Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:6]1=2.O.NN>CO.[Ni]>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][S:8][C:7]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:6]1=2
Reactant: CN(C)CCN1CCSc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN(C)CCN1CCSc2cc(N)ccc21
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a solution of N,N-dimethyl-2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (0.9695 g, 3.63 mmol) in MeOH (20 mL) was added Raney-Nickel (slurry in water; ˜0.1 g, 3.63 mmol) followed by hydrazine hydrate (1.82 mL, 37.4 mmol). The mixture was immersed in a preheated oil bath and refluxed for 20 minutes. The solution was cooled to room temperature and filtered through a pad of Celite. The filter pad was washed with MeOH, and the crude material was concentrated. The crude material was filtered through a plug of silica gel (2.5:97.5 (2M NH3 in MeOH):CH2Cl2). The collected fractions gave brown viscous oil (0.84 g, 99%). 1H NMR (CDCl3) δ 6.58 (d, J=8.7 Hz, 1H), 6.45 (d, J=2.7 Hz, 1H), 6.40 (dd, J=2.7, 8.7 Hz, 1H), 3.51-3.48 (m, 2H), 3.30 (t, J=7.2 Hz, 2H), 3.03-3.00 (m, 2H), 2.48 (t, J=7.5 Hz, 2H), 2.27 (s, 6H); ESI-MS (m/z, %): 240, 238 (MH+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[CH3:11][CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20].O>CCCCCC>[CH3:11][CH:12]([CH3:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:20]
Reactant: COc1ccc(CO)cc1
Reactant: CC(C)CCCCCCC(=O)O
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(COC(=O)CCCCCCC(C)C)cc1
Temperature: 50 °C
Yield: 90.4 %

Procedure:
4-Methoxybenzyl alcohol (603 mg, 4.35 mmol), 8-methylnonanoic acid (750 mg, 4.35 mmol) and Novozyme 435 (51 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (50 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (n-hexane:ethyl acetate=3:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give 4-methoxybenzyl 8-methylnonanoate (1.15 g, yield 90.2%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:3]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=1.C(#N)C>O>[CH:12]1([NH:11][C:4]2[N:3]=[C:2]([N:20]3[C:19]([CH3:18])=[CH:23][C:22]([CH3:24])=[N:21]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(NC2CCCCC2)c2nc[nH]c2n1
Solvent: CC#N
Solvent: O
Product: Cc1cc(C)n(-c2nc(NC3CCCCC3)c3nc[nH]c3n2)n1
Temperature: 200 °C
Yield: 19.4 %

Procedure:
(2-Chloro-9H-purin-6-yl)-cyclohexyl-amine (1.0 g, 3.47 mmol), 3,5-dimethylpyrazole (834 mg, 8.68 mmol) and acetonitrile (10 mL) were mixed in a sealed vial and heated in a microwave oven at 200° C. for 50 min. Water was added and the precipitate was collected by filtration. The crude product was purified by flash chromatography (dichloromethane/methanol) to give cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-9H-purin-6-yl]-amine (210 mg, 19%) as a white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:12]4[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:13]=4[N:14]=[CH:15][N:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:29][C:30]1[O:31][C:32]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=O)[O:41]C3C=CC=CC=3)=[CH:35][C:33]=2[CH:34]=1>C1COCC1>[CH3:29][C:30]1[O:31][C:32]2[CH:38]=[CH:37][C:36]([NH:39][C:40]([N:1]3[C:9]4[C:8](=[CH:7][C:6]([O:10][C:11]5[C:12]6[CH2:19][NH:18][CH2:17][C:13]=6[N:14]=[CH:15][N:16]=5)=[CH:5][CH:4]=4)[CH:3]=[CH:2]3)=[O:41])=[CH:35][C:33]=2[CH:34]=1
Reactant: Cc1cc2cc(NC(=O)Oc3ccccc3)ccc2o1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4[nH]ccc4c3)c2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2cc(NC(=O)n3ccc4cc(Oc5ncnc6c5CNC6)ccc43)ccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 4-(1H-indol-5-yloxy)-5H-pyrrolo[3,4-d]pyrimidine-6 (7H)-carboxylate (152.2 mg, 0.432 mmol) is suspended in THF (5 mL), flushed with nitrogen and cooled to 0° C. NaH (33 mg, 0.825 mmol, 60% in mineral oil) is added and mixture is stirred for 10 minutes. Phenyl 2-methylbenzofuran-5-ylcarbamate (280 mg, 1.048 mmol) is added neat and the reaction is allowed to stir to room temperature overnight. The reaction is cooled in an ice bath and quenched with a saturated solution of ammonium chloride (100 mL). The solution is then diluted with ethyl acetate and the product is extracted (2×100 mL ethyl acetate). The organic layers are combined, dried and concentrated to a brown oil that is dissolved in 10 mL of DCM and cooled in an ice bath upon which 10 mL of TFA is added. The TFA is removed and ethyl acetate is added to the residue and ammonium hydroxide is added to quench the remaining TFA. The solution is concentrated and dissolved in DMSO and is purified via semi-prep HPLC (C18; 20-100% I/H2O with 0.1% TFA) to give 5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (2-methyl-benzofuran-5-yl)-amide. MS (ESI) m/z 426.0 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.53 (s, 1H) 8.30 (d, J=8.84 Hz, 1H) 8.15-8.20 (m, 1H) 7.88-7.92 (m, 1H) 7.58 (ddd, J=6.13, 3.98, 2.27 Hz, 1H) 7.39-7.46 (m, 2H) 7.12 (dd, J=9.09, 2.02 Hz, 1H) 6.74 (d, J=3.79 Hz, 1H) 6.46 (s, 1H) 4.19 (d, J=9.35 Hz, 4H) 2.45 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)[CH3:2].O=[C:12]1[CH2:17][CH2:16][N:15]([C@H:18]([CH3:22])[CH2:19][C:20]#[N:21])[CH2:14][CH2:13]1>>[NH2:21][CH2:20][CH2:19][C@H:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:10][C:7]2[CH:8]=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[CH2:13][CH2:14]1)[CH3:22]
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: CCOc1ccc(N)cn1
Product: CCOc1ccc(NC2CCN([C@H](C)CCN)CC2)cn1

