Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH3:34][C@H:35]1[CH2:40][NH:39][CH2:38][C@@H:37]([CH3:41])[NH:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CS(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:39]2[CH2:38][C@H:37]([CH3:41])[NH:36][C@H:35]([CH3:34])[CH2:40]2)=[O:31])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1

Procedure:
5-[5-(2,3-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (110 mg, 0.22 mmol) was coupled with (2S,6R)-2,6-dimethyl-piperazine (31 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMSO. The reaction was concentrated and purified on a silica gel column to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Sc2ccc(Cl)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(Sc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.6 %

Procedure:
To a solution of 4-(4-chloro-phenylsulfanyl)-benzonitrile (4.91 g) in 100 mL of dry THF under nitrogen stirring at room temperature was added 40 mL of lithium aluminum hydride solution (1.0 M in THF) via syringe. The reaction mix was allowed to stir for 3.5 hours at room temperature, and was then heated to reflux for 4.5 hours, and then allowed to sit at room temperature overnight. The reaction mix was then cooled in an ice bath and quenched by addition of 10 mL water, followed by 1 mL of 15% aqueous NaOH solution and an additional 30 mL of water. Anhydrous sodium sulfate was added, and the mixture was filtered. The resulting filter cake was washed several times with Et2O. The combined ether filtrates were concentrated in vacuo to yield 4.67 g of 4-(4-chloro-phenylsulfanyl)-benzylamine as a white solid. MS M+H: 250.
Reaction SMILES: [F:1][C:2]1([F:38])[CH2:6][N:5]([C:7](=[O:17])[C@@H:8]([NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:9]([CH3:11])[CH3:10])[C@H:4]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:3]1.Br[C:40]1[CH:45]=[CH:44][C:43]([C:46]2[NH:50][C:49]([C@H:51]3[N:56]4[C:57](=[O:68])[C@@H:58]([NH:63][C:64](=[O:67])[O:65][CH3:66])[CH2:59][CH2:60][C:61](=[O:62])[N:55]4[CH2:54][CH2:53][CH2:52]3)=[N:48][CH:47]=2)=[CH:42][CH:41]=1.C(=O)(O)[O-].[Na+]>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].C(O)(C)(C)C>[CH3:66][O:65][C:64](=[O:67])[NH:63][C@H:58]1[CH2:59][CH2:60][C:61](=[O:62])[N:55]2[CH2:54][CH2:53][CH2:52][C@@H:51]([C:49]3[NH:50][C:46]([C:43]4[CH:42]=[CH:41][C:40]([C:26]5[CH:25]=[CH:24][C:23]([C:20]6[NH:19][C:18]([C@@H:4]7[CH2:3][C:2]([F:1])([F:38])[CH2:6][N:5]7[C:7](=[O:17])[C@@H:8]([NH:12][C:13]([O:14][CH3:15])=[O:16])[CH:9]([CH3:11])[CH3:10])=[N:22][CH:21]=6)=[CH:28][CH:27]=5)=[CH:45][CH:44]=4)=[CH:47][N:48]=3)[N:56]2[C:57]1=[O:68]
Reactant: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(Br)cc4)[nH]3)N2C1=O
Reactant: COC(=O)N[C@H](C(=O)N1CC(F)(F)C[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: CC(C)(C)O
Product: COC(=O)N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(-c5ccc(-c6cnc([C@@H]7CC(F)(F)CN7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc5)cc4)[nH]3)N2C1=O
Temperature: 90 °C
Yield: 33.2 %

Procedure:
In a 10 mL seal tube, methyl (S)-1-((S)-4,4-difluoro-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (52 mg, 97.7 μmol), methyl (4S,7S)-4-(5-(4-bromophenyl)-1H-imidazol-2-yl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate (46.5 mg, 97.7 μmol) and sodium bicarbonate (sat. solution, 400 μl, excess) were combined with tert-butanol (2.00 ml) to give a light brown suspension and degassed for 5 min. PdCl2(DPPF) (7.15 mg, 9.77 μmol) was added and flushed with nitrogen. It was sealed heating at 90° C. for 4 hr, diluted with EtOAc (10 ml), filtered and concentrated in vacuo. The crude mixture was purified on a silica gel column (CH2Cl2, 2%, 3%, 5%, 8% MeOH/CH2Cl2) to afford {(4S,7S)-4-[5-(4′-{2-[(S)-4,4-Difluoro-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl}-carbamic acid methyl ester as a light yellow solid (26 mg, 31.5%). ESI-LRMS m/e calcd for C40H45F2N9O7, [M+] 801. found 802 [M+H]. 1H NMR (DMSO-d6) δ: 12.23 (br. s., 1H), 11.98 (br. s., 1H), 7.72-7.84 (m, 4H), 7.62-7.72 (m, 5H), 7.57 (d, J=1.8 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 5.81 (br. s., 1H), 5.30 (t, J=7.5 Hz, 1H), 4.39-4.55 (m, 3H), 3.94 (t, J=8.2 Hz, 1H), 3.56 (s, 4H), 3.55 (br. s., 3H), 2.84-2.95 (m, 1H), 2.18-2.35 (m, 3H), 2.12 (dd, J=13.1, 6.5 Hz, 1H), 1.86-2.03 (m, 4H), 1.64 (d, J=13.3 Hz, 1H), 1.09-1.26 (m, 1H), 0.92 (d, J=6.5 Hz, 1H), 0.85 (d, J=6.5 Hz, 6H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH:14]=2)[NH2:13])[CH2:5][C@@H:4]([CH3:18])[O:3]1>[Pd].C(OCC)(=O)C.CO>[NH2:13][C:12]1[CH:14]=[C:8]([N:6]2[CH2:5][C@@H:4]([CH3:18])[O:3][C@@H:2]([CH3:1])[CH2:7]2)[CH:9]=[CH:10][C:11]=1[NH2:15]
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])c(N)c2)C[C@H](C)O1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccc(N)c(N)c2)C[C@H](C)O1
Reaction time: 25 h
Yield: 97 %

Procedure:
To a solution of 5-(cis-2′,6′-dimethylmorpholino)-2-nitroaniline (1.26 g, 5.03 mmol) in 4:1 ethyl acetate/methanol (75 ml) was added 5% palladium on carbon (0.24 g) and the reaction mixture stirred under an atmosphere of hydrogen for 25 h. The reaction mixture was then filtered through celite, the filtered solid washed with methanol, and the combined filtrate and washings concentrated in vacuo to give crude 2-amino-4-(cis-2′,6′-dimethylmorpholino)aniline (1.08 g, 97%) which was used immediately in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][CH3:13].C(Cl)(Cl)Cl.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:13])[C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CNCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 55 %

Procedure:
To a mixture of 0.42 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(methylamino)propyloxy)benzene, 0.18 ml of triethylamnine and 10 ml of chloroform was added 0.18 ml of 4-(trifluoromethyl)benzoyl chloride, while stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was dissolved in 50 ml of ethyl acetate, and the ethyl acetate layer was successively washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.35 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(N-methyl-4-(trifluoromethyl)benzamido)propyloxy)benzene (55% yield), nD24.5 1.5461.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J18) (347 mg, 1.0 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (297 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow solid (570 mg, 100%).
