Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]2[C:12](=[O:24])[N:13]([CH2:22][CH3:23])[C:14]3[C:19]([CH:20]=2)=[CH:18][N:17]=[C:16](Cl)[CH:15]=3)[CH:3]=1.[CH3:25][NH2:26]>>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]2[C:12](=[O:24])[N:13]([CH2:22][CH3:23])[C:14]3[C:19]([CH:20]=2)=[CH:18][N:17]=[C:16]([NH:26][CH3:25])[CH:15]=3)[CH:3]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C#N)cc2cnc(Cl)cc21
Reactant: CN
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2C#N)cc2cnc(NC)cc21
Temperature: 120 °C
Yield: 61 %

Procedure:
A mixture of 4-amino-2-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-5-fluorobenzonitrile (420 mg, 1.23 mmol) and methylamine (25%, 50 mL) was heated at 120° C. in a pressure vessel for 1 day. The mixture was cooled to RT, the solid collected via filtration and purified via silica gel chromatography (EtOAc/pet ether) to afford 4-amino-2-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-5-fluorobenzonitrile (250 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.42 (s, 1H), 7.81 (s, 1H), 7.72 (s, 1H), 7.53 (d, J=11.6 Hz, 1H), 7.09-7.08 (m, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.23 (s, 2H), 4.16-4.11 (q, J=6.8 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H), 1.22-1.18 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:1][C:2]1[C:11]([NH:12][C:13]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[S:23][CH3:22])[CH2:35][CH2:34]2)=[O:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CSc1ccccc1N1CCNCC1
Reactant: Cc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: CSc1ccccc1N1CCN(C(=O)Nc2cc3ccccc3nc2C)CC1
Yield: 76 %

Procedure:
Phenyl N-(2-methylquinolin-3-yl)carbamate and 1-(2-methylthiophenyl)piperazine were reacted by the same way with the example 114 to obtain the titled compound.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[CH2:22])[CH:16]=[C:15]([O:23][CH2:24][CH:25]=[CH2:26])[C:14]=1[CH2:27][CH3:28].Cl.C(=O)([O-])O.[Na+].O>CO.O1CCOCC1>[CH2:24]([O:23][C:15]1[C:14]([CH2:27][CH3:28])=[C:13]([CH2:12][CH2:11][O:10][CH2:9][CH2:8][OH:7])[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[CH2:22])[CH:16]=1)[CH:25]=[CH2:26]
Reactant: C=CCOc1cc(CCOCCOC2CCCCO2)c(CC)c(OCC=C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: C=CCOc1cc(CCOCCO)c(CC)c(OCC=C)c1
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
2-(Tetrahydro-2H-pyran-2-yloxy)-1-[2-(3,5-diallyloxy-2-ethylphenyl)ethoxy]ethane (3.0 g, 7.6 mmol) obtained in Example 59, Step 1 was dissolved in methanol (30 mL), and a 4 mol/L solution of hydrogen chloride in 1,4-dioxane (20 mL) was added thereto, followed by stirring for 30 minutes. After the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, water was added thereto, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane 1/9-1/1) to obtain 2-[2-(3,5-diallyloxy-2-ethylphenyl)ethoxy]ethanol (1.9 g, 81%) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(#N)C>[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH:2]2[CH2:3][O:4][C:5]3([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]3)[O:1]2)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(CCC2COC3(CCNCC3)O2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,4-Dioxa-8-azaspiro[4.5]-decane (18.62 g, 130 mmoles) in 50 mL of acetonitrile was stirred under argon and treated with anhydrous potassium carbonate (27.60 g, 200 mmoles). The mixture was cooled to 0° C. and 2-(4-nitrophenyl)ethylbromide (23.01 g, 100 mmoles) was added in one portion. After 10 minutes, the ice bath was removed and the reaction was stirred for 14 hrs at room temperature. The mixture was diluted with 220 mL of ethyl acetate and 200 mL of water. The aqueous phase was separated, the organic phase washed with water (3×100 mL), and brine (2×50 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give 28.60 g (98%) of N(2-(4-nitrophenyl)ethyl-1,4-dioxa-8-azaspiro[4.5]-decane as a yellow solid.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:29]2[N:30]=[C:31]([NH:34]C(=O)C(F)(F)F)[S:32][CH:33]=2)[C:7]([NH:9][C@@H:10]2[C:27](=[O:28])[N:12]3[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]4[S:20][CH:21]=[N:22][N:23]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.O.O.O.C([O-])(=O)C.[Na+]>O.O1CCCC1>[NH2:34][C:31]1[S:32][CH:33]=[C:29]([C:6](=[N:5][O:4][CH:1]2[CH2:3][CH2:2]2)[C:7]([NH:9][C@@H:10]2[C:27](=[O:28])[N:12]3[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]4[S:20][CH:21]=[N:22][N:23]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[N:30]=1
Reactant: O=C(O)C1=C(CSc2nncs2)CS[C@@H]2[C@H](NC(=O)C(=NOC3CC3)c3csc(NC(=O)C(F)(F)F)n3)C(=O)N12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Reaction time: 8 h
Yield: 83.5 %

