Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([S:11]([OH:13])=[O:12])[CH:10]=1.[OH-].[Na+].[CH:26]1([CH2:29]Br)[CH2:28][CH2:27]1>C(O)C>[Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([S:11]([CH2:29][CH:26]2[CH2:28][CH2:27]2)(=[O:13])=[O:12])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)O
Reactant: BrCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)CC1CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 14 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzenesulfinic acid (1.0 g, 2.64 mmol) in ethanol was added NaOH (116 mg, 2.89 mmol) and cyclopropylmethyl bromide (1.40 mL, 14.5 mmol). The resulting mixture was stirred at 70° C. for 6 h, then at 50° C. for 20 h and concentrated to dryness. The residue was dissolved in 1 N HCl (40 mL) and extracted with EtOAc (4×40 mL). The combined organic extracts were dried and concentrated. The residue was purified by preparative TLC (CH2Cl2:Hex=4:1) to give the title compound of Step C (160 mg) as a solid. MS (APCl−) Calc.: 431.0. Found: 430.2 (M−1).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=[CH:5][N:4]=1.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][CH3:40])[CH:33]=3)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH2:9]([C:8]1[C:3]([CH2:2][N:30]([CH2:29][C:27]2[CH:26]=[CH:25][C:24]3[O:19][CH2:20][CH2:21][O:22][C:23]=3[CH:28]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][CH3:40])[CH:33]=2)=[N:4][CH:5]=[N:6][C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1c(CBr)ncnc1-c1ccccc1
Reactant: CCOc1cccc(CNCc2ccc3c(c2)OCCO3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCCCc1c(CN(Cc2cccc(OCC)c2)Cc2ccc3c(c2)OCCO3)ncnc1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 4-bromomethyl-5-butyl-6-phenyl-pyrimidine (86 mg), (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine (93 mg, 0.310 mmol), and K2CO3 (195 mg, 1.4 mmol) in CH3CN (2.0 mL) is stirred at reflux for 1 h and at room temperature for 16 hours. The reaction mixture is then diluted with CH2Cl2 and filtered. The filtrate is concentrated, and the residue purified by preparative TLC, developing with 2:1 hexanes-EtOAc (+0.5% Et3N). The band containing product affords pure (5-butyl-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-(3-ethoxy-benzyl)-amine. 1H NMR (CDCl3, 300 MHz) δ 8.98 (s, 1H), 7.42 (m, 5H), 7.19 (t, J=8.0 Hz, 1H), 6.92–6.73 (m, 6H), 4.22 (s, 4H), 4.01 (q, J=6.9 Hz, 2H), 3.76 (s, 2H), 3.60 (s, 2H), 3.54 (s, 2H), 2.70–2.64 (m, 2H), 1.41 (t, J=6.9 Hz, 3H), 1.09–0.99 (m, 2H), 0.91 (sext, J=7.2 Hz, 2H), 0.61 (t, J=7.2 Hz, 3H) ppm. MS: m/z 524 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[CH:12]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.[NH2:20][CH:21]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([O:37][CH3:38])[CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[CH:12]1([C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:20][CH:21]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([O:37][CH3:38])[CH:31]=3)[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[O:8])=[CH:10][CH:11]=2)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1cc(CC(N)C(=O)OC(C)(C)C)ccc1O
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)C1CCCC1
Product: COc1cc(CC(NC(=O)c2ccc(NC(=O)C3CCCC3)cc2)C(=O)OC(C)(C)C)ccc1O

Procedure:
Prepared using General Procedures 5, 12 and 6 starting from methyl 4-aminobenzoate and using cyclopentane carbonyl chloride and tert-butyl 2-amino-3-(4-hydroxy-3-methoxyphenyl)propanoate. LCMS-ESI (m/z) calculated for C27H34N2O6: 482; found 505, [M+Na]+, tR=3.21 min (Method 1). NMR (400 MHz, CDCl3) δ 7.79-7.67 (m, 2H), 7.60 (d, J=8.7 Hz, 2H), 6.88-6.75 (m, 1H), 6.73-6.60 (m, 2H), 6.56 (d, J=7.4 Hz, 1H), 5.52 (s, 1H), 4.89 (ddd, J=7.3, 6.1, 5.0 Hz, 1H), 3.76 (s, 3H), 3.16 (m, 2H), 2.69 (m, 1H), 2.01-1.85 (m, 4H), 1.80 (m, 2H), 1.69-1.58 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[N+:30]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O)([O-:32])=[O:31]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:35][C:34]3[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=3[N+:30]([O-:32])=[O:31])=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2ccccc2[N+](=O)[O-])c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2ccccc2[N+](=O)[O-])c1

