Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:16][C:15]3([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:17]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:11]2[CH:12]=[CH:13][C:14]3=[O:31])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>[OH-].[Pd+2].[OH-].CO>[C:1]1([S:7]([CH:10]2[CH2:16][C:15]3([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:17]([CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:11]2[CH2:12][CH2:13][C:14]3=[O:31])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CC2C(S(=O)(=O)c3ccccc3)CC1(c1ccccc1)N2Cc1ccccc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C1CCC2C(S(=O)(=O)c3ccccc3)CC1(c1ccccc1)N2Cc1ccccc1
Temperature: 25 °C

Procedure:
To a 500 ml round bottom flask equipped with nitrogen inlet and condenser was placed 5.87 gm (13.68 mmol) of the 6-Benzenesulfonyl-8-benzyl-1-phenyl-8-aza-bicyclo[3.2.1]oct-3-en-2-one together with 150 ml of methanol, 17.25 gm (273.66 mmol) ammonium formate and 1.95 gm palladium hydroxide. The reaction mixture was heated under reflux for 1.5 hours and then cooled to room temperature. The suspension was filtered through a bed of celite which was then washed with methanol. The combined organics were evaporated in vacuo and the residue was taken up in chloroform and partitioned with saturated aqueous bicarbonate solution. The organics were washed with saturated brine solution and then dried over a bed of sodium sulfate. The mixture was filtered and the filtrate evaporated in vacuo. The residue was chromatographed on silica gel eluting with 8:2/hexane:ethyl acetate to afford 4.04 gm (68%) of an off white solid. 1H NMR (CDCl3, 400 MHz) δ 7.79 (d, 2H, J=7 Hz), 7.66 (t, 1H, J=7 Hz), 7.51 (t, 2H, J=8 Hz), 7.40–7.19 (m, 10H), 3.93 (br.s., 1H), 3.70 (d, 1H, J=15 Hz), 3.62 (t, 1H, J=7 Hz), 3.35 (d, 1H, J=14 Hz), 2.70–2.5 (m, 4H), 1.79–1.70 (m, 1H), 1.55 (br.s., 1H) ppm. Mass spectrum APCI m/z 432 (p+1).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]=[O:22])[C:17]=3[CH:23]=2)[C:3]1=[O:24].[CH2:25](O)[CH:26]([OH:28])[CH3:27].C1(C)C=CC=CC=1.O>C(OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][N:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]4[O:28][CH:26]([CH3:27])[CH2:25][O:22]4)[C:17]=3[CH:23]=2)[C:3]1=[O:24]
Reactant: CC(O)CO
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CC1COC(c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)O1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (0.500 g, 1.41 mmol), 1,2-propanediol (0.130 ml, 1.83 mmol), p-toluenesulfonic acid (0.0100 g, 0.0100 g, 0.071 mmol) and toluene is stirred at reflux with azeotropic removal of water overnight, cooled to room temperature, diluted with diethyl ether, washed twice with water and once with brine and dried over anhydrous magnesium sulfate. Concentration in vacuo affords a yellow oil, which is chromatographed on silica gel to afford the title compound as a yellow solid (0.510 g, 87.6%, mp 81-83° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[N:11]([CH2:15][C:16](=O)[CH3:17])[N:10]=1>CO>[CH3:6][O:5][C:1]([NH:2][N:3]=[C:16]([CH3:17])[CH2:15][N:11]1[N:10]=[C:9]([O:8][CH3:7])[S:13][C:12]1=[O:14])=[O:4]
Reactant: COc1nn(CC(C)=O)c(=O)s1
Reactant: COC(=O)NN
Solvent: CO
Product: COC(=O)NN=C(C)Cn1nc(OC)sc1=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 78.8 %

