Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[CH:6]([NH:24][C:25](=[O:34])[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33])[CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([O:22][CH3:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1>C1COCC1>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]([NH:24][CH:6]([CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([O:22][CH3:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[C:5]([OH:35])=[O:4])=[O:34]
Reactant: COC(=O)C(C/C=C/c1ccc(C2(OC)CCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC1(c2ccc(/C=C/CC(NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)CCOCC1
Yield: 95.3 %

Procedure:
In the same manner as in Example 2, 0.1N aqueous sodium hydroxide solution (63.1 ml) was added to a solution of (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid methyl ester (2.70 g) in THF (63.1 ml) to hydrolyze it to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid (2.50 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][C:29]=3[F:30])[N:26]([CH3:31])[C:25](=[O:32])[CH2:24][CH2:23]4)[CH:19]=2)[CH2:9]1)=O)(C)(C)C.Cl>CO>[F:30][C:29]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][C:25](=[O:32])[N:26]2[CH3:31])=[CH:21][C:20]=1[C:18]1[CH:17]=[N:16][CH:15]=[C:14]([O:13][C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:19]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3)c(F)cc21
Agent: Cl
Solvent: CO
Product: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CCNC4)c3)c(F)cc21

Procedure:
In analogy to the procedure described for the preparation of example 42, reaction of (S)-3-[5-(7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester (example 52) with hydrogen chloride (in dioxane) in methanol gave the title compound as a yellow solid. MS: 342.1 (M+H+).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([Sn](C)(C)C)=[CH:10][CH:9]=2)[O:6]C(C)(C)[N:4]1[C:20](=[O:24])[CH2:21][C:22]#[N:23].Br[C:26]1[CH:27]=[CH:28][C:29]([CH2:32][NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:30][CH:31]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.FC(F)(F)C(O)=O>CN(C)C=O.O.C(Cl)Cl.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([CH2:21][C:20]([NH:4][C@H:3]([CH2:2][F:1])[C@H:7]([OH:6])[C:8]1[CH:9]=[CH:10][C:11]([C:26]2[CH:31]=[N:30][C:29]([CH2:32][NH:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:28][CH:27]=2)=[CH:12][CH:13]=1)=[O:24])#[N:23]
Reactant: CC1(C)O[C@H](c2ccc([Sn](C)(C)C)cc2)[C@@H](CF)N1C(=O)CC#N
Reactant: CS(=O)(=O)NCc1ccc(Br)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)CC#N)cc2)cn1
Temperature: 70 °C
Yield: 2.8 %

Procedure:
A mixture of 3-((4S,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(trimethylstannyl)-phenyl)oxazolidin-3-yl)-3-oxopropanenitrile (150 mg, 0.342 mmol), N-((5-bromopyridin-2-yl)methyl) methanesulfonamide (90 mg, 0.342 mmol), tris(2-furyl)phosphine (16 mg, 0.068 mmol) and tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.034 mmol) in dimethylformamide (3 mL) is heated at 70° C. for 4 h under nitrogen. The mixture is then cooled, diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). Extracts are dried over Na2SO4 and concentrated to get crude product m/z (Cl) M+H 461. Obtained product is dissolved in CH2Cl2 (3 mL) and treated with trifluoroacetic acid (0.5 mL) for 3 hours at room temperature. Reaction is diluted with toluene (10 mL) and concentrated to syrup. Obtained crude product dissolved in dimethylformamide (2 mL) and purified using HPLC to give the title product (4 mg): m/z (Cl) M+H 421.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=2)[CH2:4][CH2:3]1>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(N)nc2)CC1
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To 1-methyl-4-(6-nitro-3-pyridyl)piperazine 3.4 g in ethyl acetate (100 mL) and ethanol (100 mL) was added 10% Pd/c (400 mg) and then contents stirred under hydrogen (10 psi) overnight. After filtration through CELITE™, the solvents were evaporated and the crude product was purified over silica gel using DCM/7N Ammonia in MeOH (0-5%) to afford 5-(4-methylpiperazin-1-yl)pyridin-2-amine (2.2 g). 1HNMR (d6-DMSO) 7.56 (1H, d, J=3 Hz), 7.13 (1H, m), 6.36 (1H, d, J=8.8 Hz), 5.33 (brs, 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).
Reaction SMILES: ClC1C=CC(N=C=O)=CC=1.[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:15][CH2:14][CH2:13][CH2:12]1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]=[C:42]=[O:43])=[CH:37][C:36]=1[N+:44]([O-:46])=[O:45]>>[N+:44]([C:36]1[CH:37]=[C:38]([NH:41][C:42]([N:27]2[C:28]3=[N:29][CH:30]=[CH:31][CH:32]=[C:33]3[C:25]([C:19]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH:11]4[CH2:12][CH2:13][CH2:14][CH2:15]4)[CH:18]=3)=[CH:26]2)=[O:43])[CH:39]=[CH:40][C:35]=1[F:34])([O-:46])=[O:45]
Reactant: O=C=Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1OC1CCCC1
Agent: O=C=Nc1ccc(Cl)cc1
Product: COc1ccc(-c2cn(C(=O)Nc3ccc(F)c([N+](=O)[O-])c3)c3ncccc23)cc1OC1CCCC1