Procedure:
To a suspension of 7β-[2-cyclopropyloxyimino-2-(2-trifluoroacetamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.1 g) in a mixture of water (23.5 ml) and tetrahydrofuran (2 ml) was added sodium acetate trihydrate (2.35 g) at ambient temperature. The mixture was stirred at the same temperature overnight to give a clear solution. The solution was washed with ethyl acetate and adjusted to pH 2 with 1N hydrochloric acid. The mixture was extracted with tetrahydrofuran twice. The extract was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (780 mg) as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OB(O)c1cccc(F)c1
Product: COc1ccc2c(-c3cccc(F)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-fluoro-phenylboronic acid to give [1-(3-Fluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 349(MH+).
Reaction SMILES: C[N+]1([O-])CCOCC1.[CH3:9][C:10]1([CH3:39])[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20]([O:34][Si](C)(C)C)=[CH:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:16]=2)[O:11]1>O.CC(C)=O.[Os](=O)(=O)(=O)=O>[CH3:9][C:10]1([CH3:39])[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:20](=[O:34])[CH2:21][C:22]3[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=3)[CH:16]=2)[O:11]1
Reactant: COc1cc(C=C(O[Si](C)(C)C)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(CC(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Reaction time: 3 h
Yield: 10.3 %

Procedure:
A solution of osmium tetroxide (25% wt., 0.574 mL) and NMO (13.24 mg, 0.113 mmol) dissolved in water (0.27 mL) and acetone (0.48 mL) were cooled to −5° C. [1-(2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-vinyloxy]-trimethyl-silane (50 mg, 0.113 mmol) dissolved in acetone (0.2 mL) was added dropwise to the cooled stirring solution. After completion of addition the reaction continued to stir at 0° C. After 3 h, the reaction was quenched with sodium hydrosulfite and florisil. The reaction mixture was filtered and the filtrate was concentrated. The crude material was purified using silica gel chromatography (4:1 pentane:ethyl acetate to 1:1 pentane ethyl acetate) to afford the desired compound (4.3 mg, 8%).
Reaction SMILES: [CH:1](=[C:3]1[CH2:8][C:7]2[CH2:9][CH:4]1[CH2:5][CH:6]=2)[CH3:2].[CH2:10]=[CH:11][CH3:12].C=C.C1(/C=C/C=C/C2C=CC=CC=2)C=CC=CC=1.B(C1C(F)=C(F)C(F)=C(F)C=1F)(C1C(F)=C(F)C(F)=C(F)C=1F)C1C(F)=C(F)C(F)=C(F)C=1F>C1(C)C=CC=CC=1>[CH2:1]=[CH2:2].[CH2:10]=[CH:11][CH3:12].[CH:1](=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)[CH3:2]
Reactant: CC=C1CC2=CCC1C2
Agent: C(/C=C/c1ccccc1)=C\c1ccccc1
Agent: C=C
Agent: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Solvent: Cc1ccccc1
Solvent: C=CC
Product: CC=C1CC2C=CC1C2
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A 2 L batch reactor is charged with 500 mL of mixed alkanes, 75 mL of 5-ethylidene-1-norbornene, and 500 mL of liquefied propylene. The reactor is heated to 60° C., and is saturated with ethylene at 500 psig (3.4 MPa). In an inert atmosphere drybox, 10 μmol of a 0.005M solution in toluene of rac-[1,2-ethanediylbis(1-(2-methyl-4-phenyl)indenyl)]zirconium (trans,trans-1,4-diphenyl-1,3-butadiene and 10 μmol of a 0.005 m solution of B(C6F5)3 in toluene are combined and the mixture is transferred to the reactor to initiate polymerization. After 15 minutes, the reactor is vented and the solution is drained from the reactor. The polymer solution is combined with 100 mg of antioxidant and the volatiles are removed under reduced pressure in order to isolate the rubbery terpolymer of ethylene/propylene/ethylidene norbornene.
Reaction SMILES: OC1C=C2C(=CC=1)C=C(C=C)C=C2.[OH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH:25]=[O:26])[CH:19]=[CH:18]2.[CH:27]([O:29][CH2:30][CH3:31])=[CH2:28]>>[CH2:27]([O:29][CH:30]([O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([CH:25]=[O:26])[CH:19]=[CH:18]2)[CH3:31])[CH3:28]
Reactant: O=Cc1ccc2cc(O)ccc2c1
Reactant: C=COCC
Agent: C=Cc1ccc2cc(O)ccc2c1
Product: CCOC(C)Oc1ccc2cc(C=O)ccc2c1

