Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[NH:21][C:20](=[O:25])[C:19]3[NH:26][CH:27]=[CH:28][C:18]=3[C:17]=2[CH:16]=1)=O.[CH2:29]([C:31]([O-:33])=[O:32])[CH3:30].C(N(CC)CC)C>C(O)C>[O:25]=[C:20]1[C:19]2[NH:26][CH:27]=[CH:28][C:18]=2[C:17]2[CH:16]=[C:15]([C:13]3[N:10]=[C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[S:9][CH:12]=3)[CH:24]=[CH:23][C:22]=2[NH:21]1.[CH2:29]([C:31]([O-:33])=[O:32])[CH3:30]
Reactant: O=C(CBr)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: NC(=S)Nc1ccccc1
Agent: CCC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(-c3csc(Nc4ccccc4)n3)cc2c2cc[nH]c12
Temperature: 90 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
34 mg (1.5 mmol) of N-phenylthiourea is added to a suspension of 57 mg (0.15 mmol) of 8-(2-bromo-acetyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 3 mL of ethanol. The mixture is stirred at 90° C. for 48 hours then the mixture is cooled to room temperature. Triethylamine (2 mmol) is added, then the solvent is evaporated and the product is purified by chromatography on silica (chloroform/methanol/triethylamine 8/2/1). After drying, 11 mg (17%) of 4-oxo-8-(2-phenylamino-thiazol-4-yl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][CH:15]=[N:14][C:13]=1[CH3:17])[C:3]([OH:5])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[F:48][C:49]1[CH:50]=[C:51]([CH:67]=[CH:68][CH:69]=1)[CH2:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]2[S:64][C:63]([CH2:65][NH2:66])=[N:62][N:61]=2)=[CH:56][CH:55]=1>CN(C)C=O>[F:48][C:49]1[CH:50]=[C:51]([CH:67]=[CH:68][CH:69]=1)[CH2:52][O:53][C:54]1[CH:55]=[CH:56][C:57]([C:60]2[S:64][C:63]([CH2:65][NH:66][C:3](=[O:5])[CH:2]([OH:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]3[S:16][CH:15]=[N:14][C:13]=3[CH3:17])=[N:62][N:61]=2)=[CH:58][CH:59]=1
Reactant: Cc1ncsc1CCCCCCC(O)C(=O)O
Reactant: NCc1nnc(-c2ccc(OCc3cccc(F)c3)cc2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncsc1CCCCCCC(O)C(=O)NCc1nnc(-c2ccc(OCc3cccc(F)c3)cc2)s1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 2-hydroxy-8-(4-methylthiazol-5-yl)octanoic acid (40.0 mg, 0.155 mmol), 1-hydroxybenzotriazole hydrate (21.0 mg, 0.155 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (44.7 mg, 0.233 mmol), triethylamine (0.06 mL, 0.466 mmol) and (5-(4-((3-fluorobenzyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)methanamine (54.7 mg, 0.155 mmol) in dimethylformamide (0.78 mL) was stirred at room temperature for 22 h. The resulting mixture was concentrated and the residue was purified via silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90:10-80:20 heptane:EtOAc) to yield N-((5-(4-((3-fluorobenzyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)-2-hydroxy-8-(4-methylthiazol-5-yl)octanamide. MS (ES+) 555 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)=[O:17])[CH:11]=[CH:12][C:13]=1[CH3:14])=[O:6].Cl[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][O:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)=[O:17])[CH:11]=[CH:12][C:13]=1[CH3:14])=[O:6]
Reactant: ClCc1ccccn1
Reactant: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1cccc(O)c1
Product: Cc1ccc(NC(=O)c2ccc3ncccc3c2)cc1NC(=O)c1cccc(OCc2ccccn2)c1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 7, N-[3-(3-hydroxybenzamido)-4-methylphenyl]quinoline-6-carboxamide was reacted with 2-chloromethylpyridine to give the title compound in 58% yield; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 5.26 (s, 2H), 7.23 (m, 2H), 7.33 (t, 1H), 7.43 (t, 1H), 7.57 (t, 1H), 7.61 (m, 4H), 7.82 (m, 1H), 7.85 (d, 1H), 8.12 (d, 1H), 8.25 (d, 1H), 8.51 (d, 1H), 8.58 (d, 1H), 8.61 (s, 1H), 8.99 (d, 1H), 9.9 (s, 1H), 10.48 (s, 1H); Mass Spectrum: M+H+ 489.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:10]1([CH2:16][CH2:17][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:23]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)=[CH:26][CH:25]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(OCCN2CCCCC2)cc1
Reactant: Nc1cc(Cl)cnc1N
Agent: Cl[Fe](Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cnc2[nH]c(-c3ccc(OCCN4CCCCC4)cc3)nc2c1
Temperature: 80 °C
Yield: 3.4 %