Procedure:
Using general procedure A with 6-ethoxy-pyridin-3-ylamine (Nishikawa, Yoshinori; et al., J. Med. Chem., 32, 3, 1989, 583-593) (210 mg, 1.52 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (278 mg, 1.67 mmol) followed by general procedure J afforded [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(6-ethoxy-pyridin-3-yl)-amine as a white solid (365 mg, 83% over 2 steps).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:15])=[CH:6][CH:7]=[C:8]2[CH:13]=[O:14])[CH3:2].S(Cl)([Cl:19])(=O)=O.O>C1C=CC=CC=1>[Cl:19][C:6]1[CH:7]=[C:8]([CH:13]=[O:14])[C:9]2[C:4]([C:5]=1[OH:15])=[C:3]([CH2:1][CH3:2])[CH:12]=[CH:11][CH:10]=2
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1cccc2c(C=O)ccc(O)c12
Solvent: O
Solvent: c1ccccc1
Product: CCc1cccc2c(C=O)cc(Cl)c(O)c12

Procedure:
0.81 g of 5-ethyl-4-hydroxy-1-naphthalenecarbaldehyde and 0.49 ml of sulfuryl chloride were heated in 30 ml of benzene under reflux for 30 minutes. The reaction solution was returned to room temperature and poured into water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate, followed by concentration under reduced pressure. The resultant crystals were washed with isopropyl ether to obtain 0.8 g of the captioned compound as yellowish brown crystals.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.[C:11](=[S:13])=[S:12].[OH-].[K+].Cl>C(O)C>[Cl:10][C:9]1[C:2]2[NH:1][C:11](=[S:12])[S:13][CH2:4][C:3]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1c(Cl)cccc1CO
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: S=C1Nc2c(Cl)cccc2CS1

Procedure:
A 9 g. portion of 2-amino-3-chlorobenzyl alcohol was combined with 15 ml. of carbon disulfide and 5 g. of potassium hydroxide in 100 ml. of ethanol. The reaction mixture was stirred at reflux temperature overnight, and was then dumped into ice. After the aqueous mixture was acidified with hydrochloric acid, the product was extracted from the mixture with methylene chloride and was purified by chromatography over alumina with chloroform-hexane as the eluent. After recrystallization from methanol, 3,2 g. of 8-chloro-1,4-dihydro-2H-3,1-benzothiazin-2-thione, m.p. 125°-126° C., was obtained.
Reaction SMILES: [OH-:1].[Li+].C([N:6]1[C:14]2[C:9](=[C:10]([CH3:20])[C:11](CC([O-])=O)=[CH:12][C:13]=2[CH3:15])[CH:8]=[N:7]1)(=O)C.[Cl-].[NH4+]>CO.O1CCCC1>[CH3:20][C:10]1[C:11]([OH:1])=[CH:12][C:13]([CH3:15])=[C:14]2[C:9]=1[CH:8]=[N:7][NH:6]2
Reactant: CC(=O)n1ncc2c(C)c(CC(=O)[O-])cc(C)c21
Reactant: [OH-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(O)cc(C)c2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A 2N-aqueous lithium hydroxide solution (85 ml, 170 mmol) was added to a solution of (1-acetyl-4,7-dimethyl-1H-indazol-5-yl)acetate (20.3 g, 82.4 mmol) in methanol-tetrahydrofuran (1:1, 170 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was poured into the reaction solution, followed by extraction with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was washed with acetonitrile by repulping to obtain 4,7-dimethyl-1H-indazol-5-ol (13.0 g, 97%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:19])[CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CN(C)CCCCN
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and N1,N1-dimethylbutane-1,4-diamine according to general procedure 1 providing the intermediate (300 mg, 74%) as a yellow oil: Rf=0.40 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J=9.6 Hz, 1H), 7.45 (s, 1H), 6.38 (d, J=9.6 Hz, 1H), 6.07 (brs, 1H), 3.40 (quart, J=5.2 Hz, 2H), 2.34 (t, J=6.8 Hz, 2H), 2.25 (s, 6H), 1.76 (quin, J=6.6 Hz, 2H), 1.64 (quin, J=6.8 Hz, 2H); ES-MS: (M+H)=312, 314 m/z.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:31]([CH3:45])[CH2:32][CH2:33][N:34]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:34][CH2:33][CH2:32][CH:31]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)[CH3:45]
Reactant: COc1ccc(N(Cc2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: COc1ccc(N(Cc2ccccc2)C2CCN(C(C)CCN)CC2)cc1

