Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[NH:33][CH2:34][CH2:35][NH:36]C(OC(C)(C)C)=O>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:31])([CH3:32])[CH3:30])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][C:10]=1[NH:33][CH2:34][CH2:35][NH2:36]
Reactant: CC(C)(C)OC(=O)NCCNc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc(Br)c(NCCN)c1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid is added to a solution of product from Step A in methylene chloride. After one hour at room temperature, the solution is evaporated, and the residue is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase is washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated to provide the title compound.
Reaction SMILES: [BrH:1].BrBr.[CH2:4]([N:11]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(=O)C>[CH2:4]([N:11]1[CH2:17][CH2:16][CH:15]([Br:1])[C:14](=[O:18])[CH2:13][CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCCN(Cc2ccccc2)CC1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C1CCN(Cc2ccccc2)CCC1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
33% hydrobromic acid in conc. acetic acid and 1.97 g bromine was added to 5 g 1-benzyl-azepane-4-one in 15 mL conc. acetic acid. The reaction was stirred 2 h at RT and completely concentrated under reduced pressure. The residue was diluted with ethyl acetate and refluxed for 1 h and crystallized with ethyl acetate to give 4 g of the desired product.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4](=O)[CH2:5][Br:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[NH2:17]>>[Br:1][CH2:2][C:3]1[C:4]([CH2:5][Br:6])=[N:17][C:11]2[C:10](=[CH:15][CH:14]=[C:13]([Cl:16])[CH:12]=2)[N:9]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C(CBr)C(=O)CBr
Product: Clc1ccc2nc(CBr)c(CBr)nc2c1

Procedure:
Following the procedure of Example 1, condensation of 1,4-dibromo-2,3-butanedione with 1,2-diamino-4-chlorobenzene yielded 2,3-bis(bromomethyl)-6-chloroquinoxaline, m.p. 149°-150° C.; 1H NMR (CDCl3, 400 MHz): δ4.89 and 4.90 (singlets, 4H, CH2), 7.74 (dd, J1 =8.9 Hz, J2 =2.3 Hz, 1H, H-7), 8.01 (d, J=8.9 Hz, 1H, H-8), 8.07 (d, J=2.3 Hz, 1H, H-5).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:31])=[C:6]([CH:30]=1)[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([C:19]([O:21][CH3:22])=[O:20])[N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][CH2:12]2.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:31])=[C:6]([CH:30]=1)[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C@H:15]([C:19]([O:21][CH3:22])=[O:20])[N:14]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:13][CH2:12]2)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: COC(=O)[C@H]1c2ccc(OCc3cc(N)ccc3Cl)cc2CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)[C@H]1c2ccc(OCc3cc(NC(C)=O)ccc3Cl)cc2CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
To a solution of (R)-2-tert-butyl 1-methyl 6-(5-amino-2-chlorobenzyloxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (15 mg, 0.033 mmol) in CH2Cl2 (1 mL) was added TEA (200 μl, 1.43 mmol) followed by the addition of acetyl chloride (10 μl, 0.05 mmol). The reaction was stirred at room temperature for 2 h. It was concentrated and purified by preparative HPLC (Phenomenex 20×100 mm eluting with 0-100% MeOH/H2O (90% in H2O, 0.1% TFA) gradient over 8 min with flow rate 25 mL/min) to yield (R)-2-tert-butyl 1-methyl 6-(5-acetamido-2-chlorobenzyloxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate as a colorless oil (2 mg, 13%). HPLC retention time (Method C)=3.86 min. LC/MS (ESI) (M+H)+=489.12. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 5H), 1.50 (s, 4H), 2.19 (s, 3H), 2.80-2.90 (m, 2H), 3.64-3.83 (m, 5H), 3.88 (s, 1H), 5.10 (s, 2H), 5.38 (s, 0.5H), 5.55 (s, 0.5H), 6.72-6.79 (m, 1H), 6.81-6.89 (m, 1H), 7.31-7.68 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11](O)=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:44]([O:46][CH2:47][CH2:48][O:49][NH2:50])=[CH2:45].[NH4+].[Cl-]>C(Cl)Cl>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:50][O:49][CH2:48][CH2:47][O:46][CH:44]=[CH2:45])=[O:12])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: C=COCCON
Reactant: O=C(O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Product: C=COCCONC(=O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylic acid (1.7 g, 5.54 mmol) in CH2Cl2 (20 mL) was added HOBt (1.21 g, 8.31 mmol) and EDCI (1.59 mg, 8.31 mmol). The mixture was stirred for 1 h and O-(2-(vinyl-oxy)ethyl)hydroxylamine (0.69 g, 6.65 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH4Cl (aq., 20 mL). The resultant mixture was extracted with CH2Cl2 (15 mL×3). The combined organic extracts were washed with water (10 mL×3) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 20:1, v/v) and gave the desired product (2.44 g, 85% yield). 1H NMR (400 MHz, d6-DMSO) δ 11.85 (s, 1H), 8.65 (s, 1H), 8.51 (s, 1H), 7.38 (d, J=10.8 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 6.64 (dd, J=13.9, 6.6 Hz, 1H), 6.42 (d, J=6.0 Hz, 1H), 4.21 (d, J=14.5 Hz, 1H), 4.01 (m, 3H), 3.83 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.BrCC1C(Cl)=NC(Cl)=CC=1.[CH3:21][C:22]1[N:27]=[C:26]([SH:28])[N:25]=[C:24]([OH:29])[CH:23]=1>C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([CH2:8][S:28][C:26]2[N:25]=[C:24]([OH:29])[CH:23]=[C:22]([CH3:21])[N:27]=2)=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: OCc1ccc(Cl)nc1Cl
Reactant: Cc1cc(O)nc(S)n1
Agent: Clc1ccc(CBr)c(Cl)n1
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2ccc(Cl)nc2Cl)n1
Yield: 82 %

