Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]2[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]3=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][N:32]1[CH:36]=[C:35]([CH2:37][CH2:38]OS(C)(=O)=O)[CH:34]=[N:33]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]2[CH2:16][CH2:15][CH:14]([NH:22][CH2:38][CH2:37][C:35]4[CH:34]=[N:33][N:32]([CH3:31])[CH:36]=4)[CH2:13][C:12]3=2)=[O:7])=[CH:23][CH:24]=1
Reactant: Cn1cc(CCOS(C)(=O)=O)cn1
Reactant: NC1CCc2[nH]c3ccc(NC(=O)c4ccc(F)cc4)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(CCNC2CCc3[nH]c4ccc(NC(=O)c5ccc(F)cc5)cc4c3C2)cn1
Temperature: 67.5 °C
Reaction time: 18 h
Yield: 33.6 %

Procedure:
To a mixture of 0.40 gm (1.24 mMol) 6-(4-fluorobenzoyl)amino-3-amino-1,2,3,4-tetrahydro-9H-carbazole and 0.257 gm (1.86 mMol) potassium carbonate in 8.0 mL dimethylform-amide were added 0.303 gm (1.49 mMol) 2-(1-methyl-1H-pyrazol-4-yl)-1-mesyloxyethane in 2.0 mL dimethylformamide and the mixture was stirred at 60-75° C. for 18 hours. An additional 0.101 gm (0.50 mMol) 2-(1-methyl-1H-pyrazol-4-yl)-1-mesyloxyethane were added and the reaction heated to 150° C. After 1.5 hours the reaction mixture was cooled to room temperature and was then partitioned between water and dichloromethane. The aqueous phase was extracted again with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 95:5:0.5 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.180 gm (33.6%) of 6-(4-fluorobenzoyl)amino-3-(2-(1-methyl-1H-pyrazol-4-yl)ethyl)amino-1,2,3,4-tetrahydro-9H-carbazole. The corresponding hydrochloride salt was prepared to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[N:26]=3)=[CH:21][CH:20]=2)[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[C:38]1([OH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O1CCOCC1>CN(C=O)C>[F:31][C:27]1[N:26]=[C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][N:3]3[C:2]([O:44][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[C:10]4[C:5]([N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7](=[O:13])[N:8]([CH3:12])[C:9]4=[O:11])=[N:4]3)=[CH:20][CH:21]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: Oc1ccccc1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Oc3ccccc3)n(Cc3ccc(-c4cccc(F)n4)cc3)nc21
Temperature: 150 °C
Yield: 67.4 %

Procedure:
3-chloro-2-(4-(6-fluoropyridin-2-yl)benzyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (40 mg, 0.095 mmol), potassium carbonate (40 mg, 0.28 mmol) and phenol (26 mg, 0.28 mmol) are placed in a Biotage microwave vial, and then 0.4 mL of dioxane is added. The vial is sealed, and then heated in a Biotage microwave instrument at 150° C. for 3 h. The reaction mixture is diluted with DMF, and then filtered. The filtrate is purified with a semi-preparative HPLC to give 32 mg of pure product as pale yellow crystals (Purity: 99.9%). MS (ESI) m/z 500.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:6][CH:7]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[CH:18]=1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:16]=[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:7][N:6]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCC(=O)Nc1cnc(Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)Nc1cnc(-c2cccnc2)cn1
Temperature: 150 °C
Yield: 36.2 %

