Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][C:3]1=[O:12]>C1COCC1.[Cl-].[NH4+].[Zn]>[Cl:11][C:9]1[C:10]2[CH2:2][C:3](=[O:12])[NH:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=C1Nc2ncnc(Cl)c2C1(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: O=C1Cc2c(Cl)ncnc2N1
Reaction time: 3 h

Procedure:
Zinc (6.05 g, 92.56 mmol) was added to a solution of 5,5-dibromo-4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Step A (3.03 g, 9.26 mmol) in THF (20 mL) and saturated aqueous ammonium chloride (5 mL). After 3 h, the reaction mixture was concentrated in vacuo and purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3 CN:CF3 CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=170 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C[S-:13].[Na+].Cl>CN(C)C(=O)C.C(OCC)(=O)C>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([SH:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[S-]
Reactant: Brc1ccc2ncccc2c1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Sc1ccc2ncccc2c1
Temperature: 150 °C

Procedure:
To a solution of 6-bromoquinoline (0.81 g, 3.89 mmol) in N,N-dimethylacetamide (4 mL) was added sodium methyl mercaptide (2.0 g, 28.5 mmol). The mixture was heated at 150° C. for 2 h. After cooling, the mixture was diluted with ethyl acetate, and neutralized with aqueous 1N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was directly used in the next step without further purification. (0.50 g, 79%) LCMS: (M+H)+=161.9.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14](O)=[O:15].C(N=C=NC(C)C)(C)C.O>N1C=CC=CC=1>[CH2:19]([O:18][C:12](=[O:17])[CH2:13][C:14]([NH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1)=[O:15])[CH3:20]
Reactant: CCOC(=O)c1cc(N)[nH]n1
Reactant: CCOC(=O)CC(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CC(=O)Nc1cc(C(=O)OCC)n[nH]1

Procedure:
To a solution of ethyl 5-aminopyrazole-3-carboxylate (5.00 g, 26.1 mmol) and ethyl hydrogen malonate (3.62 g, 27.4 mmol) in pyridine (130 mL) was added N,N′-diisopropylcarbodiimide (4.28 g, 33.9 mmol) at 0° C. After being stirred at same temperature, the reaction mixture was poured into water. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (chloroform to chloroform:methanol=19:1) and triturated with diisopropyl ether to give ethyl 5-[(3-ethoxy-3-oxopropanoyl)amino]-1H-pyrazole-3-carboxylate. MS (APCI): m/z 270 (M+H).
Reaction SMILES: [N+]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH:5]=1)([O-])=O.[F-:21].[K+]>>[F:21][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[CH:5]=1
Reactant: Nc1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cc1
Reactant: [F-]
Agent: [K+]
Product: Nc1ccc(-c2cc(F)c3ccccc3n2)cc1
Yield: 42 %

Procedure:
4-(4-Fluoroquinolin-2-yl)aniline T492 was prepared by using general procedure M from 4-(4-Nitroquinolin-2-yl)aniline (6 mg, 0.02 mmol) and KF (26 mg, 0.45 mmol), The crude product was purified by silica chromatography to afford 4-(4-fluoroquinolin-2-yl)aniline as a yellow solid (2 mg, 42%). 1H NMR (400 MHz, CDCl3): δ 8.11 (m, 1H), 8.03 (m, 1H), 8.00 (m, 2H), 7.72 (m, 1H), 7.51 (m, 1H), 7.48 (d, J=11.6 Hz, 1H), 6.80 (m, 2H), 3.93 (br s, 2H); MS (ESI): 239 (M+H+).
Reaction SMILES: C(O[C:4](=O)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)C.CCOCC>C1COCC1>[CH3:4][NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)NC1CCCc2ccccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN[C@H]1CCCc2ccccc21
Temperature: 75 °C
Reaction time: 2 h

