Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=2[C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[N:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:11])[CH2:2][CH2:3][CH3:4].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>C(OCC)(=O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=2[C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[NH:35][N:34]=[N:33][N:28]=3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)Nc1ccc(-c2ccc(OCC#N)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCc1oc2ccccc2c1C(=O)Nc1ccc(-c2ccc(OCc3nnn[nH]3)cc2)cc1
Reaction time: 5.5 h
Yield: 58.4 %

Procedure:
A mixture of 2-butyl-N-(4′-cyanomethoxy[1,1′-biphenyl]-4-yl)-1-benzofuran-3-carboxamide (400 mg, 0.942 mmol), prepared in the previous step, sodium azide (184 mg, 2.83 mmol) and ammonium chloride (151 mg, 2.83 mmol) was stirred under nitrogen at 100+ C. for 5.5 h. The reaction was diluted with ethyl acetate and extracted with 1 N NaOH. The aqueous layer was separated, extracted one additional time with ethyl acetate and acidified by the addition of 1 N HCl. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound (257 mg, 59%) as a white solid, mp 210-212° C.; MS (APCI) m/z 468 ([M+H]+. Elemental Analysis for C27H25N5O3+0.06 H2O: Calc'd: C, 69.20; H, 5.40; N, 14.94; Found: C, 68.83; H, 5.29; N, 14.98
Reaction SMILES: CO[C:3](=[O:20])[C:4]([NH2:19])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[CH3:21][CH:22]1[CH:27]2[C:28]([CH3:30])([CH3:29])[CH:25]([CH2:26]2)[CH2:24][CH:23]1[CH2:31][N:32]=[C:33]=[S:34]>C(O)C>[N:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:4]2([CH2:5][C:6]3[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=3)[NH:19][C:33](=[S:34])[N:32]([CH2:31][CH:23]3[CH2:24][CH:25]4[CH2:26][CH:27]([C:28]4([CH3:30])[CH3:29])[CH:22]3[CH3:21])[C:3]2=[O:20])=[CH:18][CH:17]=1
Reactant: CC1C(CN=C=S)CC2CC1C2(C)C
Reactant: COC(=O)C(N)(Cc1ccncc1)Cc1ccncc1
Solvent: CCO
Product: CC1C(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=S)CC2CC1C2(C)C
Temperature: 75 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
2-Amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (2.50 g, 9.23 mmol) was dissolved in absolute ethanol (50 ml). To the reaction was added 5.01 g (23.9 mmol) of (+)-3-pinanemethyl isothiocyanate. The reaction was then heated to 75° C. under an atmosphere of dry N2. After stirring for 16 hours, the reaction was subsequently concentrated under vacuum. The resulting oil was chromatographed on silica gel using a gradient of neat ethyl acetate to 5% methanol in ethyl acetate to give 3.32 g (7.41 mmol) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH3:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc([N+](=O)[O-])cc(Cl)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a stirred suspension of 3-chloro-2-hydroxy-5-nitropyridine (25 g, 143 mmol) and K2CO3 (39.6 g, 286 mmol) in DMF (250 ml) under Ar, MeI (13.43 ml, 215 mmol) was added at 0° C. and the reaction mixture was stirred 3 hours at RT. The reaction mixture was concentrated, diluted with 300 ml water and extracted twice with 400 ml EtOAc. The combined organic layers were washed once with 200 ml water, dried (Na2SO4) and evaporated to afford 25.59 g (136 mmol, 95% yield) of the title compound as a yellow solid, which was used in the next steps without further purification. LCMS: (M+H)=189; tR=0.64 min (LC-MS 1). 1H-NMR (d6-DMSO, 400.43 MHz) δ ppm 9.23 (s, 1H) 8.45 (s, 1H) 3.61 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH3:21].CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:21][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:12][CH:11]=2)[N:6]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC(F)(F)F)cc2)nc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1CO

Procedure:
1.54 g (4.95 mmol) of the above synthesized 2-methyl-6-(4-trifluoromethoxy-phenyl)-nicotinic acid methyl ester in 25 ml of abs. THF was cooled down to −20° C. and reacted with 14.84 ml of DIBAL-H-solution (1.0 M in toluene, 3 eq.) for 0.5 h. Careful quenching with ice/HCl dil., twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, hexane/AcOEt=1/1) to deliver finally 0.877 g of the title compound as off-white solid of mp. 68–69° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C@:7]2([C:11](=[O:12])[N:10]([CH3:13])[CH2:9][C@H:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4].[C:32]([O:36][C:37]([NH:39][C:40]([CH3:45])([CH3:44])[C:41](O)=[O:42])=[O:38])([CH3:35])([CH3:34])[CH3:33].C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(#N)C>[CH3:45][C:40]([NH:39][C:37](=[O:38])[O:36][C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:44])[C:41]([NH:1][C@H:2]([CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:3]([N:5]1[CH2:22][CH2:21][CH2:20][C@:7]2([C:11](=[O:12])[N:10]([CH3:13])[CH2:9][C@H:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=[O:4])=[O:42]
Reactant: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@H](N)CCOc3ccccc3)C2)C1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1C[C@@H](c2ccccc2)[C@@]2(CCCN(C(=O)[C@@H](CCOc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Reaction time: 8 h

