Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[N:15]=[CH:14][C:13]3[NH:16]/[C:17](=[N:25]\[C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)/[N:18]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:12]=3[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>CN(C=O)C.O.C(Cl)Cl>[CH2:34]([S:36]([N:22]1[CH2:21][CH2:20][CH:19]([N:18]2[C:12]3[CH:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[N:15]=[CH:14][C:13]=3[NH:16]/[C:17]/2=[N:25]\[C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:23]1)(=[O:38])=[O:37])[CH3:35]
Reactant: CCS(=O)(=O)Cl
Reactant: O=C(/N=c1\[nH]c2cnc(OCCN3CCCCC3)cc2n1C1CCNCC1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(n2/c(=N/C(=O)c3ccccc3)[nH]c3cnc(OCCN4CCCCC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12.4 %

Procedure:
A suspension of (E)-N-(6-(2-(piperidin-1-yl)ethoxy)-1-(piperidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide (0.10 g, 0.223 mmol) in DMF (1.12 mL) was cooled to 0° C. under nitrogen atmosphere. To this mixture was added TEA (0.045 g, 0.446 mmol) followed by ethanesulfonyl chloride (0.043 g, 0.334 mmol). The resulting mixture was stirred for 30 minutes and diluted with water (10 mL) and DCM (20 mL). The organic layer was collected and concentrated to yield a brown residue. The residue was purified by HPLC (10-70% ACN/H2O; 0.1% TFA) to afford (E)-N-(1-(1-(ethylsulfonyl)piperidin-4-yl)-6-(2-(piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide as an off-white solid (15 mg, 12.4%). MS m/z=541.2 [M+H]. Calc'd for C27H36N6O4S: 540.3.
Reaction SMILES: CO[CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9]CCN)[CH2:5][CH2:4]1.C[O:14]C1C=CC(CCCN)=CC=1.C1(C[CH2:32][CH2:33][NH2:34])CCCCC1>O1CCOCC1>[CH:6]1([CH2:9][O:14][CH2:32][CH2:33][NH2:34])[CH2:5][CH2:4][CH2:3][CH2:8][CH2:7]1
Reactant: NCCCC1CCCCC1
Reactant: COc1ccc(CCCN)cc1
Reactant: COC1CCC(CCCN)CC1
Solvent: C1COCCO1
Product: NCCOCC1CCCCC1

Procedure:
[(cis) and (trans)]-3-(4-Methoxycyclohexyl)-propylamine: A solution of 1.18 g (7.1 mmol) 3-(4-methoxy-phenyl)propylamine in 50 mL of dioxane was hydrogenated at 138 bar and at 160° C. for 16 h in the presence of 0.5 g of 5% Ru/Al2O3. The catalyst was removed by filtration and the filtrate was concentrated to dryness. Preparative HPLC of the crude product by elution with 10% (10% concd NH4OH in MeOH)--CH2Cl2 furnished 723.5 mg (59%) of the cis/trans mixture of cyclohexylpropylamine (c/t=~3:1 by 1H NMR): 1H NMR (CDCl3, cis-isomer only) δ3.37 (br s, 1H), 3.27 (s, 3H), 2.64 (t, J=7.0 Hz, 2H), 2.10-0.87 (M, 15H); FDMS 172 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:18][CH3:19])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].O.[NH2:21][NH2:22]>C(O)C>[CH2:1]([C:3]1[C:4]([O:18][CH3:19])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([NH:21][NH2:22])=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCOC(=O)c1cn2c(C)c(CC)c(OC)nc2n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCc1c(OC)nc2nc(C(=O)NN)cn2c1C
Yield: 86 %

Procedure:
A solution of 10.0 g of ethyl 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxylate (published UK Patent Application No. 2,128,989) and 20 ml of hydrazine hydrate in 150 ml of ethanol was refluxed for 4 hours. Most of the ethanol was evaporated and 100 ml of water were added. The resulting precipitate was filtered, washed with water, then ether and dried under vacuum over P2O5 to obtain 8.15 g of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carbohydrazide (86% yield) as an off-white solid.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH2:17][OH:18].[C:19]([N:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[OH:18][CH2:17][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:2]=1[C:29]1[CH2:30][CH2:31][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: OCc1nc2c(N3CCOCC3)ccnn2c1Br
Product: CC(C)(C)OC(=O)N1CC=C(c2c(CO)nc3c(N4CCOCC4)ccnn23)CC1

