Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16](=[O:36])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[O:32]COC.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[CH3:14][O:15][C:16](=[O:36])[C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[C:10]([C:12]#[N:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:19][C:18]=1[OH:32]
Reactant: N#Cc1cc(Cl)nc2ccccc12
Reactant: COCOc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(C#N)c3ccccc3n2)cc1O
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
2-Chloroquinoline-4-carbonitrile (0.15 g), 2-methoxymethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl)benzoic acid methyl ester (0.26 g), tetrakis(triphenylphosphine)palladium (0.045 g) and sodium carbonate (0.16 g) were suspended in a mixed solvent of dimethoxyethane (2 mL) and water (0.5 mL), and the resulting mixture was stirred at 150° C. for 30 minutes using microwave reactor (Biotage). To the reaction mixture was added ethyl acetate, and the mixture was filtered through a Celite pad. The filtrate was poured into water. The organic layer was washed with water and brine, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0-66/34) to give 4-(4-cyanoquinoline-2-yl)-2-hydroxy-benzoic acid methyl ester (0.1 g). To a mixed solution of this compound (0.1 g) in tetrahydrofuran (4 mL), ethanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.060 g), and the mixture was stirred at room temperature overnight. To this reaction mixture was added 2 mol/L hydrochloric acid (2.8 mL), and the mixture was stirred at 50° C. for 10 hours. After the reaction mixture was cooled to room temperature, the precipitated solid was collected by filtration, and dried under reduced pressure to give the title compound (0.068 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:15][S:16][CH2:17][CH2:18][NH2:19]>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:19]([CH2:18][CH2:17][S:16][CH3:15])[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Reactant: CSCCN
Solvent: CC(=O)O
Product: CSCCN1C(=O)C(Cl)=C(c2ccccc2)C1=O
Yield: 53.9 %

Procedure:
A solution of 3-chloro-4-phenylfuran-2,5-dione (1.00 mmol, 209 mg) and 2-aminoethyl methyl sulphide (1.00 mmol, 91 mg) in glacial acetic acid (2 mL) was heated in a microwave reactor at 120° C. for two min. After cooling, the solvent was evaporated at reduced pressure. The residue was partitioned between water and CH2Cl2. The organic phase was evaporated and the crude product was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 152 mg (54%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.97-7.90 (m, 2H), 7.53-7.47 (m, 3H), 3.86 (t, J=6.8 Hz, 2H), 2.78 (t, J=6.8 Hz, 2H), 2.16 (s, 3H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=4)[CH2:20][CH2:19][C:18]4(OCC[O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O.CO>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=4)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2(C#Cc3cccc(C(=O)O)c3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(C2(C#Cc3cccc(C(=O)O)c3)CCC(=O)CC2)cc1OC1CCCC1

Procedure:
A solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-1,1-(ethylenedioxy)-4-(3-carboxyphenylethynyl)cyclohexane (0.11 g, 0.23 mmol) in tetrahydrofuran (6 mL) containing 3N hydrochloric acid (0.7 mL) was heated under an argon atmosphere at 55°-70° C. for 2 h. The cooled reaction mixture was concentrated in vacuo and the residue was partitioned between cold water and methylene chloride. The organic phase was washed with saturated brine solution, was dried over magnesium sulfate and was evaporated. The residue was chromatographed (silica), eluting with methylene chloride/methanol/water (90/5/0.25 to 90/10/0.5) and was concentrated in vacuo. The residue was dissolved in methanol and was foamed in vacua to afford a white fractured glass. Anal. (C27H28O5.1/4 H2O.1/4 CH3OH) calcd: C 73.55, H 6.68, found: C 73.51, H 6.66. 