Procedure:
The synthesis of 6-hydroxy-2-vinylnaphthalene (HVN) was carried out by three step reactions starting from 6-hydroxy-2-naphthaldehyde. In the first step, 6-hydroxy-2-naphthaldeyde (HNAL) was protected with ethyl vinyl ether to give 6-(1-ethoxy ethoxy)-2-naphthaldehyde (EENAL). This was followed by the Wittig reaction of EENAL to yield 6-(1-ethoxy ethoxy)-2-vinylnaphthalene. Finally, this was deprotected using pyridinium p-toluenesulfonate to yield 6-hydroxy-2-vinylnaphthalene (HVN).
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[N:11]=[CH:10][C:9](B(O)O)=[CH:8][N:7]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][C:31]([C:33]2[CH:34]=[CH:35][C:36]3[CH2:37][C@H:38]4[N:50]([CH3:51])[CH2:49][CH2:48][C@@:44]5([C:45]=3[C:46]=2[OH:47])[C@@:39]4([OH:53])[CH2:40][CH2:41][C:42](=[O:52])[CH2:43]5)=[O:32])=[CH:24][CH:23]=1>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.O>[OH:47][C:46]1[C:45]2[C@:44]34[CH2:48][CH2:49][N:50]([CH3:51])[C@@H:38]([C@:39]3([OH:53])[CH2:40][CH2:41][C:42](=[O:52])[CH2:43]4)[CH2:37][C:36]=2[CH:35]=[CH:34][C:33]=1[C:31]([NH:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:9]2[CH:8]=[N:7][C:6]([O:5][CH3:4])=[N:11][CH:10]=2)=[CH:27][CH:26]=1)=[O:32]
Reactant: COc1ncc(B(O)O)cn1
Reactant: CN1CC[C@]23CC(=O)CC[C@@]2(O)[C@H]1Cc1ccc(C(=O)NCCc2ccc(Br)cc2)c(O)c13
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ncc(-c2ccc(CCNC(=O)c3ccc4c(c3O)[C@]35CCN(C)[C@H](C4)[C@]3(O)CCC(=O)C5)cc2)cn1
Temperature: 120 °C
Yield: 31.8 %

Procedure:
To a degassed mixture of ethanol and water (4:1, 20 mL) was added 2-methoxypyrimidin-5-ylboronic acid (0.67 g, 4.4 mmol), Na2CO3 (1.24 g, 11.7 mmol) and N-[2-(4-bromophenyl)ethyl]-4,14-dihydroxy-17-methyl-6-oxomorphinan-3-carboxamide (2) (1.5 g, 2.9 mmol). The reaction mixture was further degassed and then Pd(PPh3)4 (0.32 g, 0.3 mmol) added. The reaction mixture was heated in a microwave reactor at 120° C. for 25 min. and cooled. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with 1:1 brine/water (3×35 mL). The organic phase was dried over MgSO4, filtered and evaporated. The resulting residue was further purified on silica eluting with dichloromethane/methanol (9:1) to give 4,14-dihydroxy-N-{2-[4-(2-methoxypyrimidin-5-yl)phenyl]ethyl}-17-methyl-6-oxomorphinan-3-carboxamide (3) (0.50 g, 32%) as a yellow foam.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[S:20])(C(C)(C)C)(C)C.CCN(CC)CC.F>CC#N>[OH:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[S:20]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1NC(=S)Nc1ccccc1
Agent: F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(NC(=S)Nc2ccccc2)c(O)c1
Yield: 76.7 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-2-thiourea was prepared by treating a solution of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea (100 mg, 0.248 mmol) in CH3CN (1 mL) with Et3N·HF (100 uL, 0.62 mmol) in acetonitrile for 10 minutes at 23° C. The solution was concentrated and flushed through a silica plug with EtOAc to afford the desired compound as an orange solid (55 mg, 77%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH2:20])[CH:14]=1)(=[O:12])=[O:11])[CH2:7][OH:8].[C:25]([O:29][C:30]([NH:32][C@@H:33]([CH:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:34](O)=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:31])[NH:32][C@H:33]([C:34](=[O:35])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([N:9]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([NH2:20])[CH:14]=1)(=[O:12])=[O:11])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:7][OH:8])[CH:37]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([CH3:26])([CH3:28])[CH3:27]
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(F)c(N)c1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(c1ccccc1)c1ccccc1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(F)c(N)c1
Yield: 46 %