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.CS(O)(=O)=O.[NH2:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:5]([C:6]#[N:7])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:16]3[C:15](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=2)[CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CC1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
Into a glass flask having an internal volume of 50 mL, equipped with a stirring apparatus, a thermometer, a reflux condenser and a Dean-Stark apparatus, 10.72 g (6.6 mmol) of 3-cyclopropyl-3-oxopropanenitrile, 1.92 g (6.0 mmol) of 2-amino-4′-fluorobenzophenone methanesulfonate having a purity of 97.3% and 10 mL of toluene were put in an atmosphere of nitrogen, and reaction was carried out under at 110° C. for 2 hours while distilling off the formed water. After completion of the reaction, the reaction liquid was cooled to room temperature, 7.0 mL (7.0 mmol) of a 1 mol/L sodium hydroxide aqueous solution was added thereto to make the reaction liquid basic, followed by liquid separation, and the obtained organic layer was analyzed by high performance liquid chromatography (absolute quantitative analysis), whereupon 1.57 g (yield: 91%) of 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile was formed.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([O:16][C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[NH2:25])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH2:9]([O:16][C:17]1[C:22]([F:23])=[C:21]([Br:8])[C:20]([F:24])=[CH:19][C:18]=1[NH2:25])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cc(F)cc(F)c1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1cc(F)c(Br)c(F)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NBS (1.60 g, 9.01 mmol) in methylene chloride (20 mL) at 0° C. is added a solution of 2-benzyloxy-3,5-difluorophenylamine (2.12 g, 9.01 mmol) and the mixture is stirred at 0° C. for 30 min then at RT for 30 min. The Mixture is washed with water and the solvent evaporated under reduced pressure. The residue is purified by column chromatography to give the title compound: MS (M−H)−=313.
Reaction SMILES: O.[Sn](Cl)Cl.C1COCC1.F[B-](F)(F)F.[F:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:18][C:17]=1[N+:29]#[N:30].[OH-].[K+]>Cl>[F:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:18][C:17]=1[NH:29][NH2:30]
Reactant: N#[N+]c1cc(OC2CCCC2)c(Cl)cc1F
Agent: Cl
Agent: Cl[Sn]Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: NNc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of tin (II) chloride monohydrate (200 g, 0.886 mol) dissolved in concentrated hydrochloric acid (200 ml) and THF (200 ml) was added a THF (200 ml) solution of 2-fluoro-4-chloro-5-cyclopentyloxyphenyl-diazonium fluoroborate (31.3 g, 0.094 mol) under cooling at 0 to 5° C. After stirring for 8 hours at that temperature, an aqueous solution (1,000 ml) of potassium hydroxide (160 g) was added thereto. The solid that was formed was separated by filtration, and the filtrate was extracted with ethyl acetate (1,000 ml×3). The extract was washed with a saturated aqueous solution of sodium chloride (1,000 ml), and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and the solvent was distilled off under reduced pressure to obtain 2-fluoro-4-chloro-5cyclopentyloxyphenylhydrazine as brown crystals (20.9 g, 85.6% yield).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[N:20]=[C:19]([CH:21]=[O:22])[C:18]([F:23])=[CH:17][CH:16]=1>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:23][C:18]1[CH:17]=[CH:16][C:15]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:20][C:19]=1[CH:21]=[O:22]
Reactant: O=Cc1nc(Br)ccc1F