Procedure:
5-Chloropyridin-2,3-diamine (0.200 g, 1.39 mmol) was dissolved in DMF (5 ml). Iron(III)chloride hexahydrate (0.025 g, 0.092 mmol) was added and the mixture heated to 80° C. 4-(2-Piperidin-1-ylethoxy)benzaldehyde (0.33 g, 1.41 mmol) dissolved in DMF (2 ml) was added dropwise, and the reaction mixture was heated at 120° C. for 5 h with air bubbling through the solution. The DMF was removed by evaporation and the solid residue was washed with 1M NaOH and diethyl ether. The crude product was purified by column chromatography (EtOAc/heptane, 1:1), giving the title product (0.017 g, 3%).
Reaction SMILES: N1C(Cl)=NC(Cl)=N[C:2]=1Cl.C[C:11]1([CH3:30])[CH2:16][CH:15]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)CC(C)(C)N1.Cl[C:32]1N=NN=[C:34](Cl)[CH:33]=1>C1(C)C(C)=CC=CC=1>[CH3:27][C:20]1([CH3:26])[CH2:19][CH:18]([NH:17][CH2:15][CH2:16][CH2:11][CH2:30][CH2:32][CH2:33][CH2:34][CH3:2])[CH2:23][C:22]([CH3:24])([CH3:25])[NH:21]1
Reactant: CC1(C)CC(NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: Clc1cc(Cl)nnn1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: Cc1ccccc1C
Product: CCCCCCCCNC1CC(C)(C)NC(C)(C)C1

Procedure:
The same compound can be obtained by means of a procedure in a single reactor, by reacting 1 mol of cyanuric chloride in xylene first with 1 mol of bis(2,2,6,6-tetramethyl-4-piperidyl)amine and then with 2 mol of 2,2,6,6-tetramethyl-4-octylaminopiperidine without isolation of the dichlorotriazine formed as an intermediate.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=4)[CH2:14][CH2:13]3)[N:11]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][CH:27]=3)[C:10](=[O:34])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B1[CH:40]2[CH2:41][CH2:42][CH2:43][CH:36]1CCC2.[CH3:44]COC(C)=O>O.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>[CH:1]1([NH:7][C:8]2[C:12]34[CH2:17][CH2:16][N:15]([CH2:14][CH2:13]3)[CH2:18][C:19]3[CH:24]=[CH:23][C:22](=[CH:21][CH:20]=3)[CH2:44][C:42]3[CH:41]=[CH:40][C:33](=[CH:36][CH:43]=3)[CH2:32][C:29]3[CH:30]=[CH:31][C:26](=[CH:27][CH:28]=3)[N:11]4[C:10](=[O:34])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(C)=O
Reactant: C=Cc1ccc(N2C(=O)N=C(NC3CCCCC3)C23CCN(Cc2ccc(I)cc2)CC3)cc1
Reactant: B1C2CCCC1CCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: O=C1N=C(NC2CCCCC2)C23CCN(CC2)Cc2ccc(cc2)Cc2ccc(cc2)Cc2ccc(cc2)N13
Temperature: 25 °C