Procedure:
(4S,5R)-7-((R)-2-amino-4-phenoxybutanoyl)-2-methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one (55 mg; 0.130 mmol) was solubilised in acetonitrile (0.5 ml). 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (27 mg; 0.130 mmol) was added followed by diisopropylethylamine (0.091 ml; 0.522 mmol). The solution was stirred at RT for 5 minutes before ®T3P (50% solution in ethyl acetate) (0.152 ml; 0.261 mmol) was added. The mixture was stirred overnight, then concentrated in vacuo and purified by chromatography on silica eluting with 0-10% MeOH in TBME with ammonia to yield tert-butyl 2-methyl-1-((R)-1-((4S,5R)-2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxo-4-phenoxybutan-2-ylamino)-1-oxopropan-2-ylcarbamate.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:10]([I:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CI.[BH4-].[Na+].[C:26](=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14][CH2:15][C:16]3[CH2:17][CH2:18][N:19]([CH3:26])[CH2:20][CH:21]=3)=[C:10]([I:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CC(=O)N1CCc2cc(SCc3ccncc3)c(I)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)N1CCc2cc(SCC3=CCN(C)CC3)c(I)cc21
Temperature: 0 °C

Procedure:
1-Acetyl-2,3-dihydro-6-iodo-5-(pyridin-4-ylmethylthio)-1H-indole (D50) (0.390 g, 0.951 mmol) was dissolved in dry DMF (5 ml) and was treated with methyl iodide (0.089 ml, 1.430 mmol) with stirring. After 24 hours the reaction mixture was evaporated under reduced pressure and was triturated with ethyl acetate (~20 ml). The resultant brown solid was then filtered off, washed with diethyl ether and dried in vacuo (0.513 g). The solid was then redissolved in a mixture of ethanol (20 ml) and water (10 ml) and was cooled to 0° C. Sodium borohydride (0.069 g, 1.824 mmol) was then added. After 0.5 h a further amount of sodium borohydride (0.035 g, 0.912 mmol) was added. The reaction mixture was then allowed to warm to room temperature. After 1.5 hours the reaction mixture was treated with sodium bicarbonate solution (~15 ml) and was partitioned between dichloromethane and water. The aqueous layer was then extracted with dichloromethane (1X) and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give a yellow solid which was purified by silica-gel chromatography (5% MeOH/CH2Cl2 as eluant) to give the title compound as an off white solid (0.208 g, 53%).
Reaction SMILES: O.NN.Br[C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:8]=[CH:9][CH:10]=1.[CH2:16]([O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:6]=2)[CH:27]=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: O=C(O)CCc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1cccc(-c2cccc(OCc3ccccc3)c2)c1