Procedure:
9.1 g of methyl carbazate are added to a solution of 18.8 g of 5-methoxy-3-(2-oxo-propyl)-3H-[1,3,4]thiadiazol-2-one (Comp. 7.001) in 150 ml of methanol and the mixture is then stirred at room temperature for 36 hours. The reaction mixture is concentrated by evaporation and the residue is stirred with isopropanol and filtered with suction to yield 20.5 g of crystals of the title compound having a melting point of 142-143°.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:13]2)[C:3]=1[C:4]#[N:5].[S:24](Cl)(=[O:27])(=[O:26])[NH2:25].O>CC(N(C)C)=O>[S:24]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:13]2)[C:3]=1[C:4]#[N:5])(=[O:27])(=[O:26])[NH2:25]
Reactant: CC(C)CC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)CC(=O)N1CCC[C@H](COc2cccc(NS(N)(=O)=O)c2C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a stirred solution of (S)-2-amino-6-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)benzonitrile (example 5b, 54.55 g, 172.95 mmol) in DMA (110 mL) cooled to 0° C. in an ice bath was added sulfamoyl chloride (55 g, 476 mmol) in two portions (20 g and 35 g). The reaction mixture was stirred for 30 minutes at 0° C. under N2, then at room temperature for 4 hours. The reaction mixture was poured slowly into rapidly stirred cold water (2 L) to provide a milky solution. An additional 800 mL of water was added in several portions to precipitate the desired product (at this point the milky solution has become clear). The precipitate was collected by decantation of the water and was suspended in ethyl acetate (500 mL) then rapidly stirred until it became a fine white solid. The solid material was collected by vacuum filtration and dried under vacuum to give (S)-2-sulfamoylamino-6-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)benzonitrile as a white solid (59.25 g, 150.2 mmol) in 87% yield. MS 395 (MH+)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.Cl[C:26]1[C:27]([C:35]#[N:36])=[N:28][CH:29]=[C:30](/[CH:32]=[CH:33]/[CH3:34])[CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:26]3[C:27](=[C:35]([NH2:36])[N:8]=[C:6]2[CH:7]=1)[N:28]=[CH:29][C:30](/[CH:32]=[CH:33]/[CH3:34])=[CH:31]3
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: C/C=C/c1cnc(C#N)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CO
Product: C/C=C/c1cnc2c(N)nc3cc(C)ccc3c2c1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/Step 2) (1.0 eq.) and (E)-3-chloro-5-(prop-1-enyl)picolinonitrile (from the previous step) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give (E)-8-methyl-2-(prop-1-enyl)benzo[f][1,7]naphthyridin-5-amine as a yellow solid.
Reaction SMILES: [C:1](#[N:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([CH2:9]N)[OH:8]>O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH2:2]([C:1]1[O:8][CH2:7][CH2:9][N:6]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC#N
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: O
Product: CCCCC1=NCCO1
Temperature: 124 °C
Reaction time: 48 h

Procedure:
A mixture of about 83.1 grams (1.00 mole) valeronitrile, about 64.8 grams (1.05 mole) ethanolamine, and about 6.2 grams (0.025 mole) cadmium acetate dihydrate is heated at about 124 degrees C. to about 128 degrees C. and stirred under nitrogen for about two days. The product is then distilled under vacuum. The fraction boiling at about 67 degrees C. to about 75.5 degrees C. at about 28 mmHg is collected.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:9]=[CH:10][N:11]=2)[C:5]([Cl:8])=[CH:6][CH:7]=1.[N:12]1([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)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]>[Cl:8][C:5]1[N:4]2[N:9]=[CH:10][N:11]=[C:3]2[C:2]([NH:24][C:21]2[CH:20]=[CH:19][C:18]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: Clc1ccc(Br)c2ncnn12
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Clc1ccc(Nc2ccc(N3CCOCC3)cc2)c2ncnn12
Temperature: 90 °C
Yield: 30.8 %

