Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:27]1>>[Br:1][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:27]1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCCO)C1
Product: O=C(OCc1ccccc1)N1CCCC(CCCCBr)C1

Procedure:
Prepared similarly to Intermediate 30 from phenylmethyl 3-(4-hydroxybutyl)-1-piperidinecarboxylate.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+:2]=[N-:3].Cl[C:17](=[CH2:20])[C:18]#[N:19]>O>[C:18]([C:17]1[N:3]=[N:2][N:1]([CH:4]2[CH2:10][CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[NH:6][C:5]2=[O:15])[CH:20]=1)#[N:19]
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Reactant: C=C(Cl)C#N
Solvent: O
Product: N#Cc1cn(C2CCc3ccccc3NC2=O)nn1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 3-azido-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine (1.01 g) and 2-chloroacrylonitrile (0.95 g) in water (5 ml) is stirred at about 80° C. for 18 hours. Excess 2-chloroacrylonitrile is distilled off in vacuo, and the precipitated product is filtered off, washed with water and dried (yield 1.1 g; 87% of theory), m.p. 214-216° C. (recrystallization from ethyl acetate/toluene).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C[O:23][B:24](OC)[O:25]C.O>C(OCC)C>[Si:15]([O:14][CH2:13][CH2:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[B:24]([OH:25])[OH:23])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: COB(OC)OC
Reactant: CC(C)(C)[Si](C)(C)OCCc1occc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCc1occc1B(O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
n-Butyllithium (2.5M in hexanes, 5.78 mL) was added to a solution of [2-(3-bromofuran-2-yl)-ethoxy]-tert-butyldimethylsilane (Intermediate 34, 4.01 g) in diethyl ether (130 mL) at −60° C. under nitrogen and the resultant mixture was stirred for 30 minutes. Trimethylborate (2.73 g) was then added to the mixture and it was stirred for a further 10 minutes. The reaction mixture was warmed to 0° C., water was added and the mixture was stirred for 15 minutes. The organic layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give 2-[2-(tert-butyldimethylsilanyloxy)-ethyl]-furan-3-yl-boronic acid (1.23 g) as a colourless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:15]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:14](=[O:24])[C:13]2[C:8](=[CH:9][C:10]3[CH2:27][CH2:26][C:25](=O)[C:11]=3[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2].ClCCl.[NH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[C:1]([O:4][CH2:5][C:6]1[N:15]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:14](=[O:24])[C:13]2[C:8](=[CH:9][C:10]3[CH2:27][CH2:26][CH:25]([NH:32][C:33]4[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:35][CH:34]=4)[C:11]=3[CH:12]=2)[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(=O)CC3
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)OCc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
2-Acetoxymethyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4,6-dione (0.140 g, 0.36 mmol) was suspended in anhydrous methanol (8 ml) and then anhydrous dichoromethane (4 ml) was added until a clear solution was obtained. Tert-butyl 4-aminobenzoate (0.084 g, 0.44 mmol) was then added followed by decaborane (0.014 g, 0.12 mmol). The reaction mixture was stirred overnight at room temperature under argon. The solvent was removed in vaciio, and the residue was purified by column chromatography on elution with 40% ethyl acetate in hexane. The product was obtained as a glass (0.127 g, 63%) 1H-NMR (CDCl3) 1.20 (s, 9H, POM C(CH3)3), 1.58 (s, 9H, CO2C(CH3)3), 2.20 (s, 3H, CH3CO), 2.02, 2.72 (2×m, 2H, 7-CH2), 3.13 (m, 2H, 8-CH2), 4.36 (d, J=7.7 Hz, 1H, NH), 5.15 (q, J=6.8 Hz, 1H, 6-H), 5.21 (s, 2H, 2-CH2), 6.12 (AB system, J=10.7 Hz, 2H, POM CH2), 6.67 (d, J=8.8 Hz, 2H, 3,5′-ArH), 7.57 (s, 1H, 9-H), 7.85 (d, J=8.9 Hz, 2H, 2′,6′-ArH), 8.25 (s, 1H, 5-H); MS (ESI, m/z) 564 (M+H)+.
Reaction SMILES: C1(C[N:8]([CH2:16][C@@H:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][C@H:18]2[OH:27])CC2C=CC=CC=2)C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:8][CH2:16][C@@H:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][C@H:18]1[OH:27]
Reactant: CCCCN1CC[C@@H](CN(Cc2ccccc2)Cc2ccccc2)[C@H](O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCN1CC[C@@H](CN)[C@H](O)C1
Yield: 93.8 %

