Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[S:8][C:9]=1[C:10](O)=[O:11])#[N:2].CCN(CC)CC.[H][H]>C1COCC1>[O:4]1[C:5]2[C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=3[S:8][C:9]=2[C:10](=[O:11])[NH:2][CH2:1][CH2:3]1
Reactant: [H][H]
Reactant: N#CCOc1c(C(=O)O)sc2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NCCOc2c1sc1ccccc21
Yield: 55 %

Procedure:
A mixture of the methyl ester of 3-(cyanomethoxy)benzo[b]thiophene-2-carboxylic acid (405 mg, 1.64 mmols) [J. Hetero. Chem., 12:1037 (1975)], 0.5 mL of Et3N and 0.50 g of RaCo in 50 mL of THF is heated at 100° C. under 1200 psi of hydrogen. The reaction mixture is concentrated in vacuo. Column chromatography eluting with a gradient of 1:1 hexane:ethyl acetate to all ethyl acetate provides 2,3-dihydro-[1]benzothieno[2,3-f]1,4-oxazepin-5(4H)-one in 55% yield; mp 244°-245° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@@H:14]([OH:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@@H:14]([OH:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCC([C@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(N2CCC([C@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
(S)-Ethyl 4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 11B, 150.0 mg, 0.33 mmol) was dissolved in THF (6.0 ml) and methanol (1.4 ml). A solution of LiOH (40.6 mg) in water (1.4 ml) was added. The solution was heated at 50° overnight. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was diluted with water (5 ml), acidified with 1N aq. HCl (2.0 ml), and extracted with DCM (2×5 ml). The extract was dried (MgSO4), filtered through cotton, and evaporated under vacuum to provide the title product as a substantially separated enantiomer (155 mg, yield: almost quantitative) 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 0.79-0.94 (m, 1 H) 0.98-1.12 (m, 1 H) 1.14-1.40 (m, 4 H) 2.04 (m, 1 H) 2.67 (td, J=12.51, 2.78 Hz, 1 H) 2.78 (td, 1 H) 3.74 (d, 1 H) 3.91 (m, 1 H) 4.48 (d, 1 H) 6.81 (d, 2 H) 7.17-7.29 (m, 3 H) 7.31-7.49 (m, 4 H) 7.61 (dd, 1 H) 7.84-7.93 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:8][CH:7]([C:9]#[N:10])[C:6]=2[CH:11]=1.[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH:15]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.COC(C)(C)C.C(O)(=O)C>[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:8][CH:7]([C:9]#[N:10])[C:6]=2[CH:11]=1
Reactant: COC(C=O)OC
Reactant: N#CC1Cc2ccc(N)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: COC(C)(C)C
Product: COC(CNc1ccc2c(c1)C(C#N)C2)OC
Temperature: 29 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 13.5 g of 5-aminobenzocyclobutane-1-carbonitrile in 400 ml of 1,2-dichloroethane there are added rapidly dropwise 26.5 ml of a 45% solution of 2,2-dimethoxyacetaldehyde in tert-butyl methyl ether, followed by 16 ml of acetic acid and then, in portions, 39.7 g of sodium triacetoxyborohydride. After increasing the temperature to 29° C., the reaction mixture is brought to ambient temperature, stirred for 1 hour 15 minutes and then hydrolysed by pouring the mixture into 500 ml of a saturated aqueous solution of NaHCO3. The organic phase is removed, washed with water, and concentrated under reduced pressure to yield the desired product.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH3:32])[C:22]([C:24]5[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=5Cl)=[O:23])=[CH:17][CH:16]=4)[NH:10][C:9]=3[C:8](=[O:33])[N:7]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:6]2=[O:42])[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+]>[Pd].ClCCl.CO>[CH:1]1([CH2:4][N:5]2[C:13]3[N:12]=[C:11]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([N:21]([CH3:32])[C:22]([C:24]5[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[CH:28]=5)=[O:23])=[CH:19][CH:20]=4)[NH:10][C:9]=3[C:8](=[O:33])[N:7]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:6]2=[O:42])[CH2:2][CH2:3]1
Reactant: Cc1nn(C)c(Cl)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1nn(C)cc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reaction time: 192 h
Yield: 9 %

Procedure:
A mixture of 5-chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (81.5 mg, 0.14 mmol) (prepared as described in example 104), 10% palladium on carbon (313 mg), and sodium acetate (28.3 mg, 0.35 mmol) in dichloromethane (25 mL) and methanol (25 mL) was hydrogenated at 50 psi on a Parr apparatus for 8 days. At this time, the reaction was filtered through a pad of celite and washed with a 90/10 dichloromethane/methanol solution (100 mL). The filtrated was concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 1,3-dimethyl-1H-pyrazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (7.0 mg, 9.1%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ13.122 (broad s, 1H), 6.79 (m, 9H), 6.33 (s, 1H), 4.76 (s, 2H), 3.70 (s, 2H), 3.47 (d, J=6.96 Hz, 2H), 3.11 (s, 3H), 2.87 (s, 3H), 1.75 (s, 3H), 0.85 (broad s, 1H), 0.026 (m, 4H).
