Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][PH:8](=[O:13])[O:9][CH:10]([CH3:12])[CH3:11])=[CH:3]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:14]([O:1][CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][PH:8](=[O:13])[O:9][CH:10]([CH3:11])[CH3:12])=[CH:3]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)O[PH](=O)CC1=CC(O)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)O[PH](=O)CC1=CC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
A solution of isopropyl (3-hydroxycyclopentenyl)methylphosphinate (3) (3.5 g, 17.2 mmol) in anhydrous DMF (60 cm3) was treated with t-butyldimethylsilyl chloride (2.85 g, 18.9 mmol), triethylamine (3.6 g, 34.3 mmol) and DMAP (250 mg). The reaction mixture was stirred at room temperature for 16 h, after which time the solvent was removed in vacuo. The residue was partitioned between DCM (50 cm3) and water (30 cm3) and the aqueous layer was further extracted with DCM (3×20 cm3). The combined organic layers were washed with water (2×30 cm3) and brine (40 cm3), dried over anhydrous Na2SO4, filtered and the solvent removed under reduced pressure. The crude product was purified by short column vacuum chromatography on silica gel (5% ethanol/ethyl acetate) to yield the title compound (4) as a colourless oil (4.62 g, 85%): 1H NMR (300 MHz, CDCl3) δ 0.065 and 0.067 (6H, 2×s), 0.870 and 0.874 (9H, 2×s), 1.22 and 1.24 (3H, 2×d, J=6.3 and 6.3 Hz, OCHCH3), 1.31 and 1.33 (3H, 2×d, J=6.0 and 6.0 Hz, OCHCH3), 1.45 and 1.49 (3H, 2×d, J=14.4 and 14.4 Hz, PCH3), 1.69-1.83 (1H, m, C(5)—H), 2.24-2.46 (2H, m, C(5)—H′ and C(4)—H), 2.54-2.68 (1H, m, C(4)—H′), 4.55 (1H, m, OCHCH3), 4.95 (1H, m, C(3)—H), 6.46 (1H, m, C(2)—H), 13 C NMR (75.46 MHz, CDCl3) δ −4.81 and −4.75 (Si(CH3)2, 2×s), 14.0 and 14.19 (PCH3, d, JPC=101.3 and 101.8 Hz), 18.07 and 18.10 (SiC(CH3)3, 2×s), 23.90 and 23.96 (POCCH3, 2×d, 3JPOCC=4.8 Hz), 24.43 (POCCH3, overlapping d, 3JPOCC=3.3 Hz), 25.76 (SiC(CH3)3, br. s), 31.34 (C(4), d, 3JPC=11.5 Hz), 34.42 and 34.55 (C(5), 2×d, 2JPC=9.5 Hz), 68.95 and 68.99 (POCHCH3, d, 2JPOC=6.5 and 5.9 Hz), 77.98 and 78.24 (C(3), d, 3JPC=6.9 and 6.7 Hz), 137.78 and 138.08 (C(2), d, JPC=125.0 and 125.6 Hz), 147.2 (C(1), d, J=10.7 Hz), 31P NMR (121 MHz, CDCl3) δ 38.1, 38.5, (ESI) 319.1869 (MH+-C15H32O3PSi requires 319.1858).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](O)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.47 g, 2.2 mmol) (Example 1, step 2), trans-4-aminocyclohexanol (from Aldrich, 0.50 g, 4.4 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.6 mmol) in isopropyl alcohol (7.4 mL) was heated at 90° C. for 2 h. The reaction mixture was concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (0.266 g, 41%). LCMS calculated for C13H16N3O3S (M+H)+: m/z=294.1. Found: 294.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH3:12][C:13]1([CH3:19])[O:18][CH2:17][CH2:16][NH:15][CH2:14]1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:15]2[CH2:16][CH2:17][O:18][C:13]([CH3:19])([CH3:12])[CH2:14]2)=[N:6][CH:7]=1
Reactant: CC1(C)CNCCO1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)CN(c2ncc(Br)cc2[N+](=O)[O-])CCO1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a 100 mL round bottom flask containing 5-bromo-2-chloro-3-nitropyridine (2.00 g, 8.43 mmol) in DMSO (10 mL) was added 2,2-dimethylmorpholine (commercially available from ChemBridge Corporation) (1.9 mL, 16.9 mmol) dropwise. The reaction was heated to 60° C. and monitored with TLC and LC-MS. After 2.5 h, LC-MS showed that the reaction was complete. The mixture was cooled to rt then diluted with water. After extracting three times with EtOAc, the organic layers were combined then washed with brine and dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure to afford an orange oil as 4-(5-bromo-3-nitropyridin-2-yl)-2,2-dimethylmorpholine. 1H NMR (400 MHz, CDCl3) δ ppm 8.34 (1H, d, J=2.2 Hz), 8.25 (1H, d, J=2.2 Hz), 3.87 (2H, m), 3.36 (4H, m), 1.26 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:11][N:12]([CH:15]3[CH2:17][CH2:16]3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([Cl:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1>C(Cl)Cl.CO>[Cl:33][C:27]1[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=[C:25]([NH:24][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:11][N:12]([CH:15]3[CH2:17][CH2:16]3)[C:13]=2[CH3:14])[CH:26]=1
