Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.[CH:18]1([NH:21][C:22](=[O:50])[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][C:24]=2[OH:49])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:18]1([NH:21][C:22](=[O:50])[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[CH:25][C:24]=2[O:49][CH2:4][C@@H:2]2[CH2:3][O:1]2)[CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: O=C(NC1CC1)c1ccc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A mixture of (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (119 mg, 0.459 mmol), N-cyclopropyl-2-hydroxy-4-(trityloxy)benzamide (200 mg, 0.459 mmol) and cesium carbonate, Cs2CO3, (186.2 mg, 0.573 mmol) in dimethylformamide (3 mL) was kept on stirring at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, Na2SO4, filtered, concentrated and the residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum ether) to give the subtitled compound (160 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]SC.COS(OC)(=O)=O>FC(F)(F)C(O)=O.CO.[Zn]>[NH2:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CSCc1ccnc(Cl)c1N
Agent: [Zn]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: COS(=O)(=O)OC
Product: Cc1ccnc(Cl)c1N
Reaction time: 68 h

Procedure:
3-amino-2-chloro-4-methylthiomethylpyridine prepared above in B (90.2 mg, 0.48 mmoles) was dissolved in trifluoroacetic acid (450 μl). To the resulting solution was added dimethylsulfate (57.1 mg, 0.452 mmoles) at ambient temperature and allowed to stand at ambient temperature for 68 hours, to produce an alkylation solution. A proton NMR spectrum of the alkylation solution revealed that complete alkylation had ocurred. The alkylation solution was then evaporated to dryness and the resultant residue was twice dissolved in methanol and evaporated to dryness, to produce an amber oil weighing 306.8 mg. The oil was dissolved in methanol (500 μl) and stirred in an atmosphere of nitrogen at ambient temperature while zinc dust (63 mg, 0.98 mmoles) was added portionwise over two hours. After complete addition of the zinc dust, the resultant mixture was allowed to continue stirring for 21 hours. An aliquot of the mixture was then removed for analysis by thin layer chromatography (silica gel; 3% methanol/dichloromethane as eluant) which revealed highly selective conversion to 3-amino-2-chloro-4-methylpyridine had occurred. The mixture was then filtered and the filtrate was concentrated to produce a dry residue. The residue was partitioned between ether and water (2 ml each). The layers were separated and the aqueous phase was extracted three additional times with 2 ml portions of ether. The ethereal extracts were combined and dried with anhydrous sodium sulfate, filtered and concentrated at reduced pressure to give 3-amino-2-chloro-4-methylpyridine as an oil weighing 66.6 mg. The oil solidified on standing. Product identity is confirmed by comparison of its proton NMR and TLC chromatographic properties (5% ethylacetate/dichloromethane, R =0.45; 3% methanol/dichloromethane, R =0.70) with those of an authentic sample.
Reaction SMILES: BrC1C=C([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)C=CC=1.C(S(C1C=CC(OC)=C(C=1)N)(=O)=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:30][C:10]1[N:9]=[CH:8][N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CCS(=O)(=O)c1ccc(OC)c(N)c1
Solvent: C1COCCO1
Product: COc1cc(Nc2ncc3c(C)ncn3n2)cc(OC)c1OC
Temperature: 130 °C
Yield: 59.5 %

Procedure:
To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (49.1 mg, 0.104 mmol), 5-(ethylsulfonyl)-2-methoxyaniline (22.5 mg, 0.104 mmol), 2-(dit-butylphosphino)biphenyl (16.3 mg, 0.054 mmol), Tris(dibenzylidineacetone)dipalladium (0) (16.6 mg, 0.018 mmol) and sodium t-butoxide (26.0 mg, 0.28 mmol) was added 1,4-dioxane (1.0 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 130° C. for 50 minutes. After cooling to room temperature, removed solvent under reduced pressure and diluted residue in dichloromethane. Filtered and added silica gel (500 mg) to filtrate followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (25:75) to ethyl acetate:hexanes (95:5) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 7-(3-{[5-ethylsulfonyl)-2-methoxyphenyl]amino}phenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo-[5,1-f][1,2,4]triazin-2-amine (0.0195 g) as a yellow solid. 1H NMR (CDCl3): δ8.82 (s, 1H), 8.39 (s, 1H), 8.17 (d, J=7.7 Hz, 1H), 7.82 (s, 1H), 7.42-7.19 (m, 4H), 6.97 (d, J=7.3 Hz, 1H), 6.88 (s, 2H), 6.45 (s, 1H) 4.00 (s, 3H) 3.84 (s, 9H), 3.06 (d, J=6.6 Hz, 2H), 2.60 (s, 3H), 1.25 (m, 3H). MS m/z 605 (M+1).
