Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([CH3:28])=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([CH3:28])=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: [H][H]
Reactant: CCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)sc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)sc1C
Yield: 88.2 %

Procedure:
Ethyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-5-methyl-1,3-thiazole-4-carboxylate obtained in Example (40d) (75 mg, 0.17 mmol) was dissolved in ethanol (3 mL). A 10% palladium-carbon catalyst (40 mg) was added, and the mixture was stirred in a hydrogen atmosphere for 21 hours. The reaction solution was filtered through celite and then concentrated under reduced pressure to obtain 44.9 mg of the title compound as a colorless oily substance. The resulting compound was used for the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([CH2:20][C:21]#N)=[CH:16][CH:15]=1.C([O:28][C:29](=O)[C@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:31])(=O)C>>[OH:31][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([N:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[CH:10]=1)[CH2:21][CH2:20][C:17]1[CH:18]=[N:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=1)=[O:28]
Reactant: Cc1nc2ccc(N)cc2o1
Reactant: CC(=O)OC(=O)[C@@H](O)c1ccccc1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Product: Cc1nc2ccc(N(CCc3ccc(C(F)(F)F)nc3)C(=O)[C@@H](O)c3ccccc3)cc2o1

Procedure:
In analogy to example 49, 2-Methyl-benzooxazol-6-ylamine, (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (S)-(+)-O-acetyl-L-mandelic acid were successively coupled and hydrolysed to give the target compound. MS(m/e): 456.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[OH-].[Na+].Cl[CH:16]([F:18])[F:17].Cl>ClCCl.O.C(O)(C)C>[Cl:1][C:2]1[C:3]([O:12][CH:16]([F:18])[F:17])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: FC(F)Cl
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc(OC(F)F)c(Cl)cc1F
Reaction time: 4 h

Procedure:
To 0.53 g of 2-chloro-4-fluoro-5-nitrophenol XV-1 were added 3 ml of isopropanol, 3 ml of water and 0.72 g of sodium hydroxide, and the resultant mixture was heated at 50° to 60° C. while introducing chlorodifluoromethane gas for 4 hours. The mixture was stirred for 4 hours and during that period mixed twice with 0.50 g of sodium hydroxide at intervals of 1.5 hours. After cooling, the reaction mixture was neutralized with 2N hydrochloride acid and shaken with dichloromethane. The dichloromethane layer was dried and concentrated. The residue was chromatographed on a column of silica gel, eluting with n-hexane-ethylacetate (100:5 v/v). The eluate was concentrated to give 0.24 g of the titled compound XII-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:31])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25]OS(C)(=O)=O)[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:32])=[CH:10]2)=[C:4]([CH3:33])[CH:3]=1.[Na+].[I-:35].O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:31])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][I:35])[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:32])=[CH:10]2)=[C:4]([CH3:33])[CH:3]=1
Reactant: Cc1cc(N2CCC(CCOS(C)(=O)=O)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(N2CCC(CCI)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A mixture of methanesulfonic acid 2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethyl ester (0.70 g) and NaI (0.59 g) in acetone (14 mL) was heated at reflux for 3 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=10/1) to obtain 1-(4-bromo-2,6-dimethyl-phenyl)-4-[4-(2-iodo-ethyl)-piperidin-1-yl]-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (0.65 g) as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH2:14]OC)=[C:8]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)[C:7]([CH3:22])=[CH:6]2.C([O-])([O-])=O.[Cs+].[Cs+].FC1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>Cl.O1CCOCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1)=[C:8]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)[C:7]([CH3:22])=[CH:6]2
Reactant: O=Cc1ccc(F)cc1
Reactant: COCOc1c(-c2ccsc2)c(C)cc2cc(OC)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccsc3)c(C)cc2c1
Yield: 73.8 %

Procedure:
A solution of 3-(6-Methoxy-1-methoxymethoxy-3-methyl-naphthalen-2-yl)-thiophene (199) (0.347 g, 1.10 mmol) in 4 N HCl/Dioxane (5 mL) was stirred at room temperature for 30 min. The solvent was removed from the reaction mixture, then dissolved in DMSO (3 mL) followed by addition of Cs2CO3 (0.899 g, 2.76 mmol) and 4-fluorobenzaldehye (0.142 mL, 1.32 mmol). The reaction mixture was irradiated with microwave at 80° C. for 4.5 h. Reaction mixture was diluted with water and EtOAc, separated the layers, then the aqueous layer was extracted with EtOAc. The combined organic layer was washed with water followed by brine, dried over Na2SO4, filtered and concentrated. The crude material was purified with a gradient of 5% EtOAc in hexanes over 50 min to afford 0.304 g (74%) of the title compound (200) as oil. 1H NMR (400 MHz, d-CDCl3): δ 2.32 (s, 3H), 3.93 (s, 3H), 6.74 (d, J=8.6 Hz, 2H), 6.90-6.91 (m, 1H), 7.02-7.06 (m, 2H), 7.13 (m, 1H), 7.20-7.22 (m, 1H), 7.58 (s, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.69 (d, J=9.2 Hz, 1H), 9.81 (s, 1H).