Procedure:
Methyl 4-[(5-bromopyrazin-2-yl)amino]-4-oxo-butanoate (A2, 200 mg, 0.694 mmol) was dissolved in N,N-dimethylformamide (4.5 mL) in a microwave vial and 3-pyridyltributylstannane (0.833 mmol, 0.29 mL) and tetrakis(triphenylphosphine) palladium(0) (0.069 mmol) were added. Argon was bubbling through the mixture for ca. 5 min and the vial was heated under microwave irradiations for 10 min at 150° C. The solvent was evaporated and the residue was diluted with acetonitrile, washed with cyclohexane (2×) and evaporated. The product was purified by flash chromatography (RF-machine, AcOEt/cyclohexane: 1/1→1/0) to give methyl 4-oxo-4-[[5-(3-pyridyl)pyrazin-2-yl]amino]butanoate (compound A39) (0.072 g, 36% Yield). LCMS (Method F): RT 0.53 min, 287 (M+H+).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[CH2:26])[CH:20]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C(=O)([O-])[OH:33].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]([F:30])([F:31])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[C:21]([CH:25]3[CH2:26][O:33]3)[CH:22]=[CH:23][CH:24]=2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:6])([F:5])[F:7]
Reactant: O=C([O-])O
Reactant: C=Cc1cccc(Oc2ccc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc2CCC)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(C2CO2)c1
Yield: 78.2 %

Procedure:
To a solution of 4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propyl-1-(3-vinylphenoxy) benzene (686 mg, 1.52 mmol) in chloroform (10 mL), sodium hydrogen carbonate (510 mg), m-chloroperbenzoic acid (60%) (880 mg) were added at room temperature and the resultant mixture was stirred. After completion of the reaction, the reaction solution was added with an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (552 mg, yield 78%) was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:6]([OH:7])[C:5]=1[OH:14])([O-:3])=[O:2].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:15]([O:7][C:6]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:14])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Oc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O)c1ccccc1
Reaction time: 4 h

Procedure:
A mixture containing 2.0 g of 3,5-dinitrocatechol in 5 ml of benzoylchloride was cooked for 4 hours in 100° C. When cooled petroleum ether (b.p. 40° C.) was added and the product was filtered and washed with petroleum ether. The raw product was crystallized from ethanol. Yield 2.5 g (82%), m.p. 150°-152° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[N:19]#[C:20]Br.[OH-].[K+]>C(O)(C)C>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=[C:20]2[NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccccc1NCCCN1CCCCC1
Reactant: N#CBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Nc1nc2ccccc2n1CCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 20.0 g. (0.086 mole) of N-[3-(1-piperidinyl)propyl]-o-phenylenediamine in 80 ml. water, 20 ml. of isopropanol was added to obtain a homogenous solution. With continued stirring, 21.2 g. (0.200 mole) of cyanogen bromide was added in portions over a one hour period. Room temperature was maintained throughout the addition. After stirring for an additional 2 hours the reaction mixture was allowed to stand overnight. The mixture was then poured into ice-water, made strongly alkaline with KOH and extracted with methylene chloride. The extracts were evaporated to a red oil which crystallized from ether, 7.9 g. (36% yield), m.p. 176°-178° C. An analytical sample of 1-[3-(1-piperidinyl)propyl]-2-amino benzimidazole was obtained by crystallization from benzene-cyclohexane, m.p. 179°-181° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][C:5]=1[O:13][CH2:14][CH3:15])[CH3:2].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH:18]=[CH:17]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)(Cl)(Cl)Cl>[CH2:11]([O:10][C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH3:15])[C:4]([O:3][CH2:1][CH3:2])=[CH:9][C:8]=1[C:16](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[O:22])[CH3:12]
Reactant: O=C1C=CC(=O)O1
Reactant: CCOc1ccc(OCC)c(OCC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc(OCC)c(C(=O)/C=C/C(=O)O)cc1OCC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.1 parts by weight of 1,2,4-triethoxybenzene, 1.2 parts by weight of maleic anhydride and 30 parts by volume of carbon tetrachloride is added 5.2 parts by weight of anhydrous aluminum chloride. The mixture is stirred for 1 hour and heated at 50° C. for another 1 hour. After cooling, concentrated hydrochloric acid and ice are added to the mixture. The mixture is extracted with methylenechloride and the methylenechloride layer is washed with water and dried over anhydrous sodium sulfate. Upon removing the solvent by distillation, 3-(2',4',5'-triethoxybenzoyl)-trans-acrylic acid is obtained as crystals. Recrystallization from a mixture of ethanol and benzene gives yellow needles melting at 192°-194° C.
Reaction SMILES: C([O:5][C:6](=[O:34])[C@H:7]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)[NH:8][C:9](=[O:21])[CH:10]([CH2:16][S:17][C:18](=[O:20])[CH3:19])[CH2:11][S:12][C:13](=[O:15])[CH3:14])(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:13]([S:12][CH2:11][CH:10]([CH2:16][S:17][C:18](=[O:20])[CH3:19])[C:9]([NH:8][C@H:7]([C:6]([OH:34])=[O:5])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:21])(=[O:15])[CH3:14]
Reactant: CC(=O)SCC(CSC(C)=O)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC(CSC(C)=O)C(=O)N[C@@H](CCCCN)C(=O)O
Reaction time: 1 h

