Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]([OH:25])=O)=[CH:14]1.Cl.[C:27]1([C:33]2([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH:41]3[CH:37]([CH2:38][NH:39][CH2:40]3)[C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[O:49][CH3:50])([OH:42])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[C:51]1([C:33]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:41]3[CH:37]([CH2:38][N:39]([C:23](=[O:25])[CH2:22][C:15]4[C:16]5[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=5)[NH:13][CH:14]=4)[CH2:40]3)[C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[O:49][CH3:50])([OH:42])[CH2:35][CH2:34]2)[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
0.41 g of carbonyldiimidazole is added to a solution of 0.44 g of 3-indolylacetic acid in 20 cm3 of dry methylene chloride. The mixture is stirred at room temperature for 1 hour and a suspension of 1.1 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride in 25 cm3 of dry methylene chloride and then 0.7 cm3 of triethylamine are subsequently added in succession. The reaction mixture is stirred at room temperature for 24 hours, diluted with 100 cm3 of methylene chloride, washed with 100 cm3 of water (twice) and then with 100 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 22 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (35/65 by volume) and collecting fractions of 20 cm3. Fractions 7 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated in diisopropyl ether. 0.17 g of (3aRS,4RS,7aRS)-7,7-diphenyl-2-(3-indolylacetyl)-4-(2-methoxyphenyl)-perhydroisoindol-4-ol is obtained in the form of a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]=[C:17]=[S:18])[N:5]=1.[N:19]#[C:20]Br.O>O1CCCC1>[CH3:3][C:4]1[N:5]=[C:6]2[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=[C:17]([S:18][C:20]#[N:19])[N:7]2[N:8]=1
Reactant: N#CBr
Reactant: Cc1nc(Cc2ccccc2N=C=S)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2n(n1)C(SC#N)=Nc1ccccc1C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 0.91 g of sodium hydride in 27 ml of tetrahydrofuran is added dropwise a solution of 8.74 g of 5-methyl-3-(o-isothiocyanatobenzyl)-1,2,4-triazole in 60 ml of tetrahydrofuran over a period of 20 minutes. The mixture is stirred at room temperature for 2 hours. To the resulting suspension a solution of 4.02 g of cyanogen bromide in 35 ml of tetrahydrofuran is added dropwise at 0° over a period of 15 minutes. The mixture is stirred at 0° for 1.5 hours, poured into water and extracted three times with ethyl acetate. The organic extracts are dried over magnesium sulfate, decolorized with charcoal and evaporated to give 2-methyl-5-cyanothio-11H-1,2,4-triazolo[2,3-c][1,3]benzodiazepine; IR 2150 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:28])([CH3:27])[C:9]([C:11]2[S:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[CH:14][C:15]=2[CH3:16])=[O:10])=[CH:4][C:3]=1[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>C(#N)C>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:27])([CH3:28])[C:9]([C:11]2[S:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)=[CH:14][C:15]=2[CH3:16])=[O:10])=[CH:4][C:3]=1[CH3:29])[CH3:42]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C(C)(C)C(=O)c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C(C)(C)C(=O)c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-(4-hydroxy-3-methylphenyl)-2-methyl-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}propan-1-one (intermediate 105, 62.0 mg) in anhydrous acetonitrile (2 ml) was added caesium carbonate (106 mg) and ethyl bromoacetate (18 μl) and the reaction stirred at room temperature under nitrogen for 20 hours. The solid residue was filtered, and the filtrate was concentrated in vacuo and the residue purified by flash column chromatography, eluting with 1% EtOAc/cyclohexane yielded the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>CC#N>[F:8][C:6]1[CH:5]=[C:4]([S:9]([N:12]=[CH:15][N:16]([CH3:18])[CH3:17])(=[O:10])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)c1cc(F)cc(F)c1
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1cc(F)cc(F)c1
Reaction time: 1 h
Yield: 45829.8 %