Procedure:
The reaction of hydroxylamine 55 (0.80 g, 2 mmol) with 2-nitrobenzaldehyde (59) (0.302 g, 2 mmol) afforded, after workup, a yellow oil. The crude product was purified by flash chromatography with 1:1 ethyl acetate/hexane as the eluant to obtain 0.80 g (1.49 mmol. 75%) of 70 as a yellow oil. The oil crystallized from ether-petroleum ether to yield yellow crystalline solid: mp 114°-116° C.; IR (CH2Cl2) 3440, 2980, 1700, 1625, 1575, 1528, 1470, 1345, 1300, 1215, 1105, 905, 852, 775 cm-1 ; 1H NMR (CDCl3) δ 1.10 (d, J=6.2 Hz, 3H), 1.23 (d, J=6.2 Hz, 3H), 2.29 (s, 6H), 3.31 (s, 3H), 3.56 (t, J=4.8 Hz, 2H), 4.19 (m, 2H), 4.93 (septet, J=6.2 Hz, 1H), 5.07 (s, 1H), 6.54 (s, 1H), 7.30-9.25 (m, 9H); 13C NMR (CDCl3) δ 19.98, 20.02, 22.47, 22.72, 40.34, 51.67, 67.85, 103.69, 104.37, 120.22, 121.84, 125.25, 125.61, 128.97, 129.17, 130.11, 131.01, 131.08, 134.11, 145.29, 145.82, 148.17, 149.75, 150.35, 167.43, 168.46; mass spectrum, m/e (relative intensity) 522 (0.2), 518 (10.8), 386 (13.3), 326 (22.5), 296 (100), 254 (53.4), 196 (44.7), 121 (18.9). Anal. Calcd for C28H31N3O8 : C, 62.57; H, 5.77. Found C, 62.72; H, 5.80.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:39]1[CH:40]=[CH:41][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:37][CH:38]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1c(-c2ccc(S(C)(=O)=O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 4-(methanesulfonyl)phenylboronic acid. A colorless powder (63 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[CH:3]=1.C([Li])CCC.CN(C)[CH:18]=[O:19].Cl>O1CCCC1.O1CCOCC1.O>[CH2:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:18]=[O:19])[CH2:9][CH3:10]
Reactant: CN(C)C=O
Reactant: CCCc1cccc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: CCCc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-bromo-3-propylbenzene (16.6 g) in tetrahydrofuran (83 ml) cooled to −78° C. was added dropwise n-butyllithium (2.66M solution in n-hexane, 34 ml) over 9 minutes, and then the mixture was stirred for 1 hour. To this reaction solution was added dropwise N,N-dimethylformamide (7.7 ml) over 6 minutes, and the mixture was stirred for additional 20 minutes. To this reaction solution was added dropwise a 4M solution of hydrogen chloride in 1,4-dioxane (23 ml) over 5 minutes, and then the mixture was stirred after warming to room temperature. To this mixed solution was added water (83 ml), followed by a 6M aqueous solution of hydrochloric acid (12 ml), and then the mixture was extracted with n-hexane (80 ml). The resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product of the titled compound (14.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][CH:16]=[C:15]([C:21]#[C:22][CH2:23][OH:24])[CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C#C>C(Cl)Cl.CO.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][CH:16]=[C:15]([CH2:21][CH2:22][CH2:23][OH:24])[CH:14]=3)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(C#CCO)ccc2c1O
Agent: [Pd]
Agent: C#C
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(CCCO)ccc2c1O
Yield: 47.6 %