Reactant: CCOC(=O)c1nn(C2CC2)c(C)c1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(N)cc(Cl)c1=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1nn(C2CC2)c(C)c1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-5-methyl-1H-pyrazole-3-carboxylate (Step 17.5) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 4.81 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 475/477 [M+H]+ (LC-MS 2); Rf=0.52 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH2:14](O)[CH:15]=[CH2:16].C(B(CC)CC)C>C1COCC1.C(OCC)(=O)C.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>[CH2:16]([C:3]1[C:4]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1)[CH:15]=[CH2:14]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: C=CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCB(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCc1c[nH]c2cccc(C(=O)OC)c12
Temperature: 70 °C
Yield: 87.8 %

Procedure:
To a stirring mixture of methyl indole-4-carboxylate (5.20 g, 29.68 mmol), allyl alcohol (2.02 mL, 29.68 mmol), and triethyl borane (1.0M solution in THF, 8.90 mL, 8.90 mmol) in THF (120 mL) at room temperature under an atmosphere of nitrogen was added Pd(PPh3)4 (1.71 g, 1.48 mmol). The mixture was heated at 70° C. for 16 h then cooled to room temperature. The mixture was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate solution (200 mL), brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0 to 30% ethyl acetate in hexanes) afforded methyl 3-allyl-1H-indole-4-carboxylate (5.61 g, 88%) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.44 (b s, 1H), 7.59 (m, 1H), 7.44 (m, 1H), 7.16 (m, 1H), 7.04 (s, 1H), 6.05 (m, 1H), 5.00 (m, 2H), 3.96 (s, 3H), 3.64 (m, 2H); MS (ESI+) m/z 150 (M+H).
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+]=[N-].O.NN>[Ni].CO>[NH2:1][C@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N=[N+]=[N-])C[C@@H]12
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N)C[C@@H]12

Procedure:
1.0 g 16β-azido-3-methoxy-estra-1,3,5(10)-triene-17β-ol are reduced with 20 ml methanol, 2 ml 80% hydrazine hydrate and one spatula tip of Raney nickel by procedures as described for the purification of 16β-Amino-3-methoxy-estra-1,3,5(10)-triene-17α-ol. Recrystallization is performed from methanol/ether. Yield: 0.7 g (76%). F=152-157° C.; [α]D+59° (pyridine). IR: 3300 (broad), 3417 (OH, NH), 3601 (OH).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C[O-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CC(C)=O.CO>[CH2:20]([O:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(c1ccc(O)cc1)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 32.9 %

Procedure:
To a solution of 2.0 g (9.3 mmol) of 4,4'-dihydroxybenzophenon in 50 ml dry acetone was added 27.5 ml of 0.34M NaOMe in MeOH. After the reaction mixture had been stirred for 20 min, 1.6 g (9.3 mmol) of benzylbromide was added. The reaction was stirred at room temperature for 15 h. 250 ml EtOAc was added and then extracted with 2×50 ml 0.5M HCl, 2×50 ml H2O and 50 ml saturated NaCl(aq). Drying (MgSO4), evaporation of the EtOAc and purification on silica gave 0.93 g (33%) of 4'-benzyloxy-4-hydroxy benzophenon.