Procedure:
To a solution of 3,5-difluorobenzenesulfonamide (154 g, 0.797 mol) in CH3CN (1 L) was added N,N-dimethylformamide dimethylacetal (224 mL, 1.67 mmol, 2.1 eq). After stirring 1 h, the reaction mixture was concentrated under reduced pressure. This material was triturated with Et2O and dried in vacuo to give N′-(3,5-difluorophenylsulfonyl)-N,N-dimethylformimidamide (190 g, 96%) as a light brown solid. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.44-7.38 (m, 2H), 6.98-6.91 (m, 1H), 3.17 (s, 3H), 3.05 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15]CC)[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH2:28]([Mg]Br)[CH3:29].CCO.Cl.O1CCOCC1>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([OH:20])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:28][CH3:29])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: CC[Mg]Br
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCC(O)(c1ccccn1)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (20 mg, 0.055 mmol) was dissolved in dry THF (0.5 mL) and ethylmagnesium bromide (1.0 M, 0.27 mL, 0.27 mmol) was added dropwise. The reaction was allowed to stir at r.t. for 10 minutes and then a mixture of EtOH (1 mL) and 4.0M HCl/dioxane (0.5 mL) was added and the reaction was heated to 65° C. for 3 hours. The reaction was concentrated and purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+].[CH2:31]([Si](C)(C)C)[CH:32]=[CH2:33]>O1CCCC1.O.[I-].[Zn+2].[I-].C(OCC)(=O)C.CCCCCC>[CH2:33]([CH:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[S:10][CH2:9][C:8]1([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:13])[CH:32]=[CH2:31]
Reactant: C=CC[Si](C)(C)C
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC1c2ccc(OC)cc2SCC1(C)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
7-Methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one(2.24 g, 6.823 mmol) prepared according to the known method in WO98/25916 was dissolved in dry tetrahydrofuran(30 ml) and then cooled to −78° C. Lithium aluminum hydride(1N solution in THF, 3.41 ml, 3.412 mmol) was added dropwise thereto and the resulting mixture was stirred overnight at room temperature. The reaction mixture was treated with saturated aqueous ammonium chloride solution(100 ml), extracted twice with ethyl acetate(100 ml), washed with water and saturated saline solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in 1,2-dichloroethane(30 ml). Zinc iodide(2.61 g, 8.188 mmol) and allyltrimethylsilane(2.17 ml, 13.646 mmol) were added dropwise thereto under cooling to 0° C. and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water(200 ml), extracted twice with dichloromethane(200 ml), washed with water and saturated saline solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography(eluent:ethyl acetate/n-hexane=1/4, v/v) to give 1.4 g(Yield 58%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([F:14])([F:13])[F:12])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[N:3]1.N1C(=O)C=NC=CC=1.[Cl:34][C:35]1[CH:36]=[C:37]([CH:46]=[CH:47][C:48]=1[Cl:49])[CH2:38][C@H:39]([CH2:43][CH:44]=[CH2:45])[C:40](O)=[O:41]>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[N:7]([CH2:10][C:11]([F:14])([F:12])[F:13])[C:8](=[O:9])[C@@H:2]([NH:1][C:40](=[O:41])[CH:39]([CH2:38][C:37]2[CH:46]=[CH:47][C:48]([Cl:49])=[C:35]([Cl:34])[CH:36]=2)[CH2:43][CH:44]=[CH2:45])[N:3]=1
Reactant: C=CC[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(CC(F)(F)F)C1=O
Agent: O=c1cncccn1
Product: C=CCC(Cc1ccc(Cl)c(Cl)c1)C(=O)N[C@H]1N=C(c2ccccc2F)c2ccccc2N(CC(F)(F)F)C1=O

Procedure:
Prepared from 3-amino-5-(2-fluoro-phenyl)-1-(2,2,2-trifluoroethyl)-2-oxo-1,3-dihydro-2H-benzo[e][1,4]diazepine [available in an analogous fashion to (S)-3-amino-1-methyl-5-phenyl-1,3dihydro-2H-benzole][1,4]diazepin-2-one (i.e. J. Org. Chem. 1987, 52, 3232)] and (2S)-2-(3,4-dichlorobenzyl)-pent-4-enoic acid using the procedure of Step 1E shown in Scheme 1.
Reaction SMILES: [OH:1][C:2]([C:5]1[NH:9][N:8]=[C:7]([C:10]([OH:12])=O)[CH:6]=1)([CH3:4])[CH3:3].[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1.C1C=CC2N(O)N=NC=2C=1.CN(C=O)C>O>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:7]3[CH:6]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[NH:9][N:8]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CC(C)(O)c1cc(C(=O)O)n[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)O)[nH]n1
Yield: 19.5 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) using 5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-carboxylic acid (0.646 mmol, 110 mg) and (S)-4-(1-(2-amino-propyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (0.539 mmol, 150 mg) and only a catalytic amount of HOBt (0.054 mmol, 7.28 mg). DMF was used as the solvent. Water was added to the reaction mixture and the mixture was extracted it three times with DCM. The combined organics were washed twice with water. The organic phase was evaporated and the residue was purified by flash chromatography and preparative HPLC, respectively. 45.4 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.13 (d, 3H), 1.43 (s, 6H), 4.17-4.55 (m, 3H), 5.27 (bs, 1H), 6.37 (bs, 1H), 6.99 (d, 1H), 7.82 (d, 1H), 7.86 (d, 1H), 7.97 (s, 1H), 8.08 (bs, 1H), 12.94 (bs, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1>C(O)(=O)C.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1
Reactant: OCCCc1ccncc1
Agent: [Pd]
Solvent: CC(=O)O
Product: OCCCC1CCNCC1