Reaction SMILES: Cl.[CH:2]1([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:16](=O)([O:22]C(C)(C)C)[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:18]([O:17][C:16]([N:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:9][CH2:8][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)CCNCCC1CCCCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCC(=O)O)CCC1CCCCC1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
Next, tetrahydrofuran (8 ml) was added to 3-[N-(2-cyclohexylethyl)amino]propionic acid hydrochloride (1.0 g, 4.2 mmol), and the mixture was stirred at room temperature. Di-t-butyl carbonate (1.1 g, 5.1 mmol) and triethylamine (1.3 ml, 9.3 mmol) were added to the mixture, the whole was stirred overnight, and then a 5% aqueous citric acid solution (10 ml) was added to the reaction mixture. The whole was extracted with chloroform (60 ml), and the organic layer was washed with saturated brine (20 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 0.79 g (62%) of 3-[N-(t-butoxycarbonyl)-N-(2-cyclohexylethyl)amino]propionic acid as a colorless oily matter.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1.[CH:17]([C:20]([N:23]=[C:24]=[O:25])(C)[CH3:21])(C)C>>[CH:20]([NH:23][C:24](=[O:25])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1])=[CH:7][CH:8]=1)([CH3:21])[CH3:17]
Reactant: CC(C)=CCOc1ccc(OCCO)cc1
Reactant: CC(C)C(C)(C)N=C=O
Product: CC(C)=CCOc1ccc(OCCOC(=O)NC(C)C)cc1

Procedure:
Following the procedure of Example 9, 2[4-(3-methyl-2-butenoxy)phenoxy]ethanol and isopropyl isopropyl isocyanate are reacted together to give O-2-[4-(3-methyl-2-butenoxy)phenoxy]ethyl N-isopropylcarbamate, MS, m/e 307 (M+).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:12]1[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13]1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O.[Cl:36][CH2:37][CH2:38][N:39]=[C:40]=[O:41]>C1COCC1>[Cl:36][CH2:37][CH2:38][NH:39][C:40]([NH:17][C@H:14]1[CH2:15][CH2:16][O:12][CH2:13]1)=[O:41]
Reactant: O=C=NCCCl
Reactant: N[C@H]1CCOC1
Agent: CC[NH+](CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: O=C(NCCCl)N[C@H]1CCOC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
A solution of (S)-(−)-tetrahydro-3-furylamine p-toluenesulfonate salt (0.5 g, 1.928 mmol) in THF (20 mL) was gently agitated with MP-Carbonate Resin (1.825 g, 5.78 mmol, 3.17 mmol/g loading) for 36 h, the resin removed via filtration and the filtrate cooled to 0° C., treated drop-wise with chloroethyl isocyanate (0.224 g, 2.121 mmol), warmed to RT and stirred overnight. The mixture was washed with satd. NH4Cl (1×), satd. NaHCO3 (1×), then brine (1×), dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford (S)-1-(2-chloroethyl)-3-(tetrahydrofuran-3-yl)urea (0.11 g, 30%). 1H NMR (400 MHz, DMSO-d6): δ 6.31 (d, J=6.9 Hz, 1 H), 6.01 (t, J=5.9 Hz, 1 H), 4.11-4.08 (m, 1 H), 3.69-3.67 (m, 3 H), 3.55 (t, J=6.2 Hz, 2 H), 3.36 (dd, J=8.8, 3.8 Hz, 1 H), 3.32-3.26 (m, 2 H), 2.03 (dq, J=12.6, 7.6 Hz, 1 H), 1.59-1.61 (m, 1 H); MS (ESI) m/z: 193.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[N+:19]([O-])=O)=[O:9])[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[NH:11][C:10]([C:8]([N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)=[O:9])=[CH:18]2
Reactant: CN1CCN(C(=O)c2cc3cccc([N+](=O)[O-])c3[nH]2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CN1CCN(C(=O)c2cc3cccc(N)c3[nH]2)CC1
Yield: 76.7 %

Procedure:
The product of Example 8, (4-Methyl-piperazin-1-yl)-(7-nitro-1H-indol-2-yl)-methanone (6.4 g, 22.2 mmol), was dissolved in CH3OH (110 mL). At room temperature, ammonium formate (14.0 g, 222 mmol) was added, followed by 10% palladium on carbon (2.4 g, 2.22 mmol). The reaction mixture was heated to reflux for forty min, cooled, and then filtered through a celite pad. The filtrate was concentrated, and the residue was purified via silica gel chromatography (3-10% 2 M ammonia in methanol/dichloromethane) to give the title compound (4.4 g, 76.7%) as an off-white solid. 1H NMR (400 MHz, CDCl3/CD3OD): δ 7.08 (d, J=7.83 Hz, 1H), 6.94 (t, J=7.83 Hz, 1H), 6.73 (s, 1H), 6.58 (d, J=7.63 Hz, 1H), 4.12 (s, 2H), 3.92 (br s, 4H), 2.51 (br s, 4H), 2.34 (s, 3H). MS (electrospray): exact mass calculated for C14H18N4O, 258.15; m/z found, 259.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N:10](C)C)[C:5]([N+]([O-])=O)=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])=O.[NH4+]>[Pd].CO.C(Cl)Cl>[N:16]1([C:4]2[CH:5]=[C:6]3[CH:8]=[CH:9][NH:10][C:7]3=[CH:2][N:3]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: CN(C)C=Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: c1cc2cc(N3CCOCC3)ncc2[nH]1
Temperature: 65 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
A solution of 450 mg (2 mmol) of [2-(2-chloro-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine in a 20 mL of mixed solvent of MeOH-CH2Cl2 (1:1) was treated with 3 mL of morpholine. The reaction mixture was stirred at 65° C. for 8 h. Volatiles were then removed. CH2Cl2 (100 mL) and H2O (30 mL) were added. The organic layer was separated and washed with H2O (30 mL), brine (30 mL), dried over Na2SO4, and concentrated. The red powder was treated with 4.0 g (63 mmol, 32 eq) of ammonium formate and 10% Pd-C (120 mg). The reaction mixture was stirred at 65° C. for 30 min. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a yellow solid. Column chromatography (silica, 5% MeOH/CH2Cl2) provided 210 mg (52% for 2 steps) of 5-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridine as a yellow solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.40. MS (electrospray): exact mass calculated for C11H13N3O, 203.11; m/z found, 204.2 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([NH:15][C:16]1[CH:28]=[C:27](I)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:30]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:7]([NH:15][C:16]1[CH:28]=[C:27]([NH:39][CH2:38][CH2:37][CH2:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(I)cc1NC(=O)c1ccccc1
Reactant: NCCCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(NCCCc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
53 mg of tris(dibenzylideneacetone)dipalladium(0) and 0.17 g sodium tert-butoxide were added to 5 mL of toluene solution containing 0.50 g of tert-butyl 2-(benzamido)-4-iodobenzoate, 0.25 mL of 3-phenylpropylamine and 36 mg of rac-2,2′-bis(diphenylphosphino)-1,1-binaphthyl at room temperature and stirred at 80° C. for 7 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=6:1] to obtain 0.11 g of tert-butyl 2-(benzamido)-4-(3-phenylpropylamino)benzoate as brown oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:31]=[CH:30][N:29](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1.[OH-].[K+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:31]=[CH:30][NH:29][C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(=O)N(C)c1ccc(Nc2nc(Nc3ccc4cn[nH]c4c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N(C)c1ccc(Nc2nc(Nc3ccc4cn[nH]c4c3)c3cc[nH]c3n2)cc1
Temperature: 60 °C
Yield: 60.6 %

Procedure:
To a solution of N-(4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (45 mg, 0.080 mmol) in methanol (MeOH) (3 mL), aq. 1N potassium hydroxide (KOH) (0.50 mL, 0.50 mmol) was added. The mixture was then heated at 60° C. for 4 h before it was concentrated in vacuo. The residue was then acidified with acetic acid (HOAc) (0.5 mL) before being purified by HPLC to give the title compound (20 mg). MS 413.1 (M+H) (Compound 6-1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13]([C:15]2([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][CH2:16]2)=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>C(Cl)(Cl)Cl>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:15]1([C:13]2[C:5]3[C:4](=[CH:3][C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=3)[CH2:10][CH2:11][N:12]=2)[CH2:17][CH2:16]1
Reactant: COc1ccc(CCNC(=O)C2(c3ccc(Cl)cc3Cl)CC2)cc1F