Reaction SMILES: COCCOC.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21]([O:28][C:29]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[CH:48][C:30]=1[C:31]([NH:33][C:34]1[CH:46]=[C:45](Br)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.O>[CH2:21]([O:28][C:29]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:53][CH2:54][O:55][CH2:56][CH2:57]2)=[CH:48][C:30]=1[C:31]([NH:33][C:34]1[CH:46]=[C:45]([C:8]2[S:7][CH:11]=[CH:10][CH:9]=2)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cccs2)cc1NC(=O)c1cc(N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
Ethylene glycol dimethyl ether (2.0 mL), water (0.60 mL), thiophene-2-boronic acid (0.054 g), sodium carbonate (0.093 g), and bis(triphenylphosphine)palladium(II) dichloride (4.9 mg) were added to tert-butyl 2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-bromobenzoate (0.20 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 85-70% hexane/ethyl acetate] to obtain 0.19 g of tert-butyl 2-(2-(benzyloxy)-5-(morpholin-4-yl)benzamido)-4-(thiophen-2-yl)benzoate as a light yellow solid.
Reaction SMILES: Cl.[O:2]=[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][C:5]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:4]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[C:26]([Cl:32])[C:25]=1[Cl:33].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:23][C:24]1[CH:29]=[C:28]([CH:27]=[C:26]([Cl:32])[C:25]=1[Cl:33])[CH2:30][N:20]1[CH2:21][CH2:22][C:5]2([O:4][C:3](=[O:2])[N:7]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:6]2)[CH2:18][CH2:19]1
Reactant: Clc1cc(CBr)cc(Br)c1Cl
Reactant: COC(=O)c1ccc(N2CC3(CCNCC3)OC2=O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(Cl)c(Cl)c(Br)c4)CC3)OC2=O)cc1
Temperature: 55 °C
Yield: 94 %

Procedure:
To methyl 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoate hydrochloride salt (50 mg, 0.153 mmol; Example 1, Step 2) and 1-bromo-5-(bromomethyl)-2,3-dichlorobenzene (53.7 mg, 0.168 mmol; from Patent US2007/070805) was added DMF (1.5 mL) and DIPEA (107 μL, 0.612 mmol). The mixture was heated to 55° C. for 2 hours. The mixture was evaporated and the residue was dissolved in saturated aqueous NaHCO3 and then extracted with DCM. The organic layer was evaporated to provide the title compound as a yellow oil (76 mg) that was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH:26]([C:27]([O:29]CC)=[O:28])[CH2:25][CH:24]=[CH:23][CH2:22]2)[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:11]([CH2:20][CH:21]2[CH:26]([C:27]([OH:29])=[O:28])[CH2:25][CH:24]=[CH:23][CH2:22]2)[O:10][C:9]1([CH3:33])[CH3:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CC=CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1C(Cc2ccccc2)C(CC2CC=CCC2C(=O)O)OC1(C)C
Yield: 74.9 %

Procedure:
A solution of 4-benzyl-5-(6-ethoxycarbonyl-cyclohex-3-enylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (4.72 g) in ethanol (80 ml) was treated with a solution of sodium hydroxide (0.82 g) in water (15 ml) and the resulting solution refluxed for 18 hours. The ethanol was then evaporated and the residue partitioned between water and ethyl acetate. The organic solution was washed with saturated sodium chloride solution, dried (anhydrous magnesium sulfate) and evaporated. The residue was subjected to flash chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 4-benzyl-5-(6-carboxy-cyclohex-3-enylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.32 g, 75%) Mass spectrum 430 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH:15]([F:17])[F:16])[CH:9]=O)[C:2]#[C:3][CH3:4].C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].Cl>N1CCCCC1.N1C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:9]=[CH:19]/[C:20]([OH:22])=[O:21])[CH:11]=[CH:12][C:13]=1[O:14][CH:15]([F:17])[F:16])[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(C=O)ccc1OC(F)F
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CC#CCOc1cc(/C=C/C(=O)O)ccc1OC(F)F
Temperature: 120 °C
Reaction time: 16 h
Yield: 61.2 %

Procedure:
A solution of 3-(but-2-ynyloxy)-4-difluoromethoxybenzaldehyde (0.53 g, 2.2 mmol) and malonic acid (0.34 g, 3.3 mmol) in a mixture of piperidine (0.2 mL) and pyridine (5.0 mL) was heated to 120° C. and stirred for 16 h. The mixture was cooled to rt and acidified with 1 M HCl. The crude product was collected by filtration and recrystallised from acetonitrile to give (E)-3-(3-(but-2-ynyloxy)-4-difluoromethoxyphenyl)-2-propenoic acid (0.38 g, 61%) as a colourless crystalline solid; mp 206-208° C.; δH (500 MHz, DMSO-d6) 1.84 (t, J=2.2 Hz, 3H, C≡CH3), 4.87 (q, J=2.2 Hz, 2H, OCH2), 6.55 (d, J=16.0 Hz, 1H, CH═CHCO2H), 7.13 (t, J=72.0 Hz, 1H, CHF2), 7.19 (d, J5,6=8.0 Hz, 1H, H5), 7.30 (dd, J5,6=8.0, J2,6=2.0 Hz, 1H, H6), 7.52 (d, J2,6=2.0 Hz, 1H, H2), 7.54 (d, J=16.0 Hz, 1H, CH═CHCO2H), 12.41 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 3.1, 56.8, 74.1, 84.1, 113.6, 116.4 (t, J=256 Hz), 119.7, 120.6, 122.0, 132.4, 141.2, 142.9, 148.6, 167.4; νmax 1011, 1113, 1267, 1516, 1629, 1686, 2578, 2924 cm−1.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[Si:13]([O:20][C:21]1[CH:26]=[C:25]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[N:24]=[C:23]([S:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[N:22]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CI>O1CCCC1>[Si:13]([O:20][C:21]1[CH:26]=[C:25]([O:27][Si:28]([C:31]([CH3:33])([CH3:34])[CH3:32])([CH3:29])[CH3:30])[N:24]=[C:23]([S:35][CH:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH3:1])[N:22]=1)([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(O[Si](C)(C)C(C)(C)C)nc(SCc2ccccn2)n1
Reactant: [Li]CCCC
Solvent: CI
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(Sc1nc(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)n1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.8 %

Procedure:
A solution of n-butyllithium (11.02 ml, 17.63 mmol, 1.2 equiv., 1.6 M in hexanes) in 60 ml of tetrahydrofuran cooled at -78° C. is treated dropwise with diisopropylamine (1.93 g, 19.10 mmol, 1.3 equiv.) over a two minute period. After stirring for another 10 min, a solution of 4,6-di-(tert-butyldimethylsilyloxy)-2-(2-pyridylmethyl)thio-pyrimidine (6.80 g, 14.69 mmol) in 16 ml of tetrahydrofuran is added dropwise over a 10 min period. The reaction mixture is stirred for 30 min longer and treated dropwise with methyl iodide (2.29 g, 16.16 mmol, 1.1 equiv.) in 6 ml of tetrahydrofuran over a 3 min period. Stirring is facilitated by adding an additional 30 ml of tetrahydrofuran. One hour after the addition of the methyl iodide, the cooling bath is removed and the mixture allowed to warm to room temperature. The contents are then cast into ice water and extracted once with ethyl acetate. The organic layer washed with saturated brine, dried with anhydrous Na2SO4 and concentrated at reduced pressure. A methylene chloride solution of the crude product was treated with silica gel (36 g), concentrated to a free flowing powder and applied to the top of a 350 g silica gel column, packed and eluted with ethyl acetate-hexane (5:95), to obtain 2.23 g (32%) 4,6-di-(tert-butyldimethylsilyloxy)-2-(1-(2-pyridyl)ethyl)thio-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:31][N:30]3[C@H:16]([C:17](=[O:51])[NH:18][C@:19]4([C:42](=[O:50])[NH:43][S:44]([CH:47]5[CH2:49][CH2:48]5)(=[O:46])=[O:45])[CH2:41][C@H:20]4[CH:21]=[CH:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:29]3=[O:32])[CH2:15]1)=[O:12])[CH2:6]2.[H][H].O.S([O-])(O)(=O)=O.[K+]>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:31][N:30]3[C@H:16]([C:17](=[O:51])[NH:18][C@:19]4([C:42](=[O:50])[NH:43][S:44]([CH:47]5[CH2:49][CH2:48]5)(=[O:45])=[O:46])[CH2:41][C@H:20]4[CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][C@H:28]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[C:29]3=[O:32])[CH2:15]1)=[O:12])[CH2:6]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCOCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCCOC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCOCCC[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Reaction time: 16 h
