Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:9][C:10]2[C:20]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][C:11]=2[Cl:28])=[N:6][CH:7]=1.[Br-].[CH:30]1([CH2:36][Zn+])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:28].[Cl:28][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:20]=2[C:10]=1[S:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH2:36][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:7][N:6]=1
Reactant: [Zn+]CC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)cn3)c2CC1
Agent: [Br-]
Product: Cl
Product: Clc1ccc2c(c1SCc1ccc(CC3CCCCC3)cn1)CCNCC2

Procedure:
Use a method similar to the Example 366 to react 6-(5-bromo-pyridin-2-ylmethylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine with cyclohexylmethylzinc bromide. Use a method similar to the General Procedure 1-5, basic workup, and a method similar to the General Procedure 2-2 to give the title compound as a white solid. MS (APCI+) m/z: 401 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+].CO.[C:14](#[N:17])[CH:15]=[CH2:16].Cl>C(O)(C)(C)C>[C:2]([C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:16][CH2:15][C:14]#[N:17])[CH2:16][CH2:15][C:14]#[N:17])(=[O:9])[CH3:1]
Reactant: CCCCCCC(C)=O
Reactant: C=CC#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)(C)O
Product: CCCCCC(CCC#N)(CCC#N)C(C)=O
Temperature: 5 °C

Procedure:
In a flask, 600 g of 2-octanone (CH3 (CH2)5COCH3), 500 g of tert-butanol ((CH3)3COH) and 30 g of a KOH/CH3OH solution were mixed and then stirred under ice-cooling. To the resulting solution was added dropwise a solution of 375 g of acrylonitrile (CH2 =CHCN) in 400 g of (CH3)3COH while maintaining the temperature at 5° C. or lower. After completion of the addition, the resulting solution was further stirred continuously for 1 hour, after which this reaction solution was made neutral by addition of dilute hydrochloric acid. The deposited salt was separated by filtration, and the residue was distilled under reduced pressure to obtain 3-acetyl-1,5-dicyano-3-pentylpentane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl.O>[C:25]1([C:22]2[CH:23]=[CH:24][N:10]3[C:11]=2[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:13][C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH:7]=[N:6][CH:5]=2)=[N:9]3)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.1 %

Procedure:
2-(5-Aminopyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (80.0 mg, 0.201 mmol) was dissolved in CH2Cl2 (10 mL) and pyridine (0.0500 mL, 0.610 mmol) was added, followed by methanesulfonyl chloride (26.0 mg, 0.221 mmol). The reaction mixture was stirred at room temperature for 3 h then diluted with water (10 mL) and the aqueous solution was extracted with CH2Cl2 (25×2 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Condition B-64 as described in general methods) to obtain N-(5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)methanesulfonamide (20.0 mg, 20.0%). LCMS Condition B-39: retention time 2.02 min, [M+1]=471.80. HPLC Condition B-32: retention time 6.96 min, Purity 99.40%. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.11 (s, 3H), 4.92 (d, J=4.8 Hz, 2H), 6.82 (d, J=2.8 Hz, 1H), 7.31 (dd, J=4.4 Hz, J=8.8 Hz, 2H), 7.46-7.61 (m, 8H), 7.79 (dt, J=2.0 Hz, J=7.6 Hz, 1H), 7.92 (d, J=2.8 Hz, 1H), 8.40 (d, J=4.0 Hz, 1H), 8.44 (t, J=2.4 Hz, 1H), 9.15 (d, J=2.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[CH:25]([N:28]([CH:31]([CH3:33])[CH3:32])CC)([CH3:27])C.C[N:35](C=O)C>ClCCl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([N:28]4[CH2:25][CH2:27][CH2:33][C@H:31]4[CH2:32][NH2:35])[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C=O
Solvent: ClCCl
Product: NC[C@@H]1CCCN1c1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Temperature: 120 °C

