Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([OH:12])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44]O)[CH2:38][CH2:37]1>C(Cl)(Cl)Cl>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:37][CH2:38][N:39]([CH2:42][CH2:43][CH2:44][O:11][C:10]([C:4]23[CH2:5][CH:6]4[CH2:9][CH:2]([CH2:1][CH:8]2[CH2:7]4)[CH2:3]3)=[O:12])[CH2:40][CH2:41]1
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1N1CCN(CCCOC(=O)C23CC4CC(CC2C4)C3)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of hexahydro-2,5-methanopentalene-3a[1H]-carboxylic acid (0.6 g, 3.6×10-3 mol) in 25 ml of chloroform under a dry nitrogen atmosphere was added carbonyldiimidazole (0.58 g, 3.6×10-3 mol). The resulting solution was stirred at ambient temperature for three hours, during which time a gas (CO2) was evolved. A solution of 3-[1-(2-methoxyphenyl)-4-piperazinyl]propanol (0.91 g, 3.6×10-3 mol) in 25 ml of chloroform was then added, and the resulting reaction mixture was stirred under nitrogen at ambient temperature for two days. The mixture was diluted to 150 ml with chloroform, washed with three-one hundred ml portions of water, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator. The desired product (TLC on silica using a 30% methanol in ethyl acetate solvent system, Rf=0.52) was isolated by gravity chromatography on silica gel and converted to the hydrochloride salt with isopropanolic HCl (0.84 g, 50% yield), mp.=206°-207° C.
Reaction SMILES: N[C@H]1CCCN(C(OC(C)(C)C)=O)[C@H]1C1C=CC=CC=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][CH2:35][C:36]2[CH:41]=[C:40]([CH:42]([C:44]#[N:45])C)[CH:39]=[CH:38][C:37]=2[O:46][CH3:47])[C@@H:29]1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH2:31][C@H:30]([NH:34][CH2:35][C:36]2[CH:41]=[C:40]([CH2:42][C:44]#[N:45])[CH:39]=[CH:38][C:37]=2[O:46][CH3:47])[C@@H:29]1[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Product: COc1ccc(CC#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 71 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH:4]1[CH2:13][C:12]2[CH:11]=[C:10]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5]1)[CH3:2].C(N(CC)CC)C.[CH:41]([N:44]=[C:45]=[O:46])([CH3:43])[CH3:42]>C(Cl)Cl>[CH:41]([NH:44][C:45]([N:31]1[CH2:30][CH2:29][CH:28]([CH2:27][N:3]([CH2:1][CH3:2])[CH:4]2[CH2:5][CH2:6][C:7]3[C:12](=[CH:11][C:10]([NH:14][C:15](=[O:26])[C:16]4[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=4)=[CH:9][CH:8]=3)[CH2:13]2)[CH2:33][CH2:32]1)=[O:46])([CH3:43])[CH3:42]
Reactant: CC(C)N=C=O
Reactant: CCN(CC1CCNCC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC1CCN(C(=O)NC(C)C)CC1)C1CCc2ccc(NC(=O)c3ccc(S(C)(=O)=O)cc3)cc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.2 %

Procedure:
To an ice-cold solution of N-[7-(ethyl-piperidin-4-ylmethyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-4-methanesulfonyl-benzamide (1.3 g, 2.3 mmol) in methylene chloride (40 mL) under a nitrogen atmosphere was added the triethylamine (1.3 mL, 9.2 mmol, 4 eq.) in a single portion followed by the isopropylisocyanate (0.33 mL, 3.3 mmol, 1.4 eq). The reaction was allowed to warm to room temperature and stirred for 24 h. The reaction was concentrated in vacuo and partitioned between EtOAc (75 mL) and 10% aq. sodium hydroxide (40 mL). The aqueous layer was extracted with EtOAc (2×30 mL) and the combined EtOAc layers were dried over MgSO4, filtered, and concentrated. Trituration with ether afforded 4-({ethyl-[7-(4-methanesulfonyl-benzoylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid isopropylamide 1 as a light pink solid (1.1 g). [M+H]+=555.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:20][OH:21]>C(O)C.[Cl-].[Na+].O>[OH:21][N:20]=[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH:13]2[O:14][CH2:15][CH2:16][O:17]2)=[O:8])=[CH:18][CH:19]=1)[NH2:2]
Reactant: N#Cc1ccc(C(=O)OCCCC2OCCO2)cc1
Reactant: NO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ccc(C(=O)OCCCC2OCCO2)cc1
Temperature: 80 °C