Procedure:
The title compound was prepared from the crude amine mixture of (1S)-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-3-amino-4-fluoro-benzenesulfonamide which is described earlier (example 53, step C) and (2S)-2-tert-butoxycarbonylamino-3,3-diphenyl-propionic acid using general procedure A. The crude residue was purified by semi-preparative HPLC in several batches of 80 mg using a gradient of 50 to 80% of acetonitrile over 30 min and a flow rate of 15 mL/min, retention time=20.2 min. All the pure fractions were combined to provide 630 mg (46% yield) of the title compound.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][C:2]2=[C:10]1[CH2:17][CH2:16][CH:15]2[CH2:18][CH:11]1[CH2:12][CH2:13][CH2:14]2.[Cl:19]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:19][C:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][C:2]2=[C:10]1[CH2:17][CH2:16][CH:15]2[CH2:18][CH:11]1[CH2:12][CH2:13][CH2:14]2
Reactant: C1CC2CCC(=C3CCC4CCCC3C4)C(C1)C2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: ClC12CCCC(CCC1=C1CCC3CCCC1C3)C2
Reaction time: 1 h

Procedure:
To a solution of 200 mg (0.82 mmol) of bicyclo[3,3,1]nonylidene-bicyclo[3,3,1]nonane (formula 17) in 20 cm3CH2Cl2, 115 mg (0.86 mmol) N-chlorosuccinimide was added. The reaction mixture was refluxed and stirred for 1 hour, and CH2Cl2 was added to dilute the reaction mixture. The organic layer was washed twice with water, dried with MgSO4 and evaporated. The yield of 4-eq.-chlorobicyclo[3,3,1]nonylidene-bicyclo[3,3,1]nonane was 190 mg. Purification was effected via chromatography (hexane, Al2O3) and sublimation (45° C./0.01 mm), melting point 50.53° C., 1H NMR (CDCl3) δ 4.4-3.9 (m, 1H); 3.1 (br s, 1H): 2.85 (br s, 3H); 2.5-1.2 (br, 22H); 13C NMR (CDCl3) δ 136.8 (s); 129.7 (s); 66.0 (d) and lines between 39.7 and 21.7; mass m/e 278:280 (3:1 ); exact mass: calculated 278.180; found 278.182.
Reaction SMILES: C(OC(=NNC(N)=O)C[CH:8]([NH:11][C:12](=[O:48])[C@@H:13]1[CH2:17][CH:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][N:14]1[C:26](=[O:47])[C@H:27]([CH:44]([CH3:46])[CH3:45])[NH:28][C:29](=[O:43])[C@H:30]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)[NH:31][C:32](=[O:34])[CH3:33])[CH:9]=[O:10])(C)(C)C.F[C:55](F)(F)[C:56]([OH:58])=[O:57].CO.C=O>ClCCl.C(O)(=O)C>[C:32]([NH:31][C@H:30]([C:29]([NH:28][C@H:27]([C:26]([N:14]1[CH2:15][CH:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][C@H:13]1[C:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:55][C:56]([OH:58])=[O:57])=[O:48])=[O:47])[CH:44]([CH3:45])[CH3:46])=[O:43])[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CC(OCc2ccccc2)C[C@H]1C(=O)NC(C=O)CC(=NNC(N)=O)OC(C)(C)C)C(C)C
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CC(OCc2ccccc2)C[C@H]1C(=O)NC(C=O)CC(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N—(N-Acetyl-tyrosinyl-valinyl-(4-benzyloxyprolinyl))-3-amino-4-oxobutanoic acid tert-butyl ester semicarbazone (270 mg) was dissolved into 10 ml of 25% trifluoroacetic acid in dichloromethane and stirred at room temperature for 3 hours. The mixture was concentrated to give a solid residue. The residue was dissolved into a 10 ml mixture of methanol:acetic acid:37% formaldehyde (3:1:1) and stirred at room temperature for 1 hour. The mixture was concentrated and the resulting residue purified by flash chromatography (SiO2) eluting with dichloromethane/methanol/formic acid (100:5:0.5) to give 37 mg of the title compound.