Procedure:
3.0 g 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 2.8 g (S)-2-N-FMOC-aminomethylpyrrolidine and 2.7 ml diisopropylethylamine are placed in 24 ml DMF. The reaction mixture is divided into 3 and heated to 120° C. in the microwave for 0.3 hours. Then the reaction mixture is diluted with dichloromethane and filtered. The filtrate is evaporated to dryness. 6.6 g product are obtained as an oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:24][CH:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Br:34][CH2:35][C:36](Br)=[O:37]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]3[CH2:24][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:36](=[O:37])[CH2:35][Br:34])[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a cold (ice bath) stirred solution of racemic 4-amino-1-[2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl]-piperidine (4.25 g, 12.54 mmol, described in Example 7b), diisopropyl ethylamine (4.37 mL, 25.08 mmol) in methylene chloride (75 mL) was added bromoacetyl bromide (1.36 mL, 15.68 mmol). After stirring the resulting mixture for 1 h at 0° C., the cooling bath was removed and the reaction was allowed to reach ambient temperature and stirred for an additional 18 h. The reaction mixture was treated with saturated sodium bicarbonate (2×150 mL) and brine (100 mL), dried (sodium sulfate), filtered, and concentrated to give the title compound as a brown foamy glass (5.74 g, quant.)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:23]([OH:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: OCc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. EI-MS m/e (%): 346 (M+, 32), 91 ([PhCH2]+, 100).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](N)=[CH:32][CH:31]=1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1.[N:37]1C=CC=CC=1S(Cl)(=O)=O.[CH3:47][N:48]([CH:50]=O)[CH3:49]>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:37]=[CH:50][N:48]([CH3:49])[CH3:47])[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1
Reactant: CN(C)C=O
Reactant: Nc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C=Nc1ccccc1CN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of (1H-N-t-butoxycarbonyl-benzimidazol-2-ylmethyl)-[4-(t-butoxycarbonylamino)-benzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (62 mg, 0.106 mmol) in CH2Cl2 (2 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 2 h, then concentrated. The residue was taken up in CH2Cl2, washed with 15% NaOH (3 mL) and extracted repeatedly with CH2Cl2. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated. The crude (1H-benzimidazol-2-ylmethyl)-[4-aminobenzyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amine was then added to a solution of 2-pyridinesulfonyl chloride (27 mg, 0.15 mmol) in DMF (1 mL). The resulting solution was stirred at room temperature for 30 min. The mixture was then concentrated, taken up in CH2Cl2 and washed with aqueous potassium carbonate. The organic fraction was then dried over anhydrous sodium sulfate, filtered, concentrated and purified by chromatography on silica gel (10:1:0.1 CH2Cl2:MeOH:NH4OH) to afford N′-({[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-methyl}-phenyl)-N,N-dimethylformamidine (21 mg, 47%). 1H NMR (CDCl3) δ 1.69 (m, 1H), 2.01 (m, 3H), 2.25 (m, 1H), 2.73 (m, 2H), 2.93 (s, 3H), 3.60 (s, 3H), 3.62 (d, 1H, J=13.2 Hz), 3.68 (d, 1H, J=13.2 Hz), 3.98 (d, 1H, J=16.2 Hz), 4.01 (m, 1H), 4.12 (d, 1H, J=16.2 Hz), 6.80 (d, 2H, J=8.1 Hz), 7.16 (m, 4H), 7.26 (d, 1H, J=8.1 Hz), 7.38 (m, 2H), 7.40 (br s, 1H), 8.55 (d, 1H, J=4.8 Hz).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][PH:9](=[O:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[O-:20].[Na+]>>[C:1]1([CH2:7][CH2:8][P:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])[OH:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-]Cl
Reactant: O=[PH](CCc1ccccc1)CCc1ccccc1
Agent: [Na+]
Product: O=P(O)(CCc1ccccc1)CCc1ccccc1
Reaction time: 1 h

Procedure:
The resultant compound of Example 9 (250 mg, 0.97 mmol) was added to 10 ml of 5.25% sodium hypochlorite. The resulting solution was stirred vigorously for 1 h, acidified, extracted with chloroform, washed with 1N HCl and saturated brine, dried over MgSO4, and concentrated in vacuo to give 217 mg (82%) of the desired compound (Rf 0.12, 20% methanol in chloroform) as a glass. 1H NMR (CDCl3) δ 2.0-2.1 (m, 4H), 2.9-3.0 (m, 4H), 7.15-7.4 (m, 10H). Mass spectrum (M+H)+ =275.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].Cl.[OH-].[K+].[N+:10]([CH:13]=[C:14](S(C)=O)SC)([O-:12])=[O:11].[CH3:20][C:21]1[N:22]=[CH:23][NH:24][C:25]=1[CH2:26][S:27][CH2:28][CH2:29][NH2:30]>CO.O>[N+:10]([CH:13]=[C:14]([NH:30][CH2:29][CH2:28][S:27][CH2:26][C:25]1[NH:24][CH:23]=[N:22][C:21]=1[CH3:20])[NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])([O-:12])=[O:11]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: NCC(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2,2,2-trifluoroethylamine (4.0 g) from the hydrochloride and potassium hydroxide in methanol (45 ml) and water (5 ml) was added slowly to a suspension of 1-nitro-2-methylsulphinyl-2-methylthio ethylene (3.6 g) in methanol (150 ml) at 0°. The mixture was stirred at room temperature for 24 hours, concentrated and dissolved in chloroform. Filtration, redissolution in a small volume of chloroform and precipitation with hexane afforded an orange crystalline solid. This was dissolved in methanol (25 ml) and a solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (2.1 g) in methanol (25 ml) was added. The resulting solution was heated under reflux for 2 hours and set aside at room temperature for 18 hours. Concentration followed by chromatographic purification on a column of silica gel with chloroform-methanol (15.1) as eluant and final crystallisation from ethanol afforded the title compound as a hemi-ethanolate (2.4 g) m.p. 161° (dec).
Reaction SMILES: C(N(CC)CC)C.[O:8]([C@H:16]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([CH:28]=[O:29])[CH2:17]1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[N+:30]([CH3:33])([O-:32])=[O:31]>>[O:8]([C@H:16]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([CH:28]([OH:29])[CH2:33][N+:30]([O-:32])=[O:31])[CH2:17]1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: C[N+](=O)[O-]
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)C[N+](=O)[O-]
Yield: 65.5 %