Procedure:
21.5 g (77.2 mmol) of sodium metaborate octahydrate, 0.700 g (977 mmol) of bis(triphenylphosphine)palladium(II) chloride, 0.1 ml (2 mmol) of hydrazine hydrate and 10.0 g (42.3 mmol) of 3-(3-bromophenyl)propionic acid are initially introduced in 10 ml of tetrahydrofuran and 30 ml of water, and a solution of 10.0 g (43.9 mmol) of 3-benzyloxy-benzeneboronic acid in 30 ml of THF is added. The batch is subsequently heated under reflux overnight, added to water and extracted three times with MTB ether. The combined org. phases are filtered through silica gel with heptane/ethyl acetate (1:1), and the crude product is recrystallised from toluene, giving 3-(3′-benzyloxybiphenyl-3-yl)propionic acid as a colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40][NH2:41]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CN(C)CCCN
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 97.7 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) was added N,N-dimethyl-1,3-propanediamine (0.023 mL, 0.18 mmol). The resultant solution was stirred at room temperature over night. The result mixture was then concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (21 mg, 97%). LC-MS m/z 538 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 1.58 (m, 2H), 2.19 (s, 6H), 2.20 (m, 2H), 2.30 (s, 3H), 3.15 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[CH2:47][CH2:46][N:45]([CH3:48])[C:44]2=[O:49])=[N:41][CH:42]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[N:41][C:40]([CH:43]4[CH2:47][CH2:46][N:45]([CH3:48])[C:44]4=[O:49])=[CH:39][CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN1CCC(c2ccc(Br)cn2)C1=O
Product: C[C@@H](c1ccc(-c2ccc(C3CCN(C)C3=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 57 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 3-(5-bromo-pyridin-2-yl)-1-methyl-pyrrolidin-2-one following a procedure analogous to that described in Example 1. Yield: 57% of theory; LC (method 1): tR=1.82 min; Mass spectrum (ESI+): m/z=528 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[O:13][CH:12]([CH2:17]N(C)C)[C:11]2=[O:21]>O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[O:13][CH:12]([CH2:17][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)[C:11]2=[O:21]
Reactant: CN(C)CC1Oc2ccc(Cl)cc2C1=O
Reactant: c1c[nH]cn1
Agent: Cl
Solvent: O
Product: O=C1c2cc(Cl)ccc2OC1Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve imidazole (37.44 gms., 550 mmols) in water (200 ml.) and add 5-chloro-2-(dimethylaminomethyl)coumaran-3-one hydrochloride (25 gms., 55 mmols). Stir the reaction mixture overnight at room temperature, then add water (2 liters) and extract with chloroform (1 liter). Wash the chloroform solution with another 2 liter portion of water, dry over anhydrous magnesium sulfate, filter and evaporate in vacuo to give 5-chloro-2-(1'-imidazolylmethyl)coumaran-3-one.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>C(OCC)(=O)C>[F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: COc1c(F)ccc(C(=O)O)c1F
Solvent: CCOC(C)=O
Product: COc1c(F)ccc(C(=O)Cl)c1F

Procedure:
A mixture of 2,4-difluoro-3-methoxybenzoic acid (2.1 g, 11.1 mmol), thionyl chloride (5 mL), and ethyl acetate (30 mL) is refluxed for 4 h. All volatiles are removed in vacuo, and the remaining residue is used directly in the next synthetic step.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[CH:7][C:2]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[N:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=C1NCCO1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(N3CCOC3=O)cn2)CC1
Yield: 47.3 %

Procedure:
Using (5-bromopyrazin-2-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (100 mg) described in Preparation Example 243 and oxazolidin-2-one (26 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (48 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]([C:6]1[C:15]([N+:16]([O-])=O)=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[N+:19]([O-])=O)[C:3](=[O:5])[CH3:4]>[Pd].CO>[NH2:19][C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([NH2:16])[C:6]=1[N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N(C)C(C)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(N(C)C(C)=O)c(N)c1

Procedure:
9.7 G. of methyl 4-(N-methylacetamido)-3,5-dinitrobenzoate in 100 ml. of methanol were hydrogenated under normal pressure and at room temperature in the presence of 1 g. of palladium/carbon. After uptake of the theoretical amount of hydrogen, the solution was filtered off from the catalyst and evaporated. The residue was recrystallized from methanol, there being obtained methyl 3,5-diamino-4-(N-methylacetamido)-benzoate having a melting point of 221°-222° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[CH:39]=[N:38][CH:37]=[CH:36]2.[CH3:43][N:44]1[CH:48]2[CH2:49][CH:50](O)[CH2:51][CH:45]1[CH2:46][CH2:47]2>ClCCl.C(N(CC)CC)C>[CH3:43][N:44]1[CH:48]2[CH2:47][CH2:46][CH:45]1[CH2:51][CH:50]([O:32][C:33]1[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=1)[CH:39]=[N:38][CH:37]=[CH:36]3)[CH2:49]2
Reactant: CN1C2CCC1CC(O)C2
Reactant: Oc1ccc2cnccc2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C2CCC1CC(Oc1ccc3cnccc3c1)C2
Reaction time: 0.33 h
Yield: 18 %

Procedure:
625 mg of triphenyl phosphine were dissolved in 20 mL of dry dichloromethane, 0.095 mL of diethyl azodicarboxylate were added and the solution was shaken for 20 minutes. 69 μL of triethyl amine, 72.6 mg of 6-hydroxy isoquinoline and 67.1 mg of tropine were added and the mixture was shaken overnight. The reaction mixture was filtered, the remainders washed thoroughly with dichloromethane and the combined organic layer was extracted twice with 1N sodium hydroxide and water, respectively. The organic layer was dried, evaporated to dryness and the crude material was purified by HPLC. The product was dissolved in 2N HCl and lyophilized to give 23 mg of 6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-isoquinoline (52) as the hydrochloride. Rt=0.52 min (Method A). Detected mass: 269.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:16]=[C:15]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]=[CH:13][C:11]=1[NH2:12])=[O:5])[CH3:2].[Br:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](O)=[O:44])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23>C(O)(=O)C.C(OCC)(=O)C>[Br:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](=[O:44])[NH:12][C:11]3[CH:13]=[CH:14][C:15]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[CH:16][C:10]=3[CH2:9][CH2:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23
Reactant: O=C(O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CCOC(=O)CCCCc1cc(CNC(=O)OC(C)(C)C)ccc1N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 74.5 %