Procedure:
To a solution of 3-(1,3-dioxolan-2-yl)propyl 4-cyanobenzoate (1.00 g, 4.38 mmol) in ethanol (5 mL), was added hydroxylamine (50% aqueous solution, 5 mL), and the mixture heated at 80° C. for 4 hours. The reaction was diluted with saturated brine and extracted with ethyl acetate (×3). The combined organic fractions were dried with magnesium sulphate, and the solvent evaporated at reduced pressure. The material was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([N+:11]([O-])=O)=[C:5]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[C:4]=1[F:25].[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([NH2:11])=[C:5]([N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[C:4]=1[F:25]
Reactant: [H][H]
Reactant: COc1c(F)c(F)c([N+](=O)[O-])c(N2C(=O)c3ccccc3C2=O)c1F
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1c(F)c(F)c(N)c(N2C(=O)c3ccccc3C2=O)c1F
Yield: 75.8 %

Procedure:
1.3 g of 5% w/w palladium-on-carbon was added to a solution of 4.2 g (0.012 mole) of 4-methoxy-2-phthalimido-3,5,6-trifluoro-1-nitrobenzene (XXXIV) [prepared as described in Step (F1) above] in 150 ml of acetic acid, and the mixture was agitated vigorously for 1 hour in an atmosphere of hydrogen. At the end of this time, the reaction mixture was filtered, the filtrate was concentrated by evaporation under reduced pressure. and the solid which separated was washed with toluene, to afford 2.93 g of 4-methoxy-2-phthalimido-3,5,6-trifluoroaniline (XXXV) as colorless sandy crystals.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:10]([O:9][C:3]1[C:2]([C:16]2[CH:17]=[C:18]([C:21]([F:23])([F:24])[F:22])[CH:19]=[CH:20][C:15]=2[F:14])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOc1ncc(C)cc1Br
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCOc1ncc(C)cc1-c1cc(C(F)(F)F)ccc1F
Temperature: 90 °C
Reaction time: 18 h
Yield: 77.6 %

Procedure:
3-Bromo-2-butoxy-5-methyl-pyridine (0.96 g, 3.9 mmol) was dissolved in toluene (6 mL). To this solution was added [2-fluoro-5-(trifluoromethyl)phenyl]-boronic acid (1.2 g, 5.9 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloro-methane complex (161 mg), and 2 N sodium carbonate solution (5.9 mL). The whole mixture was heated with stirring at 90° C. for 18 h, cooled to room temperature and eluted with ethyl acetate over 10 g ChemElut (Varian). The solvent was evaporated and the residue was purified by column chromatography on silica (n-heptane/ethyl acetate gradient) to yield 0.99 g of the title compound as a yellow oil, MS (ISP) 328.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].Cl.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH:29]([OH:34])[C:30](=N)OC>C(O)C.C(=O)([O-])O.[Na+].O>[NH2:1][C:2]1[C:3]2[N:9]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[C:30]([CH:29]([C:23]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=3[Cl:21])[OH:34])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cccc1N
Reactant: COC(=N)C(O)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCn1c(C(O)c2ccc(Cl)cc2Cl)nc2cccc(N)c21
Reaction time: 12 h
Yield: 99.5 %

Procedure:
To a stirred solution of tert-butyl {2-[(2,6-diaminophenyl)amino]ethyl}carbamate (5.00 g, 18.8 mmol) in ethanol (38 mL) was added methyl 2-(2,4-dichlorophenyl)-2-hydroxyethanimidoate hydrochloride (5.59 g, 20.7 mmol) at room temperature. After 12 h, the reaction mixture was diluted with aqueous sodium hydrogen carbonate and water. The resultant mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate to give the title compound as a brown amorphous solid (8.46 g, 18.7 mmol, 99%).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([OH:34])[CH:28]=[CH:27]2.[C:35]1(B(O)O)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][CH:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[C:43]1([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[CH:30]=[C:29]([OH:34])[CH:28]=[CH:27]3)[C:44]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc2cc(-c3cccc4ccccc34)ccc2c1