Yield: 49.8 %

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,8,9,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate (0.022 g, 0.030 mmol) and Rh/Al (5%) (0.0062 g, 0.0030 mmol) in Ethyl acetate (5 mL) was charged with 1 atmosphere of hydrogen and stirred for 16 hrs. Water (3 mL) and saturated potassium hydrogen sulfate (3 mL) was added and stirred for 10 minutes. The organic phase was separated and aqueous phase extracted with ethyl acetate (10 mL), washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:2) to give (2R,6S,13aR,14aR,16aS)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxohexadecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate as white solid (0.011 g, 50%). MS: Calcd.: 735; Found: [M+H]+ 736. 1H NMR (400 MHz, CD2Cl2) δ9.69 (s, 1H), 7.18 (m, 1H), 6.84-7.15 (m, 2H), 5.24 (m, 1H), 5.04 (m, 1H), 4.65 & 4.61 (s, 4H), 4.15 (m, 2H), 3.70 (m, 1H), 3.44 (m, 2H), 3.34 (m, 1H), 3.28 (m, 1H), 2.84 (m, 1H), 2.52 (m, 1H), 2.35 (m, 1H), 1.86 (m, 2H), 0.97-1.56 (m, 22H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C>C1COCC1>[F:13][C:14]1[C:19]([B:25]([OH:26])[OH:24])=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1
Reactant: Cc1ccc(F)nc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cnc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
n-Butyllithium (2.5M solution in hexane, 9.6 mL, 24 mmol) was added to a mixture of diisopropylamine (3.4 mL, 24 mmol) in THF (5.00 mL, 61 mmol) at 0° C. and the resulting pale yellow solution was stirred at the same temperature for 30 min and then cooled down to −78° C. A suspension of 2-fluoro-5-methylpyridine (Aldrich, St. Louis, Mo.) (2.22 g, 20 mmol) in THF (5.00 mL, not complete dissolved) was slowly added. The resulting bright yellow solution was stirred at −78° C. for 1 h, treated with a solution of tri-i-propylborate (6.9 mL, 30 mmol) in THF (10.00 mL) and then allowed to warm up to room temperature. The yellow suspension was quenched with 1 N NaOH until basic (pH about 10) and the organic layer was separated. The aqueous layer was collected and carefully acidified with 6 N aqueous HCl until slightly acidic, and then extracted with EtOAc (×3). The combined organic layers were dried (Na2SO4), filtered and concentrated. The resulting white solid was washed with ether to give 2-fluoro-5-methylpyridin-3-ylboronic acid (2.9196 g, 94% yield) as a white solid. LCMS (API-ES) m/z 156 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:42]([CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:43]=[CH:44][N:45]=5)=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:54]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:63])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:40][C:41]5[N:42]([CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH:43]=[CH:44][N:45]=5)=[O:63])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:54]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCCC(=O)OCC)cc2)CCCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCCC(=O)OCC)cc2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a solution of ethyl 4-(2-(((4-(((8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydro-1-benzazocine-5-yl)carbonyl)amino)phenyl)sulfanyl)methyl)-imidazol-1-yl)butanoate (400 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloroperbenzoic acid (144 mg) in dichloromethane (10 ml) at −78° C. As such, the mixture was stirred for 1 hour. Then, dry ice-acetone bath was removed and an aqueous sodium thiosulfate solution was added with vigorous stirring. After stirring the mixture at room temperature for 30 minutes, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (hexane:ethyl acetate=1:1→ethyl acetate), and recrystallized from hexane-ethyl acetate to give ethyl 4-(2-(((4-(((8-(4-(2-butoxyethoxy)phenyl)-1-isobutyl-1,2,3,4-tetrahydro-1-benzoazocine-5-yl)carbonyl)amino)phenyl)sulfinyl)methyl)imidazol-1-yl)butanoate (317 mg) as yellow crystals (Compound 54).