Procedure:
A procedure similar to that described in Example 18-6) was performed with 2-(4-ethoxycarbonylbutyl)-4-tert-butoxycarbonylaminomethylaniline (256 mg, 0.73 mmol) and (S)-9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (297 mg, 0.88 mmol) to give 365 mg of the title compound after silica gel column chromatography with 0.3% acetic acid/ethyl acetate (74%).
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.II.[CH3:10][O:11][Si:12](OC)(OC)[O:13][CH3:14]>O1CCCC1>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[Si:12]([C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)([O:13][CH3:14])[O:11][CH3:10]
Reactant: CO[Si](OC)(OC)OC
Reactant: Brc1cccs1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CO[Si](OC)(c1cccs1)c1cccs1
Temperature: 25 °C

Procedure:
With protection of nitrogen gas, 3.50 g magnesium powder, 1.30 g bromothiophene and 20 ml tetrahydrofuran were added to a 250 ml three-necked flask equipped with a stirrer, a reflux condenser tube and a thermometer. After the mixed system was refluxed for 0.5 hour, 0.26 g iodine was added until the reaction got severe. After the reaction was stable, a mixed solution of 20.74 g bromothiophene, 60 ml tetrahydrofuran and 9.99 g tetramethoxysilane was added dropwise from an upper part of tube within about 2 hours. After being heated with stirring and refluxing for 5 hours, the mixed system was slowly cooled to room temperature, filtered by a filter tube with protection of nitrogen gas, and the solid substance was washed with tetrahydrofuran several times. The resulting filtrate was subjected to distillation at normal pressure and solvent recovery, and then subjected to distillation at reduced pressure. The product at 130° C. to 131° C. and 25 mmHg column pressure were collected. Te infrared spectrum and 13C nuclear magnetic resonance spectrum of the synthesized compound are substantially identical with that in FIG. 1 and FIG. 2. The infrared spectrum preliminarily approves the occurrence of the synthetic reaction, and the 13C nuclear magnetic resonance spectrum effectively demonstrates the formation of the product.
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:35]1(=[O:45])[NH:39][C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C1(C)C=CC=CC=1>[O:40]=[C:38]1[C:37]2[C:36](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:35](=[O:45])[N:39]1[C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 7 h
Yield: 244 %

Procedure:
To a stirred slurry of trans-tert-butyl 2-hydroxycyclohexylcarbamate (1.00 g, 4.64 mmol), PPh3 (1.34 g, 5.10 mmol) and phthalimide (1.50 g, 10.20 mmol) in a 2:1 mixture of toluene and THF (15 mL) was added diisopropyl azodicarboxylate (1.0 mL, 5.10 mmol) dropwise over a period of 1 h. Once the addition was complete, the mixture was stirred at about 0° C. for 7 h and was then warmed slowly to 7° C. over a period of 14 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a yellow oil (3.90 g). The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CCCOCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COCCC[C@H]2CCNC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of tert-butyl 3(S)-[3-(benzyloxy)propyl]pyrrolidine-1-carboxylate (495 mg, 1.55 mmol) in 6 mL of CH2Cl2 was added CF3COOH (1.5 mL) at room temperature under N2. The resulting solution was stirred for 3 h at room temperature and then concentrated under vacuum. To the residue was added 20 mL of water, and the solution was washed with 30 mL of petroleum ether. The water layer was adjusted to pH 8.0 with 2 M aqueous NaHCO3 solution and extracted with CH2Cl2 (3×40 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to give 3(S)-[3-(benzyloxy)propyl]pyrrolidine (330 mg, 97%) as a yellowish oil. LC-MS (ESI) m/z 220 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1.[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3([OH:17])[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC1(c2c[nH]c3cc(Cl)ccc23)CCNCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 7.7 %

Procedure:
A mixture of 2.0 gm (13.2 mMol) 6-chloroindole and 4.06 gm (26.3 mMol) 4-piperidinone in 30 mL ethanol which contained 2.21 gm (39.6 mMol) potassium hydroxide was stirred at room temperature for 48 hours. Water (50 mL) was added dropwise to the reaction mixture over 30 minutes. The reaction mixture was allowed stir an additional 2 hours and the solid which formed was collected by filtration to provide a sticky orange solid. A portion of the solid was triturated with acetonitrile and filtered, washed with diethyl ether and dried under reduced pressure to provide 0.254 gm (7.4%) of the title compound as a colorless powder.