Procedure:
A mixture of the title compound of Example 101 (0.190g) and Pd/C (10%, 37.9 mg) is dissolved in 3:1 CH2Cl2 :MeOH. The reaction mixture is placed under the Parr hydrogenator at 25 psi H2 and monitored with the OAMS for complete reduction of the acetylene. The reaction is filtered and fresh catalyst is added each time the reaction is taken off the Parr. The reaction is completed in 31/2 hrs and filtered over celite to remove the palladium. The filtrate is condensed to obtain a residue. The residue is dissolved in MeOH, adsorbed onto silica, and chromatographed eluting with 4% MeOH in CH2Cl2. Fractions homogenous by TLC are combined, condensed and recrystallized with EtOAc/hexanes to yield 91.4 mg of the desired product as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=O)[C:14]([Cl:20])=[C:15]([Cl:19])[C:16]([OH:18])=[O:17])=[C:5]1[CH3:22])[CH:2]=[CH2:3].[CH2:23]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CC1NC2C(C=1)=CC=CC=2>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:30]=3)[O:18][C:16](=[O:17])[C:15]([Cl:19])=[C:14]2[Cl:20])=[C:5]1[CH3:22])[CH:2]=[CH2:3]
Reactant: CCCCCCn1ccc2ccccc21
Reactant: C=CCn1c(C)c(C(=O)C(Cl)=C(Cl)C(=O)O)c2ccccc21
Agent: Cc1cc2ccccc2[nH]1
Product: C=CCn1c(C)c(C2(c3cn(CCCCCC)c4ccccc34)OC(=O)C(Cl)=C2Cl)c2ccccc21

Procedure:
Following a procedure similar to that described above in part B of this example except that 4-(1-allyl-2-methyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid is used in place of 4-(1-ethyl-2-methyl-3-indolyl)-2,3-dichloro-4-oxo-2-butenoic acid and 1-n-hexylindole is substituted for 2-methylindole, there is obtained 5-(1-allyl-2-methyl-3-indolyl)-5-(1-n-hexyl-3-indolyl)-3,4-dichloro-2(5H)-furanone (Formula V: R=CH2 =CHCH2 ; R1 =CH3 ; R2 =CH3 (CH2)4CH2 ; R3 =Y=Y1 =H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]1([CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=1)[OH:11]>CS(C)=O.O.C1OCCOCCOCCOCCOCCOC1>[Cl:8][C:7]1[C:2]([O:11][C:10]2[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: Oc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: O
Solvent: CS(C)=O
Product: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
2,3,5-Trichloropyridine (69.32 g, 0.38 mol) and 18-crown-6 (4.0 g, 0.015 mol) are added to a mixture of the dipotassium salt of hydroquinone (prepared from hydroquinone (44.0 g, 0.4 mol) and potassium hydroxide (45.0 g, 0.8 mol)) in dimethyl sulfoxide (700 mL). The reaction mixture is stirred overnight at room temperature, heated at 60° C. for 21/2 hours, diluted with water and extracted with ether. The combined organic extracts are washed with water, treated with charcoal, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain the title product as a white solid (47.23 g, mp 122°-123.5° C.).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24]2)[CH:20]=[CH:19][C:18]=1[Cl:34])=O)(C)(C)C>ClCCl.Cl.CCOCC>[CH2:32]([O:31][C:29]([C@@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:21]2[CH:20]=[CH:19][C:18]([Cl:34])=[C:17]([C:9]3[NH:8][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]=3)[CH:22]=2)[CH2:24]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4ccccc4n3C(=O)OC(C)(C)C)c2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)[C@@H]1CCCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
Method 2—Step d To a mixture of 2-[2-Chloro-5-((R)-3-ethoxycarbonyl-piperidin-1-yl)-phenyl]-benzoimidazole-1-carboxylic acid tert-butyl ester (1.30 g, 2.68 mmol) in dichloromethane (2 mL), 2M HCl in Et2O (10 mL) was added and the resulting mixture was stirred overnight at room temperature. The solid was filtered off, then recovered with 10% NaOH (10 mL) and extracted with dichloromethane (3×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure, to get 0.81 g of the title compound without further purifications (85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2(CCO)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:31]([O:34][C:35](=O)[CH3:36])(=[O:33])[CH3:32]>ClCCl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:35]([O:34][C:31](=[O:33])[CH2:32][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10]1)[CH3:36]
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)c2cc(OC)c(OC)c(OC)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl]-ethanol (4.5 g, 9.9 mmol) was dissolved in dichloromethane/pyridine (70 mL, 6/1). The solution was treated with acetic anhydride (1.04 mL, 11.02 mmol, 1.1 eq.) and 4-dimethylaminopyridine (50 mg, 0.41 mmol, 0.04 eq.). The solution was allowed to stir for 2 h at ambient temperature. The organics were concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with 1N HCl (2×200 mL), 5% NaHCO3 (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel (300 g) with ethyl acetate to afford the title compound:
Reaction SMILES: C([O:8][C:9]([C:11]1[C:21]2[NH:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[CH:14]=[C:13]([C:22]#N)[CH:12]=1)=[O:10])C1C=CC=CC=1.[OH-:24].[Na+].[OH2:26].C(O)C.Cl>O>[NH:20]1[C:21]2[C:11]([C:9]([OH:8])=[O:10])=[CH:12][C:13]([C:22]([OH:26])=[O:24])=[CH:14][C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: [OH-]
Reactant: N#Cc1cc2c(c(C(=O)OCc3ccccc3)c1)NCCCC2
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1cc2c(c(C(=O)O)c1)NCCCC2
Yield: 85 %

