Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][Sn:5]([O:14][Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9].[CH3:28][N:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)[CH3:30].O>C1C=CC=CC=1>[CH3:28][N:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:23][CH2:22][CH2:21][CH2:20][Sn:15]([O:14][Sn:5]([CH2:10][CH2:11][CH2:12][CH2:13][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:29]([CH3:30])[CH3:28])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][CH2:3][CH2:2][CH3:1])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:24][CH2:25][CH2:26][CH3:27])[CH3:30]
Reactant: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Reactant: CN(C)Cc1ccccc1O
Solvent: c1ccccc1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCCc1ccccc1CN(C)C)O[Sn](CCCC)(CCCC)CCCCc1ccccc1CN(C)C

Procedure:
2-(Dimethylaminomethyl)phenyltributylstannyl Ether is prepared as follows: 59.6 gm (0.1 mole) bis(tributyltin) oxide and 30.0 gm (0.2 mole) 2-dimethylaminomethyl phenol (as just prepared) are placed in 200 ml benzene. This is slowly heated to reflux in a system equipped with a Dean-Starke tube. After about 30 minutes water began to separate in the Dean-Starke tube. After 72 hours at reflux 1.9 ml of water had separated (theory 1.8 ml). A clear straw colored reaction mixture resulted and benzene is evaporated therefrom on a rotating evaporator to provide 87.7 gm of a yellow liquid. This is fractionated at reduced pressure. The product collected at 165°-168° C. at 0.5 mm is 75.0 gm of a straw colored liquid (Percent yield - 82). Infrared spectral analysis provided bands characteristic of the desired product.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@@H:4]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH2:26][N:27]([CH2:38][CH3:39])[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH3:5].[OH-].[Li+].OO.Cl>O.C1COCC1>[CH2:31]([NH:30][C:28](=[O:29])[N:27]([CH2:26][C:17]1[CH:18]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=[CH:21][C:16]=1[C:8]1[CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=[C:6]([C@@H:4]([CH3:5])[C:3]([OH:40])=[O:2])[CH:7]=1)[CH2:38][CH3:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)OC)cc(C(F)(F)F)c1)C(=O)NCc1ccccc1
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)O)cc(C(F)(F)F)c1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-[2′-(3-benzyl-1-ethyl-ureidomethyl)-5,4′-bis-trifluoromethyl-biphenyl-3-yl]-propionic acid methyl ester (0.036 g, 0.06mmol) in 1:1 THF:H2O was added lithium hydroxide (0.005 g, 0.12 mmol) and hydrogen peroxide (29% in water; 0.01 mL, 0.12 mmol). The reaction was stirred at room temperature overnight, and then the mixture was acidified to pH 5 with 10% aqueous HCl. The solution was extracted with EtOAc, and the crude material was purified by preparative HPLC to give the title compound. M+H is 553.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20]I>O>[Cl:17][CH2:18][CH2:19][CH2:20][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a stirred solution of 6-nitro-3,4-dihydroquinolin-2(1H)-one (2 g, 10.41 mmol) at 0° C. under argon was added sodium hydride, 60% (0.624 g, 15.61 mmol). The mixture was stirred at 0° C. until bubbling ceased, approximately 30 min. To this mixture was then added 1-chloro-3-iodopropane (3.29 ml, 31.2 mmol). The mixture was then allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate (2×). The combined organics were then washed with a 1:1 mixture of water and brine (3×) then brine (1×). The organic phase was then dried, filtered and concentrated on to silica gel, then chromatographed in 10-50% ethyl acetate in hexanes, giving the desired 1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (2.05 g, 7.63 mmol, 73.3% yield) as a yellow solid. 1H NMR (DMSO-d6) δ 8.15 (m, 1H), 8.13 (dd, J=9, 2.7 Hz, 1H), 7.36 (d, J=9 Hz, 1H), 4.07 (t, J=7.4 Hz, 2H), 3.71 (t, J=6.5 Hz, 2H), 3.02 (t, J=7.4 Hz, 2H), 2.63 (t, J=7.4 Hz, 2H), 1.99 (quint, J=7.2 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([NH:18][C:17](=[O:19])[C:16]3[CH:20]=[C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][O:29]C4CCCCO4)=[O:27])[CH:22]=[CH:23][C:15]=3[O:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([NH:18][C:17](=[O:19])[C:16]3[CH:20]=[C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][OH:29])=[O:27])[CH:22]=[CH:23][C:15]=3[O:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccccc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(Cc3ccccc3)C1)O2)NO
Yield: 81.3 %