Procedure:
Nα -[2-(acetylthiomethyl)-3-(acetylthio)propanoyl]-Nε -tert.-butyloxycarbonyl-L-lysine tert.butyl ester (3 g.) is dissolved in a mixture of trifluoroacetic acid and anisole, and the mixture is stored at room temperature for one hour. The trifluoroacetic acid is removed in vacuo, the residue is distributed between ether and water and the aqueous layer is applied to a column of Dowex 50. After washing the acidic material with water, the Nα -[2-(acetylthiomethyl)-3-(acetylthio)propanoyl]-L-lysine is eluted with a buffer of pyridineacetic acid at pH 6.5.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[O:41]1[C:45]2[CH:46]=[CH:47][C:48]([CH2:50][NH2:51])=[CH:49][C:44]=2[O:43][CH2:42]1>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([NH:51][CH2:50][C:48]2[CH:47]=[CH:46][C:45]3[O:41][CH2:42][O:43][C:44]=3[CH:49]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1NC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.6 %

Procedure:
To a mixture of 2-cyclopentylamino-5-nitrobenzoic acid (1.00 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.15 g), 1-hydroxybenzotriazole (810 mg) in anhydrous dimethylformamide (10 mL) was added (1,3-benzodioxol-5-ylmethyl)amine (725 mg), and the mixture was stirred for 15 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with an aqueous saturated sodium bicarbonate solution, water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of chloroform and methanol (50:1). The obtained product was triturated with diisopropyl ether and recrystallized from a mixture of hexane and ethyl acetate to give 2-cyclopentylamino-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (1.51 g).
Reaction SMILES: [NH3:1].CO.[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[O:10][C:9]([CH2:16][C:17]([O:19][CH2:20]C)=[O:18])=[CH:8]2>>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:10])[NH:1][C:9]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:8]2
Reactant: CCOC(=O)Cc1cc2cc(Br)ccc2c(=O)o1
Reactant: N
Solvent: CO
Product: COC(=O)Cc1cc2cc(Br)ccc2c(=O)[nH]1

Procedure:
A solution of 7 N ammonia in MeOH (3.14 mL, 21.95 mmol, 10.0 equiv.) and ethyl 2-(6-bromo-1-oxo-1H-isochromen-3-yl)acetate (683 mg, 2.195 mmol) was stirred at room temperature for 1 h. Upon completion of the reaction, the excess solvent was concentrated, diluted with 1 N HCl (5 mL), and extracted with EtOAc (2×5 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0-40% EtOAc/hexanes to give 250 mg of methyl 2-(6-bromo-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([OH:21])=[C:6]([Cl:20])[C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:8]=2[CH:19]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C=O)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:21][C:5]1[C:4]([Cl:3])=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])=[N:10][O:11][C:7]=2[C:6]=1[Cl:20])[CH3:28]
Reactant: Oc1c(Cl)cc2c(-c3ccccc3F)noc2c1Cl
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1c(Cl)cc2c(-c3ccccc3F)noc2c1Cl
Temperature: 45 °C