Procedure:
3-(4-piperidinyl)propanol was prepared by hydrogenation of 3-(4-pyridyl)propanol in acetic acid in the presence of Pd/C according to the method described in J. Org. Chem., 1962, 27, 2966-2967.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([C:9]1[CH:20]=[CH:19][C:12]([S:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)=[O:8]>O.C(Cl)(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[N:1]([CH2:6][C:7]([C:9]1[CH:20]=[CH:19][C:12]([S:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: COC(=O)CSc1ccc(C(=O)CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)CSc1ccc(C(=O)CN=[N+]=[N-])cc1
Reaction time: 16 h
Yield: 80 %

Procedure:
A solution of sodium azide (17.0g.) in water (100ml.) was added to a solution of methyl 4-(chloroacetyl)thiophenoxyacetate (60.1g.) in chloroform (350ml.). Benzyl triethylammonium chloride (300mg.) was then added, and the two phase mixture was shaken for 16 hours. The organic phase was separated, washed with water (2 × 100ml.), dried (MgSO4) and then evaporated in vacuo. The residue was recrystallised from methanol to give methyl 4-(azidoacetyl)thiophenoxyacetate (49.3g.), having a characteristic azide absorption at 2110cm-1 in the infra-red spectrum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.OO.C(=O)(O)[O-].[Na+]>C(O)=O.O>[CH2:15]1[N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18][N:13]2[C:3]3[CH:4]=[CH:5][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:7][C:2]=3[N:1]=[C:14]12
Reactant: CCOC(=O)c1ccc(N2CCN(C(=O)OCC)CC2)c(N)c1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CCOC(=O)c1ccc2c(c1)nc1n2CCN(C(=O)OCC)C1
Temperature: 50 °C
Yield: 11.1 %

Procedure:
Formic acid (0.29 g, 6.22 mmol) and purified water (5 ml) were added to ethyl 4-(2-amino-4-ethoxycarbonylphenyl)piperazine-1-carboxylate (2.0 g, 6.22 mmol) prepared in the Step 38-1-2. A 30% hydrogen peroxide solution (0.63 g, 18.67 mmol) was further added thereto, and the mixture was heated and stirred at 50° C. Formic acid (2 ml) and 2 ml of a 30% hydrogen peroxide solution were further added to the mixture. The resulting mixture was stirred for another one hour, then allowed to cool, and stirred. After being cooled to a room temperature, the mixture was neutralized with a saturated sodium bicarbonate solution and subjected to extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1 to 1:2) to give the title compound (0.22 g, 11%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:13][C:14]1[CH:27]=[CH:26][C:17]([CH2:18][N:19]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([N:22]2[CH2:23][CH2:24][CH2:25][N:19]([CH2:18][C:17]3[CH:26]=[CH:27][C:14]([F:13])=[CH:15][CH:16]=3)[CH2:20][CH2:21]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Fc1ccc(CN2CCCNCC2)cc1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCCN(Cc3ccc(F)cc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 1-(4-fluorobenzyl)-1,4-diazepane×2HCl (0.155 g, 0.55 mmol) followed by diisopropylethylamine (0.30 ml, 1.70 mmol). The reaction mixture was heated at 45° C. for 24 h, then allowed to cool to room temperature. The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.110 g, 52%); 1H-NMR (500 MHz, DMSO-d6) 1.82 (m, 2H), 2.67 (m, 4H), 3.17 (m, 2H) and 3.24 (t, J=5.85 Hz, 2H) (homopiperazine protons), 3.61 (s, 2H, N—CH2), 6.95 (s, 2H, NH2), 7.15 (t, J=9.10 Hz, 2H) and 7.35 (dd, J=10.20, 3.60 Hz, 2H) (3,5-ArH and 2,6-ArH), 8.17 (s, 1H, 6-H);
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[NH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[CH2:31][CH2:32][O:33][CH3:34].[F-].[Cs+]>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[N:25]([CH2:31][CH2:32][O:33][CH3:34])[CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc[nH]c3=O)cc1-2
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COCCn1cccc(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)c1=O
Temperature: 80 °C
Yield: 25.2 %