Procedure:
(1,2,3,4-Tetrahydro-naphthalen-1-yl)carbamic acid ethyl ester (5.0 g, 22.8 mmol) is added slowly under nitrogen to a suspension of LiAlH (2.6 g, 68 mmol) in THF (50 mL). The resulting mixture is heated at 75° C. with stirring for 2 h. On cooling, Na2SO4.10H2O (15.0 g) and ether (100 mL) are added to the mixture. The resulting mixture is stirred at room temperature for 1 hour, filtered through celite, and concentrated in vacuo. 1 N HCl (20 mL) and ether (20 ML) are added to the residue. The organic layer is separated and discarded. The aqueous layer is basified with 1 N NaOH and extracted with CH2Cl2 (2×25 mL). The combined extract is washed with water (2×), dried (Na2SO4) and concentrated to give (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine as an oil. [α]RT=−10.6 (0.02, EtOH). 1H NMR (CDCl3) 7.30 (m, 1H), 7.06-7.20 (m, 3H), 3.66 (t, 1H), 2.78 (m, 2H), 2.50 (s, 3H), 1.70-2.00 (m, 4H).
Reaction SMILES: [CH3:1][C:2]12[CH2:20][CH:5]([C:6]3([CH3:19])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2>C(Cl)(Cl)Cl>[CH3:1][C:2]12[CH2:20][CH:5]([C:6]3([CH3:19])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16]([O:18][C:8]4[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:9]=4)=[O:17])[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: CC12CCC(C1)C1(C)Oc3ccc(C(=O)O)cc3C21C
Solvent: ClC(Cl)Cl
Product: CC12CCC(C1)C1(C)Oc3ccc(C(=O)Oc4ccc(C(=O)O)cc4)cc3C21C

Procedure:
The same synthesis as that carried out in the case of Example 11, from (+)-(1,2,3,4,4a,9b-hexahydro-1,4a,9b-trimethyl-1,4-methanodibenzofuran-8-yl)carboxylic acid, followed by hydrogenation under the same conditions as in Example 21, results in the laevorotatory enantiomer 13 exhibiting the same physicochemical characteristics as those of the enantiomer 12; αD =-3.2° (c=1, CHCl3).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[C:10]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1>C(OCC)(=O)C.ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[C:10]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(CO)c(NC3CCOCC3)c2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(C=O)c(NC3CCOCC3)c2)CC1
Reaction time: 5 h
Yield: 50.3 %

Procedure:
85 mg (0.982 mmol) of manganese dioxide is added at room temperature to a solution of (4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl)methano 1 (100 mg, 0.327 mmol) in a mixture of ethyl acetate (10 ml) and dichloromethane (9 ml). The reaction mixture is placed in an ultrasonic bath for 5 hours. The reaction mixture is filtered, the solvents are evaporated and the crude product is purified by chromatography to yield 50.0 mg (yield=50.3%) of (4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzaldehyde in the form of a white solid.
Reaction SMILES: [Na].[I:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH2:11][CH2:12][OH:13].[Cl-].[NH4+]>C(O)C>[I:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1
Reactant: OCCCl
Reactant: Oc1ccc(I)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: OCCOc1ccc(I)cc1
Yield: 50 %

Procedure:
Sodium (0.53 g) was dissolved in ethanol (50 ml) under nitrogen and 4-iodophenol (5.0 g), and 2-chloroethanol (3.93 g), were added successively. The mixture was refluxed for 18 h, treated with saturated aqueous ammonium chloride (50 ml) and evaporated. The aqueous residue was extracted with ER (3×100 ml) and the dried extract was evaporated onto silica (Merck 9385; 50 ml) and purified by [C] eluted with cyclohexane-ER (7:3) followed by cyclohexane-ER (1:1) to give the title compound (3.0 g) m.p. 76°-77°.
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=C[C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:28]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[CH2:45][CH2:44][CH3:43]
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Solvent: CC(=O)Cl
Product: CCCC(=O)N1CC=C(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 278, substituting butyryl chloride for acetyl chloride and N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (s, 1H), 7.55-7.58 (m, 2H), 7.27-7.38 (m, 6H), 6.09-6.11 (m, 1H), 4.77 (s, 4H), 4.08-4.14 (m, 2H), 3.58-3.68 (m, 2H), 2.39-2.51 (m, 2H), 2.34 (dt, J=19.8, 7.3 Hz, 2H), 1.46-1.62 (m, 2H), 0.88-0.93 (m, 3H); MS (ESI(+)) m/e 390 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:7]=[CH:6][C:5]=1[C:19](=[O:21])[CH3:20].[NH4+].[Cl-].[CH2:24]1COCC1.CS(C)=O>C1COCC1.CC(OC)(C)C>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:7]=[CH:6][C:5]=1[C:19]1([CH3:24])[CH2:20][O:21]1
Reactant: CC(=O)c1ccc(Oc2ccc(F)cc2F)cc1Cl
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: CC1(c2ccc(Oc3ccc(F)cc3F)cc2Cl)CO1
Reaction time: 8 h

