Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:18][O:17]2)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:20]([NH2:25])([CH2:23][CH3:24])([CH3:22])[CH3:21]>C(O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:17])[CH2:18][NH:25][C:20]([CH3:22])([CH3:21])[CH2:23][CH3:24])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)N
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C2CO2)cc1
Solvent: CCO
Product: CCC(C)(C)NCC(O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
30 mg of the compound [7-2] was dissolved in 2 mL of ethanol, then 2 mL of tert-amylamine was added thereto, and the mixture was stirred overnight at 50° C. The reaction solution was concentrated, and then the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-20/80), to obtain 31 mg of tert-butyl[(1S)-1-(4-{2-[(1,1-dimethylpropyl) amino]-1-hydroxyethyl}phenyl)ethyl]carbamate [7-3] (hereinafter, referred to as the compound [7-3]) as a colorless oily product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[CH3:28]>C(#N)C.O>[CH3:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: C[C@@H]1CCCN1CCCCl
Reactant: O=C1CCc2cc(O)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCOc1ccc2c(c1)CCC(=O)N2
Temperature: 100 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of 6-hydroxy-3,4-dihydroquinolin-2(1H)-one (0.55 g) in acetonitrile (10 mL), cesium carbonate (2.0 g) and (2R)-1-(3-chloropropyl)-2-methylpyrrolidine prepared in Example 1-(1) (0.50 g) were added and stirred at 100° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=1/1). The resulting solid was subjected to recrystallization from n-hexane to give the titled compound (0.33 g, 37%) as a colorless powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH2:8]([O:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ccccn1
Reactant: OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(COc2ccccn2)cc1
Temperature: 110 °C
Yield: 22.7 %

Procedure:
2-Chloro-pyridine (5 g, 44 mmol) was added to a stirred solution of benzylalcohol (6.1 g, 57.2 mmol), KOH (2.9 g, 52.8 mmol) and 18 crown[6] (50 mg) in toluene (20 mL) and the resulting mixture was heated to reflux at 110° C. for 6 hours. The reaction mixture was then cooled to room temperature and concentrated. The residue was diluted with waster and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 1.85 g (22%) of 2-benzyloxy-pyridine.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@H:16]1[C@H:19]([CH3:20])[N:18]([OH:21])[C:17]1=[O:22])=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:23]1([CH:29]([O:36][C:37](=[O:40])[CH2:38]Cl)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[C:8]([O:12][C:13]([NH:15][C@H:16]1[C@H:19]([CH3:20])[N:18]([O:21][CH2:38][C:37]([O:36][CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:40])[C:17]1=[O:22])=[O:14])([CH3:9])([CH3:11])[CH3:10]
Reactant: O=C(CCl)OC(c1ccccc1)c1ccccc1
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0 61 g, 6.0 mmol was dropped into a solution of (3S-trans)-3-(t-butyloxy-carbonylamino)-1-hydroxy-4-methyl-2-azetidinone (1.08 g. 5.0 mmol) and diphenylmethylchloroacetate (1.43 g. 5.5 mmol) in 10 ml of dry dimethylformamide. The mixture was stirred overnight at room temperature. The precipitate was removed by filtration and the solvent was stripped in vacuo. The residue was taken up in ethyl acetate, filtered, washed with 5% NaHCO3 solution and with water, dried over MgSO4 and evaporated in vacuo to give a colorless oil; yield 2.0 g. By storing in a refrigerator the title compound crystallized, melting point 73°-74° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:24][O:25][C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:32]([C:27]3[C:26]([O:25][CH3:24])=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: COc1cccnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Product: COc1cccnc1C(=O)Nc1ccc(F)c([C@]2(C)CCOC(N)=N2)c1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F (R1=Me) and 3-methoxy-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH:6]([N:8]1[C:21]2[CH:20]=[C:19]([C:22](=[S:24])[NH2:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7])[CH3:4])[CH3:2].[CH3:25][CH:26]([CH3:30])[CH2:27][CH2:28]N.S>C(O)C>[CH3:25][CH:26]([CH3:30])[CH2:27][CH2:28][NH:23][C:22]([C:19]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH:6]([CH3:7])[CH2:5][N:3]([CH2:1][CH3:2])[CH3:4])[C:21]=2[CH:20]=1)=[S:24]
Reactant: CC(C)CCN
Reactant: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(=S)NCCC(C)C)cc21
Temperature: 100 °C