Procedure:
7-Cyano-2,3,4,5-tetrahydro-1H-1-benzazepine-9-carboxylic acid benzyl ester (3.30 g) and sodium hydroxide (2 g) in a mixed solution of water-ethanol (1:1, 60 ml) was refluxed for 8 hours. After cooled, water (100 ml) was added to the reaction mixture, which was then rendered to have pH 3 with concentrated hydrochloric acid. The deposited crystal was collected by filtration, washed with water and dried to give the intended compound 1.84 g (85.0%), which was then recrystallized from ethanol to give slightly yellow crystal. M.P.: 287°-288° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10]#N)=[C:4]([F:12])[CH:3]=1.[OH:13]S(O)(=O)=O.[OH2:18]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10]([OH:13])=[O:18])=[C:4]([F:12])[CH:3]=1
Reactant: N#CCc1c(F)cc(Br)cc1F
Reactant: O=S(=O)(O)O
Reactant: O
Product: O=C(O)Cc1c(F)cc(Br)cc1F
Yield: 33.3 %

Procedure:
A solution of 2-(4-bromo-2,6-difluorophenyl)acetonitrile (0.5 g, 2.155 mmol) in H2SO4 (3 mL, 56.3 mmol) and H2O (3 mL, 167 mmol) was stirred at 60° C. for 16 h. After LCMS analysis showed the starting material had disappeared, the mixture was dissolved in H2O (20 mL) and extracted by EA (2×30 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=3/1 to 1/1) to yield 2-(4-bromo-2,6-difluorophenyl)acetic acid (0.3 g, 0.718 mmol, 33.3% yield): 1H NMR (400 MHz, CD3OD) δ 7.13-7.05 (m, 2H), 3.71 (s, 2H).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[CH:6]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[SH:18])([CH3:8])[CH3:7].[Cl:19][C:20]1[CH:25]=[C:24]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:41]([C:45]1[CH2:49][C:48](=[O:50])[N:47]([C:51]2[C:56]([Cl:57])=[CH:55][C:54]([Cl:58])=[CH:53][C:52]=2[Cl:59])[N:46]=1)[C:42](=[O:44])[CH3:43].Cl>ClCCl.CN(C)C=O>[Cl:19][C:20]1[CH:25]=[C:24]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=[O:27])=[O:28])[CH:23]=[CH:22][C:21]=1[N:41]([C:45]1[CH:49]([S:18][C:10]2[CH:11]=[CH:12][C:13]([CH:15]([CH3:17])[CH3:16])=[CH:14][C:9]=2[CH:6]([CH3:8])[CH3:7])[C:48](=[O:50])[N:47]([C:51]2[C:56]([Cl:57])=[CH:55][C:54]([Cl:58])=[CH:53][C:52]=2[Cl:59])[N:46]=1)[C:42](=[O:44])[CH3:43]
Reactant: CC(C)c1ccc(S)c(C(C)C)c1
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(N(C(C)=O)C2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c(Cl)c1
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(N(C(C)=O)C2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2Sc2ccc(C(C)C)cc2C(C)C)c(Cl)c1
Reaction time: 2 h