Reaction SMILES: Br[CH:2]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[NH:4][C:3]1=[O:15].[N-:16]=[N+:17]=[N-:18].[Na+]>CS(C)=O>[N:16]([CH:2]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[NH:4][C:3]1=[O:15])=[N+:17]=[N-:18]
Reactant: O=C1Nc2ccccc2CCCCC1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1CCCCc2ccccc2NC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one (14.2 g) and sodium azide (7.1 g) in dimethylsulfoxide (400 ml) is maintained at 80° C. under an atmosphere of nitrogen for 3 hours. The reaction mixture is poured into ice/water (1200 ml) and the suspension is stirred for 30 minutes. The solid is filtered off, washed with water (300 ml) and dried to give 3-azido-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:24]([NH:31][C:32]([N:15]1[CH2:16][CH2:17][CH2:18][CH:13]([N:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:3]([Cl:2])[C:4]=3[C:5]3=[N:22][O:21][C:20]([CH3:23])=[C:6]3[C:7]2=[O:19])[CH2:14]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Agent: I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1onc2c1c(=O)n(C1CCCN(C(=O)NCc3ccccc3)C1)c1cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a suspension of 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (50 mg, 0.11 mmol) in tetrahydrofuran (3 mL) add benzyl isocyanate (16 μL, 0.12 mmol) and follow by potassium carbonate (23 mg, 0.17). Stir the mixture at room temperature under nitrogen overnight. concentrate the mixture, partition between 20% isopropanol/chloroform and water, and separate. Wash the organic layer with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–0.5% methanol/chloroform) to give 44.4 mg of the title compound as an orange solid, 88% yield. 1H NMR: consistent with structure. MS (ion spray) 451 (M+).
Reaction SMILES: C(OC([N:8]([C:13]1[CH:51]=[CH:50][C:16]([C:17]([S:19][CH2:20][C:21]([O:23][C@H:24]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]3[CH2:49][CH2:48]3)[CH:36]=2)[CH2:25][C:26]2[C:31]([Cl:32])=[CH:30][N+:29]([O-:33])=[CH:28][C:27]=2[Cl:34])=[O:22])=[O:18])=[CH:15][C:14]=1[O:52][CH2:53][CH:54]1[CH2:56][CH2:55]1)[S:9]([CH3:12])(=[O:11])=[O:10])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:34][C:27]1[CH:28]=[N+:29]([O-:33])[CH:30]=[C:31]([Cl:32])[C:26]=1[CH2:25][C@@H:24]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:43])[F:44])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:23][C:21](=[O:22])[CH2:20][S:19][C:17](=[O:18])[C:16]1[CH:50]=[CH:51][C:13]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:14]([O:52][CH2:53][CH:54]2[CH2:55][CH2:56]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoylthio)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.046 g, 0.053 mmol) in DCM (2 ml), HCl 4M in dioxane (0.013 ml, 0.053 mmol) was added and the resulting mixture was stirred at RT overnight. Three more additions of HCl 4M in dioxane (0.265 ml, 1.06 mmol) over five days were performed. The volatiles were removed under vacuum and the crude was purified by filtration through a silica gel cartridge (DCM:Et2O=7:3) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3-(cyclopropylmethoxy)-4-(methylsulfonamido)-benzoylthio)acetoxy)ethyl)pyridine 1-oxide as a colorless oil (0.032 g, 0.042 mmol, 79% yield, MS/ESI+ 761.26 [MH]+, [αD]=−46.44, c=0.5, MeOH).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C.O>ClCCCl>[O:2]=[CH:3][CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc2nc(-c3ccccc3)n(CC(OC)OC)c12
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cccc2nc(-c3ccccc3)n(CC=O)c12
Yield: 85.1 %

Procedure:
Methyl 1-(2,2-dimethoxyethyl)-2-phenyl-1H-benzo[d]imidazole-7-carboxylate (719 mg, 2.1 mmol) from Step A above was heated to reflux in 1:1 trifluoroacetic acetic acid/water (6 mL) and 1,2-dichloroethane (2 mL) for 2 h. The reaction mixture was concentrated, diluted with ethyl acetate, and pH adjusted to 8 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with additional ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methyl 1-(2-oxoethyl)-2-phenyl-1H-benzo[d]imidazole-7-carboxylate as a light pink solid (526 mg, 85%): 1H NMR (500 MHz, CDCl3) δ 9.80 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.54-7.50 (m, 3H), 7.37 (d, J=7.5 Hz, 1H), 5.26 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[N:30]([C:33]1[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=1[C:35]([O:37][CH3:38])=[O:36])=[C:31]=[O:32]>C(Cl)Cl>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[CH:40][CH:41]=[CH:42][C:33]=1[NH:30][C:31]([N:16]([C:12]1[N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[CH:15]=[CH:14][N:13]=1)[CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=[O:32]