Procedure:
3-(3-Cyclopentyloxy-4-methoxy-phenyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid (3-nitro-4-fluoro-phenyl)-amide 98 was prepared using the same protocol as described in Example 25, substituting 3-(3,4-dimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine 1 and 4-chlorophenyl isocyanate with 3-(3-Cyclopentyloxy-4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine 88 and 4-fluoro-3-nitrophenyl isocyanate respectively. MS(ESI) [M+H+]+=491.10.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([N+:18]([O-:20])=[O:19])=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:14]=2[CH:27]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B#B.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([N+:18]([O-:20])=[O:19])=[C:15]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:14]=2[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1)c1ccccc1
Agent: B#B
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1oc2ccc(NCc3ccccc3)cc2c1-c1ccccc1

Procedure:
The product of Step A is dissolved in 50 ml. of tetrahydrofuran and treated with 5 ml. of 1 N diborane in tetrahydrofuran at about 20° C. over a period of about 16 hours. The mixture is treated with 5 ml. of 6 N hydrochloric acid and heated on a steam bath for about 1/2 hour. 20 ml. of saturated sodium bicarbonate solution is added, the mixture is extracted with chloroform and the extracts are dried, then evaporated to provide a residue. The residue is recrystallized from a mixture of isopropanol and water to yield red needles of 5-benzylamino-2-nitro-3-phenylbenzofuran, m.p. 118°-120° C. having the structure ##STR12##
Reaction SMILES: [CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:17]([OH:19])=O)[CH3:16])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[O:7][CH:8]=1.NC(CC1C=CC=CC=1)CC(O)C(NC(OCC1SC=NC=1)=O)CC1C=CC=CC=1.[NH2:50][C@@H:51]([CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[CH2:52][C@H:53]([OH:72])[C@@H:54]([NH:62][C:63]([O:65][CH2:66][C:67]1[O:71][N:70]=[CH:69][CH:68]=1)=[O:64])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.C(Cl)Cl>CO>[CH3:1][N:2]([C:12]([NH:14][C@H:15]([C:17]([NH:50][C@@H:51]([CH2:73][C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)[CH2:52][C@H:53]([OH:72])[C@@H:54]([NH:62][C:63]([O:65][CH2:66][C:67]1[O:71][N:70]=[CH:69][CH:68]=1)=[O:64])[CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:19])[CH3:16])=[O:13])[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:10])[CH3:11])[O:7][CH:8]=1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@@H](C)C(=O)O)co1
Agent: NC(Cc1ccccc1)CC(O)C(Cc1ccccc1)NC(=O)OCc1cncs1
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc(CN(C)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccno2)co1
Yield: 64 %

Procedure:
Using the procedure of Example 1U but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-alanine and replacing 2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxy-carbonyl)amino)-1,6-diphenyl-3-hydroxyhexane provided, after silica gel chromatography using 92:8 CH2Cl2:CH3OH, the desired compound (Rf 0.48, 92:8 CH2Cl2:CH3OH) in 64% yield. 1H NMR (DMSO-d6) δ 1.08 (d, 3H), 1.24 (d, 6H), 1.50 (m, 2H), 2.82 (s, 3H), 3.0 (m, 1H), 4.25 (s, 2H), 4.60 (d, 1H), 5.05 (s, 2H), 6.20 (br d, 1H), 6.32 (d, 1H), 7.20 (m, 11H), 7.50 (br d, 1H), 7.78 (s, 1H), 8.51 (d, 1H). Mass spectrum: (M+H)+=661.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: CCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f19) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14]CC)=O)=[C:7]2[OH:17].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=1)=[O:14])=[C:7]2[OH:17]
Reactant: CCOC(=O)c1cnc2c(Cl)cccc2c1O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(Cl)cccc2c1O
Temperature: 25 °C