Procedure:
NaH (4.39 g) was suspended in THF/DMSO (400 mL) and Me3S—I (35.4 g) was added carefully in small portions. 30 min after completed addition, a solution of 1-[2-chloro-4-(2,4-difluorophenoxy)phenyl]ethanone (25 g) in 50 mL THF was added. After stirring overnight, the reaction mixture was diluted with MTBE and sat aq. NH4Cl-Sol was added. The organic phase was separated and the aqueous phase was three times extracted with MTBE (300 mL). the combined organic layers were washed with sat NaHCO3-solution, sat aq. NaCl and dried over Na2SO4. 2-[2-chloro-4-(2,4-difluorophenoxy)phenyl]-2-methyl-oxirane (23.5 g) was obtained as a brown oil and used in the next step without further purification. 1H-NMR (CDCl3; 400 MHz) (ppm)=1.65 (s, 3H); 2.8-3.0 (dd, 2H); 6.75-7.1 (m, 5H); 7.4 (d, 1H).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9](=[O:13])[O:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C=O.[C:16](=O)([O-])[O-:17].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[OH:17][CH2:16][N:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)[C:9](=[O:13])[O:10][CH2:11][CH3:12]
Reactant: CCOC(=O)NCC1CC=CCC1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Cs+]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)N(CO)CC1CC=CCC1
Yield: 60.3 %

Procedure:
A sample of ethyl cyclohex-3-en-1-ylmethylcarbamate (5.1 g, 28 mmol) in 500 mL of THF was treated with paraformaldehyde (16.7 g, 560 mmol), potassium carbonate (7.8 g, 56 mmol) and cesium carbonate (1.8 g, 5.6 mmol). The mixture was stirred vigorously and heated under reflux for 4 h. The mixture was cooled, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel, using 3:1 hexane/ethyl acetate as eluent, to give a colorless oil (3.6 g, 61%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][NH:12][CH3:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23].O>C(Cl)Cl>[CH3:13][N:12]([CH2:11][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1])[C:21](=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)Cl
Reactant: CNCc1c(C)[nH]c2ccccc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1c(C)[nH]c2ccccc12

Procedure:
To a solution of 2-methyl-3-(methylaminomethyl)indole (1.5 g, 8.6 mmole) and triethylamine (1.7 g, 17.3 mmole) in CH2Cl2 at 5° C. under a nitrogen atmosphere was added acryloyl chloride (0.86 g, 9.48 mmole). After 1 hr the reaction solution was poured into H2O (100 mL) and the layers were separated. The organic fraction was washed with H2O (100 mL) followed by brine and then dried over Na2SO4. Concentration under vacuum gave the title compound as an orange oil which solidified under high vacuum: MS (ES) m/e 457 (2M+H)+. This material was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:5]=1[C:6]#[N:7])([O-])=O.S(=O)(=O)(O)[OH:16].[OH-].[Na+]>O1CCCC1>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:5]=1[C:6]([NH2:7])=[O:16]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1c(N)cccc1N
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5 g (25.373 mmol) 2,6-dinitro-benzonitrile is combined with 20 ml of an aqueous 80% sulphuric acid and stirred for 2 h at 80° C. The reaction mixture is combined with 100 ml of tetrahydrofuran and neutralised with 10% aqueous sodium hydroxide solution. The organic phase is separated off, combined with another 100 ml of tetrahydrofuran and 200 mg palladium on charcoal and stirred for 20 h at 8 bar H2 pressure and 25° C. The solids are filtered off. The filtrate is combined with 300 ml of ethyl acetate and extracted with saturated potassium hydrogen carbonate solution. The organic phase is separated off, dried and the solvent is eliminated in vacuo. The residue is purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 7% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution are added.
Reaction SMILES: C([NH:5][C:6](=O)[O-:7])(C)(C)C.[C:9]([C:17]1OC=[CH:20][C:21]=1NC(=O)OC(C)(C)C)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[NH2:5][C:6]1[O:7][CH:20]=[CH:21][C:17]=1[C:9](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccoc1C(=O)c1ccccc1
Reactant: CC(C)(C)NC(=O)[O-]
Product: Nc1occc1C(=O)c1ccccc1