1H-NMR (400 MHz, CDCl3) δ 8.22 (t, J=1.5 Hz, 1H), 8.09 (d-d, J=1.3 Hz;J=7.9 Hz, 1H), 7.72 (d-d, J=1.3 Hz, J=7.8 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.22 (d, J=2.2, 1H), 7.13 (d-d, J=2.3 Hz, J=8.4 Hz, 1H), 6.88 (d, J=8.5 Hz,1H), 4.82 (p, 1H), 3.86 (s, 3H), 3.25 (d, J=20 Hz, CH3OH, 0.55H), 3.04 (d-t, J=5.8 Hz, J=14.5, 1.7H), 2.50 (d,br, J=14.8, 1.8H), 2.4-2.2 (m, 4H), 2.0-1.5 (m).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([F:9])=[C:6]([F:8])[F:7].[C:10](Cl)(Cl)=[S:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:9][C:5](=[C:6]([F:8])[F:7])[CH2:4][CH2:3][N:2]=[C:10]=[S:11]
Reactant: NCCC(F)=C(F)F
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: FC(F)=C(F)CCN=C=S
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a stirred solution of 0.4 gram (0.0027 mole) of 4-amino-1,1,2-trifluoro-1-butene hydrochloride in 15 ml of chloroform was added 0.3 gram (0.003 mole) of thiophosgene, followed by 0.7 ml (0.009 mole) of triethylamine. Upon completion of addition the reaction mixture was stirred at ambient temperature for three hours. The reaction mixture was then washed in succession with one 25 ml portion of water, two 25 ml portions of aqueous 5% sodium hydroxide, and, finally, one 25 ml portion of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 0.3 gram of (3,4,4-trifluoro-3-butenyl) isothiocyanate as an oil. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:23]([O:25]CC)=[O:24])[CH:15]([C:19]([F:22])([F:21])[F:20])[O:16]3)=[CH:11][CH:10]=2)=[O:8])[CH:2]=1.[OH-].[Na+]>CO.C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:23]([OH:25])=[O:24])[CH:15]([C:19]([F:21])([F:22])[F:20])[O:16]3)=[CH:11][CH:10]=2)=[O:8])[CH:2]=1
Reactant: CCOC(=O)C1=Cc2ccc(C(=O)c3cccnc3)cc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2ccc(C(=O)c3cccnc3)cc2OC1C(F)(F)F
Temperature: 50 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
The ester from Step 1 (38 mg, 0.08 mmole) was dissolved in 0.5 mL methanol and 0.5 mL THF. Sodium hydroxide (2.5 N) (0.2 mL, 0.5 mmole) was added to above solution and stirred at 50° C. for 4 h. The crude was purified by RPHPLC with 45% ACN in water to afford a white solid (15 mg,41%): LCMS m/z 350.05 (M+H). 1H NMR (DMSO-d6/400 MHz) 8.87 (s, 1H), 8.83 (d, 1H, J=6.8 Hz), 8.11 (d, 1H, J=10.4 Hz), 7.94 (s,1H), 7.69 (d, 1H, J=14 Hz), 7.60 (m, 1H), 7.42 (d, 1H, J=10.4 Hz), 7.34 (s, 1H), 6.03 (q, 1H, J=9.6 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([C:20]([F:23])([F:22])[F:21])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:15]1[C:14]2[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[N:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(C(F)(F)F)sc1N
Reactant: N#Cc1cnccn1
Product: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyrazine and 2-amino-5-trifluoromethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:6]([CH3:18])=[C:7]([N+:15]([O-:17])=[O:16])[C:8](O)=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)(=[O:4])=[O:3].O.P(Cl)(Cl)([Cl:22])=O>CN(C)C1C=CC=CC=1>[Cl:22][C:8]1[C:7]([N+:15]([O-:17])=[O:16])=[C:6]([CH3:18])[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1c(S(C)(=O)=O)cc([N+](=O)[O-])c(O)c1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: O