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1nc(-c2ccc(C(F)(F)F)nc2)ccc1F
Temperature: 80 °C
Yield: 69.5 %

Procedure:
Nitrogen was bubbled through a mixture of 6-(trifluoromethyl)pyridin-3-ylboronic acid (3.74 g, 19.61 mmol), 6-bromo-3-fluoropicolinaldehyde (4.0 g, 19.61 mmol), Pd(Ph3P)4 (0.340 g, 0.294 mmol) was added and nitrogen was bubbled for 10 minutes, and the reaction mixture was heated overnight at 80° C. EtOAc (300 mL) was added and the mixture was washed with water (300 mL) and brine (300 mL), dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 80 g column, eluted with 0-40% EtOAc in Heptane (30 mL/min) to provide the title compound (3.681 g, 13.62 mmol, 69.5% yield). MS (ESI+) m/z 303.0 (M+H+MeOH); 1H NMR (300 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.50 (d, J=2.0, 1H), 8.82-8.75 (m, 1H), 8.58 (dd, J=8.9, 3.7, 1H), 8.23-8.13 (m, 1H), 8.10 (d, J=8.3, 1H).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)O)=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOCC>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:34]([C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)[C:36]1[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=1)=[O:11])[CH2:3]2
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(O)C1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(OC(c1ccc(F)cc1)c1ccc(F)cc1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (96 mg, 0.50 mmol), EDC (131 mg, 0.68 mmol), and HOBT (104 mg, 0.68 mmol) were suspended in dry DMF (5 ml). Bis(4-fluorophenyl)methanol (100 mg, 0.45 mmol) and DIPEA (278 μl, 1.59 mmol) were added, and the mixture was stirred at room temperature for 24 hours. Then, quinuclidine-3-carboxylic acid hydrochloride (43.5 mg, 0.23 mmol), EDC (43.5 mg, 0.23 mmol), HOBT (34.8 mg, 0.23 mmol), and DIPEA (79 μl, 0.45 mmol) were added again and stirring was continued for 4 days. Finally quinuclidine-3-carboxylic acid hydrochloride (43.5 mg, 0.23 mmol), EDC (43.5 mg, 0.23 mmol), and DIPEA (79 μl, 0.45 mmol) were added, and the suspension was stirred for additional 24 hours. The reaction was portioned between sat. NaHCO3 and Et2O, and the organic layer was separated, washed again with sat. NaHCO3 and then brine. The organic phase was dried over Na2SO4, filtered, and evaporated to afford bis(4-fluorophenyl)methyl quinuclidine-3-carboxylate (51 mg, racemic mixture). The compound was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: O=C(CCl)N1CCOCC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCOCC3)c(F)c2)C(C)C)c1
Yield: 46.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-morpholin-4-ylethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (12 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH:13]=O)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][N:29]2[CH2:30][CH2:31][CH:26]([C:24](=[O:25])[C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)[CH2:27][CH2:28]2)[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CN2CCC(C(=O)c3ccc(Cl)cc3)CC2)COC1(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of (R)4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.5 g, 2.18 mmol) in tetrahydrofuran (15 ml) is added (4-chloro-phenyl)-piperidin-4-yl-methanone (0.49 g, 2.18 mmol) and sodium triacetoxyborohydride (0.69 g, 3.27 mmol), and the reaction mixture stirred for 3.5 hours at ambient temperature. The solvent is evaporated and the residue partitioned between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml). The ethyl acetate is dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (ethyl acetate:hexane, 1:1 elution) to afford (S)-4-[4-(4-chloro-benzoyl)-piperidin-1-ylmethyl]-2,2-dimethyl-oxazoldine-3-carboxylic acid tert-butyl ester, [MH]+437.2.