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: CC(C)c1ccc(-c2ccnc(NCc3cccs3)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)N(Cc1cccs1)c1nccc(-c2ccc(C(C)C)cc2)n1
Temperature: 100 °C
Yield: 2.6 %

Procedure:
To a solution of [4-(4-isopropyl-phenyl)-pyrimidin-2-yl]-thiophen-2-ylmethyl-amine (50 mg, 0.16 mmol) in DCM (2 mL) was added triethylamine (33 μL, 0.24 mmol) and methyl 2-isocyanatobenzoate (32 mg, 0.18 mmol). The resulting reaction mixture was heated in a CEM Exployer PLS™ microwave at 100° C. for 30 min. After cooling to room temperature the solvent was evaporated. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate 9:1 to give 2 mg of 2-{3-[4-(4-isopropyl-phenyl)-pyrimidin-2-yl}-3-thiophen-2-ylmethyl-ureido}-benzoic acid methyl ester. LCMS m/z: 488 (M+1)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[NH:8][C:7]=1[Si](CC)(CC)CC)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[F:17][C:15]([F:16])([F:18])[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][NH2:1]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: NCCc1c[nH]c2ccc(C(F)(F)F)cc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(2-azidoethyl)-2-(triethylsilyl)-5-(trifluoromethyl)-1H-indole (0.400 g; 1.09 mmol) and triphenylphosphine (0.427 g; 1.63 mmol) in methanol (5 mL) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude material was dissolved in a solution of tetrabutylamonium fluoride (3.26 mL, 1M) in THF, stirred at room temperature for 36 hours, and concentrated under reduced pressure. The crude material was used without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C@H:29]([OH:33])[C:30]([NH2:32])=[O:31])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[O-:34][CH2:35]C.[Na+].C(=O)(OCC)OCC>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][CH:29]3[O:33][C:35](=[O:34])[NH:32][C:30]3=[O:31])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)N1C(=O)[C@@](C)(C[C@H](O)C(N)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Solvent: CO
Product: CCC(CC)N1C(=O)[C@@](C)(CC2OC(=O)NC2=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
To a solution of 10.3 mg (0.02 mmol) of (S)-3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanamide (Example 81, Step D) in MeOH (2.5 mL) was added 0.50 mL (1.22 mmol) of sodium ethoxide (21 wt. % solution in ethanol) and 1.20 mL (9.90 mmol) of diethyl carbonate. The resulting mixture was heated at reflux for 15 min, and then was concentrated under reduced pressure. The residue was partitioned between 0.5 M HCl and EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 60 MeCN in water to 80 MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound (mixture of ether epimers) as a white solid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:27])=O>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([Cl:27])=[O:24])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
After 4-n-octyloxybiphenyl-4'-carboxylic acid (3.0 g) was heated under reflux together with an excessive amount of thionyl chloride for 6 hours, unaltered thionyl chloride was removed by distillation to give 4-n-octyloxybiphenyl-4'-carboxylic acid chloride.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([C:13](=O)[C:14](C)(C)C)[C:11](=[O:19])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.BrCC#[N:34]>C1COCC1.CCCCCC>[C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]2[CH2:9][CH2:10][C:11](=[O:19])[N:12]2[CH2:13][C:14]#[N:34])=[CH:3][CH:2]=1
Reactant: CC(C)(C)C(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Reactant: N#CCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#CCN1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.5 g (5.97 mmol) (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1, R1═H) is dissolved in 15 ml dry THF and cooled to −78° C. After the addition of 4.13 ml butyl lithium in hexane (1.59 M) the yellow solution is stirred at −78° C. for 30 min. Subsequently, 475 □l (855 mg, 7.16 mmol) bromoacetonitrile is added and the mixture is warmed up to room temperature overnight. The reaction is then quenched on addition of 10 ml saturated NH4Cl solution followed by the addition of 6 ml water and the mixture is extracted with 2×40 ml ethyl acetate. The combined organic layers are separated, dried over MgSO4, filtered and evaporated. The resulting residue is purified by column chromatography (dichloromethane:methanol=99:1) to give ((S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidin-1-yl)acetonitrile (1-a, R1=cyanomethyl) as off-white solid. NMR (400 MHz, DMSO-d6, □/ppm): 7.65 (m, 4 H); 7.47 (t, J=7.4, 2 H); 7.40 (m, 3 H); 4.57 (d, J=17.7, 1 H); 4.44 (d, J=17.7, 1 H); 3.91 (m, 1 H); 3.19 (dd, J=3.9, 13.8, 1 H); 2.70 (dd, J=9.2, 13.8, 1 H); 2.18 (m, 2 H); 1.95 (m, 1 H); 1.77 (m, 1 H). MS (ESI, m/e) 291 [M+H]+. IR (solution in CH2Cl2, □/cm−1): 3025; 2985; 2257; 1697; 1688; 1486; 1421; 1323; 1271; 1182; 760; 699.