Product: Cc1c(S(C)(=O)=O)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a slurry of 4-(methylsulfonyl)-2,6-dinitro-m-cresol (4.9 g.) in phosphorus oxychloride (21 ml.), N,N-dimethylaniline is added at such a rate that the temperature does not exceed 34° C. When the addition is complete and the initial exotherm has subsided, the mixture is heated to 60°-65° C. and held there for 10 minutes. The reaction mixture is carefully decomposed by pouring into a ice and water mixture. The desired product as a precipitated solid (4.49 g.) is collected and recrystallized from benzene-pet ether to give a solid with m.p. of 174°-175° C. Analysis: Calcd. for C8H7ClN2O6S: C, 32.59; H, 2.37; N, 9.50; S, 10.86; Cl, 12.05. Found: C, 32.62; H, 2.37; N, 9.39; S, 10.65; Cl, 12.25.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[CH:6][CH:5]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>>[OH:1][CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]([OH:12])[CH2:11][NH:18][CH:15]([CH3:17])[CH3:16])=[CH:6][CH:5]=1
Reactant: CC(C)N
Reactant: OCCc1ccc(OCC2CO2)cc1
Product: CC(C)NCC(O)COc1ccc(CCO)cc1

Procedure:
10 g of 1-[4-(2-hydroxyethyl)phenoxy]-2,3-epoxypropane produced in Example 1 was refluxed in 50 mL of isopropylamine for 16 hrs. The amine was removed under reduced pressure, the residue dissolved in warm toluene and the toluene removed under reduced pressure. On standing the oil solidified. Yield=12.8 g (98%). After recrystallization in petroleum ether this solid had a melting point of 77°-78° C.
Reaction SMILES: [CH2:1]([C:3]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([CH2:16][CH3:17])[C:4]=1[CH2:5][C:6]1[NH:7][CH2:8][CH2:9][N:10]=1)[CH3:2].C1(N(Cl)C(=O)N(Cl)C(=O)N1Cl)=O.C1CCN2C(=NCCC2)CC1>>[CH2:1]([C:3]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([CH2:16][CH3:17])[C:4]=1[CH2:5][C:6]1[NH:10][CH:9]=[CH:8][N:7]=1)[CH3:2]
Reactant: CCc1ccc(F)c(CC)c1CC1=NCCN1
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1ccc(F)c(CC)c1Cc1ncc[nH]1

Procedure:
2-(2,6-Diethyl-3-fluoro-benzyl)-1H-imidazole was prepared from 2-(2,6-diethyl-3-fluoro-benzyl)-4,5-dihydro-1H-imidazole (Example 197), TCCA and DBU in analogy to Example 194e): light yellow crystals; MS (ISP): 233.3 ([M+H]+).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:35])([F:34])[C:12]1[CH:26]=[C:25]2[C:15]([C:16]([OH:33])=[C:17]([C:28](OCC)=[O:29])[C:18](=[O:27])[C:19]32[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=1.Cl.[C:37]([O:41][C:42](=[O:45])[CH2:43][NH2:44])([CH3:40])([CH3:39])[CH3:38]>O1CCOCC1.CCOCC>[F:10][C:11]([F:34])([F:35])[C:12]1[CH:26]=[C:25]2[C:15]([C:16]([OH:33])=[C:17]([C:28]([NH:44][CH2:43][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:45])=[O:29])[C:18](=[O:27])[C:19]32[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C2(CCOCC2)C1=O
Temperature: 75 °C
Reaction time: 17 h
Yield: 79.6 %

Procedure:
DIPEA (0.931 mL, 5.35 mmol) was added to a mixture of ethyl 7-trifluoromethyl-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (1.32 g, 3.56 mmol) and glycine tert-butyl ester hydrochloride (0.717 g, 4.28 mmol) in dioxane (30 mL). The reaction mixture was stirred at 75° C. for 17 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude solid was suspended in ether and filtered to give the desired compound as a light yellow solid (1.29 g). MS (m/e)=456.2 (M+H)+.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[CH3:30][C:31]([C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1)=[O:32]>ClCCl>[C:33]1([C:31]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:6]=2)([OH:32])[CH3:30])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CC(=O)c1cccc2ccccc12
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2ccccc12

Procedure:
A mixture of 4-iodo-1-tritylimidazole (commercially available) (4.5 g, 10.3 mmol) in dichloromethane (50 mL) at 22° C. was treated with ethyl magnesium bromide (3.48 mL, 10.4 mmol, 3M in ether) and allowed to react for 1 h. Anhydrous CeCl3 (3.3 g, 13.4 mmol) was added and the mixture was stirred for 30 m. A solution of 1-acetonaphthone (commercially available from Aldrich) (2.6 g, 15.9 mmol) in dichloromethane was added via syringe at 22° C. and stirred for 16 h. The mixture was quenched with a sat. solution of ammonium chloride (50 mL). The residue was isolated in a typical aqueous workup and purified by chromatography on silica gel with 50% EtOAc:hexane to give 1-naphthalen-1-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate H1) as a solid, 2.44 g (49%).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[CH2:11]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([N:4]3[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N+:2]([O-:1])=[N:3]3)=[O:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: On1nnc2ccccc21
Reactant: CCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCCCCc1ccc(-c2ccc(C(=O)n3n[n+]([O-])c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 1-hydroxybenzotriazole (501 mg) and 4-(4-heptylphenyl)benzoic acid (1 g) in dichloromethane (30 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (839 mg), and stirred for 3 hours at ambient temperature. The reaction mixture was added to water. The organic layer was separated, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-[4-(4-heptylphenyl)benzoyl]benzotriazole 3-oxide. To a solution of The Starting Compound (2.49 g) and 1-[4-(4-heptylphenyl)benzoyl]benzotriazole 3-oxide in N,N-dimethylformamide (25 ml) was added 4-(N,N-dimethylamino)pyridine (381 mg), and stirred for 12 hours at ambient temperature. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration, and dried under reduced pressure. The residue was dissolved in water, and subjected to column chromatography on ion exchange resin (DOWEX-50WX4) eluting with water. The fraction containing the object compound were combined, and subjected to column chromatography on ODS (YMS-gel.ODS-AM-S-50) eluting with 30% acetonitrile aqueous solution. The fractions containing the object compound were combined, and evaporated under reduced pressure to remove acetonitrile. The residue was lyophilized to give The Object Compound (32) (1.99 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[O:30]1[CH2:35][CH2:34]OCC1>>[C:5]([NH:7][CH2:34][CH2:35][O:30][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])(=[O:6])[CH3:4]
Reactant: C1COCCO1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCCNC(C)=O)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and N-acetylethiazolamine in dioxane. ES-MS m/e (%): 472 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])[CH3:3].C(OC([N:22]1[CH2:28][CH2:27][CH2:26][C@H:23]1[CH2:24]O)=O)(C)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl>[CH3:1][N:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:24][CH:23]1[CH2:26][CH2:27][CH2:28][NH:22]1)[C:7]([O:9][CH3:10])=[O:8])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: COC(=O)c1ccc(O)c(N(C)C)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCC2CCCN2)c(N(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
To a stirred mixture of methyl 3-(N,N-dimethylamino)-4-hydroxybenzoate (0.817 g, 4.18 mmol), N-tert-butoxycarbonylprolinol (0.926 g, 4.60 mmol), Ph3P (1.21 g, 4.60 mmol) in THF (20 mL) was added dropwise DIAD (95%) (0.953 mL, 4.60 mmol) at 0° C. The resulting mixture was heated under reflux for 41 hr. After cooling, the mixture was evaporated off in vacuo. The residue was chromatographed on silica-gel with EtOAc-n-hexane (1:10 to 1:6, v/v) as eluent to give a syrup which was used for the subsequent reaction without further purification. This syrup was dissolved in CH2Cl2 (10 mL) and added TFA (10 mL). After the solution was stirred for 5 hr at room temp, the solution was evaporated in vacuo. Water was added to the residue and washed with CHCl3. The aqueous layer was neutralized by the addition of sat. NaHCO3 and extracted with CHCl3. The extract was dried over Na2SO4 and evaporated in vacuo to afford 1.03 g (89%) methyl 3-(N,N-dimethylamino)-4-(2-pyrrolidinylmethoxy)benzoate as a gum.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4].[Br:22]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:22])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CC(C)N(C(=O)C(F)(F)F)CC2C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Reaction time: 8 h