Procedure:
913 mg (3 mmol) of tri-o-tolylphosphine and then 112 mg (0.5 mmol) of palladium(II) acetate are added to a suspension of 111.5 g (500 mmol) of 6-bromo-2-naphthol, 111.8 g (650 mmol) of naphthaleneboronic acid and 224.1 g (1150 mmol) of tripotassium phosphate in a mixture of 1000 ml of toluene, 200 ml of dioxane and 1000 ml of water, and the mixture is heated under reflux for 18 h. After cooling, 200 ml of 2 N hydrochloric acid are added, and the organic phase is separated off, washed three times with 500 ml of 1 N hydrochloric acid, once with 500 ml of saturated sodium chloride solution, filtered through silica gel and evaporated to dryness in vacuo. The residue is recrystallised from 150 ml of toluene. Yield: 113.3 g (419 mmol), 83.8% of theory; purity: 98% according to NMR.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1.[H-].[Na+]>>[O:10]1[CH2:13][CH:12]([O:14][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][OH:8])[CH2:11]1
Reactant: c1ccc([C@H]2CO2)cc1
Reactant: OC1COC1
Agent: [H-]
Agent: [Na+]
Product: OC[C@H](OC1COC1)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
Into a 50-mL round-bottom flask was placed (2S)-2-phenyloxirane (4 g, 33.29 mmol, 1.00 equiv) and oxetan-3-ol (16 mL). This was followed by the addition of sodium hydride (1.3 g, 32.50 mmol, 1.00 equiv, 60%) in several batches. The resulting solution was stirred for 1 h at 80° C. in an oil bath. The reaction was then quenched by the addition of 50 mL of NH4Cl (sat., aq.). The resulting solution was extracted with 2×50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (8:1). Purification afforded 1.6 g (25%) of (2R)-2-(oxetan-3-yloxy)-2-phenylethan-1-ol (73.2) as a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[CH:9][C:2]1=2
Reactant: N#Cc1ccc2ccsc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc2ccsc2c1
Temperature: 2.5 °C
Reaction time: 20 h
Yield: 81.8 %

Procedure:
Benzo[b]thiophene-6-carbonitrile (9.70 g, 61.1 mmol) is dissolved in THF (400 mL) and cooled to 0-5° C. Lithium aluminum hydride (183 mL of 1.0 M solution in THF) is added dropwise over 30 minutes and the reaction is stirred for 20 hours while warming to 25° C. The reaction is cooled with an ice bath and water (6.94 mL) is slowly added followed by 15% sodium hydroxide (6.94 mL) and water (20.83 mL). The resulting precipitate is filtered and washed with diethyl ether. The filtrate is concentrated to give the title compound as a colorless oil (8.16 g, 82% yield). ES+(m/z) 164 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].Br[C:25]([CH3:30])([CH3:29])[C:26]([NH2:28])=[O:27].[OH-].[Na+].Cl>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11])[O:23][C:25]([CH3:30])([CH3:29])[C:26]([NH2:28])=[O:27]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CC(C)(Br)C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC(c1ccc(OC(C)(C)C(N)=O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
3-Chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 133, 200 mg) and 2-bromo-2-methyl-propionamide (272 mg) in dimethyl acetamide (1 mL) were treated with sodium hydroxide (66 mg) and stirred at r.t. for 17 h. A second portion of 2-bromo-2-methyl-propionamide (272 mg) followed by sodium hydroxide (66 mg) was added and the reaction mixture further stirred for 2 h at r.t. This process was repeated a last time and the reaction mixture was diluted with ice-water (10 mL), neutralized with 1N aqueous HCl, extracted with ethyl acetate (2×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20 g silica gel, ethyl acetate/heptane 1:2) to give the title compound as off-white waxy solid (170 mg). MS (m/e)=451.0 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C)C=O>[CH3:21][N:22]([CH:24]=[C:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:18])[CH3:23]
Reactant: COC(OC)N(C)C
Reactant: CSc1ccc(CC(=O)c2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Product: CSc1ccc(C(=CN(C)C)C(=O)c2ccc(F)cc2)cc1
Temperature: 75 °C