Procedure:
Ethyl 8-chloro-4-hydroxyquinoline-3-carboxylate (1.21 g) and 4-chlorobenzyl-amine (1.8 mL) are heated at 180° C. for 2 hours. The reaction is cooled to room temperature and the resulting solid filtered, washed thoroughly with diethyl ether and methylene chloride, and dried to give the desired product (1.44 g).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11](=[O:29])[NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[C@H:6]1[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1)=[O:4].[OH-].[Li+].Cl>O1CCCC1>[F:37][C:32]1[CH:31]=[C:30]([C@H:6]2[C@H:5]([C:3]([OH:4])=[O:2])[O:9][C:8](=[O:10])[N:7]2[C:11](=[O:29])[NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)[CH:35]=[CH:34][C:33]=1[F:36]
Reactant: COC(=O)[C@@H]1OC(=O)N(C(=O)NCCCN2CCC(c3ccc(F)cc3)CC2)[C@H]1c1ccc(F)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1OC(=O)N(C(=O)NCCCN2CCC(c3ccc(F)cc3)CC2)[C@H]1c1ccc(F)c(F)c1
Temperature: 0 °C

Procedure:
A solution of the hydrochloride salt of (4S, 5R)-4-(3,4-difluorophenyl)-3-{3-[4-(4-fluorophenyl)piperidin-1-yl]propylcarbamoyl}-2-oxo-oxazolidine-5-carboxylic acid methyl ester (300 mg, 0.54 mmol) in tetrahydrofuran (5 mL) was cooled to 0° C. and treated with 0.5M aqueous lithium hydroxide solution (2.2 mL, 1.1 mmol). The reaction mixture was stirred at 0° C. 20 minutes when 1N aqueous HCl was added dropwise until the pH of the reaction mixture reached 6. The volatile organics were removed under reduced pressure and the resulting aqueous solution extracted with dichloromethane (3×50 mL). The combined organics were dried over sodium sulfate, filtered and the volatiles removed to provide (4S, 5R)-4-(3,4-difluorophenyl)-3-{3-[4-(4-fluorophenyl)piperidin-1-yl]propylcarbamoyl}-2-oxo-oxazolidine-5-carboxylic acid as a foam.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([O:36]C)=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[F:48])[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]([C:34]([OH:36])=[O:35])=[CH:24][C:23]=5[C:22]4=[O:38])[CH2:17][CH2:16]3)[C:11]([O:39][CH2:40][CH3:41])=[CH:10][C:9]=2[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[F:48])[CH2:6][CH2:7]1
Reactant: CCCc1nc2c(cc1C(=O)OC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccccc4F)cc3OCC)CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1nc2c(cc1C(=O)O)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccccc4F)cc3OCC)CC1)CC2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (5 mL)-THF (5 mL) solution of methyl 6-(1-((2-cyclopropyl-5-ethoxy-2′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (250 mg), and the mixture was stirred at 60° C. for 30 minutes. The reaction mixture was neutralized with 2 M hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration. The obtained solid was recrystallized (DMSO/ethanol/hexane) to obtain the title compound (153 mg).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:13]3[N:14]=[C:15]([NH2:17])[S:16][C:12]=3[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C(OCC)(=O)C.C1COCC1>[CH3:29][O:28][C:26](=[O:27])[C:25]1[CH:30]=[CH:31][C:22]([CH2:20][NH:17][C:15]2[S:16][C:12]3[CH:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:19]=[CH:18][C:13]=3[N:14]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1nc2ccc(OCCN3CCOCC3)cc2s1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNc2nc3ccc(OCCN4CCOCC4)cc3s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
To a round-bottom flask containing benzothiazole 226 (5.80 g, 20.8 mmol) was added methyl 4-formylbenzoate (5.11 g, 31.1 mmol), followed by THF (8 mL), dibutyltin dichloride (315 mg, 1.04 mmol) and dropwise addition of phenylsilane (3.24 mL, 31.1 mmol). The resulting mixture was stirred overnight at room temperature under nitrogen. The mixture was diluted in ethyl acetate and filtered. The filtrate was partitioned between ethyl acetate and water and the combined organic layers were washed with 1N HCl. The combined acidic layers were neutralized using a saturated aqueous solution of NaHCO3 and the precipitate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The resulting crude was purified by flash chromatography using MeOH/CHCl3 (10:90) to afford 227 (3.69 g, 42% yield). 1H NMR: (Acetone-d6) δ (ppm): 8.04 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.94 (dd, J=8.5, 2.7 Hz, 1H), 4.50 (t, J=5.5 Hz, 2H), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[C:20]([NH:22][CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)=[O:21])=[CH:5][CH:4]=1.Cl.C([S:53][CH2:54][CH2:55][NH2:56])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[C:20]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:56][CH2:55][CH2:54][SH:53])=[O:29])=[CH:31][CH:32]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)NCc2ccc(C(=O)O)cc2)cc1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)NCc2ccc(C(=O)NCCS)cc2)cc1