Procedure:
Compound 14a (2.5 g, 8.0 mmol) was subjected to Suzuki coupling conditions with N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester as described in Example 38, Step A to obtain compound 41a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H29N5O4: 416.2 (M+H). found: 416.2.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:23]=1[C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1>ClCCl.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:30][C:20]2[CH:21]=[CH:22][C:23]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)=[C:18]([O:17][CH3:16])[CH:19]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N)ccc1-c1cnn(C)c1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-c1cnn(C)c1
Yield: 22.2 %

Procedure:
The title compound was prepared from 4-benzyl-2-chloro-6-methyl-pyrimidine (119 mg, 0.54 mmol) and 3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-phenylamine (100 mg, 0.49 mmol) using in analogous manner the procedure described in example 206c). Column chromatography (25 g silica, dichloromethane/ethyl acetate 0-25% v/v) afforded the title compound (42 mg, 22%) as a light yellow viscous oil. MS ISP (m/e): 386.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.82 (s, 1H), 7.76 (m, 2H), 7.39 (d, 1H), 7.29 (m, 5H), 7.08 (s, 1H), 6.98 (dd, 1H), 6.44 (s, 1H), 3.96 (s, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](NC)=[O:8])=[CH:5][CH:4]=1.C([Li])(CC)C.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCCCCC.C(OCC)(=[O:34])C>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[C:7](=[O:34])[O:8][CH:18]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(C)=O
Reactant: CNC(=O)c1ccc(OC)cc1
Reactant: O=Cc1ccccc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2c(c1)C(c1ccccc1)OC2=O
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
A solution of 8 (15 g, 91 mmol) in THF was cooled to −70° C. under Argon. To this was added sec-butyllithium (147 mL, 1.3M). After stirring 0.5 h a tan suspension resulted. Added benzaldehyde (9.2 mL, 91 mmol.) and stirred 1 h. Quenched with ice then removed THF in vacuo. Added sat. sodium bicarbonate and extracted with ethyl acetate (4×). Dried the combined organic portions with sodium sulfate (anh.) and removed the solvent in vacuo. Added toluene and heated to reflux for 18 h. Removal of the solvent in vacuo followed by trituration with hexane/ether gave unreacted starting material 8 (4.63 g). Concentration of the filtrate in vacuo followed by flash column chromatography (hexane:ethyl acetate 80:20) gave 9 as a yellow solid (12.0 g, 50.1 mmol, 55.1%)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][OH:5].Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18]Cl)[CH:13]=1.Cl[C:21]([N:23]1[C@H:28]([CH3:29])[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C@@H:24]1[CH3:37])=[O:22]>>[CH3:37][C@H:24]1[CH2:25][NH:26][CH2:27][C@@H:28]([CH3:29])[N:23]1[C:21]([O:5][CH2:4][C:3]1[CH:6]=[C:7]([O:10][CH2:18][C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:9][C:2]=1[F:1])=[O:22]
Reactant: OCc1cc(O)ccc1F
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: ClCc1cccnc1
Agent: Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1cc(OCc2cccnc2)ccc1F