Procedure:
1.4 g NaH is suspended in 50 ml DMF with stirring. A solution of 7.2 g of 5,7-dichloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole in 50 ml DMF is added dropwise. The solution is heated to 45° C. for one hour. Ethyl bromoacetate (4.0 g) in 20 ml DMF is added dropwise and the reaction is stirred at 40° C. for two hours. The solution is poured into 1 l of water, stirred and extracted with ethylacetate. The organic extracts are washed with saturated NaCl solution and the solvent removed in vacuo affording ethyl{[5,7-dichloro-3-(2-fluorophenyl)-1,2-benzisoxazole-6-yl]oxy}acetate, mp 105°-106° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)=[O:3].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[CH2:16][S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18]>>[NH2:1][C:2]([C:4]1[S:5][C:6](/[CH:9]=[C:20](/[S:17]([CH2:16][C:15]2[CH:23]=[CH:24][CH:25]=[C:13]([C:12]([F:27])([F:11])[F:26])[CH:14]=2)(=[O:19])=[O:18])\[C:21]#[N:22])=[CH:7][CH:8]=1)=[O:3]
Reactant: N#CCS(=O)(=O)Cc1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1ccc(C=O)s1
Product: N#C/C(=C\c1ccc(C(N)=O)s1)S(=O)(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
Reaction of 2-aminocarbonylthiophen-5-carboxaldehyde and 3-trifluoromethylbenzylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-aminocarbonylthien-5-yl)-2-[3-(trifluoromethyl) benzylsulfonyl]acryionitrile
Reaction SMILES: [CH3:1][C:2]1[CH:3]=C([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)C#N.Cl.[C:17]([OH:20])(=[O:19])[CH3:18]>>[CH3:3][C:2]1[CH:1]=[C:18]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:17]([OH:20])=[O:19]
Reactant: CC(=O)O
Reactant: Cc1cc(C#N)ccc1N1CCOCC1
Agent: Cl
Product: Cc1cc(C(=O)O)ccc1N1CCOCC1
Yield: 91 %

Procedure:
To a solution of 3-methyl-4-morpholinobenzonitrile (1.0 g, 4.9 mmol) in glacial acetic acid (10 mL) was added a 20% aqueous hydrochloric acid solution (60 mL) and the reaction was heated at reflux for 35 h. The acetic acid was evaporated in vacuo and the remaining water solution was alkalized with 2 M aqueous sodium hydroxide solution to pH 8. The solution was washed, twice, with chloroform and the water phase was adjusted to pH 4 with a 2 M aqueous hydrochloric acid solution. The product was filtered off and dried in vacuo to afford 1.0 g (91% yield) of the title compound as white crystals: mp 220-221° C.; EIMS (70 eV) m/z (relative intensity) 221 (100, M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(CO)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Benzyloxy-4-nitrobenzaldehyde (10.3 g, 0.040 mol) is dissolved in methanol (120 mL) with heating and then cooled to 0° C. To this stirred solution, sodium borohydride (1.5 g, 0.40 mol) is added in portions over a period of 5 min. The mixture is allowed to warm to ambient temperature and stirred overnight. The solvent is removed under reduced pressure and EtOAc is added. The organic layer is washed with 1N HCl and brine, dried over sodium sulfate/magnesium sulfate, and concentrated to afford (3-benzyloxy-4-nitrophenyl) -methanol as a yellow-brown solid: MS (M+NH4)+=277.
Reaction SMILES: [CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])[C@H:6](O)[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)[F:36])(=O)=O>C(Cl)Cl>[CH2:1]([C@@H:5]([C:12]([N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])[C@@H:6]([F:36])[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@H](O)C(=O)OC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)[C@@H](F)C(=O)OC
Temperature: -20 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To methyl 3-(R)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-ylcarbonyl)-2-(S)-hydroxypropionate G-3 (5 mmol) in DCM (5 mL) was added pyridine (15 mmol), the reaction was cooled to −20° C., then triflic anhydride was added (7.5 mmol). The solution was stirred for 1 hour, then washed with aqueous citric acid, sodium bicarbonate and brine, then dried (Na2SO4) and concentrated. The intermediate triflate was then resuspended in DCM and cooled to −50° C. Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (5 mmol) and the solution allowed to warm to rt. The reaction mixture was washed with aqueous sodium bicarbonate and brine, dried (Na2SO4) and concentrated then purified on silica gel (ethylacetate/hexanes) to afford 2.3 mmol (45%) of methyl 3-(S)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-1-yl-carbonyl)-2-(R)-fluoropropionate G-4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[N:6][CH:7]=1.Cl[C:11]1[CH:16]=CC(C#C)=CN=1>>[C:11]([C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[N:6][CH:7]=1)#[CH:16]
Reactant: C#Cc1ccc(Cl)nc1
Reactant: COc1cncc(Br)c1
Product: C#Cc1cncc(OC)c1