Procedure:
(±)-(E)-3-{1′-Benzyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (120 mg, 0.25 mmol) in DCM (7 ml) was treated with 4 M HCl in dioxane (1.0 ml) as described in Example 30, STEP C to give (±)-(E)-3-{1′-benzyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-hydroxy-acrylamide (80 mg, hydrochloride salt) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13](CC4C=CC(OC)=CC=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:23][CH:22]5[N:24]([CH3:25])[CH:19]([CH2:20][CH2:21]5)[CH2:18]4)[C:8]=23)=[C:4]([F:37])[CH:3]=1.[F:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH:50]=[CH:49][N:48]=[C:47]([C:51]([OH:53])=O)[C:46]2=[O:54])=[CH:41][CH:40]=1>>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:51]([C:47]2[C:46](=[O:54])[N:45]([C:42]3[CH:41]=[CH:40][C:39]([F:38])=[CH:44][CH:43]=3)[CH:50]=[CH:49][N:48]=2)=[O:53])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[NH:13][N:14]=[C:15]([NH:16][CH:17]3[CH2:23][CH:22]4[N:24]([CH3:25])[CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[C:8]=12
Reactant: COc1ccc(Cn2nc(NC3CC4CCC(C3)N4C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)c1nccn(-c2ccc(F)cc2)c1=O
Product: CN1C2CCC1CC(Nc1n[nH]c3nccc(Oc4ccc(NC(=O)c5nccn(-c6ccc(F)cc6)c5=O)cc4F)c13)C2
Yield: 18 %

Procedure:
Prepared by a 2-step process from 4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (prepared as described in Example 101, Step A except using 8-methyl-8-azabicyclo[3.2.1]octan-3-amine) and 4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (Example 125, Step E) according to the procedure of Example 101, Step B. The crude was rinsed with Et2O to afford 7 mg (18%) of the desired product. The desired product was treated with 2N HCl (Et2O solution) in a solution of MeOH and EtOAc to afford HCl salt compound. LRMS (ESIpos) m/e 599.2 (M+1). 1H-NMR (400 MHz, CD3OD) δ 8.36 (m, 1H), 8.14 (d, 1H), 7.94 (m, 1H), 7.80 (m, 1H), 7.60 (m, 4H), 7.35 (t, 2H), 6.54 (d, 1H), 4.07 (m, 1H), 3.93 (m, 2H), 2.81 (s, 3H), 2.35-2.58 (m, 8H); 19F NMR (376 MHz, CD3OD) δ −113.5, −129.6.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[N:8]O.C([O-])(=O)C.[NH4+].[OH-].[Na+]>C(O)C.[Zn]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[NH2:8]
Reactant: ON=C(c1ccccn1)c1ccccn1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: NC(c1ccccn1)c1ccccn1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
Dipyridin-2-ylmethanone oxime (500 mg, 2.510 mmol) and ammonium acetate were solubilized in ethanol and the mixture was reflux for 3 hours adding portion of zinc at 0 h, 1 h and 2 h. The reaction mixture was cooled down to room temperature and stirred over night. The pH was adjusted to 12 with sodium hydroxide and the mixture was filtered through celite. The mixture was diluted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to afford title compound 405 (282 mg, 61%) as a light yellow oil. MS (m/z): 186.2 (M+H). 1H NMR (CDCl3) δ (ppm): 8.50-8.49 (m, 2H), 7.56 (td, J=7.7, 1.8 Hz, 2H), 7.33 (dt, J=8.0, 0.9 Hz, 2H), 7.08 (ddd, J=7.4, 4.9, 1.2 Hz, 2H), 5.26 (s, 1H), 2.38 (s, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:24][C@@:22]2([CH3:23])[C@@H:18]([CH2:19][CH2:20][C:21]2=[O:25])[C@H:17]2[C:8]1=[C:9]1[C:14]([CH2:15][CH2:16]2)=[CH:13][C:12](=[O:26])[CH2:11][CH2:10]1>C(O)C.[Pd]>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:24][C@@:22]2([CH3:23])[C@@H:18]([CH2:19][CH2:20][C:21]2=[O:25])[C@H:17]2[C@H:8]1[C:9]1[CH:10]=[CH:11][C:12]([OH:26])=[CH:13][C:14]=1[CH2:15][CH2:16]2
Reactant: C[C@]12CC(CCCCCCl)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Agent: [Pd]
Solvent: CCO
Product: C[C@]12CC(CCCCCCl)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Yield: 103.3 %