Procedure:
To a 500 ml 2-necked flask fitted with a thermometer and magnetic stirrer was added 20 g (76.9 mMol) of 1-(4-fluorophenyl)-2-(4-(methylthio)phenyl)ethan-1-one, Example 1, Step 3, 18.3 g (154 mMol) of dimethylformamide dimethyl acetal and 50 ml dry dimethylformamide (DMF). The reaction mixture was heated to 75° C. for 3 hours, cooled to room temperature and evaporated to dryness and to recover 26.1 g a yellowish orange solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:8]([O:10]C)=O)[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:12](#[N:14])[CH3:13]>C1COCC1.C(OCC)(=O)C.Cl>[CH:3]1([C:8](=[O:10])[CH2:13][C:12]#[N:14])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC#N
Reactant: COC(=O)C1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCC(=O)C1CCCC1
Temperature: 71 °C
Reaction time: 16 h

Procedure:
To a suspension of NaH (2.75 g, 68.7 mmol) in THF (15 mL) at 70° C. was added dropwise a solution of methyl cyclopentanecarboxylate (8.00 g, 62.4 mmol) and anhydrous acetonitrile (3.91 mL, 74.9 mmol) in THF (5 mL). The mixture was stirred for 16 h at 70-72° C., cooled to rt, and diluted with ethyl acetate and aqueous HCl. The organic layer was washed with water and brine and dried (MgSO4). Removal of the solvent provided 3-cyclopentyl-3-oxopropanenitrile, which was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].N([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=C=O>O1CCOCC1>[O:10]=[C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1.[CH3:20][CH2:19][CH:18]([C:2]([NH2:3])=[O:10])[CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCN=C=O
Agent: O=c1[nH]c2ccccc2s1
Solvent: C1COCCO1
Product: CCCCC(CC)C(N)=O

Procedure:
300 mg (1.98 mmol) of 3H-benzothiazol-2-one were reacted in analogy to Example 1 with 336 mg (2.38 mmol) of 1-isocyanatoheptane in dioxane at 80° C. Yield: 125 mg (22%), M+H+: 293.11.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:25]([O:24][CH2:23][CH2:22][CH2:21][C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=2)[S:10][C:6]=1[CH2:4][OH:3])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CCCOCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a solution of 2.76 g of 4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester in 50 mL of tetrahydrofuran was added 6.14 mL of a 1M solution of lithium aluminium hydride in tetrahydrofuran. The resulting mixture was stirred at room temperature for 1 h. Ethyl acetate was added followed by a saturated aqueous solution of ammonium chloride. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 70/ethyl acetate 30) to give 1.69 g of [4-(3-benzyloxy-propyl)-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol as a white solid.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:15])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([NH2:14])[C:10]([CH3:13])=[N:11][CH:12]=1.C(#N)C.Cl.[Cl:20][C:21]([NH2:23])=[NH:22]>C(O)(=O)C>[ClH:20].[ClH:1].[ClH:20].[CH3:15][N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:14][C:21]([NH2:23])=[NH:22])[C:10]([CH3:13])=[N:11][CH:12]=1
Reactant: Cc1ncc(CCCN(C)C)cc1N
Reactant: N=C(N)Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1ncc(CCCN(C)C)cc1NC(=N)N
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 136.9 %