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1F)CCN=C2C1(c2ccc(Cl)cc2Cl)CC1

Procedure:
A mixture of N-[2-(3-fluoro-4-methoxyphenyl)ethyl]-1-(2,4-dichlorophenyl)cyclopropanecarboxamide (19.7 g, prepared in a similar manner to that described in Example E4), 52% polyphosphate ester in chloroform (200 g) was heated under reflux for 52 hours, then cooled and poured onto ice. The organic layer was separated, the aqueous layer extracted with dichloromethane and the combined organic layers were basified by addition of aqueous ammonia solution, washed with brine, dried over magnesium sulphate and filtered. The solvent was removed in vacuo to yield a solid which was triturated with petroleum ether (b.p. 40°-60° C.) and propan-2-ol. The solid was collected by filtration and dried to yield 1-[1-(2,4-dichlorophenyl)cyclopropyl]-6-fluoro-7-methoxy-3,4-dihydroisoquinoline (10.3 g), m.p. 151°-154° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:16]([O:18][C:19]([CH2:21][N:22]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25][C:24](=O)[C:23]1=[O:34])=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([CH2:21][N:22]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH2:26][CH2:25][CH:24]([NH:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:23]1=[O:34])=[O:20])[CH3:17]
Reactant: CCOC(=O)C(N)CCc1ccccc1
Reactant: CCOC(=O)CN1C(=O)C(=O)CCc2ccccc21
Product: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCC)CCc2ccccc21

Procedure:
Ethyl 2-amino-4-phenylbutyrate is treated under conditions of reductive alkylation as described in the previous examples with 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepine-2,3-dione to give 1-ethoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one of example 10.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[S:11][C:7]=2[CH:6]=1.O.[Cl-].[NH4+]>C(O)C>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[CH:19]=[CH:18][C:8]3[N:9]=[C:10]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[S:11][C:7]=3[CH:6]=2)=[C:2]([F:1])[CH:23]=1
Reactant: O=C(Nc1nc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2s1)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c(F)c1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
To a suspension of N-[6-(2-fluoro-4-nitrophenoxy)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (1.15 g, 3.07 mmol) in ethanol (50 mL)/water (10 mL) were added ammonium chloride (1.64 g, 30.7 mmol) and reduced iron (856 g, 15.3 mmol), and the mixture was heated under reflux for 4 hr. The reaction mixture was cooled to room temperature, filtered through celite, and washed with a mixed solution of ethanol/water. The solvent was evaporated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate/tetrahydrofuran. The combined organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/diisopropyl ether and collected by filtration to give the title compound (644 mg, 61%) as a pale-yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)[C:10](=[O:20])[N:9]3[C:21]4([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[NH:22][C:23](=[O:24])[C:8]=23)[CH2:3][CH2:2]1.[OH-].[NH4+].[H][H]>CO.O1CCCC1.[Pd].ClCCl>[N:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]2[C:10](=[O:20])[N:9]3[C:21]4([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[NH:22][C:23](=[O:24])[C:8]3=[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:12]=2)=[N:15][CH:16]=1
Reactant: O=C1NC2(CCCCC2)n2c1c(C1=CCOCC1)cc(Nc1ccncn1)c2=O