Procedure:
Triethylamine (1.27 ml, 9.55 mmol) was added to a solution of (2S,4R)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonylprolinal (19.1 g, 57.87 mmol) in nitromethane (95 ml) under stirring and cooling with ice. This solution was left to stand at room temperature for hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel™ C-300, 350 g, hexane-ethyl acetate 9:1) to obtain oily (2S,4R)-4-tert-butyldimethylsiloxy-N-tert-butoxycarbonyl-2-(1-hydroxy-2-nitroethyl)pyrrolidine (14.81 g, yield: 65.5%). IR(KBr)cm-1 : 3420, 1675, 1700, 1560, 1415, 1255, 1165, 840, 780
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:9]2[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1>O1CCOCC1>[N:1]1([C:8]2[C:9]3[N:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Solvent: C1COCCO1
Product: Clc1ccc2ncnc(N3CCNCC3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of piperazine (7.0 g) in 1,4-dioxane (100 ml) was added a solution of crude 4,6-dichloro-pyrido[3,2-d]pyrimidine in 1,4-dioxane (50 ml). The resulting mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a methanol/dichloromethane mixture (in a ratio gradually ranging from 1:10 to 1:5), resulting in the pure title compound as a yellowish solid (3.1 g, yield 76%) which was characterized by its mass spectrum as follows: MS (m/z): 250.1 ([M+H]+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:19][CH2:18][CH:17]2[CH:13]([CH2:14][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:19][CH2:18][CH:17]3[CH:13]([CH2:14][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]3)[CH2:12]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(N)CC2C1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CCC(Nc3nc(Cl)ncc3Cl)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.3 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (0.60 g, 3.27 mmol) and tert-butyl 5-aminohexahydro-1H-isoindole-2(3H)-carboxylate (2.79 g, 11.61 mmol) in EtOH (10 mL) was added Et3N (1.30 g, 12.84 mmol). After addition, the reaction mixture was stirred at rt overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the title compound as a pale yellow solid (1.60 g, 100%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][C@H:3]1[C:6]([O:8][CH3:9])=[O:7].[C:10]1([CH2:16][S:17](Cl)(=[O:19])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:9][O:8][C:6]([C@@H:3]1[CH2:4][CH2:5][N:2]1[S:17]([CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:19])=[O:18])=[O:7]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC(=O)[C@@H]1CCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCN1S(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
(2S)-Methyl azetidine-2-carboxylate hydrochloride from Reference Example 1 (361.4 mg, 2.26 mmol, 1.0 eq) was dissolved in dry dichloromethane (10.0 mL) and treated with α-toluenesulfonyl chloride (458.1 mg, 2.40 mmol, 1.1 eq). After cooling to about 0° C. under argon atmosphere, diisopropylethylamine (420 μL, 2.41 mmol, 1.1 eq) was added and the reaction mixture was stirred at about room temperature overnight. The solvent was evaporated and the residue was subjected to flash chromatography (in dichloromethane) to give 431.2 mg (71 % yield) of the product as a colorless oil. 1H NMR (CDCl3) δ 2.29-2.51 (m, 2H); 3.21-3.29 (m,1H); 3.81 (s, 3H); 4.02 (q,1H, J=8.6); 4.32 (d, 1H, J=9.4, 6.9); 4.46 (d, 1H, J=14.6); 4.86 (dd, 1H, J=9.4, 6.9); 7.34-7.43 (m, 3H); 7.46-7.54 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:5][C:6](=[O:28])[CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27])[CH3:4].[OH:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33].N1C=CN=C1.C1CCC(N=C=NC2CCCCC2)CC1>CC(=O)OCC>[C:6]([NH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[OH:29])(=[O:28])[CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CN
Reactant: O=C(O)c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NC(C)CNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a solution of (4Z,7Z,10Z,13Z,16Z,19Z)—N-(1-aminopropan-2-yl)docosa-4,7,10,13,16,19-hexaenamide (1.60 g, 4.2 mmol), 2-hydroxybenzoic acid (0.57 g, 4.2 mmol) and imidazole (0.29 g, 4.2 mmol) in EA (40 mL) at 0° C. was added a solution of DCC (0.87 g, 4.2 mmol) in EA (40 mL). The mixture was allowed to warm to RT, stirred (16 h) and filtered. The solvent was removed under reduced pressure and the crude product was purified by chromatography on silica gel, eluting with EA-PE (0-50%) to afford N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropyl)-2-hydroxybenzamide (1.07 g, 50.5%) as a light yellow oil. Mass calculated for C32H44N2O3=504.70. found: [M+H]+=505.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[C:45]#[N:46]>CN(C=O)C.O>[C:45]([C:44]1[CH:43]=[C:42]([NH:41][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:49]=[CH:48][CH:47]=1)#[N:46]
Reactant: N#Cc1cccc(N)c1
Reactant: COc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cccc(C#N)c2)cc1
Reaction time: 0.25 h