Procedure:
A solution of 10-[(2RS)-1-(N-ethyl-N-methyl-amino)-2-propyl]-2-phenothiazinecarbothioamide (1 g) and 3-methylbutylamine (4.9 cc) in absolute ethanol (15 cc) is saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 100° C. After being cooled, the orange solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil is purified by chromatography on a column (height: 25 cm; diameter 2 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (80:20 by volume) (500 cc) of ethyl acetate and cyclohexane and collecting 30-cc fractions. Fractions 4 to 8 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-(3-Methylbutyl)-10-[(2RS)-1-(N-ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbothioamide (1.3 g) is thereby obtained in the form of an orange-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][CH:11]([O:16][CH2:17][CH3:18])[CH2:12][N:13]=[C:14]=[NH:15])[CH3:9].CS(O)(=O)=O.[OH-].[Na+]>C(O)C>[CH2:17]([O:16][CH:11]([O:10][CH2:8][CH3:9])[CH2:12][NH:13][C:14]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[NH:15])[CH3:18]
Reactant: Nc1ccccc1
Reactant: CCOC(CN=C=N)OCC
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(CNC(=N)Nc1ccccc1)OCC
Yield: 73.8 %

Procedure:
Aniline (1.66 g, 17.8 mmol) was dissolved in ethanol (25 mL), and N-(2,2-diethoxyethyl)carbodiimide (a), (2.82 g, 17.8 mmol), was added dropwise. Then methanesulfonic acid (1.71 g, 17.8 mmol) was added, and the mixture was warmed at reflux for 24 h. The reaction mixture was poured into NaOH (0.5 M) and extracted with CH2Cl2. Drying and concentration afforded a product that was subjected to flash chromatography to give the intermediate guanidine (b) (3.3 g, 73.8%). 1H NMR (500 MHz, DMSO-d6) δ 7.27-6.90 (m, 5H), 4.55 (t, 1H), 3.76-3.70 (m, 2H), 3.60-3.54 (m, 2H), 3.35-3.34 (d, 2H), 1.22 (pent, 6H). MS: 249.8 (M−H)−; 252.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH2:9][CH:10]([O:19][C:20](=[O:22])C)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3]C(OCC)=O.[OH-].[Na+].Cl.C(OCC)(=O)C>CO>[OH:1][C:2]1([CH3:3])[CH2:9][CH:10]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:19][C:20](=[O:22])[CH2:23]1
Reactant: CCOC(=O)CC(C)(O)CC(CCc1ccccc1)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(O)CC(=O)OC(CCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.2 %

Procedure:
Using 1.48 g of 4-acetoxy-6-phenylhexan-2-one, 1 ml of ethyl bromoacetate and 0.62 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 1.03 g of ethyl 3-hydroxy-3-methyl-5-acetoxy-7-phenylheptanoate. The ester (0.90 g) thus obtained was dissolved in 5 ml of methanol and 2 ml of 4 N sodium hydroxide was added thereto. The mixture was stirred for 4 hours at room temperature, acidified by the addition of 4 N hydrochloric acid, 5 ml of ethyl acetate was added and the mixture was stirred for 3 days. The usual treatment of the organic solvent layer afforded 400 mg of the desired compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)O>>[CH3:2][C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3]
Reactant: CC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
nitrating acetanilide using a mixture of nitric acid and sulfuric acid to produce 4-nitroacetanilide and nitrating further using a mixture of nitric acid and sulfuric acid to produce compound VI;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH:30]1[CH2:35][C:36]([O:38][CH3:39])=[O:37])(=[O:28])=[O:27]>>[CH3:39][O:38][C:36]([CH2:35][CH:30]1[CH2:31][N:32]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:33][CH2:34][N:29]1[S:26]([C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)(=[O:27])=[O:28])=[O:37]
Reactant: COC(=O)CC1CNCCN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: COC(=O)CC1CN(C(=O)C2CCN(c3ccncc3)CC2)CCN1S(=O)(=O)c1ccc2ccccc2c1
Yield: 90 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with methyl 2-[l-(2 -naphthylsulphonyl)piperazin-2-yl]acetate to give 2-methoxycarbonylmethyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 90% yield as a glass;
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[N:27]2[C:22]([CH2:23][O:24][CH2:25][CH2:26]2)=[CH:21][C:20]=1[C:28](O)=[O:29]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:20]3[CH:21]=[C:22]4[CH2:23][O:24][CH2:25][CH2:26][N:27]4[N:19]=3)=[O:29])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc2n(n1)CCOC2
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc2n(n1)CCOC2