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NC2(CCCCC2)n2c1c(C1CCOCC1)cc(Nc1ccncn1)c2=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A double neck round bottom flask was charged with 8′-(3,6-dihydro-2H-pyran-4-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (3, 0.22 g, 0.57 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL). Palladium on carbon (0.10 g) was added followed by ammonium hydroxide (1.0 mL) under nitrogen atmosphere. The reaction was filled with hydrogen and stirred at room temperature for 3 d. After completion of reaction monitored by TLC and LCMS, the reaction mass was diluted with 5% methanol in dichloromethane (100 mL) and passed through celite bed and washed with 10% methanol/dichloromethane (3×50 mL). Solvent was removed under vacuum and crude material was purified by prep HPLC to afford 6′-(pyrimidin-4-ylamino)-8′-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 201) as a white solid. Yield: 0.11 g, 49%; MS (ESI) m/z 396.4 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.16 (6, 1H), 9.40 (s, 1H), 8.85 (s, 1H), 8.81 (s, 1H), 8.38 (d, J=5.88 Hz, 1H), 7.37 (d, J=5.88 Hz, 1H), 4.20 (m, 1H), 3.96 (m, 2H), 3.42 (t, J=11.3 Hz, 2H), 3.01 (m, 2H), 1.70 (m, 9H), 1.58 (m, 2H), 1.22 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@:3]1([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[CH2:9][C@H:8]2[C@@H:4]1[CH:5]=[C:6]([CH:10]([CH3:12])[CH3:11])[CH2:7]2>Cl.C(OCC)(=O)C>[NH2:1][CH2:2][C@@:3]1([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C@H:8]2[C@@H:4]1[CH:5]=[C:6]([CH:10]([CH3:12])[CH3:11])[CH2:7]2
Reactant: CC(C)C1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
Tert-butyl(±)-[(1S,5R,6R)-6-aminomethyl-3-isopropylbicyclo[3.2.0]hept-3-en-6-yl]acetate (2.50 g, 9.0 mmol) was dissolved in a 4 N hydrochloric acid-ethyl acetate solution (25 mL), and the solution was stirred at room temperature for 2 hours. Then, the solvent was distilled off under reduced pressure. The residue was suspended by the addition of dichloromethane. To the suspension, triethylamine was then added dropwise, and the resulting powder was collected by filtration. The obtained powder was washed with dichloromethane to obtain the compound of interest as a white powder (1.01 g, 51%).
Reaction SMILES: OO.[F:3][C:4]([F:24])([F:23])[C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([S:19][CH2:20][CH2:21][CH3:22])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1.C(O)(=[O:27])C>O>[F:24][C:4]([F:23])([F:3])[C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([S:19]([CH2:20][CH2:21][CH3:22])=[O:27])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)O
Reactant: CCCSc1cc(Oc2cccc(C(F)(F)F)c2)ccc1C
Agent: OO
Solvent: O
Product: CCCS(=O)c1cc(Oc2cccc(C(F)(F)F)c2)ccc1C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
Thirty-five percent hydrogen peroxide solution (1.6 g, 0.016 mole) was added at 8°-10° C to a mixture of 4-methyl-3-n-propylthiophenyl 3-trifluoromethylphenyl ether (3.8 g, 0.012 mole) and glacial acetic acid (30 ml). After 5 hr at room temperature, the reaction mixture was poured into water (100 ml) and extracted three times with benzene. The combined organic layers were washed with 5 % sodium carbonate solution, then water and dried over sodium sulfate. Evaporation of the solvent gave 3.8 g (92.5 %) of 4-methyl-3-n-propylsulfinylphenyl 3-trifluoromethylphenyl ether, colorless oil, nD25 1.5350. Anal. Found: C, 59.50; H, 5.11. Calcd. for C17H17F3O2S : C, 59.64; H, 5.01 %.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH:22]=[O:23])=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[OH-].[Na+]>C(O)C>[CH:22]([C:6]1[C:5]([OH:4])=[CH:21][CH:20]=[CH:19][C:7]=1[O:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])=[O:23]
Reactant: CC(=O)Oc1cccc(OCc2ccccc2C(=O)O)c1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1c(O)cccc1OCc1ccccc1C(=O)O

Procedure:
A mixture of methyl and ethyl 2-(2-methyl-4-benzofuranyloxymethyl) benzoates (1.212 g) was dissolved in absolute ethanol (180 ml) and ozonised in an analogous manner so that described in Example 5(B) to give a mixture of methyl and ethyl esters of 2-(3-acetoxy-2-formylphenoxymethyl)benzoic acid, as an oil. This oil was dissolved in 95% ethanol (15 ml) and treated with 1N sodium hydroxide solution (15 ml) in an analogous manner to that described in Example 6 to give 2-(2-formyl-3-hydroxyphenoxymethyl)benzoic acid, m.p. 218°-219.5° C. (Found: C, 65.91; H, 4.50. C15H12O5 required C, 66.17; H, 4.44%).