Procedure:
To a 0° C. degassed THF (10 mL) solution containing 4-(cyclohexylamino)-8-(4-iodobenzyl)-1-(4-vinylphenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (860 mg, 1.5 mmol, Intermediate III.3.1b.1) was added 9-BBN (0.5 M THF, 6.0 mL, 3.0 mmol) dropwise. The vessel was warmed to rt and then heated at 70° C. for 40 min. Reaction was diluted with 290 mL degassed THF and 70 mL degassed 3.2 N NaOH. To the biphasic mixture Pd(PPh3)4 (346 mg, 0.3 mmol) was added and the reaction heated at 65° C. for 2 h. The mixture was cooled to rt and diluted with EtOAc (200 mL) and water (200 mL). The layers were separated and the aqueous layer extracted twice more with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated to give 2 g of crude material. Purification via flash silica chromatography using 10% MeOH in CH2Cl2 gave, upon solvent removal and further drying in vacuo, 546 mg of semi-pure material. Further purification via RP-HPLC (95/5 to 5/95 H2O/AcCN+0.1% TFA, YMC C18 column) gave two separable products, the first more polar product (15 mg) identified as the title example III.3.1c.1: 1H NMR (400 MHz, MeOD) δ 6.90 (dd, J=8.0, 2.0 Hz, 4H), 6.73 (dd, J=8.2, 2.0 Hz, 4H), 3.74 (m, 1H) 3.70 (s, 2H), 3.17 (m, 4H), 2.41 (bd, J=11.2 Hz, 2H), 2.07-1.92 (m, 7H), 1.80-1.65 (m, 6H), 1.39-1.30 (m, 4H); HRMS calc for C28H34N4O [M+H]+: 443.2806; measured: 443.2802
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][C@H:35]1[O:40][CH2:39][CH2:38][NH:37][CH2:36]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:37]5[CH2:38][CH2:39][O:40][C@H:35]([CH2:34][O:33][CH3:32])[CH2:36]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: COC[C@@H]1CNCCO1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COC[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCO1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[2-(S)-(methoxymethyl)morpholin-4-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2S)-2-Methoxymethyl-morpholine following General Procedure C.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O.Cl>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCOc1ccc2oc(C(=O)C3CCCCC3)c(C)c2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1ccc2oc(C(O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Cyclohexyl[5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl]methanone (10.3 g) synthesized in the above-mentioned (2) was dissolved in a mixed solvent of tetrahydrofuran (180 mL) and methanol (20 mL). The reaction mixture was ice-cooled, and sodium borohydride (90%, 2.7 g) was added, and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was ice-cooled again, water (10 mL) and 1N hydrochloric acid (100 mL) were carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (10.3 g) of the title object compound as a pale-yellow oil.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH3:6][C:7]([CH:10]=O)([CH3:9])[CH3:8].N1CCCC1>CO>[C:7]([C:10]1[C:2](=[CH2:3])[CH:1]=[CH:5][CH:4]=1)([CH3:9])([CH3:8])[CH3:6]
Reactant: CC(C)(C)C=O
Reactant: C1=CCC=C1
Solvent: CO
Solvent: C1CCNC1
Product: C=C1C=CC=C1C(C)(C)C

Procedure:
6,-tert-butyl-fulvene was prepared analogously by reaction of cyclopentadiene (31.7 g, 480 mmole), pivaldehyde (19.825 g, 230 mmol), and pyrrolidine (25 ml, 300 mmole) in methanol (250 ml). The yellow oil is kugel-rohr distilled at 70° C. and <1 torr yielding a bright yellow oil; 20.5 g (66.4%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[CH:10][C:9]([Cl:31])=[CH:8][CH:7]=2.[F:45][C:46]([F:60])([F:59])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH:53]([S:55](Cl)(=[O:57])=[O:56])[CH3:54]>>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:31])[CH:10]=3)[N:5]([CH:32]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:4]=2[CH2:3][CH2:2][NH:1][S:55]([CH:53]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[C:46]([F:45])([F:59])[F:60])[CH3:54])(=[O:57])=[O:56])(=[O:16])=[O:17])=[CH:19][CH:20]=1)[CH3:30]
Reactant: CC(c1ccccc1C(F)(F)F)S(=O)(=O)Cl
Reactant: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: CCOC(=O)CCc1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)C(C)c3ccccc3C(F)(F)F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 40 %

Procedure:
Using the procedure in Example 1, Step 9, ethyl 3-[4-({2-[2-(2-aminoethyl)-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate (Example 38, Step 14) was reacted with 1-(2-trifluoromethyl-phenyl)-ethanesulfonyl chloride (0.13 g, 0.46 mmol) to afford 3-{4-[2-(1-benzhydryl-5-chloro-2-{2-[1-(2-trifluoromethyl-phenyl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethanesulfonyl]-phenyl}-propionic acid ethyl ester (0.110 g, 40%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[C:5]#[N:6].C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC.O1CCOCC1.C1C(=O)N([Br:44])C(=O)C1>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:44][CH2:20][C:18]([C:2]1[C:3]([CH3:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[C:5]#[N:6])=[O:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(Br)c(C)c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)CBr)c(C)c1C#N
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a flask charged with 3-bromo-6-methoxy-2-methylbenzonitrile (0.98 g, 4.33 mmol) and a stir bar was added BIS(TRIPHENYLPHOSPHINE)PALLADIUM(II) CHLORIDE (0.152 g, 0.217 mmol), tributyl(1-ethoxyethenyl)stannane (2.35 g, 6.50 mmol), and dioxane (20 mL). The mixture was fitted with a condenser and purged three times with nitrogen, and heated to 100° C. for 3 hours. The reaction was cooled, and to the solution was added THF (16 mL) and water (8 mL). After cooling the solution to 0° C. with an ice bath, NBS (1.543 g, 8.67 mmol) was added into the reaction. The dark solution turned brownish orange within 5 minutes. TLC showed a more polar spot. The reaction was diluted with EtOAc (100 mL), washed with brine, dried over sodium sulfate, and purified by flash chromatography to afford the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>>[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:21][CH:20]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3ccc(O)cc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril and 4-hydroxy-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([OH:22])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].ClC1C=C(C(=O)CCC2C=CC=C(O)C=2)C=CC=1C(O)=O>>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([OH:22])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Agent: O=C(CCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Product: O=C(O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Yield: 90 %