Procedure:
Sulfuryl chloride (6.2 g, 46 mmol) was added dropwise to a stirred solution of 2,4-diisopropylthiophenol (8.9 g, 46 mmol) in dichloromethane (50 ml) and stirring was continued at room temperature for 2 hrs. Volatiles were removed by rotary evaporation to give an oil. A solution of N-(2-chloro-4-dodecylsulfonylphenyl)-N-[4,5-dihydro-5-oxo-1-(2,4,6-trichlorophenyl)-1H-pyrazol-3-yl]acetamide (29.0 g, 44 mmol) in N,N-dimethylformamide (75 ml) was added to the oil and the mixture was stirred at room temperature for 26 hrs. The solution was poured into 3N hydrochloric acid (750 ml) and the resulting sticky solid was collected by filtration. The solid was dissolved in ethyl acetate (200 ml) and the organic solution was washed with brine (100 ml), dried (MgSO4) and evaporated to an orange glass. The crude material was purified by column chromatography on 63-200 mesh silica gel eluting with 1:4 ethyl acetate/60-80 petroleum ether. Pure product was obtained as a cream colored glass, 11.7 g, 31%. C41H51Cl4N3O4S2Req: C 57.5%,H 6.0%,Cl 16.6%,N 4.9%,S 7.5%; Fd: C 57.1%,H 6.1%,Cl 16.4%,N 4.8%,S 7.2%
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C:19]#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:21].[Na+].C[OH:24]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C:19]([OH:24])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CO
Reactant: N#CCc1c[nH]c2c(OCc3ccccc3)cccc12
Agent: [Na+]
Product: O=C(O)Cc1c[nH]c2c(OCc3ccccc3)cccc12
Temperature: 25 °C
Yield: 86 %

Procedure:
Under nitrogen atmosphere, to a suspension of (7-(benzyloxy)-1H-indol-3-yl)acetonitrile (13.2 g, 50.3 mmol) in methanol (400 mL) is added 10N aqueous sodium hydroxide solution (130 mL), and the mixture is refluxed for 5 hours. The reaction solution is cooled to room temperature, and methanol alone is distilled off. The pH value of the resultant is adjusted to pH 1 with conc. hydrochloric acid while the mixture is cooled with ice. The precipitates are collected by filtration, and dissolved in chloroform, and dried over anhydrous sodium sulfate. The solvent is evaporated to give (7-(benzyloxy)-1H-indol-3-yl)acetic acid (12.2 g, 43.4 mmol, yield: 86%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][OH:12].C(N(C(C)C)CC)(C)C.[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH2:11][OH:12])[CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Reactant: CN1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCCN(c2ccc([N+](=O)[O-])cc2CO)CC1

Procedure:
A mixture of (2-fluoro-5-nitrophenyl)methanol (4.500 g, 26.3 mmol), diisopropylethylamine (6.89 mL, 39.4 mmol), and 1-methyl-1,4-diazepane (4.25 mL, 34.2 mmol) in acetonitrile (150 mL) was refluxed for 24 hours. The solvent was evaporated. The residue was treated with saturated aqueous NaHCO3 and extracted with ethyl acetate (twice). The combined organic layers were dried over MgSO4 and filtered. The title compound was crystallized from the organic layers.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:23][CH:24]1[CH2:26][CH2:25]1)(=[O:21])[NH2:22]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (S)-2-amino-3-cyclopropyl-propanamide (CAN 156077-93-9) as starting materials, MS (LC/MS): m/e=344.3 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([OH:14])=[CH:9][CH:8]=2)=[O:4].C1(O)C=CC=CC=1.[CH2:22]([C:29]1[CH:30]=[N:31][C:32]2[C:37]([C:38]=1[C:39]1[CH:40]=[C:41]([CH2:45]O)[CH:42]=[CH:43][CH:44]=1)=[CH:36][CH:35]=[CH:34][C:33]=2[C:47]([F:50])([F:49])[F:48])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([C:29]1[CH:30]=[N:31][C:32]2[C:37]([C:38]=1[C:39]1[CH:40]=[C:41]([CH:42]=[CH:43][CH:44]=1)[CH2:45][O:14][C:10]1[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:13]3)=[CH:36][CH:35]=[CH:34][C:33]=2[C:47]([F:50])([F:49])[F:48])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COC(=O)c1cc2cc(O)ccc2[nH]1
Solvent: Oc1ccccc1
Product: O=C(O)c1cc2cc(OCc3cccc(-c4c(Cc5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)ccc2[nH]1

Procedure:
The title compound was prepared using the procedure of example 69 using 5-Hydroxy-1H-indole-2-carboxylic acid methyl ester as the phenol and [3-(3-Benzyl-8-trifluoromethyl-quinolin-4-yl)-phenyl]-methanol as the alcohol. MS (ESI) m/z 553.