Procedure:
The crude (2,6-dichloropyridin-3-yl)methanol was converted to 3-(bromomethyl)-2,6-dichloropyridine, which was then reacted with 6-methyl-2-sulfanylpyrimidin-4-ol in the presence of triethylamine to provide 2-{[(2,6-dichloropyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (0.822 g, 82% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.15 (s, 3H), 4.36 (s, 2H), 5.95 (bs, 1H), 7.40 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H); M+ 302.5.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(O)cc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)c2ccc(O)cc2)c(-c2cccnc2F)c1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-hydroxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (300 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 40° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate, and further recrystallized from a mixed solvent of ethyl acetate-methanol (4:1) to give the title compound as colorless crystals (yield 208 mg, 81%).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-].[Li+]>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:18])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.835 g, 3.34 mmol) in THF (10 mL) was treated with lithium hydroxide (0.383 g, 16.70 mmol) in water (10 mL) at 0° C. The solution was stirred at 0° C. for 1 hour then quenched with 2N HCl to pH 2. The mixture was concentrated to approximately half of the entire volume. The solid that precipitated was collected by vacuum filtration, then rinsed with cold water and dried to give (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid as a light yellow solid (0.65 g, 88%). mp 165-166° C. 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.30 (s, 1H), 9.08 (s, 1H), 6.88 (s, 1H), 6.66 (s, 1H), 5.38 (d, J=9.38 Hz, 1H), 3.00 (d, J=15.24 Hz, 1H), 2.20 (s, 3H), 2.00 (dd, J=15.24, 10.16 Hz, 1H). MS (ESI) m/z: 221 [M−1].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH:28]([NH2:32])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][CH:28]3[CH2:29][CH2:30][CH2:31][NH:26][CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC1CCCNC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3CCCNC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and piperidin-3-amine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.09-8.07 (d, J=8 Hz, 1 H), 7.99 (s, 1 H), 7.89-7.87 (q, J=7.2 Hz, 1 H), 7.73-7.68 (q, J=14 Hz, 2 H), 7.62-7.55 (m, 2 H), 6.14 (s, 1 H), 5.36 (s, 2 H), 4.58-4.51 (m, 2 H), 4.34 (s, 1 H), 3.75 (s, 2 H), 3.63-3.60 (d, J=11.6 Hz, 1 H), 3.47-3.44 (m, 1 H), 3.07-3.02 (d, J=11.6 Hz, 2 H), 2.47 (s, 3 H), 2.17-2.14 (m, 2 H), 2.05-2.00 (m, 1 H), 1.85-1.84 (m, 1 H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:14])=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:9]=1)(=[O:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])[CH:19]=[CH:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:14])=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:9]=1)=[O:3]
Reactant: CC(=O)Nc1cc(C(C)=O)ccc1F
Reactant: COC(OC)N(C)C
Product: CC(=O)Nc1cc(C(=O)C=CN(C)C)ccc1F
Yield: 78.5 %