Procedure:
5.0 g (33 mmol) 4-methoxybenzoic acid were dissolved in 50 ml DMF. 12.8 g (66 mmol) EDCl, 9.2 g (66 mmol) HOBt and 14.8 ml (132 mmol) 4-methylmorpholine were added and the mixture was stirred for 15 min. Subsequently, 3.9 g (33 mmol) 3-aminobenzonitrile were added and the mixture was stirred for 48 h at room temperature and 6 h at 80° C. The reaction mixture was poured in 500 ml water and the precipitate was filtered, washed and dried.
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)C(=O)OC(C)(C)C)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:27]([Cl:35])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[ClH:35].[C:27]([N:24]1[CH2:25][CH2:26][CH:22]([CH2:21][NH:13][C@@H:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH3:12])[CH2:23]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNC1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](NCC1CCN(C(=O)c2ccccc2)C1)c1cccc2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 8.0 ml THF solution of 124 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl](pyrrolidin-3-ylmethyl)carbamate was mixed with 45 μl of benzoyl chloride and stirred overnight at room temperature. A 20 ml portion of saturated sodium bicarbonate aqueous solution was added thereto, and the solvent was evaporated. This was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate, and the solvent was evaporated. The thus obtained residue was treated with 4 M hydrogen chloride/ethyl acetate and recrystallized from isopropanol-diethyl ether to obtain 100 mg of (1R)—N-[(1-benzoylpyrrolidin-3-yl)methyl]-1-(1-naphthyl)ethanamine hydrochloride as colorless crystals.
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)=[C:11]([NH2:24])[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1>C(O)(C)C>[OH2:23].[OH2:23].[CH3:2][CH:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]3[N:15]=[C:16]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:24][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)c2cccnc2)c(N)c1
Agent: Cl
Solvent: CC(C)O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3cccnc3)[nH]c2c1
Product: O

Procedure:
HCl gas is passed for 2 hours into a boiling suspension of 1 g of 5-methyl-6-(3-amino-4-nicotinamidophenyl)-4,5-dihydropyridazin-3-one in 50 ml of isopropanol. After evaporation and the usual working up, 5-methyl-6-[2-(3-pyridyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one, dihydrate, decomposition above 173°, is obtained.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=3[F:32])[CH:14]=2)=[N:11][CH:12]=1>C(O)(=O)C.O>[F:32][C:24]1[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=[CH:28][C:23]=1[O:22][C:19]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:14]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([CH:2]=[O:1])=[CH:12][N:11]=3)[S:21][C:20]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 90 °C
Yield: 76.5 %

Procedure:
A suspension of 318 (2.64 g, 5.82 mmol) in 80% aqueous acetic acid (42 mL) was heated at 90° C. for 18 h. The reaction mixture was cooled to r.t. and diluted with water. The resulting precipitate was collected by suction filtration. The solid was transferred to a round-bottomed flask, the remaining water was removed by azeotropic distillation with toluene (4 times), and the solid dried in vacuo yielding 325 (1.76 g, 76%). LRMS (M+H): 396.3
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield a yellow solid (38%). LCMS: m/z=511.18 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.52 (s, 1H), 7.34 (d, 1H, J=7.6 Hz), 7.14 (m, 5H), 3.54 (m, 2H), 3.35 (s, 3H), 2.86 (s, 3H), 2.20 (m, 2H), 1.95 (m, 2H), 1.26 (s, 6H), 1.06 (m, 3H).