Procedure:
A mixture of intermediate (29) (0.079 mol) in methanol (250 ml) was hydrogenated with palladium-on-carbon (10%) (2 g) as a catalyst. After uptake of hydrogen (2 equivalents), the catalyst was filtered over celite and the filtrate was evaporated, yielding 13.8 g of (trans)-4-(aminomethyl)-1-butyl-3-piperidinol (intermediate 30).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:16])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[C:17]([NH:24][C:25]1([C:30](O)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.CCN(CC)CC>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:16])[CH:6]([NH:7][C:30]([C:25]1([NH:24][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:31])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[CH3:3]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(O)cc1)NC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 g (12.2 mmol) of tyrosine ethyl ester hydrochloride and 2.8 g (12.2 mmol) of N-Boc-cycloleucine are suspended in 10 mL of CH2Cl2. 1.65 g (12.2 mmol) of HOBT, 3.02 g (14.6 mmol) of DCC, and 1.7 mL (12.2 mmol) of Et3N are added, and the solution is stirred at room temperature overnight. The reaction mixture is filtered, and CH2Cl2 is removed in vacuo. The residue is taken up in EtOAc, filtered, and washed successively with 1 N HCl, water, saturated aqueous NaHCO3 solution, and brine, then dried over MgSO4, filtered, and concentrated. The residue is purified by chromatography on silica gel (50% EtOAc/hexane) to yield 2-[(1-tert-butoxycarbonylamino-cyclopentanecarbonyl)-amino]-3-(4-hydroxy-phenyl)-propionic acid ethyl ester; 1H NMR (250 MHz, CDCl3) δ 7.97 (d, 2H), 6.7 (d, 2H), 7.51 (d, 1H), 5.58 (s, 1H), 4.70-4.80 (m, 2H), 4.12 (q, 2H), 3.02 (d, 2H), 2.07-2.35 (m, 2H), 1.60-2.00 (m, 6H), 1.40 (s, 9H), 1.20 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[O:31]C(=O)C)=[CH:7][CH:6]=[C:5]([O:36][CH3:37])[N:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[OH:31])=[CH:7][CH:6]=[C:5]([O:36][CH3:37])[N:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)nc3OC)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(OC)nc3OC)c2)=C(C)C1=O
Yield: 86.2 %

Procedure:
N-(2,6-Dimethoxypyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.100 g, 0.196 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.079 g, 0.169 mmol, 87%).
Reaction SMILES: [OH-].[Na+].CO.[F:5][C:6]1[CH:30]=[CH:29][C:9]([NH:10][C:11]2[CH:20]=[C:19]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=1>O1CCCC1>[F:5][C:6]1[CH:30]=[CH:29][C:9]([NH:10][C:11]2[CH:20]=[C:19]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:12]=2[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(COc2ccccc2)cc1Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(COc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
2.0 mol/L Sodium hydroxide aqueous solution 0.92 mL was added to a mixed solution of methanol 2.0 mL and tetrahydrofuran 2.0 mL of methyl 2-(4-fluoroanilino)-4-(phenoxymethyl)benzoate 0.22 g, and it was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure, water was added to it, and it was adjusted to pH4.0 with 1.0 mol/L hydrochloric acid. Solid matter was filtrated to give 2-(4-fluoroanilino)-4-(phenoxymethyl)benzoic acid 0.14 g of white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[Br:20][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:2]=1[CH3:1]
Reactant: Cc1oc(-c2ccccc2)nc1CCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Cc1oc(-c2ccccc2)nc1CCCCCBr
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.6 %

Procedure:
5-(5-Methyl-2-phenyloxazol-4-yl)-1-pentanol (2.9 g) was dissolved in 62 ml of dry ether, and 8.4 g of carbon tetrabromide was added. To the mixture was added gradually 6.6 g of triphenylphosphine under ice-cooling. The mixture was then stirred for 2.5 hours at room temperature, filtrated to remove insolubles and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=10:1) to provide 2.61 g of the objective compound as yellowish oil.
Reaction SMILES: C(OCC([O-])=O)(C)(C)C.[CH2:10]([O:13][C:14]1([CH3:54])[CH2:19][CH2:18][N:17]([C:20]2[N:25]3[N:26]=[C:27]([C:29]4[CH:30]=[C:31]([C:35]5[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=5[OH:42])[CH:32]=[CH:33][CH:34]=4)[CH:28]=[C:24]3[N:23]=[C:22]([CH3:43])[C:21]=2[CH:44]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C:45]([O:47][CH3:48])=[O:46])[CH2:16][CH2:15]1)[CH:11]=[CH2:12]>>[CH2:10]([O:13][C:14]1([CH3:54])[CH2:15][CH2:16][N:17]([C:20]2[N:25]3[N:26]=[C:27]([C:29]4[CH:30]=[C:31]([C:35]5[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=5[OH:42])[CH:32]=[CH:33][CH:34]=4)[CH:28]=[C:24]3[N:23]=[C:22]([CH3:43])[C:21]=2[C@H:44]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C:45]([O:47][CH3:48])=[O:46])[CH2:18][CH2:19]1)[CH:11]=[CH2:12]
Reactant: C=CCOC1(C)CCN(c2c(C(OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(Cl)ccc5O)c4)nn23)CC1
Agent: CC(C)(C)OCC(=O)[O-]
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(Cl)ccc5O)c4)nn23)CC1