Procedure:
A solution of 6 g of 11-(5-chloropentyl)-estra-4,9-diene-3,17-dione in 100 ml of ethanol is mixed at room temperature with 1 g of palladium on carbon and refluxed under a hydrogen atmosphere for 0.5 hour. Then, the catalyst is filtered off, it is evaporated to the dry state in a vacuum and chromatographed on silica gel with hexane/acetone. 6.2 g of 11-(5-chloropentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:33])[C:18]([C:20]1[O:21][C:22]3[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=3[C:24]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])=[CH:7]2.[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:36][N:35]=[N:34][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:33])[C:18]([C:20]1[O:21][C:22]3[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=3[C:24]=1[CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])=[CH:7]2
Reactant: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)oc2ccccc12
Temperature: 100 °C
Reaction time: 5 h
Yield: 56.6 %

Procedure:
A mixture of 3-butyl-benzofuran-2-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (1.90 g, 3.77 mmol), prepared in the previous step, sodium azide (735 mg, 11.3 mmol) and ammonium chloride (607 mg, 11.3 mmol) in 50 mL of DMF was stirred under nitrogen at 100° C. for 5 h. By TLC starting material remained. An additional 732 mg (11.3 mmol) of sodium azide was added and the stirring continued at 100° C. for 2 h. The reaction was diluted with 50 mL of water, made basic by the addition of 1 N NaOH and then extracted three times with ethyl acetate. The aqueous layer was acidified with 1 N HCl and the solid that formed was collected by filtration and dried under reduced pressure to give the title compound (1.17 g, 57%) as a light brown solid, mp 180-183° C.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:16](=[O:36])[CH2:17][CH2:18][C:19](=[O:35])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]1(=[O:43])[O:42][C:40](=[O:41])[CH2:39][CH2:38]1>N1C=CC=CC=1>[CH2:28]([O:27][N:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19](=[O:35])[CH2:18][CH2:17][C:16](=[O:36])[N:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:37](=[O:43])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCC(=O)O1
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCNOCc1ccccc1
Solvent: c1ccncc1
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCC(=O)NCCCCCN(OCc1ccccc1)C(=O)CCC(=O)O
Yield: 96.6 %

Procedure:
5,16-Bis(benzyloxy)-20-cyano-4,12,15-trioxo-5,11,16-triazaeicosanoic acid (10) was prepared by heating a solution of (9) (0.365 g, 0.738 mmol) and succinic anhydride (0.113 g, 1.13 mmol) in pyridine (10 mL) at 106° C. for 1.5 hours under N2. After removing the pyridine in vacuo, the residue was diluted with ether (25 mL) and then extracted with saturated NaHCO3 (3×25 mL). The combined aqueous portion was extracted further with ether (2×25 mL), then cautiously acidified with cold 6N HCl (20 mL). Extraction with CHCl3 (3×40 mL), followed by a final water wash (40 mL) and solvent removal led to 0.424 g of (10) (96% yield): NMR δ 1.25-1.84 (m, 10 H), 2.2-2.92 (m, 10 H), 3.05-3.33 (m, 2 H), 3.5-3.8 (m, 4 H), 4.80 and 4.83 (2 s, 4 H), 6.6 (br s, 1 H), 7.34 (s, 10 H). Anal. calcd. for C32H42N4O7 : C, 64.63; H, 7.12; N, 9.42. Found: C, 64.70; H, 7.16; N, 9.39.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:55][CH3:56])[CH2:11][N:10]([C:12](=[O:41])[C@@H:13]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:14][N:15]([CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[C@H:9]([C:42]([NH:44][C@:45]3([C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:47][C@H:46]3C=C)=[O:43])[CH2:8]2)=[CH:3][CH:2]=1>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[C:1]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([O:55][CH3:56])[CH2:11][N:10]3[C@H:9]([C:42](=[O:43])[NH:44][C@:45]4([C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:47][C@H:46]4[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28][N:15]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])[CH2:14][C@H:13]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[C:12]3=[O:41])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: C=CCCCN(C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c3ccc(-c4ccccc4)cc3)C[C@H]1C(=O)N2
Solvent: ClCCl
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c3ccc(-c4ccccc4)cc3)C[C@H]1C(=O)N2

