeOH (30 mL) was added a solution of sodium hydroxide (1.12 g, 27.9 mmol) in water (15 mL). After stirring at 60° C. for 4 h, 6 M aqueous HCl (2.9 mL) was added to the mixture to adjust the pH to 10. After removal of the solvent at reduced pressure, the residue was diluted with DMF (70 mL). Then, triethylamine (25.8 mL, 186 mmol) and ammonium chloride (10.0 g, 186 mmol) were added. After stirring at room temperature for 10 min, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.7 g, 55.9 mmol) and 1-hydroxybenzotriazole (7.55 g, 55.9 mmol) were added to the mixture and the stirring was continued for 17 h. Then, water and EtOAc were added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, hexane to 70:30 hexane/EtOAc) to give the title compound (0.97 g, 42%) as a pale green solid:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.[NH2:38][C@H:39]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=2)=[CH:47][CH:46]=1)[CH2:40][C:41]([OH:43])=[O:42].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([NH:38][C@H:39]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=2)=[CH:47][CH:46]=1)[CH2:40][C:41]([OH:43])=[O:42])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Reactant: N[C@@H](CC(=O)O)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
A solution of succinic acid mono-benzyl ester (71.1 mg, 0.342 mmol), EDCl (65.5 mg, 0.342 mmol) and HOAt (46.5 mg, 0.342 mmol) in DMF (1 ml), which is allowed to stir at room temperature for 1 hour, is added to a solution of (R)-3-amino-4-(3′-chlorobiphenyl-4-yl)butanoic acid (66 mg, 0.228 mmol) and DIPEA (0.080 ml, 0.456 mmol) in a mixed solvent DMF (2 ml) and water (2 ml). The reaction mixture is allowed to stir for 3 hours, and then diluted with H2O. The products are extracted twice with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give crude. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-3-(4-(benzyloxy)-4-oxobutanamido)-4-(3′-chlorobiphenyl-4-yl)butanoic acid (42.4 mg) as a white solid; HPLC retention time=1.22 minutes (condition B); MS (m+1)=480.35; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.44-2.75 (m, 6H) 2.86-2.99 (m, 2H) 4.48-4.56 (m, 1H) 5.11 (s, 2H) 6.29 (br d, J=8.6 Hz, 1H) 6.97-7.07 (m, 10H) 7.25-7.36 (m, 2H) 7.42-7.50 (m, 2H) 7.54 (br t, J=1.6 Hz, 1H).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH3:11][S:12](O)(=[O:14])=[O:13].C(N(CC)CC)C.S(Cl)(Cl)=O>ClCCl>[CH3:11][S:12]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)O
Reactant: On1nnc2ccccc21
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)On1nnc2ccccc21
Reaction time: 8 h
Yield: 28.2 %

Procedure:
In dichloromethane (20 ml) are added 1-hydroxy-1,2,3-benzotriazole (2.70 g) and methanesulfonic acid (1.92 g) and thereto is added triethylamine (5.6 ml). To the solution is added dropwise thionyl chloride (1.43 ml) with stirring under ice-cooling during 15 minutes. The mixture is stirred at the same temperature for 1 hour and 10 minutes and at room temperature for 7 hours and 45 minutes, and then allowed to stand overnight. Dichloromethane is distilled off under a reduced pressure. To the residue are added water (30 ml) and ethyl acetate (100 ml). The ethyl acetate layer is washed with a saturated aqueous sodium hydrogen carbonate and water in order and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off. To the residue is added petroleum ether and the mixture is filtered to give 1-methanesulfonyloxy-1,2,3-benzotriazole (1.2 g).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[C:16]([C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[O:27])[C:17]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:12][C:11]([CH3:44])([CH3:43])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[Na].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[C:16]([CH:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=3)[OH:27])[C:17]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:12][C:11]([CH3:44])([CH3:43])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)C[C@H](O[Si](C)(C)C(C)(C)C)c2c(cc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC1(C)C[C@H](O[Si](C)(C)C(C)(C)C)c2c(cc(C3CCCC3)c(C(O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)cc2)O1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under argon, 102 mg (0.16 mmol) of [(4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-7-cyclopentyl-5-(4-fluorophenyl)-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl][4-(trifluoromethyl)phenyl]methanone (Example 13A) are initially charged in 2 ml of abs. toluene and cooled to −78° C. 250 μl (0.25 mmol) of a diisobutylaluminum hydride solution (1 M in hexane) are slowly added dropwise, and the mixture is stirred at −78° C. After 30 min, another 80 μl (0.08 mmol) of diisobutylaluminum hydride solution (1 M in hexane) are added dropwise, and the mixture is stirred for another 30 min. 20% strength sodium/potassium tartrate solution is added, and the mixture is extracted repeatedly with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product obtained is purified by preparative thick-layer chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). This gives 47 mg (46% of theory) of the title compound which is used in the next step without further characterization.