Procedure:
A 1 L, three-neck, round-bottom flask equipped with an overhead stirrer, a reflux condenser, an N2 inlet tube, and a temperature probe was charged with 5-(3-(dimethylamino)propyl)-2-methylpyridin-3-amine hydrochloride (25 g, 0.109 mol). Acetonitrile (275 mL, 11 vol) was added to it followed by acetic acid (25 mL, 1 vol). The initial suspension turned into a clear solution after the addition of acetic acid. Chloroformamidine hydrochloride (15.6 g, 0.136 mol, 1.25 equiv) was added to the solution resulting in a suspension. The reaction was heated at 40° C. for 30 min and at 50° C. for another 30 min. Then the temperature was raised to 60° C. and the reaction was continued at this temperature. After 1-2 h at 60° C., the reaction mixture became turbid and after 3-4 h, solid started separating out. The reaction was continued at 60° C. for 20 h and was judged complete by LC-MS analysis. The reaction was cooled to ambient temperature and the solid was collected by filtration (N2 flow was used during the filtration). The filter cake was washed with acetonitrile (50 mL, 2 vol). The solid was dried under high vacuum overnight to obtain N-{5-[3-(Dimethylamino)propyl]-2-methylpyridin-3-yl}guanidine trihydrochloride (32.1 g, 85% recovery) as a light brown solid. Elemental analysis Calcd: C, 41.81; H, 7.02; Cl, 30.85; N, 20.32. Found: C, 41.09; H, 6.72; Cl, 31.51; N, 20.47. 1H NMR (500 MHz, DA)) δ ppm: 8.57 (s, 1H), 8.45 (s, 1H), 3.22-3.19 (m, 2H), 2.90 (t, 2H, J=10 Hz), 2.86 (s, 6H), 2.69 (s, 3H), 2.15-2.07 (m, 2H); ESI-MS m/z 236 (M+H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[O:15][C:16]3[C:22]([C:23]4[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[CH:27][CH:28]=4)=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:31]CN=C=NCCCN(C)C.Cl.C(O)=O>CN(C1C=CN=CC=1)C.ClCCl>[NH:29]1[C:26]2[CH:27]=[CH:28][C:23]([C:22]3[C:16]4[O:15][C:14]([NH:13][C:5]5[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=5)=[N:18][C:17]=4[CH:19]=[CH:20][CH:21]=3)=[CH:24][C:25]=2[N:30]=[CH:31]1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(N)c(N)c4)c3o2)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=CO
Solvent: ClCCl
Product: COc1cc(Nc2nc3cccc(-c4ccc5[nH]cnc5c4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 0.16 g (0.228 mmol) 4-[2-(3,4,5-trimethoxy-phenylamino)-benzooxazol-7-yl]-benzene-1,2-diamine, 0.068 g (0.346 mmol) EDC-HCl, 0.043 g (0.345 mmol) DMAP, 0.012 g (0.27 mmol) formic acid), and 7 ml dichloromethane is stirred at room temperature for 20 h. Then the reaction mixture is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc:MeOH=9:1) to afford ca. the title compound. 4-[2-(3,4,5-trimethoxy-phenylamino)-benzooxazol-7-yl]-benzene-1,2-diamine is prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene-1,2-diamine as described in Example 1.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([C:24]1[N:28]3[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]3=[N:26][N:25]=1)[CH:20]=[CH:19]2)[CH2:3][NH:4]C(=O)OC(C)(C)C.[ClH:35]>ClCCl>[ClH:35].[ClH:35].[ClH:35].[CH3:1][C:2]([CH3:34])([CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[C:21]([C:24]1[N:28]3[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]3=[N:26][N:25]=1)[CH:20]=[CH:19]2)[CH2:3][NH2:4]
Reactant: Cc1ccn2c(-c3ccc4cccc(OCC(C)(C)CNC(=O)OC(C)(C)C)c4n3)nnc2c1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccn2c(-c3ccc4cccc(OCC(C)(C)CN)c4n3)nnc2c1
Reaction time: 8 h
Yield: 69.9 %

Procedure:
A mixture of tert-butyl 2,2-dimethyl-3-(2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)propylcarbamate (35 mg, 0.076 mmol) and hydrochloric acid (4 M in dioxane, 0.57 mL, 2.3 mmol) in dichloromethane (0.5 mL) was stirred overnight. The reaction was concentrated under reduced pressure. The residue was evaporated from twice from toluene, once from hexanes, triturated with hexanes, filtered and dried in vacuo to provide 25 mg (70%) of desired product as the trihydrochloride salt. MS ESI (+) m/z 362 (M+1) detected.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[O:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:21]2[CH:22]=[CH:23][O:19][CH:20]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccoc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and furan-3-boronic acid according to the general procedure B. Obtained as an orange solid (855 mg).