Procedure:
Hydrolysis of the t-butylcarbamate according to the procedure for compounds 5 and 6 in which compound 28 is substituted for compound 4 gives the 2-amino-3-benzoylfuran, compound 29.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1.[OH-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9]([N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reactant: C1CSCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Brc1ccc2c(c1)N=C(N1CCSCC1)c1cccc3c1N2CC3
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A mixture of 7.88 g (0.025 mole) of 9-bromo-1,2-dihydro-benzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one and 1200 ml of toluene was heated under nitrogen, with stirring, until a solution resulted. Then there was added 25.8 g (0.250 mole) of thiomorpholine, followed by 14.2 g (0.075 mole) of titanium tetrachloride. The mixture was heated under reflux for 3 hours, cooled to room temperature and treated with 500 ml of 2N sodium hydroxide solution. After stirring vigorously for 15 minutes, the layers were separated. The aqueous phase was extracted with 300 ml of toluene. The toluene layers were combined, washed once with 2N sodium hydroxide solution, twice with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was crystallized from 100 ml of hot methanol to give 8.8 g (88%) of product. Recrystallization from a hot solution of dichloromethane (50 ml, charcoal) to which methanol (100 ml) was added provided the analytical sample, mp 165°-167° C..
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[CH3:10][NH2:11]>>[CH3:10][NH:11][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1
Reactant: CN
Reactant: N#Cc1ccc(Cl)nc1
Product: CNc1ccc(C#N)cn1
Temperature: 80 °C

Procedure:
Four batches of 6-chloro-3-pyridinecarbonitrile (0.40 g, 2.89 mmol) in methylamine (16 mL, 2M solution in THF) were each heated at 80° C. for 30 minutes in a microwave reactor. The reaction mixtures were combined and concentrated in vacuo. The residue was re-dissolved in EtOAc/water and the organic layer was separated, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography; elution with EtOAc/petroleum ether gave the title compound as a white solid (1.46 g). δH (CDCl3, 400 MHz) 8.37 (1H, d), 7.59 (1H, dd), 6.39 (1H, dd), 5.19 (1H, br.s), 2.99 (3H, d). MS (ES): MH+ 134.2.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:18]=3[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7]>[OH-].[Na+]>[F:25][C:24]1[C:18]2[CH:17]=[C:16]([CH2:15][O:14][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:26])=[O:2])[C:5]=3[C:6]([OH:8])=[O:7])[S:20][C:19]=2[CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cccc(OCc2cc3c(F)cccc3s2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(OCc2cc3c(F)cccc3s2)c1C(=O)O
Yield: 86.6 %

Procedure:
A solution of 3-(4-fluoro-benzo[b]thiophen-2-ylmethoxy)-phthalic acid dimethyl ester (1.5 g, 4.0 mmol) in reagent alcohol (120 mL) and 3 N sodium hydroxide (60 mL) was refluxed for two hours. The solution was evaporated and the residue was dissolved in water (100 mL) and washed with methylene chloride (3×100 mL) then acidified to pH around 4. The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined organic layers was washed with water (2×100 mL), dried and concentrated to give 3-(4-fluoro-benzo[b]thiophen-2-ylmethoxy)-phthalic acid as an off-white solid (1.2 g, 84% yield). The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(OCC)(=O)C>O.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:35][CH2:34][CH2:33][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Reactant: NCCN1CCOCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1c(CCCNCCN2CCOCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 35.2 %