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-2-carboxylic acid (166 mg, 0.997 mmol). The product was triturated with acetonitrile. Yield 95 mg (46%). 1H-NMR (400 MHz; d6-DMSO): δ 1.09 (d, 3H), 4.09 (t, 2H), 4.18 (t, 2H), 4.26-4.39 (m, 2H), 4.42-4.49 (m, 1H), 4.79 (s, 2H), 6.38 (s, 1H), 6.95 (d, 1H), 7.82 (d, 1H), 7.97-7.99 (m, 2H), 8.09 (s, 1H), 8.26 (d, 1H).
Reaction SMILES: C([O:9][CH2:10][C@:11]12[C@@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:14]([O:15][CH2:16]1)[C@H:13]([N:26]1[CH:34]=[N:33][C:32]3[C:31](=[O:35])[NH:30][CH:29]=[N:28][C:27]1=3)[O:12]2)(=O)C1C=CC=CC=1.[OH-].[Na+].C(O)(=O)C>CO>[CH2:19]([O:18][C@H:17]1[C@H:14]2[O:15][CH2:16][C@:11]1([CH2:10][OH:9])[O:12][C@H:13]2[N:26]1[CH:34]=[N:33][C:32]2[C:31](=[O:35])[NH:30][CH:29]=[N:28][C:27]1=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OC[C@]12CO[C@@H]([C@H](n3cnc4c(=O)[nH]cnc43)O1)[C@@H]2OCc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]cnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2OCc1ccccc1

Procedure:
To a solution of compound 22 in methanol (20 mL) was added 2M NaOH (2 mL) and 15 min later acetic acid (2 mL). The mixture was cooled in ice-bath, the precipitate was filtered off, washed with water and dried in vacuo. Yield: 0.69 g (85%) of compound 23 as a white solid material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C[C:12]([O-])=[O:13].[Na+].C=O>CC(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:12][OH:13])=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(=O)[O-]
Reactant: Clc1ccc2nccn2n1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: OCc1cnc2ccc(Cl)nn12
Yield: 72.3 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine (1.5 g, 9.8 mmol) in AcOH (50 mL) was added NaOAc (1.4 g, 17.1 mmol) and paraformaldehyde (1.5 g). The mixture was heated at reflux overnight and concentrated under reduced pressure. The residue was basified to pH 12. Then the mixture was filtered and the solid was washed with EtOH to afford (6-chloro-imidazo[1,2-b]pyridazin-3-yl)-methanol (1.3 g) in 72% yield.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26](=O)[C:27](O)=[O:28])[CH:20]=1>C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:11]2[C:27](=[O:28])[C:26]([CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[N:18][C:17]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]2=3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Nc2ncccc2N)c1
Reactant: O=C(O)C(=O)Cc1cccnc1
Solvent: CCO
Product: CC(=O)Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Yield: 67.8 %

Procedure:
A mixture of 2-(3-acetamidophenylamino)-3-aminopyridine (1.0 g) and 3-(3-pyridyl)pyruvic acid (0.82 g) in ethanol (50 ml) was stirred under reflux for 6 hours. After evaporation of the solvent, crude residue was chromatographed on silica gel and crystallized from ethyl acetate to give 4-(3-acetamidophenyl)-2-(3-pyridyl-methyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (1.04 g).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[ClH:19]>C(Cl)Cl.CCOCC>[Cl:19][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: Cl
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCO)CC2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCN(CCCl)CC2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
1-(2-Hydroxyethyl)-4-(4-nitrophenyl)piperazine (5 g, 0.02 mol) was dissolved in 50 mL of DCM and treated with HCl (40 mL of a 1M solution in Et2O) under a drying tube for 90 min. The solvent was evaporated, the residue dissolved in thionyl chloride (60 mL) and the mixture refluxed at 80° C. After 5 h, the reaction was complete as shown by LCMS and the thionyl chloride was removed under reduced pressure redissolving in DCM and evaporating three times to give the title compound as the HCl salt. LCMS: 93%, t=0.88 min, [MH+]=270.23.
Reaction SMILES: CO[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=CC=1.[NH:31]1C=CC=C1C=O>>[NH:31]1[CH:3]=[CH:30][CH:29]=[C:6]1[CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13]
Reactant: O=Cc1ccc[nH]1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: O=C(NCCNCc1ccc[nH]1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using pyrrol-2-carboxaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 379 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.54 (1H, br. s.) 10.31 (1H, s) 8.00-8.07 (2H, m) 7.77 (1H, d, J=5.42 Hz) 7.47 (1H, d, J=5.47 Hz) 7.31 (1H, dd, J=3.22, 2.59 Hz) 6.81 (1H, d, J=5.42 Hz) 6.57-6.62 (1H, m) 6.43 (1H, dd, J=3.44, 1.88 Hz) 5.88 (1H, q, J=2.64 Hz) 5.82-5.86 (1H, m) 3.61 (2H, s) 2.63 (2H, t, J=6.47 Hz)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.[C:26]([N:28]=[C:29](SC)[S:30][CH3:31])#[N:27].CCN(CC)CC>CC#N>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:29](=[N:28][C:26]#[N:27])[S:30][CH3:31])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CSC(=NC#N)SC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSC(=NC#N)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 57.8 %