Procedure:
A suspension of 8-bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyridine (160 mg, 0.69 mmol), 4-morpholin-4-yl-phenylamine (135 mg, 0.76 mmol), sodium-tert-butoxide (93 mg, 0.96 mmol), tris(dibenzylideneacetone)dipalladium (0) (13 mg, 13.76 μmol) and Xantphos (16 mg, 27.52 μmol) in dry toluene is heated at 90° C. in a sealed tube under a nitrogen atmosphere for 16 hours. The reaction mixture is evaporated to dryness and the residue partitioned between dichloromethane and 10% aqueous citric acid. The organic phase is further washed with water (1×) and brine (1×), dried over magnesium sulfate, filtered and evaporated. The solid residue (207 mg) is purified by flash chromatography (silica gel, dichloromethane/methanol 97:3) affording the title compound (70 mg) as a solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17](C(OCC2C=CC=CC=2)=O)[CH2:16][CH2:15]3)[CH2:7]1)(=[O:3])[CH3:2]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[CH2:18]1[C:19]2[C:14](=[CH:13][C:12]([N:8]3[CH2:7][C@H:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][C:9]3=[O:11])=[CH:21][CH:20]=2)[CH2:15][CH2:16][NH:17]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)OCc2ccccc2)C3)C(=O)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Reaction time: 1 h

Procedure:
A mixture of phenylmethyl 6-[(5S)-5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Step 5, 1.71 g, 4.04 mmol) and 20% Pd(OH)2/C (567 mg) in MeOH (40 mL) in a Parr bottle is shaken under 20 psi H2 for 1 hr. The resulting slurry is then diluted with MeOH (100 mL) and THF (100 mL), filtered through Celite to remove the catalyst, and concentrated under reduced pressure to give a quantitative yield of the title compound as an amorphous solid which is used without further purification. 1H NMR (400 MHz, CD3OD) δ 7.36 (bd, 1H), 7.31 (s, 1H), 7.08 (d, 1H), 4.78 (m, 1H), 4.14 (t, 1H), 3.98 (s, 2H), 3.82 (dd, 1H), 3.57 (m, 2H), 3.13 (m, 2H), 2.88 (m, 2H), 1.98 (s, 3H); MS (ESI+) for C15H19N3O3 m/z 290 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([CH3:14])[C:4]=1[C:5]([O:7]C)=O)#[N:2].BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.[F:48][C:49]1([F:62])[CH2:54][CH2:53][CH:52]([N:55]2[CH2:60][CH2:59][CH:58]([NH2:61])[CH2:57][CH2:56]2)[CH2:51][CH2:50]1>C(OC)(=O)C(C)(C)C.ClCCl.ClCCl.C(O)C>[F:62][C:49]1([F:48])[CH2:54][CH2:53][CH:52]([N:55]2[CH2:56][CH2:57][CH:58]([N:61]3[C:5](=[O:7])[C:4]4[C:3]([C:1]#[N:2])=[C:12]([F:13])[CH:11]=[CH:10][C:9]=4[CH2:14]3)[CH2:59][CH2:60]2)[CH2:51][CH2:50]1
Reactant: COC(=O)c1c(C)ccc(F)c1C#N
Reactant: NC1CCN(C2CCC(F)(F)CC2)CC1
Agent: COC(=O)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1c(F)ccc2c1C(=O)N(C1CCN(C3CCC(F)(F)CC3)CC1)C2