Reaction SMILES: S(C)C#N.Cl.CN[OH:8].C(=O)([O-])[O-].[Na+].[Na+].C(OC)(=O)C#CC(OC)=O.CO[C:27](=[O:41])[CH2:28][C:29]1([C:37]([O:39][CH3:40])=[O:38])O[N:32]([CH3:34])[C:31]([S:35][CH3:36])=[N:30]1>O.C1(C)C(C)=CC=CC=1.CCOC(C)=O.CCO>[CH3:40][O:39][C:37]([C:29]1[N:30]=[C:31]([S:35][CH3:36])[N:32]([CH3:34])[C:27](=[O:41])[C:28]=1[OH:8])=[O:38]
Reactant: CNO
Reactant: COC(=O)CC1(C(=O)OC)N=C(SC)N(C)O1
Agent: COC(=O)C#CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CSC#N
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)c1nc(SC)n(C)c(=O)c1O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
In a round-bottomed flask, thiocyanatomethane (17.5 g, 239 mmol) and N-methylhydroxylamine hydrochloride (20 g, 239 mmol) were combined with EtOH (100 ml) to give a light yellow solution. A solution of sodium carbonate (12.7 g, 120 mmol) in water (50 ml) was added slowly over 8 min at RT. The resulting mixture was stirred at RT for 2.5 days and then cooled in an ice bath. Dimethyl but-2-ynedioate (34.0 g, 239 mmol) was added slowly over 10 min and the resulting mixture was stirred for 2 hours, keeping the internal temperature below 22° C. Ice water and EtOAc were added. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting methyl 5-(2-methoxy-2-oxoethyl)-2-methyl-3-(methylthio)-2,5-dihydro-1,2,4-oxadiazole-5-carboxylate (62.7 g, 239 mmol) was placed in a round-bottomed flask, dissolved in xylene (110 ml), then heated at 140° C. for 48 hours, cooled and then evaporated to dryness to give the crude title product as a brown solid. LCMS: m/z=231 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH:24]([C:26]1[S:27][C:28]([O:31][CH2:32][CH3:33])=[N:29][N:30]=1)[CH3:25]>O.CN(C)C=O>[CH2:32]([O:31][C:28]1[S:27][C:26]([CH:24]([O:14][C:11]2[CH:12]=[CH:13][C:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:9][CH:10]=2)[CH3:25])=[N:30][N:29]=1)[CH3:33]
Reactant: CCOc1nnc(C(C)Br)s1
Reactant: Oc1ccc(Oc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1nnc(C(C)Oc2ccc(Oc3ccccn3)cc2)s1
Yield: 61.1 %

Procedure:
To a mixture of 4-(2-pyridyloxy)phenol (0.75 g), anhydrous potassium carbonate (0.67 g), potassium iodide (0.07 g), cupuric oxide (0.02 g) and 7 ml of dimethyl formamide, was added 2-(1-bromoethyl)-5-ethoxy-1,3,4-thiadiazole (0.95 g) under stirring, and further stirred at 80° C. for one hour. After cooling and pouring water, the resulting solution was extracted with ethyl acetate, washed with water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under a reduced pressure and the residue was purified on column chromatography to obtain 0.84 g of the compound (No. 1) described in Table 1.
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10]>>[CH2:12]([O:11][C:9](=[O:10])[C:2]#[C:1][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:13]
Reactant: C#CC1CCCC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)C#CC1CCCC1

Procedure:
The title compound was prepared from ethynyl-cyclopentane and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, 5697-5708.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:19]=[CH:18][CH:17]=[C:15]([NH2:16])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: Nc1cccc(Br)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cccc(N)c2)cc1
Temperature: 25 °C
Yield: 68 %

Procedure:
4-methoxyphenyl boronic acid (0.105 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum. And the resulting residue was resuspended in H2O and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.063 g in 68% yield.