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][NH:7][C@H:6]([C:9]2[NH:13][C:12]3[C:14]4[C:19]([CH:20]=[CH:21][C:11]=3[N:10]=2)=[CH:18][C:17]2[C:22]3[C:27]([CH2:28][O:29][C:16]=2[CH:15]=4)=[CH:26][C:25]([C:30]2[NH:34][C:33]([C@@H:35]4[CH2:39][C@H:38]([CH3:40])[CH2:37][N:36]4[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[N:32][CH:31]=2)=[CH:24][CH:23]=3)[CH2:5]1.[CH3:52][O:53][C:54]([NH:56][CH:57]([CH:61]([CH3:63])[CH3:62])[C:58](O)=[O:59])=[O:55].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:52][O:53][C:54]([NH:56][C@@H:57]([CH:61]([CH3:63])[CH3:62])[C:58]([N:7]1[CH2:8][C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@H:6]1[C:9]1[NH:13][C:12]2[C:14]3[C:19]([CH:20]=[CH:21][C:11]=2[N:10]=1)=[CH:18][C:17]1[C:22]2[C:27]([CH2:28][O:29][C:16]=1[CH:15]=3)=[CH:26][C:25]([C:30]1[NH:34][C:33]([C@@H:35]3[CH2:39][C@H:38]([CH3:40])[CH2:37][N:36]3[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[N:32][CH:31]=1)=[CH:24][CH:23]=2)=[O:59])=[O:55]
Reactant: COC[C@@H]1CN[C@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4C[C@H](C)CN4C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]3)ccc2-5)C1
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4C[C@H](C)CN4C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]3)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl {(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-(methyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (57 mg, 0.08 mmol), 2-methoxycarbonylamino-3-methylbutyric acid (19 mg, 0.1 mmol), HATU (303 mg, 0.79 mmol) in DMF (1 mL) was added diisopropylethylamine (43 μL, 0.24 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with 5% NaHCO3 solution, water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 43% ACN/H2O+0.1% TFA). The product fractions were lyophilized to give methyl {(2S)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methyl butanoyl}-4-methoxymethylpyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate. (13 mg, 19%). MS (ESI) m/z 850 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]3[CH:15]4[CH2:16][CH:12]([CH2:13][CH2:14]4)[C:11]=13)[O:8][C:7]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH3:17])[CH2:6][CH2:5]2.[OH-].[Na+].[CH2:25](Br)[CH:26]=[C:27]([CH3:29])[CH3:28].Cl>CCOC(C)=O>[OH:1][C:2]1[C:3]([CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])=[C:4]2[C:9](=[C:10]3[CH:15]4[CH2:16][CH:12]([CH2:13][CH2:14]4)[C:11]=13)[O:8][C:7]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])([CH3:17])[CH2:6][CH2:5]2
Reactant: CC(C)=CCBr
Reactant: CC1(CCC(=O)O)CCc2cc(O)c3c(c2O1)C1CCC3C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)=CCc1c(O)c2c(c3c1CCC(C)(CCC(=O)O)O3)C1CCC2C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of 3-(6-hydroxy-2-methyl-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl)-propionic acid, (2.39 mmol) in 1M aq. NaOH (4.8 mL, 4.8 mmol) was cooled to 0° C., and treated with prenyl bromide (0.277 mL, 2.39 mmol). Following stirring for 7 h at ambient temperature the reaction mixture was made slightly acidic with 0.5M HCl and shaken with EtOAc. The organic phase was evaporated yielding 1. The mixture was subjected to column chromatography on silica gel (SiO2:hexane:EtOAc, 85:15 v/v eluting yielded 3-[6-hydroxy-2-methyl-5-(3-methyl-but-2-enyl)-3,4,7,8,9,10-hexahydro-7,10-methano-2H-benzo[h]chromen-2-yl]-propionic acid 1H-NMR (300 MHz, CDCl3) δ (ppm): 5.17 (t, J=6, 1H), 3.54 (br s, 1H), 3.49 (br s, 1H), 3.18-3.37 (m, 2H), 2.70 (t, J=7, 2H), 2.49-2.62 (m, 2H), 1.60-2.07 (m, 13H), 1.39-1.48 (m, 1H), 1.05-1.32 (m, 5H). 13C-NMR (75 MHz CDCl3) δ (ppm): 180.1, 141.1, 133.9, 133.3, 132.9, 122.9, 122.3, 117.4, 73.2, 49.0, 48.9, 40.0, 39.8, 33.6, 32.0, 28.7, 26.7, 25.9, 25.6, 23.8, 233.2, 20.5, 18.0. MS ESI-Pos m/z 371.2 (M+H+)
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][O:17][CH:18]1[CH2:21][N:20]([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N:30]=2)[CH2:19]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH3:16][O:17][CH:18]1[CH2:21][N:20]([CH2:22][CH2:23][CH2:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N+:30]=2[O-:4])[CH2:19]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC1CN(CCCc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1CN(CCCc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.5 %