Procedure:
This compound was prepared in 90% yield from rac.-2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoic acid, methyl ester (Example 94) by the procedure described for 2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoic acid (Example 95). The product was a racemic mixture and was not resolved.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][S:27]([CH3:26])(=[O:29])=[O:28])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CN(CCc1ccccc1N)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CCc1ccccc1NS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
A solution of N-(2-(2-aminophenyl)ethyl)-N-methylcarbamic acid tert-butyl ester (723 mg, 2.9 mmol) and triethylamine (0.48 ml, 3.5 mmol) in dichloromethane (10 ml) was cooled to −78° C. A solution of methanesulfonyl chloride (0.22 ml, 2.9 mmol) in dichloromethane (2 ml) was added dropwise. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (50 ml) and washed with 10% aqueos sodium hydrogen sulfate solution (150 ml). The aqueous phase was extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution (150 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (60 g), using ethyl acetate/heptane (1:1) as eluent, to give 870 mg of N-(2-(2-(methylsulfonylamino)phenyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]([OH:16])=[O:15])[CH:13]=1)[NH:10][CH2:9][CH2:8][CH:7]2[C:17]([OH:19])=[O:18])(=[O:3])N.[OH-:20].[Na+]>>[NH:10]1[C:11]2[C:6](=[CH:5][C:4]([C:1]([OH:20])=[O:3])=[CH:13][C:12]=2[C:14]([OH:16])=[O:15])[CH:7]([C:17]([OH:19])=[O:18])[CH2:8][CH2:9]1
Reactant: [OH-]
Reactant: NC(=O)c1cc(C(=O)O)c2c(c1)C(C(=O)O)CCN2
Agent: [Na+]
Product: O=C(O)c1cc(C(=O)O)c2c(c1)C(C(=O)O)CCN2
Yield: 72.9 %

Procedure:
A solution of 6-carbamoyl-1,2,3,4-tetrahydroquinoline-4,8-dicarboxylic acid (1.77 g) in 10% aqueous sodium hydroxide solution (20 ml) was refluxed for 10 hours and after cooling, adjusted to pH 1. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound (1.29 g, 72.9%) which was recrystallized from ethanol to white crystals, mp 240° C.-241° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].[C:18]1([CH:24](OC(=N)C(Cl)(Cl)Cl)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.B(F)(F)F.CCOCC>C(Cl)(Cl)Cl.C1CCCCC1>[C:18]1([CH:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=2)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N=C(OC(c1ccccc1)c1ccccc1)C(Cl)(Cl)Cl
Reactant: COC(=O)COc1cccc(CCCCO)c1
Agent: FB(F)F
Solvent: C1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COC(=O)COc1cccc(CCCCOC(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution of methyl 3-(4-hydroxybutyl)phenoxyacetate (372 mg) and diphenylmethyltrichloroacetoimidate (771 mg) in chloroform (4 ml) and cyclohexane (8 ml) was added a catalytic amount of boron trifluoride etherate at 0° C. After being stirred for 30 min at 0° C., the mixture was quenched by addition of a saturated aqueous solution of sodium bicarbonate and extracted with ether. The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (343 mg) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH:53]([NH2:55])[CH3:54])=[CH:49][CH:48]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38]([NH:55][CH:53]([C:50]2[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=2)[CH3:54])=[O:44])=[C:18]([C:23]([F:25])([F:26])[F:24])[CH:17]=1
Reactant: CC(N)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C(F)(F)F)c3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ccc(F)cc4)c(C(F)(F)F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-(trifluoromethyl)aniline (91 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-fluorophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (64 mg, yield 49%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.Cl[CH2:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1>>[Cl-:11].[NH2:1][C:2]1[N:6]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:5]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:4]=2[N+:3]=1[CH2:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1
Reactant: Nc1nc2c(Cl)cccc2[nH]1
Reactant: Cc1cccc(SCCl)c1
Product: Cc1cccc(SCn2c(N)[n+](CSc3cccc(C)c3)c3cccc(Cl)c32)c1
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-7-chlorobenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 3-methylphenyl chloromethyl sulfide, the title compound is obtained.