Procedure:
2-Fluoro-5-(3-pyridylmethyl)oxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 3-pyridylmethyl chloride hydrochloride and 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 54 and 121 to give the product as a yellow oil (5.4%); HPLC (XTERRA, 50/80, 220 nm) 91% (1.64 min); δH (400 MHz, DMSO-d6) 1.172 (6H, d, J 7.0 Hz), 2.673 (4H, m), 3.294 (3H, s), 3.900 (2H, m), 5.075 (2H, s), 5.138 (2H, s), 7.052 (2H, m), 7.172 (1H, t, J 9.0 Hz), 7.424 (1H, m), 7.849 (1H, m), 8.546 (1H, m) and 8.654 (1H, m).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:17][O-:18].[Na+].Cl>CO>[Cl:8][C:6]1[N:7]=[C:2]([O:18][CH3:17])[C:3](=[O:16])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: C[O-]
Reactant: O=c1c(Cl)nc(Cl)cn1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)cn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
3,5-dichloro-1-(4-fluorophenyl)pyrazin-2(1H)-one (13.0 g, 50.2 mmol; prepared by according to the general methods described by M. Tutonda, et al., Tetrahedron, 1990, 46, 5715) dissolved in absolute methanol (100 mL) was treated with NaOMe (6.78 g, 125 mmol). The reaction mixture was stirred at room temperature for 1 hour, neutralized with 2 N HCl (Et2O solution), and evaporated the solvent under reduced pressure. The residue was treated with EtOAc, washed with 0.5 N HCl, dried over MgSO4, and concentrated under reduced pressure to give the desired product (12.8 g, 100%). LRMS (ESI pos) m/e 254.9, 256.9 (M+1, Cl pattern).
Reaction SMILES: [CH:1]1([C:7](=O)[CH2:8][CH2:9][CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][NH:13][CH2:14][C:15]([OH:17])=[O:16].S1C=CC=C1.C([O-])(=O)C.[K+].[H][H]>CO.[Pd]>[CH3:12][N:13]([CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:8][CH2:9][CH3:10])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: CNCC(=O)O
Reactant: [H][H]
Reactant: CCCC(=O)C1CCCCC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: c1ccsc1
Product: CCCC(C1CCCCC1)N(C)CC(=O)O
Yield: 22.4 %

Procedure:
A mixture of 130 parts of 1-cyclohexyl-1-butanone, 225 parts of methyl glycine, 2 parts of a solution of thiophene in methanol 4%, 960 parts of methanol and 200 parts of potassium acetate was hydrogenated overnight in a Parr apparatus with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in water and 1,1'-oxybisethane. The whole was extracted with a hydrochloric acid solution 10%. The aqueous layer was treated with a sodium hydroxide solution and the product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated, yielding 46 parts (22.4%) of methyl N-(1-cyclohexylbutyl)glycine as a residue (int. 3).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([C:8]2[NH:9][CH2:10][CH2:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1>CN(C)C=O.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C2=NCCN2)c1[N+](=O)[O-]
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ncc[nH]2)c1[N+](=O)[O-]
Temperature: 120 °C
Yield: 28.8 %