Procedure:
Using general procedure C with the above carbamate (303 mg, 0.765 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (320 mg, 1.47 mmol) and then using general procedure D gave [1-(3-amino-1-methylpropyl)-piperidin-4-yl]-benzyl-(4-methoxy-phenyl)-amine as a colorless oil (190 mg, 68% over 3 steps).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[N:21]1([C:27]2[O:28][C:29]3[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[N:21]1[CH2:22][CH2:23][N:24]([C:9]([C:8]2[CH:12]=[C:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:14]=[CH:15][C:7]=2[O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:11])[CH2:25][CH2:26]1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: c1ccc2oc(N3CCNCC3)nc2c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3nc4ccccc4o3)CC2)c1

Procedure:
Prepared in analogy to example 1.1 b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example 2.3) and 2-piperazin-1-yl-benzoxazole hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate) to yield the title compound as a colorless solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)=O.CO.[CH2:18]([NH2:20])[CH3:19]>C(Cl)Cl>[CH2:9]([O:8][CH2:7][CH2:6][NH:20][CH2:18][CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CCNCCOCc1ccccc1
Temperature: 110 °C
Yield: 72 %

Procedure:
To 7.0 g (30 mmol) of 2-(benzyloxy)ethyl methanesulfonate, a 75 ml methanol solution of 2M ethylamine was added, and the mixture was heated at 110° C. in a sealed tube for 2 hours. Then, the reaction mixture was returned to room temperature, and then diluted with methylene chloride. The dilution was washed with a saturated aqueous solution of sodium hydride. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain 3.85 g (72%) of the captioned compound.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br.Br[CH:7]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[S:3][C:7]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[N:4]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)C(Br)c2cccnc2)cc1
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(N)sc2-c2cccnc2)cc1
Yield: 82 %

Procedure:
In 40 ml of acetonitrile was dissolved 516 mg of thiourea. In the solution was suspended 2.5 g of 2-bromo-1-(4-methoxyphenyl)-2-(3-pyridyl)-ethanone hydrobromide. To the suspension was added dropwise slowly 0.95 ml of triethylamine while stirring. The mixture was stirred for 3 hours at a refluxing temperature, which was then left standing for cooling. Precipitating crystals were collected by filtration. The crystals were washed with an aqueous solution of saturated hydrogen carbonate, water, ethanol and ethylether in that order, followed by drying. The crystals were recrystallised from tetrahydrofuran to yield 1.5 g (90%) of 2-amino-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazol, m.p. 265°-266° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C@H:12]([NH:18][S:19]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]2[N:47]=[C:46]3[C:41]([CH2:42][CH2:43][CH2:44][NH:45]3)=[CH:40][CH:39]=2)[CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:22]1([S:19]([NH:18][C@@H:12]([CH2:11][N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[N:32]2[CH2:37][CH2:36][CH:35]([C:38]3[CH:39]=[CH:40][C:41]4[CH2:42][CH2:43][CH2:44][NH:45][C:46]=4[N:47]=3)[CH2:34][CH2:33]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:21])=[O:20])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)[C@H](Cn1cnc2c(Cl)ncnc21)NS(=O)(=O)c1cccc2ccccc12
Reactant: c1cc2c(nc1C1CCNCC1)NCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)NS(=O)(=O)c1cccc2ccccc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
3.21 g of ethyl (2S)-3-(6-chloropurin-9-yl)-2-(naphthalene-1-sulfonylamino)propionate (Example 2) in 20 ml of abs. DMF were treated with 4.0 g of 7-(piperidin-4-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine and 3.88 g of diisopropylethylamine, and the mixture was stirred at 70° C. for 3 h. The solvent was distilled off in vacuo, the residue was taken up in EA and the mixture was extracted three times with water. The aqueous phases were extracted three times with DCM. The combined organic phases were dried over MgSO4 and filtered, and the solvent was distilled off in vacuo. For purification, the residue was chromatographed over silica gel (DCM/CH3OH/CH3COOH/H2O 95:5:0.5:0.5). Yield: 3.29 g.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([CH:18]=[O:19])[CH:12]=2)[CH:3]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[C:15]([O:17][CH3:22])[CH:14]=[C:13]([CH:18]=[O:19])[CH:12]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cc(O)cc(C=O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(Oc2cc(Cl)ccc2C#N)c1
Reaction time: 16 h