Procedure:
(S)-Methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5′-chloro-2′4(S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate: Prepared from S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5′-chloro-2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate using the same procedure as intermediate 169 in 94% yield. LCMS (M+1)=701.35.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][N:14]2[CH2:17][C:18](=[O:35])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=2)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:18](=[O:35])[CH2:17][N:14]2[C:15]3[C:11](=[CH:10][CH:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:16]=3)[CH:12]=[CH:13]2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCc1ccc(OCC(=O)Cn2ccc3ccc(C(=O)OC(C)(C)C)cc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(OCC(=O)Cn2ccc3ccc(C(=O)O)cc32)cc1
Temperature: 25 °C

Procedure:
59 mg (0.12 mmol) tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-6-carboxylate are dissolved in 15 ml absolute dichloromethane and mixed with 1.05 g (9.20 mmol) trifluoroacetic acid. After stirring at room temperature for 2½ hours, concentration to dryness is carried out on the rotary evaporator. Three admixtures with 10 ml of a mixture of petroleum ether and ethyl acetate (1:2) each and respective concentration to dryness on the rotary evaporator leave as a crude product a solid which is purified on an RP-HPLC column (stationary phase: cromasil, mobile phase: acetonitrile/water 9:1) by means of chromatography.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>CN(C)C=O>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:31](=[O:33])[CH3:32])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 50 mg (0.125 mmol) of trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine in 2 ml of anhydrous N,N-dimethylformamide is added 13 μl (0.138 mmol) of acetic anhydride (Fluka, Buchs, Switzerland). After stirring 1 h at RT, working-up is effected by partitioning between water and ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated to dryness to provide trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-acetamide. Analytical HPLC: tR=6.65 min (Grad 2); ES-MS: m/eo=442.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][C:10]([NH:13][C:14](=[O:19])C(F)(F)F)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)=O.ClC1C=C(N2CC(C)C(NC=O)=N2)C=CC=1Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][C:10]([NH:13][CH:14]=[O:19])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1=NN(c2cccc(Cl)c2)CC1)C(F)(F)F
Agent: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: ClCCl
Solvent: O=CO
Product: O=CNC1=NN(c2cccc(Cl)c2)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 2.0 g. of 3-amino-1-(m-chlorophenyl)-2-pyrazoline (prepared in Example 10) and 10 ml. of a mixture of formic acid and acetic anhydride (Example 15) is allowed to stand at room temperature for 30 minutes. Then the solvent is evaporated in vacuo to give an oil. The oil is dissolved in dichloromethane and is columnized and recrystallized as described in Example 5 to give 1.32 g. of the desired product as pale yellow needles, m.p. 143°-145° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][C:9]#[N:10]>CO>[C:8]([CH2:9][NH:10][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])#[N:7]
Reactant: C=C1CC(=O)O1
Reactant: N#CCN
Solvent: CO
Product: CC(=O)CC(=O)NCC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
While stirring at -10° to 0° C, 92 g of freshly distilled diketene are added dropwise to a solution of 400 ml of methanol and 56 g of freshly distilled aminoacetonitrile. The mixture is allowed to warm to room temperature and stirring is continued for 2 hours at 35° C in a water bath. The solvent is distilled off by rotary evaporation and the solid residue is suspended in cold ether. Suction filtration yields the colourless, crystalline, pure acetoacetic N-cyanomethylamide with a melting point of 63°-65° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([N:16]([CH2:21][CH3:22])[CH2:17][CH2:18][CH2:19]O)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:9]([N:16]([CH2:17][CH2:18][CH2:19][Br:1])[CH2:21][CH3:22])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CCN(CCCO)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CCCBr)C(=O)OC(C)(C)C

Procedure:
11 g (0.0618 mol) of N-bromosuccinimide are added in the course of 5 minutes, with stirring, to a solution, which has been cooled to 0° C., of 10.49 g (0.0516 mol) of 3-(N-BOC-ethylamino)-1-propanol and 16.23 g (0.0619 mol) of triphenylphosphine in 160 ml of methylene chloride. The reaction mixture is stirred for a further 30 minutes at 0°-20° C. and is then concentrated by evaporation in vacuo. The dark-colored oily residue is stirred with 200 ml of hexane, whereupon a brown precipitate forms. After filtration and concentration of the filtrate by evaporation in vacuo, the title compound is obtained in the form of an oil, Rf value=0.71 (silica gel/tert-butyl methyl ether).
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].O[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)=[O:14])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: O=Cc1ccc(O)cc1
Reactant: N=C(N)N1CCC(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)N1CCC(CCC(=O)Oc2ccc(C=O)cc2)CC1
Yield: 36.4 %