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[C:18]([C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[C:32](=NO)[CH2:31][CH2:30]5)[CH:17]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N1CC[O:41]CC1.C(N(CC)CC)C>ClCCl>[N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)=[C:18]([C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[C:32](=[O:41])[CH2:31][CH2:30]5)[CH:17]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(CN1CCOCC1)N1CCCC(c2cc(-c3ccc4c(c3)CCC4=NO)c(-c3ccncc3)o2)C1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCc2cc(-c3cc(C4CCCN(C(=O)CN5CCOCC5)C4)oc3-c3ccncc3)ccc21
Yield: 54.7 %

Procedure:
A solution of the product of Step 1 (140 mg, 0.32 mmol) in dry dichloromethane (10 ml) was treated with morpholine (0.031 ml, 0.35 mmol) and triethylamine (0.049 ml, 0.35 mmol) and heated at reflux for 3 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried, concentrated in vacuo and then purified by silica gel chromatography eluting with chloroform/ethanol/0.880 ammonia solution (98:1.8:0.2) to yield the title compound (85 mg, 55%); MS(ES+) m/e 486 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:37]([CH3:38])=[CH:36][C:5]2[NH:6][C:7]([CH2:9][N:10]([CH:26]3[C:35]4[N:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:29][CH2:28][CH2:27]3)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)=[N:8][C:4]=2[CH:3]=1.O.NN>C(O)C.C(OCC)C>[CH3:38][C:37]1[C:2]([CH3:1])=[CH:3][C:4]2[NH:8][C:7]([CH2:9][N:10]([CH:26]3[C:35]4[N:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:29][CH2:28][CH2:27]3)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:6][C:5]=2[CH:36]=1
Reactant: Cc1cc2nc(CN(CCCCN3C(=O)c4ccccc4C3=O)C3CCCc4cccnc43)[nH]c2cc1C
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc2nc(CN(CCCCN)C3CCCc4cccnc43)[nH]c2cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
To a stirred solution of 2-{4-[(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (60 mg, 0.118 mmol) in ethanol (2.5 mL) was added hydrazine hydrate (0.05 mL, 1.03 mmol) and the mixture stirred at room temperature for 16 hours. The mixture was then diluted with diethyl ether, dried (MgSO4), filtered and concentrated under reduced pressure to give a crude yellow oil. The oil was purified by flash chromatography (1.75 cm ID, 12 g silica, 10:1:1 CH2Cl2: MeOH: NH4OH) to give pure N1-(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (18 mg, 38%). 1H NMR (CDCl3) δ 1.30-1.46 (m, 4H), 1.60-1.75 (m, 1H), 1.82-1.96 (m, 1H), 1.98-2.08 (m, 1H), 2.14-2.24 (m, 1H), 2.35 (s, 6H), 2.47-2.59 (m, 3H), 2.65-2.90 (m, 3H), 3.92-4.06 (m, 3H), 7.13 (dd, 1H, J=7.9, 4.8 Hz), 7.34 (s, 2H), 7.40 (d, 1H, J=7.1 Hz), 8.58 (s, 1H, J=3.5 Hz).