Procedure:
4-Chloro-2-(3-formyl-5-hydroxyphenoxy)benzonitrile (0.20 g, 0.75 mmol) in DMF (5 ml) was treated with sodium hydride (60% in mineral oil, 30 mg, 0.78 mmol) followed after 10 min by methyl iodide (0.1 ml). After 16 h, a further amount of sodium hydride (8 mg) and methyl iodide (0.1 ml) were added. After 3 h, the mixture was diluted with water, extracted with ethyl acetate, the extracts washed with water, dried over sodium sulphate and evaporated to give the sub-title compound as a pale yellow solid (213 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12](OS(C)(=O)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:24]=[N+:25]=[N-:26])(C)C.[F-].[Cs+].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:24]=[N+:25]=[N-:26])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N=[N+]=[N-])CC1
Temperature: 25 °C

Procedure:
A solution of Intermediate 36 (196 g) and trimethylsilyl azide (283 ml, Tokyo Kasei Kogyo) in dimethylformamide (667 ml) was added with cesium fluoride (305 g, Wako Pure Chemical Industries) with stirring and stirred at 70° C. for 4 days. The reaction mixture was cooled to room temperature and then added twice with water in a volume of 2.75 l in total. This reaction mixture was stirred with ice cooling for 2 hours, and the deposited precipitates were collected by filtration. Then, the precipitates were washed with water to obtain a roughly purified product of the title compound (142 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([OH:10])=[O:9].Cl.[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>>[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH:2][C@@H:3]3[CH2:7][CH2:6][CH2:5][C@@H:4]3[C:8]([OH:10])=[O:9])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: N[C@@H]1CCC[C@@H]1C(=O)O
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@@H]3C(=O)O)cc2)c2ccccc2n1
Yield: 87.6 %

Procedure:
According to the procedure of Example 10, Step 1, the reaction of 141 mg (0.85 mmol) of (+)-(1S,2R)-2-amino-1-cyclopentane-carboxylic acid hydrochloride with 400 mg (1.04 mmol) of 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride provided 327.9 mg of (1S,2R)-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid in 86% yield. MS: 441.1 (M+H)+
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C)C=O>C(O)(C)(C)C>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Reactant: Sc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: N=C(N)N1CCC(CCC(=O)OSc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 35 %

Procedure:
A mixture of 2.4 g of 1-amidino-4-piperidinepropionic acid hydrochloride, 1.1 g of thiophenol, 2.1 g of dicyclohexylcarbodiimide and 15 ml of dry dimethylformamide was stirred at room temperature for 17 hours. After removal of any insoluble materials, the solvent was removed. The residue was washed with ether and then with t-butanol to obtain 1.2 g (yield: 36.4%) of phenylthio 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 168° to 170° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[H-].[Na+].[CH3:32]I>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:12]([CH3:32])[C:11](=[O:27])[C:10]=2[CH:28]=1
Reactant: CI
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)N(C)C1(CCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
(E)-3-{1′-Tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (4.02 g, 10.0 mmol) was dissolved in DMF (35 ml) and added to a stirred suspension of NaH (60% oil dispersion, 480 mg, 12 mmol) in DMF (35 ml) at 4° C. After 10 min CH3I (2.13 g, 15.0 mmol) was added, the resulting mixture was stirred at RT for 30 min and then partitioned between saturated aqueous solution of NH4Cl and AcOEt. The organic phase was rinsed with water, dried over Na2SO4 and evaporated. The crude mixture was purified by trituration in AcOEt and petroleum ether to give (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-3-methyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (3.66 g).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[S:21]1[CH:25]=[C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:23]=[CH:22]1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:24]3[N:23]=[CH:22][S:21][CH:25]=3)[CH:27]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2cscn2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2cscn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 3-(thiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.87 min.; [M+H]+: 423.08 g/mol.