Procedure:
A solution N-trifluoroacetyl-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.452 g, 1.50 mmol) in acetonitrile (20 mL) was treated with N-bromosuccinimide (0.294 g, 1.65 mmol) and stirred overnight at 20 C. The product mixture was diluted with EtOAc (100 mL), washed with sodium bisulfite (50 mL) and brine (50 mL), dried with Na2SO4 and concentrated. Flash chromatography (20% EtOAc in hexane, silica) resulted in a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.32 (s, 1 H), 6.62 (m, 1 H), 4.37 (m, 1 H), 3.87 (s, 3 H), 3.81 (m, 1 H), 3.28−3.10 (m, 3 H), 2.73 (m, 1 H), 1.31 (m, 3 H), 1.25 (m, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25](Br)=[O:26].[NH2:28][CH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:24][C:25]([NH:28][CH:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:26])=[CH:21][CH:22]=1
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)NCC2
Reactant: NC1CCc2ccccc21
Product: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)N(CC(=O)NC1CCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-(4-Fluoro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-indane
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:10]2C(O)=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1.C1C[O:54][CH2:53]C1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:10]2[N:43]([CH2:44][C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)[CH:53]=[O:54])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1c(OCc2ccccc2)c2ccccc2n1Cc1ccc(F)cc1
Reactant: NCc1cccnc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=CN(Cc1cccnc1)c1c(OCc2ccccc2)c2ccccc2n1Cc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
Following the procedure describing the preparation of example 166, 1-[(4-fluorophenyl)methyl]-3-(phenylmethoxy)indole-2-carboxylic acid (50 mg) in THF (3.0 mL) at 0° C. was treated with i-Pr2NEt (0.1 mL), MsCl (10 μL), stirred for 0.5 hours and then added 3-(aminomethyl)pyridine (20 mg). After work-up and purification by flash chromatography eluting with 30% EtOAc/hexanes the title amide (27.4 mg) was isolated as a light yellow oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([N:15]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30]OS(C4C=CC=C([N+]([O-])=O)C=4)(=O)=O)[O:27][C:26]3=[O:44])=[CH:21][C:20]=2[F:45])[CH2:16]1)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]>CN(C=O)C>[C:5]([N:15]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@@H:28]([CH2:30][N:1]=[N+:2]=[N-:3])[O:27][C:26]3=[O:44])=[CH:21][C:20]=2[F:45])[CH2:16]1)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(OCc1ccccc1)N1CC(c2ccc(N3C[C@H](COS(=O)(=O)c4cccc([N+](=O)[O-])c4)OC3=O)cc2F)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 16 h

Procedure:
A mixture of sodium azide (1.44 g, 22.1 mmol) and (R)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-[[(3-nitrophenylsulfonyl)oxy]-methyl]-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 6, 2.60 g, 4.44 mmol) in DMF (30 mL) was stirred for 16 hr, then filtered. The solvent was removed at 38°/0.75 mm and the residue extracted with ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL). After drying over magnesium sulfate, filtration and evaporation gave a yellow oil. Chromatography over silica gel (150 g, 40-60 μm) eluting with 1-3% methanol-methylene chloride gave the title compound as a pale yellow foam. FAB-HRMS: theory 426.1577 (M+1); meas. 426.1580.