Procedure:
To a solution of the title compound of Example 1, Step A (0.35 g, 1.71 mmol) in dimethylformamide (20 mL) was added activated manganese dioxide (4.46 g, 51.3 mmol) and the mixture was heated at 120° C. for 2 hours. After cooling, the mixture was diluted with ethyl acetate, filtered through a pad of Celite® and washed three times with water and once with a saturated solution of sodium chloride. The organic phase was dried (magnesium sulfate), concentrated and purified by flash column chromatography (silica gel, 60% then 80% ethyl ether in hexanes then ethyl ether) to give the title compound of Step A (0.1 g) as a white solid.
Reaction SMILES: [N:1]#[C:2][NH2:3].[F:4][C:5]1[CH:6]=[C:7]([N:18]2[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]2=[O:28])[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.C1C=CC=CC=1>O>[C:2]([N:3]=[C:14]1[CH2:15][CH2:16][N:11]([C:10]2[CH:9]=[CH:8][C:7]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:6][C:5]=2[F:4])[CH2:12][CH2:13]1)#[N:1]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: N#CN
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=NC#N)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
Cyanamide (601 mg) and 500 mg of the (S)-N-{3-[3-fluoro-4-(4-oxo-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (Compound No. 7) which was synthesized in Example 3 were added to benzene (70 ml), and the mixture was heated under reflux for 2 h, with water being removed continuously by means of a water separator. The reaction mixture was cooled to room temperature and the resulting crystal was collected by filtration. After being washed with water, the crystal was dried overnight at 40° C. under vacuum to afford the title compound (423 mg) in a yield of 79%.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].IC.[C:19](=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH3:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:14])[F:15])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:19])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)O)cnc1OCC(F)(F)F
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cnc(OCC(F)(F)F)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A mixture of 5-methyl-6-(2,2,2-trifluoroethoxy)nicotinic acid (3.08 g, 13.1 mmol, Step-1 of Amine-2), iodomethane (0.983 ml, 15.72 mmol) and potassium carbonate (5.43 g, 39.3 mmol) in DMA (40 ml) is stirred at rt for 2 hours. The reaction mixture is poured into water (200 mL) and extracted with n-hexane/EtOAc (1:10, 500 mL). The organic layer is washed with 2M hydrochloric acid (300 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (5:1) to give 2.87 g (88% yield) of the title compound as white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1.[Br:20][Si](C)(C)C>C(Cl)Cl>[Br:20][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([O:18][CH3:19])=[O:17])=[CH:5][CH:4]=1
Reactant: COC(=O)Nc1ccccc1-c1ccc(CO)cc1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: COC(=O)Nc1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
A solution of 4-hydroxymethyl-2'-(methoxycarbonyl)amino-1,1'-biphenyl (239 mg, 0.93 mmol) in methylene chloride (4 mL) was treated with bromotrimethylsilane (3.0 mL, 22.7 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with additional methylene chloride and washed with saturated aqueous sodium chloride. After drying over magnesium sulfate, the filtered organic layer was evaporated under vacuum The residue was purified by preparative thin layer chromatography on silica gel, eluting with methylene chloride-methanol (100:3) to give 190 mg of the product.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5]=2[NH:4][N:3]=1.[CH2:23](Cl)[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>C(#N)C>[CH2:16]([N:6]1[C:5]2=[N:4][N:3]3[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:1][C:2]3=[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7]1=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: CCCn1c(=O)c2c(N)n[nH]c2n(Cc2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1c(=O)c2c(nn3cc(-c4ccccc4)[nH]c23)n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.2 %

Procedure:
A suspension of 3-amino-7-benzyl-5-propylpyrazolo [3,4-d]pyrimidine-4,6(5H,7H)-dione (2.0 g), phenacyl chloride (4.4 g), K2CO3 (2.5 g) and potassium iodide (1.4 g) in acetonitrile (150 ml) was stirred for 3 days at room temperature. Precipitating crystals were collected by filtration and washed with water. The filtrate was concentrated to give a syrup. The syrup was crystallized by the addition of isopropyl ether. The crystals were combined and dissolved in toluene (200 ml). To the solution was added p-toluenesulfonic acid (0.1 g), followed by heating for 3 hours under reflux. The reaction mixture was concentrated to dryness and then was added isopropyl ether to give crude crystals, followed by recrystallization from methanol to afford colorless crystals (1.1 g, 43%), m.p. 261°-262° C.
Reaction SMILES: [C:1]([O:5]C([N:8]1C[C@@H](C=O)[C@H](CN(C(=O)C2C=CC(C)=[C:23]([O:28][CH2:29][CH2:30]COC)[CH:22]=2)C(C)C)C1)=O)(C)(C)C.CN.C[OH:38].[BH4-].[Na+]>CCOC(C)=O.CO>[CH3:30][CH2:29][O:28][C:23]([CH3:22])=[O:38].[CH3:1][OH:5].[NH4+:8].[OH-:5]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1C
Agent: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: [NH4+]
Product: [OH-]

Procedure:
In a similar manner as described in Example 9 for the reaction step J, the following starting materials is prepared from (3R,4S)-3-({[4-methyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared under C in example 190) (2 g, 4.2 mmol), 2N solution of methylamine in MeOH (10.5 mL, 21 mmol) and NaBH4 (0.318 g, 8.40 mmol) and purification by flash chromatography on silica gel (AcOEt/MeOH 90:10, then AcOEt/MeOH/NH4OH 89:10:1) to give a colorless oil. MS: 492.1 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2](NC)[C@H:3](O)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.S(=O)(=O)([O-])N.[NH4+].[NH2:19][C:20]([NH2:22])=[O:21].[CH3:23]N1C(=O)CCC1>O>[CH3:23][N:19]1[CH:2]([CH3:1])[CH:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:22][C:20]1=[O:21]
Reactant: CN1CCCC1=O
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Reactant: NC(N)=O
Agent: NS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CC1C(c2ccccc2)NC(=O)N1C
Temperature: 177.5 °C
Reaction time: 2.5 h