Procedure:
A mixture of 4.0 g of 1-amidino-4-piperidinepropionic acid hydrochloride and 2.1 g of p-hydroxybenzaldehyde was suspended in 20 ml of dry pyridine. 3.5 g of dicyclohexylcarbodiimide was added with stirring to the suspension, and the resulting mixture was stirred overnight at room temperature. After removal of any insoluble materials, the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was stirred to give crystals. The crystals were recrystallized from methanol-ether to obtain 2.1 g (yield: 36.4%) of p-formylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless crystals having a melting point of 144° to 147° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13].I[CH3:15].O>CN(C=O)C>[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:15]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=O)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60 percent in mineral oil, 1.44 g, 36 mmol) in anhydrous DMF (30 mL) was added dropwise a solution of 4-hydroxy-3-methylacetophenone (4.5 g, 30 mmol) in dry DMF (20 mL) at 0° C. over a period of 20 minutes. After addition, the mixture was stirred at 0° C. for 30 minutes and iodomethane (2.2 mL, 36 mmol) was added in one portion. The mixture was then stirred at approximately 25° C. overnight. Water was added (10 mL) and the mixture was extracted with ether three times. The combined organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and dried under vacuum to give crude product as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].C(N(C(C)C)C(C)C)C>ClCCl>[Br:1][C:2]1[S:6][C:5]([CH2:7][NH:8][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([F:9])([F:21])[F:22])(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)s1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCc1ccc(Br)s1)c1ccccc1C(F)(F)F
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a stirred suspension of 1-(5-bromo-2-thienyl)-methanamine (0.5 g) in dichloromethane (8 mL) were added 2-(trifluoromethyl)-benzenesulfonyl chloride (0.67 g) and N-ethyl-diisopropylamine (0.37 g) at 0° C. After stirring for 10 min, the ice bath was removed and the mixture was stirred for 40 min. The reaction mixture was diluted with dichloromethane and washed with 0.5 M HCl and with water. The organic phase was dried (MgSO4), filtered and concentrated. The residue was suspended in cyclohexane. The solid was collected by filtration and dried to give N-(5-bromo-thiophen-2-ylmethyl)-2-trifluoromethyl-benzenesulfonamide (0.596 g) as a colorless solid. MS: 417.1 ([M+NH4]+)
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]1[CH2:40][C:39]2=[CH:41][CH:42]=[C:36]([CH:37]=[CH:38]2)[O:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][C@H:28]([CH:43]([CH3:45])[CH3:44])[NH:27][C:26]1=[O:46])=[O:23])[C:14]([O:16]C(C)(C)C)=[O:15])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]1[CH2:40][C:39]2=[CH:38][CH:37]=[C:36]([CH:42]=[CH:41]2)[O:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:29][C@H:28]([CH:43]([CH3:44])[CH3:45])[NH:27][C:26]1=[O:46])=[O:23])[C:14]([OH:16])=[O:15]
Reactant: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCN)C(=O)O)C(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
0.71 g (1.10 mmol) of tert-butyl (S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)ureido]hexanoate was dissolved in 11 ml of dichloromethane, and the same volume of trifluoroacetic acid was added. Stirring at RT for 4 h was followed by concentration and fractionation of the residue by preparative HPLC. The required fractions were combined and, after evaporation of acetonitrile, mixed with dilute hydrochloric acid, concentrated further and finally freeze dried. 0.42 g of the title compound was obtained as hydrochloride.
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:28][C:29]([O:31][CH2:32][C:33]12[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][CH:35]([CH2:36]3)[CH2:34]1)[CH2:40]2)=[O:30])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:15][CH:16]=1)=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:33]12([CH2:32][O:31][C:29]([NH:28][C@@H:7]([CH2:8][NH:9][C:10]([C:12]3[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]4[NH:22][CH2:23][CH2:24][CH2:25][N:26]=4)=[CH:15][CH:16]=3)=[O:11])[C:6]([OH:43])=[O:5])=[O:30])[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][CH:35]([CH2:36]3)[CH2:34]1)[CH2:40]2
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)O)s1)NC1=NCCCN1

Procedure:
117 mg (0.19 mmol) of the product obtained in step c) were dissolved in 5 ml of dichloromethane and stirred for 3 hours with 1 ml of trifluoroacetic acid under an inert gas atmosphere at room temperature. The solvents were removed in vacuo, and the residue was dissolved in acetic acid and again evaporated to dryness. This procedure was repeated once. The resinous residue was triturated with diethyl ether. After filtration 90 mg of a colourless amorphous powder were obtained.