Temperature: 85 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
To a solution of methyl 2-cyano-3-fluoro-6-methylbenzoate (208 mg, 1.07 mmol) in methyl pivalate (2 mL), N-bromosuccinimide (310 mg, 1.74 mmol) and benzoylperoxide (20 mg, 0.097 mmol) were added. The reaction mixture was stirred at 85° C. under nitrogen atmosphere for 3 hours. Crude was filtered on Gooch and washed with toluene. Volatiles were evaporated and the residue was dissolved in acetonitrile (3 mL). Triethylamine (0.41 mL, 2.9 mmol) and 1-(4,4-difluorocyclohexyl)-piperidin-4-ylamine (280 mg, 0.97 mmol) were added and the reaction mixture was stirred at 90° C. for 3 hours. Crude was diluted with dichloromethane and washed with 15% ammonium hydroxide Organic phase was dried over sodium sulfate, filtered and evaporated. Column chromatography (dichloromethane/ethanol:95/5) afforded title compound (222 mg, 60% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[N-]1C=CN=C1.[NH2:19][C:20]1[C:21]([NH:30][CH3:31])=[N:22][CH:23]=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([NH:19][C:20]2[C:21]([NH:30][CH3:31])=[N:22][CH:23]=[C:24]([CH:29]=2)[C:25]([O:27][CH3:28])=[O:26])=[O:13])=[CH:7][CH:8]=1)#[N:2]
Reactant: CNc1ncc(C(=O)OC)cc1N
Reactant: N#Cc1ccc(CCC(=O)O)cc1
Agent: c1c[n-]cn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1ncc(C(=O)OC)cc1NC(=O)CCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2.6 g (15 mMol) of 3-(4-cyanophenyl)propionic acid in 25 ml of absolute tetrahydrofuran was mixed with 2.4 g (15 mMol) of N,N'-carbonyldiimidazole and stirred for 20 minutes at room temperature. Then the imidazolide was mixed with a solution of 2.3 g (13 mMol) of methyl 5-amino-6-methylamino-nicotinate in 25 ml of dimethylformamide and heated for 3 hours to 100° C. After the removal of the solvent in vacuo the crude product obtained was taken up in ethyl acetate, the organic phase was washed with water and after drying over sodium sulphate it was again freed from solvent. The residue obtained was purified by flash chromatography (silica gel; gradient: dichloromethane to dichloromethane/ethanol=19:1). Yield: 2.1 g (50% of theory) of beige solid Rf value: 0.54 (silica gel; ethyl acetate/ethanol/ammonia=90:10:1)
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([OH:24])[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:25]>CO>[NH2:25][C:2]1[C:11]2[N:12]=[C:13]([OH:24])[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COc1ccc(Cn2c(O)nc3c(Cl)nc4ccccc4c32)cc1
Reactant: N
Solvent: CO
Product: COc1ccc(Cn2c(O)nc3c(N)nc4ccccc4c32)cc1
Temperature: 150 °C