Procedure:
1 mol of an ephedrine, 1.025 mol of ammonium sulfamate, 3 mol of urea and the proton-donating compound were introduced into 200 ml of NMP. The reaction mixture was heated to 175 to 180° C. and stirred at this temperature for 2.5 h. It was then cooled to 130° C. and, at this temperature, water was added dropwise to the reaction mixture. Two phases formed. The lower phase was removed at 95° C. The upper phase was further cooled initially to 65° C. Crystals formed at this temperature. It was cooled further to 10° C. and stirred at this temperature for 1 h. The crystals were filtered off with suction and washed twice with cold water. The solid was dried in vacuo at RT overnight.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][C:3]=1[F:19].[ClH:20].O1CCOCC1>C(OCC)(=O)C.C(OCC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][C:3]=1[F:19].[ClH:20]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(F)c(Br)cc2C1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1cc2c(cc1Br)CNCC2

Procedure:
tert-Butyl 7-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.272 g, 1.0 mmol) in ethyl acetate (1 mL) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (1.0 mL, 4.0 mmol) at r.t. for 2 h. The mixture was diluted with ethyl ether, and centrifugalized. The solvents were decanted. The residue was dried in-vacuo to afford the desired product as HCl salt which was directly used in next step reaction without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]1[O:18][CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:15]1[CH2:16][CH2:17][O:18][CH:14]1[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: ClCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NCC1OCCO1
Reaction time: 18 h

Procedure:
2,6-Diethylaniline (75 grams; 0.5 mole), 2-chloromethyl-1,3-dioxolane (25 grams; 0.2 mole), potassium carbonate (22 grams; 0.2 mole) and dimethylformamide (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated, with stirring, for a period of about 18 hours. After this time the reaction mixture was filtered and then distilled to yield the desired product N-(1,3-dioxolan-2-ylmethyl)-2,6-diethylaniline.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19])=[O:24]
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (250 mg, 0.93 mmol) was suspended in methylene chloride (10 ml) and treated with o-chlorobenzoylchloride (0.124 ml, 0.97 mmol) followed by triethylamine (0.143 ml, 0.97 mmol). The solution was stirred at room temperature overnight. The reaction solution was chromatographed on silica gel (chloroform followed by 97/3 chloroform/methanol) and the combined product fractions were evaporated to dryness in vacuo. TLC: Silica gel (90:10:1, CHCl3 :CH3OH:H2O), Rf =0.85.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2)([OH:3])=O.[Cl:14][C:15]1[CH:16]=[C:17]([NH2:23])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([NH:23][C:1]([C:4]2[C:5]3[CH2:6][C:7](=[O:13])[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)=[O:3])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(N)cc1Cl
Reactant: O=C1Cc2c(cccc2C(=O)O)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc3c2CC(=O)N3)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-carboxy-2-oxindole (200 mg, 1.13 mmol) and 3-chloro-4-methoxyphenylamine (178 mg, 1.13 mmol) in dimethylformamide (15 mL) at room temperature was added benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 997 mg, 2.26 mmol) followed by 4-dimethylaminopyridine (206 mg, 1.69 mmol). The mixture was stirred at room temperature for 72 hours. The reaction was then diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate (100 mL), water, 2N hydrochloric acid (100 mL), water (3×200 mL) and brine. It was then dried over magnesium sulfate and concentrated. The residue was triturated with ethyl acetate to give 2-oxo-2,3-dihydro-1H-indole-4-carboxylic acid (3-chloro-4-methoxyphenyl)-amide as a pink solid.