Procedure:
A mixture of (1R,2S)-ethyl 1-((2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3-(2-nitro-N-(pent-4-enyl)phenylsulfonamido)propanoyl)-4-methoxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (95 mg, 0.109 mmol) and Grubbs II (18.46 mg, 0.022 mmol) in DCM (200 mL) was refluxed for 4 h. The reaction mixture was then concentrated in vacuo. The residue was purified by Biotage eluting with 60% EtOAc/hexane to isolate 65 mg (71%) of (2R,6S,13aS,14aR,16aS,Z)-ethyl 2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-methoxy-8-(2-nitrophenylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[n]pyrrolo[2,1-c][1,4,8]triazacyclopentadecine-14a-carboxylate as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=O)[CH:5]=[CH:6][CH:7]=1.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[CH:16][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCc1cccc(Br)c1
Solvent: ClCCl
Product: CCOC(=O)C=CCc1cccc(Br)c1
Reaction time: 16 h

Procedure:
60 g (246 mmol) of ethyl (3-bromophenyl)acetate (Compound B1) was converted into the title compound (oil) using 255 ml (255 mmol) of diisobutyl aluminum hydride (DIBAL-H, 1M in hexane), 85.8 g (250 mmol) of (carbethoxy methylene)triphenylphosphorane and 1.7 g of 10% Pd/C. The procedure was as follows: To a cold solution (−78° C.) of Compound B1 in CH2Cl2 was added dropwise (over a span of 1 hour) the diisobutyl aluminum hydride (DIBAL-H, 1M solution in hexane). After the DIBAL-H addition was complete, the reaction was stirred at −78° C. for an additional hour. The reaction was quenched by the dropwise addition of methanol, followed by water and 10% HCl. The mixture was then warmed to 0° C., stirred for 10 minutes and then washed with water, 10% aqueous NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent distilled off at ambient temperature to give crude (3-bromophenyl)acetaldehyde. To a cold solution (0° C.) of this crude aldehyde in CH2Cl2 was added a solution of the (carbethoxy methylene)triphenylphosphorane reagent in CH2Cl2. The mixture was stirred for 16 hours, concentrated in vacuo and purified by flash chromatography (silica, 10% EtOAc-hexane) to give ethyl 4-(3-bromophenyl)but-2-enoate as a mixture of E:Z isomers. This isomeric mixture was dissolved in EtOAc and hydrogenated over 10% Pd/C for 6 hours. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound as a white solid. PMR (CDCl3): δ1.26 (3H, t, J=7.1 Hz), 1.89-2.00 (2H, m), 2.31 (2H, t, J=7.5 Hz), 2.63 (2H, t, J=7.2 Hz), 4.15 (2H, q, J=7.1 Hz), 7.10-7.35 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[I:9]I>C1COCC1>[F:1][C:2]1[C:7]([I:9])=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: Cc1ccc(F)nc1
Reactant: II
Solvent: C1CCOC1
Product: Cc1cnc(F)c(I)c1
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A solution of 2-fluoro-5-methyl-pyridine (1.0 g, 9.000 mmol) in dry THF (10 mL) was added dropwise and the solution was stirred at this temp for 2 hours. A solution of iodine (2.284 g, 463.3 μL, 9.000 mmol) in THF (10 mL) was then added and the resultant mixture stirred for a further 1 hour at this temp before being quenched with water. The resulting mixture was partitioned between sodium thiosulfate solution and Et2O, organics separated and washed further with saturated NaCl. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a colourless oil. The resulting mixture was purified by column chromatography (30% EtOAc in hexanes, ˜200 mL silica) to give a colourless foam (1.409 g, 66% Yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][S:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][Mg]Cl)=[CH:14][CH:13]=1>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:16][C:15]2[CH:19]=[CH:20][C:12]([S:11][CH3:10])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CSc1ccc(C[Mg]Cl)cc1
Solvent: C1CCOC1
Product: CSc1ccc(CC(O)c2ccc(F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