Procedure:
To 330 (0.075 g, 0.18 mmol) in DMF (2 mL) was added 1-bromo-2-methoxyethane (0.1 mL, 0.55 mmol) and cesium fluoride (0.084 g, 0.55 mmol). The reaction mixture was allowed to stir and heat at 80° C. for 2 days while monitoring by LCMS. To the reaction mixture was added bromo-2-methoxyethane (1 mL, 7.2 mmol) and cesium fluoride (1.0 g, 6.6 mmol). The reaction mixture was allowed to stir and heat at 80° C. for 2 days before cooling, concentrating under reduced pressure, and diluting with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 477 (21 mg, 24%). 1H NMR (400 MHz, DMSO) δ 9.08 (d, J=2.3, 1H), 8.10 (s, 1H), 7.73-7.55 (m, 3H), 7.08 (d, J=8.4, 1H), 6.34 (t, J=6.9, 1H), 5.95 (dt, J=13.1, 6.5, 1H), 4.40 (t, J=4.9, 2H), 4.16 (t, J=5.3, 2H), 3.66 (t, J=5.3, 2H), 3.46 (t, J=5.0, 2H), 3.27 (s, 3H), 1.55 (d, J=6.6, 6H). MS (ESI(+)): m/z 464.1 (M+H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@H:25]([CH2:33][N:34]([CH3:44])[C:35]([O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])=[O:36])[CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[C:45]([Cu])#[N:46]>CN(C=O)C>[C:45]([C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@H:25]([CH2:33][N:34]([CH3:44])[C:35]([O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])=[O:36])[CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1)#[N:46]
Reactant: COCCCC[C@@](O)(c1cccc(Br)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COCCCC[C@@](O)(c1cccc(C#N)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 220 °C
Yield: 22 %

Procedure:
To a stirred mixture of (3R)-3-((S)-1-(3-bromophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide (40.0 mg, 0.06 mmol) in DMF (0.5 mL), was added CuCN (excess), and the resulting solution was heated in a CEM microwave reactor at 220° C. for 20 min. The mixture was cooled to rt, and purified by preparative HPLC to give (3R)-3-((S)-1-(3-Cyanophenyl)-1-hydroxy-5-methoxypentyl)-N—((S)-1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)piperidine-1-carboxamide (8.0 mg, 22%). MS m/z 665 (M+Na+).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][C:3]=1[Br:20].B(F)(F)F.CCOCC.N(OC(C)(C)C)=O.O[PH2]=O>C(Cl)Cl>[Br:20][C:3]1[CH:4]=[C:5]([N+:17]([O-:19])=[O:18])[C:6]2[C:11]([CH:2]=1)=[CH:10][CH:9]=[C:8]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])[CH:7]=2
Reactant: CC(C)(C)Oc1ccc2c(N)c(Br)cc([N+](=O)[O-])c2c1
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Agent: O=[PH2]O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)Oc1ccc2cc(Br)cc([N+](=O)[O-])c2c1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-amino-2-bromo-6-tert-butoxy-4-nitronaphthalene, as described above in Step F, (2.40 g, 7.08 mmol) in CH2Cl2 (150 mL), at −15° C., was added BF3.OEt2 (1.35 mL, 10.6 mmol). To this mixture was added a solution of 90% tert-butyl nitrite (1.12 mL, 8.49 mmol) in CH2Cl2 (9 mL), dropwise. The reaction mixture was stirred at −15° C. for 1 hour, then 50 wt % H3PO2 (9.34 mL, 70.8 mmol) and CuO2 (50 mg, 0.349 mmol) were added and the resulting mixture was stirred vigorously at 0° C. for 40 min. The mixture was partitioned between saturated aqueous Na2CO3 (75 mL) and CH2Cl2 (150 mL). The aqueous layer was extracted further with CH2Cl2 (150 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane—0% to 8% diethyl ether to yield the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH:24]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:29]([O:23][C@@:9]2([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12][C@@H:13]3[C@H:8]2[CH2:7][CH2:6][N:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: O=C(O)C1CCCC1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)C1CCCC1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and cyclopentanecarboxylic acid to yield (3aR,4S,7aR)-methyl 4-(cyclopentanecarbonyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester eliminated ion); RT=4.183 min; HPLC Method III
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)=S>C(#N)C>[C:2]([NH:3][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)=[N:6][CH3:5])#[N:1]
Reactant: CNC(=S)NCCSCc1c[nH]cn1
Reactant: N#CN
Agent: [Pb]
Solvent: CC#N
Product: CN=C(NC#N)NCCSCc1c[nH]cn1
Yield: 31.1 %

Procedure:
Lead cyanamide (24.7 g.) was added to a solution of N-methyl-N'-[2-(4-imidazolylmethylthio)ethyl]thiourea (11.5 g.) in acetonitrile (250 ml.) containing demethylformamide. The stirred suspension was heated under reflux for 48 hours. Filtration followed by concentration under reduced pressure and purification of the product on a column of silica gel with ethyl acetatle-isopropyl alcohol (2.1) as eluant gave N-cyano-N'-[2-(4-imidazolylmethylthio)ethyl]-N"-methylguanidine (3.7 g.), m.p. 138°-140° (from acetonitrile). (Found: C, 45.7; H, 5.9; N, 35.5; S, 13.5. 9H14N6S requires: C, 45.4; H, 5.9; N, 35.3; S, 13.5).