Procedure:
3.3 g (16.9 mmol) of N-(5-acetyl-2-fluoro-phenyl)-acetamide were dissolved in 8.36 ml (7.49 g) (62.89 mmol) of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 6.5 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was crystallized from ethyl acetate. 3.32 g of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-acetamide as a yellowish-white solid were obtained (yield 78.6%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:9]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccccc23)CC1
Product: CN1CCC(c2cn(C(=O)c3ccccc3)c3ccccc23)CC1

Procedure:
(28.1 mg, 88%); from 3-(1-methyl-4-piperidinyl)-1H-indole (Example 5d, 21.5 mg, 0.10 mmol) and benzoyl chloride (21.1 mg, 0.15 mmol), HRMS-FAB+ for C21H21N2O, calculated MH+ : 319.18103; found: 319.18293.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:33][NH:34][CH3:35].O1CCCC1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.ClCCCl.C(O)(=O)C>[CH3:33][N:34]([CH2:1][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH3:35]
Reactant: CC(C)(C)OC(=O)N1Cc2cccc(C=O)c2C1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN(C)Cc1cccc2c1CN(C(=O)OC(C)(C)C)C2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 238 mg of tert-butyl 4-formyl-1,3-dihydro-2H-isoindole-2-carboxylate, 612 mg of sodium triacetoxyborohydride, 963 μL of a 2 M dimethylamine-tetrahydrofuran solution, 12 μL of acetic acid, and 14 mL of 1,2-dichloroethane was stirred at 60° C. overnight. After cooling to room temperature, to the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and chloroform was added and the aqueous layer was separated. The obtained organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 123 mg of tert-butyl 4-[(dimethylamino)methyl]-1,3-dihydro-2H-isoindole-2-carboxylate as an orange oil.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[C:20]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[CH:20]1([N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1ccc(-n2cc3c(n2)CCN(C2CCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide (may be prepared as described in Description 37) (31 mg, 0.12 mmol) in dichloromethane (3 ml) was added cyclopentanone (20 mg, 0.24 mmol) and acetic acid (2 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added and stirring continued for 2 hours. A further 6 eq. of cyclopentanone was added and stirring continued over the weekend. Methanol was added and the crude mixture was purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E23). MS (ES+) m/e 325 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:12]Cl)=[C:8]([CH2:10]Cl)[CH:9]=1)=[O:4].[S-2:14].[Na+].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH2:12][S:14][CH2:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: [S-2]
Reactant: COC(=O)c1cc(CCl)c(CCl)s1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2c(s1)CSC2
Yield: 49.9 %

Procedure:
A solution of 4.8 g (20 mmol) (2) in 240 mL methanol was heated up and kept mild boiling. Sodium sulfide solution (1.7 g, 22 mmol) in 160 mL methanol was added dropwise in 2 h. After cooling of the reaction mixture, the precipitate was filtered off. The solvent was removed by evaporation and the residue was washed by water. Column chromatography on silica gel using dichloromethane yielded the pure title compound as a white solid 2.0 g (50%). 1HNMR (CDCl3): δ 3.87 (3H, s), 4.05-4.06 (2H, t, J=3 Hz), 4.19-4.20 (2H, t, J=3 Hz), 7.48 (1H, s). 13CNMR (CDCl3): δ33.12, 33.47, 52.19, 127.90, 137.30, 143.90, 146.64, 162.51.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([C:28](OC)=[O:29])([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:13]3[C:18]([N:19]([CH3:22])[C:20]=2[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3.O>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]([CH2:28][OH:29])([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:13]3[C:18]([N:19]([CH3:22])[C:20]=2[CH:21]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: COC(=O)C1(CCN(C)C)c2ccccc2N(C)c2cc(Cl)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCC1(CO)c2ccccc2N(C)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
25.7 gm of the fumarate of 3-chloro-9-methoxy-carbonyl-9-(β-dimethylaminoethyl)-10-methyl-acridane were suspended in 250 cc of water and after refrigeration, 25 cc of sodium hydroxide solution were added. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over magnesium sulfate and distilled to dryness in vacuo to obtain 20 gm of 3-chloro-9-methoxycarbonyl-9-(β-dimethylaminoethyl)-10-methylacridane. First 10 gm of lithium aluminum hydride and then 20 gm of 3-chloro-9-methoxycarbonyl-9-(β-dimethylaminoethyl)-10-methylacridane in solution in 200 cc of tetrahydrofuran were added to 200 cc of cold tetrahydrofuran at a temperature below 10°C and after stirring for 10 minutes at 0°C, it was refluxed for 15 minutes. After cooling the reaction mixture, excess reactants were decomposed by 200 cc of tetrahydrofuran containing 20% of water at a temperature below 10°C. After filtering and distilling the mixture to dryness in vacuo, the residue was dissolved in methylene chloride and the solution was washed with water, dried over magnesium sulfate and distilled to dryness in vacuo. The residue was dissolved in 80 cc of ethyl acetate and the resulting solution was filtered and concentrated to 50 cc after which crystallization began. After being iced for 30 minutes, the mixture was filtered and the precipitate was washed with ethyl acetate and then ether and dried to obtain 14.35 gm of 3-chloro-9-hydroxymethyl-9-(β-dimethylaminoethyl)-10-methyl-acridane melting at 120°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:18][S:19]([O:22][C:23]1[CH:24]=[C:25]([CH2:29][CH2:30][CH2:31]CS([O-])(=O)=O)[CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:20]>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:14][CH2:15][CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:31][CH2:30][CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][S:19]([CH3:18])(=[O:21])=[O:20])[CH:24]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CS(=O)(=O)Oc1cccc(CCCCS(=O)(=O)[O-])c1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Product: CCOC(=O)C(Cc1ccc(OCCCc2cccc(OS(C)(=O)=O)c2)cc1)OCC