Procedure:
5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 g (5.812 g, 15 mmol) obtained from step 6 of Example 1 and 2-morpholin-4-yl-ethylamine (10.725 g, 82.5 mmol) was dissolved in water bath at 30° C. and stirred for 5.5 hours at room temperature. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with ethyl acetate (100 ml) and saturated brine (100 ml), stirred for 5 minutes, and separated into layers. The organic phase was washed with saturated brine (100 ml×4), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3-methyl-5-[3-(2-morpholin-4-yl-ethylamino)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 10a (2.238 g, yield 87%) as a light yellow oil.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[S:16]([OH:19])(=O)=[O:17])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].S(Cl)([Cl:22])=O>N1C=CC=CC=1>[CH2:1]([O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[S:16]([Cl:22])(=[O:19])=[O:17])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCCOc1cc(OC)ccc1S(=O)(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C=CCCCCOc1cc(OC)ccc1S(=O)(=O)Cl
Reaction time: 4 h
Yield: 51 %

Procedure:
To a stirring solution of sulfonic acid 6a (266 mg, 0.9 mmol) in pyridine (2 mL) was added thionyl chloride (0.2 mL, 2.8 mmol) dropwise. The resulting solution was allowed to stir for 4 h and then the reaction mixture concentrated in vacuo. The resulting residue was purified using column chromatography (5:1 hexanes:EtOAc) to give 7a (140 mg, 50%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.63-1.70 (m, 2H), 1.87-1.93 (m, 2H), 2.10-2.16 (m, 2H), 3.88 (s, 3H), 4.14 (t, J=6.2 Hz, 2H), 4.95-5.05 (m, 2H), 5.76-5.86 (m, 1H), 6.51-6.54 (m, 3H), 7.84 (d, J=9.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 24.9, 28.1, 33.1, 55.9, 69.2, 99.9, 104.6, 114.7, 124.3, 131.7, 138.3, 158.7, 166.8.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH:18]=[C:17]([C:19](OCC)=[O:20])[N:16]=[CH:15]2)[CH2:10][CH2:9]1>O1CCCC1.C(OCC)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>[CH3:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([N:14]2[CH:18]=[C:17]([CH2:19][OH:20])[N:16]=[CH:15]2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1cn([C@H]2CC[C@H](C)CC2)cn1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](n2cnc(CO)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Lithium aluminum hydride (92%, 0.31 g) was suspended in tetrahydrofuran (6 mL). The compound (1.50 g) obtained in Step 1 of this Reference Example was dissolved in tetrahydrofuran (6 mL), and this solution was slowly added dropwise to the suspension at 0° C. After stirring at 0° C. for 30 minutes, the reaction solution was diluted with diethyl ether, and saturated aqueous sodium sulfate was added thereto. After stirring at room temperature for 1 hour, the formed inorganic salt was removed by filtration through celite. The filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was washed with a mixed solvent of hexane and ethyl acetate (5:1) to obtain the title compound (1.09 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1ccc(CCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1
Reaction time: 1 h
Yield: 103.4 %

Procedure:
A mixture of 4-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenol (6.00 g, 17 mmol), methyl bromoacetate (2.96 g, 1.83 mL, 19 mmol), potassium carbonate (2.91 g, 21 mmol), potassium iodide (catalyic amount) and acetonitrile (80 mL) was stirred at reflux. After 1 hour, the mixture was cooled, filtered and the solvent removed to leave a crystalline solid that was tritrated with hexanes and filtered to give methyl 2-[4-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetate (7.27 g, 100%). An analytical sample was obtained by recrystallizing a 2.25 g batch from methanol to give 1.70 g of pure material which had m.p. 122°-125° C.