A solution of 4-fluorobenzaldehyde (70 mL, 660 mmol) in THF (150 mL) was added to a cold (-78° C.) solution of 4-(methylthio)benzylmagnesium chloride (660 mmol in 1 L of ether) (J.Org. Chem. 42, 19 14, 1977). The mixture was stirred at -78° C. for 10 min then warmed to 0° C. NH4OAc was added and the mixture was extracted with EtOAc. The EtOAc extracts were washed with brine, dried over MgSO4, filtered and concentrated to an oil. Chromatography of the oil on silica gel (eluted with 2.5 % EtOAc/toluene) gave 42 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH:20]=[CH:21][C:22]#[N:23])([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N>CO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:20][CH2:21][CH2:22][NH2:23])([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=CC#N)(C2CCCCC2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCCN)(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-(2-cyanovinyl)-4-cyclohexylpiperidine-1-carboxylic acid tert-butyl ester, 14, (800 mg, 2.35 mmol) in MeOH (33 mL) is added ammonia (16 mL) and Raney Ni (50 mg). The reaction mixture is degassed with nitrogen, purged with hydrogen gas and shaken under an atmosphere of hydrogen (45 psi) on a standard hydrogenation apparatus at room temperature for 6 hours. The reaction solution is filtered to remove the catalyst and the solvent removed in vacuo to afford the desired product was obtained as a colorless, sticky oil in quantitative yield.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH2:10]1[O:12][CH:11]1[CH2:13][CH2:14][CH:15]1[O:17][CH2:16]1>O>[C:2]1([CH2:1][O:8][CH2:16][CH:15]2[O:17][CH:11]([CH2:10][OH:12])[CH2:13][CH2:14]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C(CC1CO1)C1CO1
Agent: [Na]
Solvent: O
Product: OCC1CCC(COCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
100 ml of benzyl alcohol (0.97 mol) is cooled to 5° in an ice-bath and under a nitrogen atmosphere. 0.32 g of sodium (0.0139 mole; washed with hexane to remove the mineral oil) is slowly added to the rapidly stirred benzyl alcohol. The addition of the sodium is made at such a rate that the temperature remains below 20°. After the addition of the sodium has been completed the mixture is allowed to stir for 1/2 hour and slowly warmed to room temperature. Slowly, and with stirring 20 g of 1,5-hexadiene diepoxide (0.175 mole) is added to the mixture. After the addition of the diepoxide has been completed, the reaction mixture is heated at 150° for 16 hours. The mixture is then cooled to room temperature and with stirring is poured into 350 ml of water. The aqueous mixture is extracted with 2×250 ml portions of chloroform, the CHCl3 extracts are combined and dried over anhydrous sodium sulfate. The CHCl3 is removed in vacuo and the colorless oil vacuum distilled through a 10 cm vigreux distilling column. The fraction distilling at 151°-155° @0.5 mm is collected yielding 18.52 g (48%) of the above compound.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:23]2[CH2:28][CH2:27][N:26](CCOCCOCCO)[CH2:25][CH2:24]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)=[CH:20][CH:21]=1
Reactant: OCCOCCOCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1

Procedure:
dextrorotatory dihydrochloride of 2-[2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethoxy]ethanol (compound J, prepared in Example 5.8);
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:17])[NH:14][C:13](=[S:15])[NH:12][C:11]1=[S:16]>C(O)C>[CH2:1]([S:15][C:13]1[NH:14][C:10]([CH3:17])([CH3:9])[C:11](=[S:16])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)NC(=S)NC1=S
Reactant: BrCc1ccccc1
Solvent: CCO
Product: CC1(C)NC(SCc2ccccc2)=NC1=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Initially, 1.91 mL of benzylbromide was added to a solution of 1.6 g of 5,5-dimethyl-2,4-dithiohydantoin in 50 mL of ethanol (EtOH). The reaction mixture was stirred at the room temperature for one hour, and concentrated in vacuo. The residue was treated following the procedure used in Example 62, and purified by column chromatography (CHCl3). Recrystallization from diethyl ether-n-hexane gave 2-benzylthio-5,5-dimethylimidazolin-4-thione in the form of a needle-like crystal. The yield of this compound was 0.87 g with a yield ratio of 34.8%, and the melting point was 133°-134° C.