Procedure:
2-Ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 20b) was alkylated with 3-(3-methanesulfonyloxyphenyl)propylmethanesulfonate using the same method as in example 1 (b) to give 2-ethoxy-3-{4-[3-(3-methanesulfonyloxyphenyl)propoxy]-phenyl}propanoic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([Cl:15])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.4 %

Procedure:
A solution of 3-bromo-4-fluorobenzoic acid (976 mg, 4.46 mmol) in DCM (25 mL) was stirred at rt and treated with oxalyl chloride (1.950 mL, 22.28 mmol), followed by a drop of DMF, causing gas evolution to commence. After 2.5 h, the solution was heated to boiling for 1-2 min and allowed to cool to rt. After 3 h total, the solution was concentrated to provide 3-bromo-4-fluorobenzoyl chloride as a white solid (1.00 g, 94%). A portion of this material (200 mg, 0.842 mmol) was added to an ice-cold solution of 4-fluoroaniline (0.081 mL, 0.842 mmol) in pyridine (4 mL), and the solution was stirred at rt for 65 h The solution was concentrated and the residue was stirred in 1 M hydrochloric acid, forming a precipitate which was collected by filtration, washed with water and dried to provide 3-bromo-4-fluoro-N-(4-fluorophenyl)benzamide as an off-white solid (227.5 mg, 80%). 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H) 8.29 (dd, J=6.7, 2.1 Hz, 1H) 8.01 (ddd, J=8.6, 4.8, 2.2 Hz, 1H) 7.75 (dd, J=9.0, 5.1 Hz, 2H) 7.55 (t, J=8.6 Hz, 1H) 7.20 (t, J=8.9 Hz, 2H). Mass spectrum m/z 312, 314 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:12]2[N:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8]1.[NH2:21][C:22]1[CH:34]=[C:33]([CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=[CH:31][C:23]=1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].Cl>C(OCC)(=O)C.C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[CH2:35]([C:33]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[C:22]([NH:21][C:18]([C:15]2[CH:16]=[N:17][C:12]([N:7]3[CH:8]=[CH:9][CH:10]=[CH:11]3)=[CH:13][CH:14]=2)=[O:20])[CH:34]=1)[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(O)c1ccc(-n2cccc2)nc1
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1ccc(-n2cccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.015 mL of N,N-dimethylformamide was added to a mixed solution of 2.0 mL of methylene chloride and 0.024 mL of oxalyl chloride containing 47 mg of 6-(1H-pyrrol-1-yl)pyridine-3-carboxylic acid and stirred at room temperature for 30 minutes. 74 mg of tert-butyl 2-amino-4-phenethylbenzoate and 0.090 mL of triethylamine were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 1 hour and 40 minutes. 1.0 mol/L hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; chloroform] to obtain 62 mg of tert-butyl 4-phenethyl-2-(6-(1H-pyrrol-1-yl)pyridine-3-carboxamido)benzoate as white solid.