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:14][C:15]1[CH:16]=[C:17]([NH2:29])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26].C(N(C(C)C)C(C)C)C>S(Cl)(Cl)=O.ClCCl>[Cl:14][C:15]1[CH:16]=[C:17]([NH:29][C:11](=[O:13])[CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(NC(=O)CCc2ccc(Cl)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 0.271 g (1.236 mmol) of (3-(2,4-dichloro-phenyl)-propionic acid in 3.00 mL thionyl chloride was stirred for 2 hours at RT, evaporated down i. vac. and dissolved in 10 mL dichloromethane. This solution of the acid chloride was slowly added dropwise, while cooling with ice, to a solution of 0.300 (1.236 mmol) of 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (intermediate product Z1b) and 0.32 mL (1.854 mmol) of ethyl-diisopropylamine in 10 mL dichloromethane and the mixture was stirred for 16 hours at RT. The reaction mixture was washed with sat. aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated down i. vac. The residue was dissolved in EtOAc and purified by column chromatography (silica gel, EtOAc/MeOH/conc. aqueous ammonia 90:10:1).
Reaction SMILES: O.Cl.[CH2:3]([N:10]1[CH2:15][C:14]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21](O)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[O:13][CH2:12][C:11]1=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N1CC(CCN2CCC(C3C=CC=CC=3)(O)CC2)(C2C=CC([Cl:59])=C(Cl)C=2)OCC1=O)C1C=CC=CC=1.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:89][N:90]([CH3:108])[C:91]1[S:92][CH:93]=[C:94](C2(C3C=CC=CC=3)CCNCC2)[N:95]=1>CN(C=O)C>[ClH:37].[ClH:59].[CH2:3]([N:10]1[CH2:15][C:14]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][C:21]([C:94]3[N:95]=[C:91]([N:90]([CH3:108])[CH3:89])[S:92][CH:93]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)[O:13][CH2:12][C:11]1=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)c1nc(C2(c3ccccc3)CCNCC2)cs1
Reactant: O=C1COC(CCN2CCC(O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1nc(C2(c3ccccc3)CCN(CCC3(c4ccc(Cl)c(Cl)c4)CN(Cc4ccccc4)C(=O)CO3)CC2)cs1
Yield: 223.7 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 41 from 1.1 g of the compound obtained in step B of EXAMPLE 14, 1.3 g of 4-[2-(dimethylamino)thiazol-4-yl]-4-phenylpiperidine p-toluenesulfonate, 0.97 g of K2CO2 and 4 ml of DMF to give 0.76 g of the expected product. M.p.=155-160° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[C:26]=1[F:27])(=O)=O.[CH3:30][O:31][C:32]1[CH:41]=[C:40]([CH3:42])[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1.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>[F:27][C:26]1[C:11]2[C:12]([C:22](=[O:25])[NH:23][CH3:24])=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[O:14][C:10]=2[CH:9]=[CH:8][C:7]=1[C:39]1[C:40]([CH3:42])=[CH:41][C:32]([O:31][CH3:30])=[C:33]([CH:38]=1)[C:34]([O:36][CH3:37])=[O:35]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)c(F)c12
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1OC
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)c(F)c12
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A mixture of the above prepared 4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (assumed 0.211 mmol), methyl 2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.078 g, 0.253 mmol), (Ph3P)4Pd (0.024 g, 0.021 mmol) and cesium carbonate (0.103 g, 0.317 mmol) in a mixture of H2O (0.2 mL)/1,4-dioxane (1 mL) was stirred at 95° C. for 2 hours 30 min. The mixture was left standing at r.t. overnight. The mixture was diluted with 3.5 ml 1,4-dioxane, filtered through a Whatman PVDF 0.45 um disk (with 3×1 ml washing). The filtrate was concentrated. The mixture was added with 3.5 ml 1N HCl, and then 6 ml H2O (yellow solid deposited on the wall of the flask). The aqueous was decanted, and the residue washed with 3×2 ml H2O and dried. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O—0.1% TFA, Solvent B=90% MeOH-10% H2O—0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=466.27, HPLC Rt=1.708 min.