Procedure:
5-Ethynyl-3-methoxy pyridine was prepared from 5-bromo-3-methoxy-pyridine (Frontier) in the same manner as 2-chloro-5-ethynyl-pyridine (Example 1).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19]=[O:20])=[CH:13][CH:12]=1.CO.[OH-].[K+]>ClCCl>[Cl:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[OH:20])=[CH:13][CH:12]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: COc1nc(Cl)ccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1nc(Cl)ccc1C(O)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine (1, 0.455 g, 3.85 mmol) and 6-chloro-2-methoxypyridine-3-carbaldehyde (26, 0.661 g, 3.85 mmol) was added methanol (10 mL) followed by potassium hydroxide (0.310 g, 5.52 mmol). The reaction was allowed to stir at room temperature overnight. The reaction was extracted with diethyl ether/ethyl acetate and water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and volatiles were removed by rotary evaporation to provide a solid that was treated with dichloromethane and stored in a freezer overnight. The white solid was collected by vacuum filtration and dried in vacuo to give 613 mg of compound 27 (2.12 mmol, 55%). MS (ESI) [M+H+]+=290.1.
Reaction SMILES: [C:1]1([C@@H:7]([CH2:11][CH2:12][OH:13])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]([O-])=O.[Na+]>OS(O)(=O)=O>[C:1]1([C@H:7]([NH2:14])[CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@H](CCO)c1ccccc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@H](CCO)c1ccccc1
Temperature: 2.5 °C

Procedure:
The hydrazide of (R)-2-phenyl-4-hydroxybutanoic acid (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (R)-1-phenyl-3-hydroxypropylamine is isolated as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1Br.[NH2:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][CH2:23][N:17]3[CH2:16][C@@H:15]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@@H:14]23)[CH:20]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][CH2:23][N:17]3[CH2:16][C@@H:15]3[CH2:24][NH:25][CH2:26][C@@H:14]23)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCc4cc(N)cc(c43)[C@@H]2C1
Reactant: Clc1cccc(Br)c1Cl
Product: Clc1cccc(Nc2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c1Cl

Procedure:
Using 2,3-dichlorobromobenzene and following the procedures described in EXAMPLE 72, (±)-trans tert-butyl 2-amino-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate was converted into the title compound of EXAMPLE 74 as an off-white powder. 1H NMR (300 MHz, CDCl3) δ 1.25 (br s, 1H), 1.95-2.05 (m, 2H), 2.10-2.30 (m, 1H), 2.80 (m, 4H), 2.95 (t, 1H, J=9.5 Hz), 3.30-3.55 (m, 5H), 3.54 (dd, 1H, J=9.5, 7.0 Hz), 5.93 (br s, 1H), 6.50 (s, 1H), 6.71 (s, 2H), 6.74-6.79 (m, 1H), 6.92 (t, 1H, J=8.1 Hz). LRMS (ES)+: 374 (M+H)+.