Procedure:
H2O2 (70%, 2.0 mL, 39 mmol) was added dropwise to a stirred solution of TFAA (5.4 mL, 39 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 82 (0.93 g, 3.0 mmol) and TFA (1.5 mL, 19.5 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (30 mL) and extracted with DCM (3×150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 83 (0.60 g, 60%) as a red gum: 1H NMR δ 8.31 (s, 1H, H-9), 8.28 (s, 1H, H-5), 4.60-4.70 (m, 2H, CH2N), 4.33-4.40 (m, 1H, CHO), 3.60-3.75 (m, 2H, CH2N), 3.33 (s, 3H, CH3O), 3.25-3.32 (m, 2H, CH2N), 3.12-3.25 (m, 6H, H-6, H-8, CH2), 2.27-2.33 (m, 4H, H-7, CH2); 13C NMR δ 155.5, 152.3, 151.2, 139.1, 134.1, 115.9, 113.9, 67.8, 61.0, 58.9, 56.9, 55.6, 32.9, 32.4, 26.9, 25.6, 22.9; HRMS (FAB+) calcd for C17H23N4O3 (MH+) m/z 331.1770, found 331.1771.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](\[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)#[CH:33]>O1CCCC1.C(N(CC)CC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)\[C:25]2[CH:26]=[CH:27][C:28]([C:33]#[C:32][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:29][CH:30]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(I)cc2)cc1C
Reactant: C#Cc1ccccn1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(C#Cc3ccccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl (Z)-[2-methyl-4-[3-(4-iodophenyl)-3-(4-methylphenyl)allyloxy]-phenoxy]acetate (310 mg, 0.587 mmol; example 3) in a mixture of tetrahydrofuran (9 mL) and triethylamine (9 mL) was degassed and 2-ethynylpyridine (121 mg, 1.17 mmol) was added in argon atmosphere. The solution was cooled down; tetrakis(triphenylphosphine)-palladium (55 mg, 0.047 mmol) and copper(I) iodide (17.8 mg, 0.094 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h, then evaporated in vacuo and the residue was dissolved in ethyl acetate (20 mL). The solution was washed with water (3×15 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (Z)-[2-methyl-4-[3-(4-methylphenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]-phenoxy]acetate.
Reaction SMILES: [CH3:1][C:2]1([S:15]([CH3:18])(=[O:17])=[O:16])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([S:15]([CH3:18])(=[O:17])=[O:16])[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(S(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(S(C)(=O)=O)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-methyl-4-methylsulfonyl-piperidine-1-carboxylate (430 mg, 1.550 mmol) in DCM (10 mL) was added TFA (3 mL, 38.94 mmol) and the solution stirred at room temperature for 1 h. The reaction was concentrated and azeotroped twice with DCM to give 4-methyl-4-(methylsulfonyl)piperidine as a sticky oil that was used in next step without further purification. MS (ES+) 178.0.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>C1COCC1>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:21])[O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: OC1CN2CCC1CC2
Reactant: O=C=Nc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1Br)OC1CN2CCC1CC2
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of quinuclidin-3-ol (382 mg, 3.00 mmol) in THF (15 mL) was added NaH [60% dispersion in mineral oil] (156 mg, 3.90 mmol) at room temperature. The mixture was stirred for 15 min and 2-bromophenyl isocyanate (594 mg, 3.00 mmol) was added under stirring. The resulting mixture was stirred at room temperature for 18 h, quenched with brine and extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting crude product was purified by silica gel column chromatography (EtOAc/methanol 3:1) to give the product quinuclidin-3-yl 2-bromophenylcarbamate as viscous oil (0.80 g, 82%).