Procedure:
4-Chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-ol (2.0 g, 5.9 mmol) and ammonia (30 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated at 150° C. for two days. An analysis by LC/MS indicated the reaction was incomplete, and the vessel was sealed and heated at 165° C. for three days. The volatiles were removed under reduced pressure, and the residue was purified twice by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.5:9.5:90). The resulting white solid was mixed with acetonitrile, isolated by filtration, and dried overnight under vacuum to provide 4-amino-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-ol as a white solid, mp greater than 260° C.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=2)[NH:22][CH:21]=1)=O)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C(OCC)(=O)C>O1CCCC1>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@@H:14]1[CH2:18][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=2)[NH:22][CH:21]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc2[nH]cc(C(=O)[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]cc(C[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1

Procedure:
To a stirred mixture of lithium borohydride (0.092 g, 4.22 mmol, 2 eq) in anhydrous tetrahydrofuran (5 mL) at 0° C. was added a solution of the (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-methoxy-1H-indole (0.80 g, 2.11 mmol) in anhydrous tetrahydrofuran (8 mL). The resultant mixture was heated at reflux under nitrogen for 1 hour. The reaction mixture was cooled, and water (1 mL) was added carefully, followed by ethyl acetate (20 mL). The resultant mixture was stirred at room temperature for 30 minutes, dried (MgSO4), filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure. The residue was column chromatographed using silica gel (approximately 50 g) and elution with ethyl acetate/hexanes [1:1] afforded (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-5-methoxy-1H-indole as a colorless gum: 13C NMR [Note: due to slow nitrogen inversion two conformers of the products are seen by NMR spectroscopy] (CDCl3) δ 162.5, 136.9, 136.2, 128.4, 127.8, 127.6, 124.5, 123.3, 120.8, 120.3, 111.5, 66.8, 57.4, 39.5, 36.5, 31.4, 29.8, 25.8, 25.5, 18.8; LRMS (m/z, relative intensity) 364 (30, M+), 204 (17), 160 (92), 145 (17), 117 (13), 91 (100). Anal. calcd for C22H24N2O3 ·0.5 H2O: C, 70.76; H, 6.75; N, 7.50. Found: C, 70.70; H, 6.94; N, 7.15.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:8]=[C:7]2[OH:16].[C:18]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:8]=[C:7]2[O:16][CH3:18]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(C(F)(F)F)nc2c(Cl)ccc(F)c12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C(F)(F)F)nc2c(Cl)ccc(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 8-Chloro-5-fluoro-2-(trifluoromethyl)quinolin-4-ol (Step 1, 3.54 g, 13.3 mmol, 1 eq.) in acetone (75 mL) was added anhydrous K2CO3 (3.88 g, 28.0 mmol, 2.1 eq.), followed by iodomethane (1.8 mL, 28.9 mmol, 2.17 eq.). The resulting mixture was stirred at reflux for 1.5 hours. An additional aliquot of iodomethane (1.8 mL, 28.9 mmol, 2.17 eq.) was added and reflux was continued for an additional 1 hour. The reaction was cooled to room temperature, poured onto ice and extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator to give 3.72 g (100% yield) of the desired product as a yellow solid, which was used in subsequent reactions without further purification. An analytical sample was prepared by recrystallization from hexane/ethyl acetate; MP=198-200° C.; MS (ES) m/z (relative intensity): 280 (M+H)+ (100).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]([N:15]1[C@H:22]([CH3:23])[CH2:21][CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>CO.O>[CH2:5]([O:12][C:13]([N:15]1[CH2:16][C@H:17]([OH:18])[C@@H:19]([N:1]=[N+:2]=[N-:3])[CH2:20][CH2:21][C@H:22]1[CH3:23])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@@H]1CC[C@H]2O[C@H]2CN1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H]1CC[C@H](N=[N+]=[N-])[C@@H](O)CN1C(=O)OCc1ccccc1
Yield: 88.9 %

Procedure:
Sodium azide (0.139 g, 2.14 mmol) was added to a solution of (1S,4R,7R)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.186 g, 0.71 mmol) and ammonium chloride (0.114 g, 2.14 mmol) in MeOH (1.5 ml) and H2O (0.15 ml), then was refluxed for 6 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then was diluted with water (5 ml) and extracted with EtOAc (10 ml). The organic layer was then extracted with water, brine, dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 20% EtOAc/hexanes) to yield the title compound (0.192 g, 89%): 7.39-7.30 (m, 5H), 5.15 (2H, s), 4.10-3.67 (m, 2H), 3.10 (1H, d), 1.85-1.53 (m, 4H), 1.09 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=305.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:12](=[O:35])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][C:28]([C:32]([OH:34])=O)=[C:29]([CH3:31])[N:30]=1)=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:43]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[N:11]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:12](=[O:35])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([C:26]1[S:27][C:28]([C:32]([NH2:43])=[O:34])=[C:29]([CH3:31])[N:30]=1)=[CH:15][CH:14]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)sc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)sc1C(N)=O
Yield: 86.9 %

Procedure:
A solution of 2-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-4-methyl-1,3-thiazole-5-carboxylic acid (0.44 g, 0.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.31 g, 1.6 mmol) and 1-hydroxybenzotriazole ammonium salt (0.24 g, 1.6 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl{6-[5-(aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.38 g, 86.4%) as crystals.
Reaction SMILES: C(COC1C2N=NNC=2C=CC=1)(=O)C=C.[C:16]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28](C)[C:23]=2[N:22]=[N:21]1)(=[O:19])[CH:17]=[CH2:18].[N-]1C=CN=C1.C(N1C(=O)CCC1=O)(=O)C=C.C(N)(=O)C=C>>[C:16]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)n1nnc2c(C)cccc21
Agent: C=CC(=O)COc1cccc2[nH]nnc12
Agent: C=CC(=O)N1C(=O)CCC1=O
Agent: C=CC(N)=O
Product: C=CC(=O)n1nnc2ccccc21

Procedure:
1-acryloyl methoxybenzotriazole; 1-acryloyl methylbenzotriazole; 1-acryloil imidazolide; N-acryloyl-succinimide; N-2,4,5-trichlorophenil acrylamide.