Reaction SMILES: OCCCCC1C=CC(C2C=CC(NC(C3C=C(S(C4C=C5C(=C(C)C=4)N=CC(C(N)=O)=C5NC4C=CC=C(OC)C=4)(=O)=O)C=CC=3)=O)=CC=2)=CC=1.[C:53]([C:56]1[CH:57]=[N:58][C:59]2[C:64]([C:65]=1[NH:66][C:67]1[CH:72]=[CH:71][CH:70]=[C:69]([O:73][CH3:74])[CH:68]=1)=[CH:63][C:62]([S:75]([C:78]1[CH:79]=[C:80]([CH:103]=[CH:104][CH:105]=1)[C:81]([NH:83][C:84]1[CH:85]=[C:86]([C:90]3[CH:95]=[CH:94][C:93]([CH2:96][CH2:97][CH2:98][C:99](OC)=[O:100])=[CH:92][CH:91]=3)[CH:87]=[CH:88][CH:89]=1)=[O:82])(=[O:77])=[O:76])=[CH:61][C:60]=2[CH3:106])(=[O:55])[NH2:54]>>[OH:100][CH2:99][CH2:98][CH2:97][CH2:96][C:93]1[CH:94]=[CH:95][C:90]([C:86]2[CH:87]=[CH:88][CH:89]=[C:84]([NH:83][C:81]([C:80]3[CH:79]=[C:78]([S:75]([C:62]4[CH:63]=[C:64]5[C:59](=[C:60]([CH3:106])[CH:61]=4)[N:58]=[CH:57][C:56]([C:53]([NH2:54])=[O:55])=[C:65]5[NH:66][C:67]4[CH:72]=[CH:71][CH:70]=[C:69]([O:73][CH3:74])[CH:68]=4)(=[O:76])=[O:77])[CH:105]=[CH:104][CH:103]=3)=[O:82])[CH:85]=2)=[CH:91][CH:92]=1
Reactant: COC(=O)CCCc1ccc(-c2cccc(NC(=O)c3cccc(S(=O)(=O)c4cc(C)c5ncc(C(N)=O)c(Nc6cccc(OC)c6)c5c4)c3)c2)cc1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCCO)cc6)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5cccc(-c6ccc(CCCCO)cc6)c5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 90, using Intermediate 87 as a substrate. ES/MS calcd. for C41H39N4O6S+ 715.3. Found m/z=715.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[S:17]([CH3:19])=O)[N:10]3CCCC(CC(O)=O)C=23)=[CH:4][CH:3]=1.[CH3:28][CH2:29][O:30][C:31]([CH3:33])=[O:32]>[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[S:17][CH3:19])[NH:10][C:33]=2[C:31]([O:30][CH2:29][CH3:28])=[O:32])=[CH:4][CH:3]=1
Reactant: CS(=O)c1cccc2c1c(-c1ccc(Cl)cc1)c1n2CCCC1CC(=O)O
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCOC(=O)c1[nH]c2cccc(SC)c2c1-c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
To a solution of the indole of step 3 (2.1 g) in 200 mL of EtOAc was added 5% palladium on carbon (1 g). The mixture was shaken under H2 atmosphere (50 psi) for 24 hours, filtered on a silica gel pad eluted with EtOAc and the filtrate concentrated to give the title compound as a white solid (1.5 g) used as such.
Reaction SMILES: C(O[CH:5]1[S:9][C@H:8]([CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)(=O)C.[Cl:29][C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[NH:32][CH:33]=[N:34]2.C1(C)C=CC=CC=1.[Cl-].C([Al+]CC)C>C(#N)C>[Si:12]([O:11][CH2:10][C@H:8]1[S:9][CH:5]([N:34]2[CH:33]=[N:32][C:31]3[C:35]2=[N:36][CH:37]=[N:38][C:30]=3[Cl:29])[CH2:6][CH2:7]1)([C:25]([CH3:27])([CH3:26])[CH3:28])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OC1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Reactant: Clc1ncnc2nc[nH]c12
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)(C)[Si](OC[C@@H]1CCC(n2cnc3c(Cl)ncnc32)S1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 10 (0.43 g, 1.04 mmol) and 6-chloropurine (0.24 g, 1.56 mmol) in 17 mL acetonitrile was cooled to 0° C. and a 1.8M toluene solution of diethylaluminum chloride (0.59 mL, 1.06 mmol) was added over 1 minute. Stirring was continued at 0° C. for 5 minutes and at 25° C. for 10 minutes. The reaction mixture was quenched by pouring into a mixture of 20 mL dichloromethane and 10 mL saturated NaHCO3. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was flash chromatographed with 9:1 -hexane/ethyl acetate followed by 4:1 -hexane/ethyl acetate. Solvent removal gave a 1:1 α/β anomeric mixture: yield 0.315 g (59%); FAB MS 509 (M+H)+ ; 1H NMR (CDCl3) of β anomer, δ 8.7 (s, 1, H-2), 8.45 (s, 1, H-8), 7.7 (m, 4, ArH), 7.4 (m, 6, ArH), 6.27 (m, 1, 7'-H), 3.95 (m, 1, 5'-H), 3.85 (m, 2, 4'-H, 5'-H), 2.45 (m, 2, 2'-H's), 2.25 (m, 1, 3'-H), 1.85 (m, 1, 3'-H), 1.1 (s, 9, t-butyl).