Reaction SMILES: [CH3:1][C:2]12[O:10][B:9]([C@@H:11]([NH:28][C:29]([C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[CH2:36][NH:35][CH2:34]4)=[O:30])[CH2:12][C:13]3[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[O:8][CH:7]1[CH2:6][CH:5]1[CH2:40][CH:3]2[C:4]1([CH3:42])[CH3:41].C([O-])([O-])=O.[K+].[K+].Br[CH2:50][CH2:51][NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56].O>CN(C=O)C>[C:55]([O:54][C:53]([NH:52][CH2:51][CH2:50][N:35]1[CH2:34][C:33]2[C:37](=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C@H:11]([B:9]3[O:8][CH:7]4[C:2]([CH3:1])([CH:3]5[CH2:40][CH:5]([CH2:6]4)[C:4]5([CH3:42])[CH3:41])[O:10]3)[CH2:12][C:13]3[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=3)[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[O:30])[CH:32]=2)[CH2:36]1)=[O:59])([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COc1c(C[C@H](NC(=O)c2ccc3c(c2)CNC3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C[C@H](NC(=O)c2ccc3c(c2)CN(CCNC(=O)OC(C)(C)C)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-((2R)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-2-(isoindoline-5-carboxamido)ethyl)-2-methoxybenzoate from Example 9 step 2 (263 mg, 0.46 mmol) in DMF (5 mL) was added K2CO3 (252 mg, 1.84 mmol) and tert-butyl 2-bromoethylcarbamate (122 mg, 0.54 mmol). The resulting reaction was stirred at room temperature overnight. Water (15 mL) was added and the aqueous phase was extracted with EtOAc. The organic phase was washed with 1N HCl, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (Hexane/EtOAc, 2:1 to 1:2). ESI-MS m/z 718.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](O[C@H]2C[C@H](C(O)=O)C2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.FC1C=CC(OCC2CC(C(O)=O)C2)=C2C=1NC(=O)NC12CCCCC1.C(C1C=CC([O:70][C@H:71]2[CH2:74][C@H:73]([C:75]([OH:77])=[O:76])[CH2:72]2)=C2C=1NC(=O)NC12CCCCC1)#N.FC1C=CC(OCC2(C(O)=O)CCC2)=C2C=1NC(=O)NC12CCCCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[NH:8][C:7]12[CH2:17][CH:16]([O:70][C@@H:71]2[CH2:74][C@H:73]([C:75]([OH:77])=[O:76])[CH2:72]2)[CH2:15][CH2:14][CH2:13]1
Reactant: N#Cc1ccc(O[C@H]2C[C@H](C(=O)O)C2)c2c1NC(=O)NC21CCCCC1
Reactant: O=C1Nc2c(Cl)ccc(O[C@H]3C[C@H](C(=O)O)C3)c2C2(CCCCC2)N1
Agent: O=C1Nc2c(F)ccc(OCC3(C(=O)O)CCC3)c2C2(CCCCC2)N1
Agent: O=C1Nc2c(F)ccc(OCC3CC(C(=O)O)C3)c2C2(CCCCC2)N1
Product: O=C1Nc2c(Cl)cccc2C2(CCCC(O[C@H]3C[C@@H](C(=O)O)C3)C2)N1

Procedure:
trans-3-[(8′-Chloro-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-quina-zolin]-5′-yl)oxy]cyclobutanecarboxylic acid; 3-[(8′-fluoro-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-quinazolin]-5′-yl)oxymethyl]cyclobutanecarboxylic acid; trans-3-[(8′-cyano-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-quinaz-olin]-5′-yl)oxy]cyclobutanecarboxylic acid; 1-[(8′-fluoro-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclohexane-1,4′-quinazolin]-5′-yl)oxymethyl]cyclobutanecarboxylic acid; trans-3-[(8′-chloro-2′-oxo-2′,3′-dihydro-1′H-spiro[cycloheptyl-1,4′-quina-zolin]-5′-yl)oxy]cyclobutanecarboxylic acid; and trans-3-[(8′-chloro-2′-oxo-2′,3′-dihydro-1′H-spiro[cyclopentyl-1,4′-quinazolin]-5′-yl)oxy]cyclobutanecarboxylic acid; or a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[N:15]=[C:14]([Cl:16])[N:13]=[C:12]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[CH:11]=1>CN(C)C=O>[ClH:16].[CH3:9][C:10]1[N:15]=[C:14]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=[C:12]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[CH:11]=1
Reactant: Cc1cc(N2CCc3ccccc3C2)nc(Cl)n1
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cc1cc(N2CCc3ccccc3C2)nc(Nc2ccc(F)cc2)n1
Product: Cl
Yield: 42.6 %

Procedure:
After 4-fluoroaniline(0.7 ml, 7.4 mmol) was added to a mixture solution of 6-methyl-4-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-chloropyrimidine(1.0 g, 3.8 mmol) and dimethylformamide(10 ml), 0.6 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.