Procedure:
A 25 mL flask was charged with (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (3 g, 8.15 mmol) and dimethyl cyanocarbonimidodithioate (1.2 g, 8.15 mmol) dissolved in 50 mL of MeCN, and 1 mL Et3N was added and the mixture was stirred for overnight. The mixture was evaporated in vacuo and the residue was purified by chromatography to give desired (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-((cyanoimino)(methylthio)methylamino)ethoxy)methyl)-piperidine-1-carboxylate (2.2 g, 58%). 1H NMR (CDCl3, 400 MHz) δ 7.28 (m, 2H), 7.23 (m, 1H), 7.16 (m, 1H), 4.10 (m, 2H), 3.86 (m, 1H), 3.68 (m, 2H), 3.22 (m, 2H), 2.72 (m, 2H), 1.62 (m, 2H), 1.46 (s, 9H), 1.40-1.10 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:10]=3[CH:11]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:39]1(=[O:49])[NH:43][C:42](=[O:44])[C:41]2=[CH:45][CH:46]=[CH:47][CH:48]=[C:40]12.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([CH2:16][N:43]4[C:39](=[O:49])[C:40]5[C:41](=[CH:45][CH:46]=[CH:47][CH:48]=5)[C:42]4=[O:44])=[CH:12][C:10]=3[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1ccc2oc(Cc3ccc(F)cc3)cc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2oc(Cc3ccc(F)cc3)cc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.9 %

Procedure:
To a tetrahydrofuran (5 mL) solution of (2-(4-fluoro-benzyl)-benzofuran-5-yl)-methanol (83 mg, 0.324 mmol) described in Production Example 76-1-2 were added triphenylphosphine (93.5 mg, 0.356 mmol), phthalimide (52.4 mg, 0.356 mmol) and diethylazodicarboxylate (62.1 mg, 0.356 mmol). This mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain the title compound (81 mg, 65%).
Reaction SMILES: [CH2:1]([N:5]1[N:14]=[C:13]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[CH3:24])[CH:12]2[CH:7]([CH2:8][CH:9]=[CH:10][CH2:11]2)[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]([O:36]C(C)(C)C)=[O:35]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:5]1[C:6](=[O:25])[CH:7]2[CH:12]([CH2:11][CH:10]=[CH:9][CH2:8]2)[C:13]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:33][C:34]([OH:36])=[O:35])[C:16]=2[CH3:24])=[N:14]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1N=C(c2c(C)[nH]c3ccccc23)C2CC=CCC2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN1N=C(c2c(C)n(CC(=O)O)c3ccccc23)C2CC=CCC2C1=O
Temperature: 75 °C

Procedure:
The product of step b) was dissolved in DMF (4 mL) and treated with K2CO3 (0.7 mmol, 97 mg) and t-butyl bromoacetate (0.5 mmol, 74 uL). After heating at 75° C. for 2 h, the reaction was cooled, diluted with EtOAc (10 mL) and washed 3× water. The organic solution was concentrated to dryness and treated with 4 mL TFA for 1.5 h. The reaction was concentrated and the title compound was purified by preparative LCMS. 1H NMR (DMSO-d6) δ 7.76 (d, J=8.1 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.09-6.99 (m, 2H), 5.70 (d, J=10.8 Hz, 1H), 5.63 (d, J=10.8 Hz, 1H), 3.91 (dt, J=6.9, 13.2 Hz, 1H), 3.62 (dt, J=6.6, 13.2 Hz, 1H), 3.36 (quint., J=5.7 Hz, 1H), 2.96 (t, J=5.1 Hz, 1H), 2.79-2.71 (m, 1H), 2.35-1.94 (m, 4H), 1.64 (quint., J=7.1 Hz, 2H), 1.31 (sext., J=7.5 Hz, 1H), 0.91 (t, J=7.2 Hz, 3H); MS: ESI (negative): 392 (M−H).