Procedure:
This material was prepared using a method substantially similar to that of Example 22 from 4-[({[3-(4-methoxyphenyl)-5-phenyl-1H-pyrrol-2-yl]carbonyl}amino)methyl]benzoic acid and 2-(tritylsulfanyl)ethanamine hydrochloride, yielding the title compound 3-(4-methoxyphenyl)-5-phenyl-N-(4-{[(2-sulfanylethyl)amino]carbonyl}benzyl)-1H-pyrrole-2 carboxamide: Yield 70%; m.p. 131-132° C.; IR 3396, 3280, 1635, 1524, 1499, 1246 cm−1; 1H-NMR (500 MHz, δ ppm, CDCl3) 9.99 (s, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.59 (d, J=7.6 Hz, 2H), 7.38 (t, J=7.7 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.28 (t, J=7.5 Hz, 1H); 7.17 (d, J=8.0 Hz, 2H), 7.03 (t, J=5.5 Hz, 1H), 6.89 (d, J=8.5 Hz, 2H), 6.47 (d, J=2.9 Hz, 1H), 6.17 (t, J=5.8 Hz, 1H), 4.45 (d, J=5.9 Hz, 2H), 3.85-3.73 (m, 5H), 2.97 (t, J=6.2 Hz, 2H), 1.62 (s, 1H); 13C-NMR (75 MHz, δ ppm, CDCl3) 167.7, 161.7, 159.6, 142.4, 134.6, 133.4, 131.6, 130.8, 129.6, 129.2, 128.7, 128.5, 128.3, 127.7, 127.6, 124.9, 122.3, 114.7, 109.8, 55.6, 43.1, 39.5, 38.4, 29.9.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[N-:22]=[C:23]=[O:24]>>[Cl:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[CH:5]([O:13][CH:14]1[CH2:17][N:16]([C:23]([NH:22][C:4]([CH3:18])([CH2:3][CH3:21])[CH3:5])=[O:24])[CH2:15]1)[C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[CH:10][CH:11]=1
Reactant: [N-]=C=O
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Agent: Cl
Product: CCC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccccc2Cl)C1

Procedure:
This material was prepared from 3-(2,4′-dichlorobenzhydryloxy)azetidine hydrochloride (9) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH:15]C(=O)C(C)(C)C)[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(COCc2ccc(Cl)cc2)n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(COCc2ccc(Cl)cc2)n1

Procedure:
This material was prepared in analogy to example 86 step B] from N-[6-(4-chloro-benzyloxymethyl)-pyridin-2-yl]-2,2-dimethyl-propionamide (0.868 g) and 3M aqueous NaOH (5.22 mL) as a light yellow liquid (0.63 g). MS (ESI): 249.1 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:19]=1[C:20]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=1)=[O:21]
Reactant: Cc1cccc(C)c1C(=O)Cl
Reactant: CC(=O)c1cccc(O)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1cccc(OC(=O)c2c(C)cccc2C)c1
Reaction time: 16 h

Procedure:
To a stirred solution of 3′-Hydroxyacetophenone (4.84 g, 35.5 mmol) in anhydrous CH2Cl2 (50 ml) was added at room temperature pyridine (25 ml) followed by addition of 2,6-Dimethylbenzoyl chloride (Step A, 6 g, 35 mmol) in anhydrous CH2Cl2 (10 ml) under argon. The reaction mixture was stirred for 16 hours, concentrated under reduced pressure, diluted with CH2Cl2, and washed with 0.1M HCl, water and brine. The organic layer was dried over Na2SO4, concentrated and purified by flash chromatography eluted with ethyl acetate:hexane (1:2) to give the title compound.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:49][CH:50]([CH3:52])[CH3:51])=[N:40][C:41]([CH3:48])=[CH:42][C:43]=2[O:44][CH:45]([CH3:47])[CH3:46])=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:63][C:64]1[O:65][C:66]2[C:67]([N:72]=1)=[N:68][CH:69]=[CH:70][CH:71]=2>>[O:65]1[C:66]2[C:67](=[N:68][CH:69]=[CH:70][CH:71]=2)[N:72]=[C:64]1[S:63][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([O:49][CH:50]([CH3:51])[CH3:52])=[N:40][C:41]([CH3:48])=[CH:42][C:43]=2[O:44][CH:45]([CH3:46])[CH3:47])=[O:36])[CH2:30][CH2:29]1
Reactant: Sc1nc2ncccc2o1
Reactant: Cc1cc(OC(C)C)c(NC(=O)CN2CCN(CCO)CC2)c(OC(C)C)n1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(OC(C)C)c(NC(=O)CN2CCN(CCSc3nc4ncccc4o3)CC2)c(OC(C)C)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(1-methylethoxy)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptooxazolo[4,5-b]pyridine, to thereby yield the title compound as a yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NC(=O)C)C=CC=1.C(=O)CCCCC.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:29]([NH:28][C:24]1[CH:23]=[C:22]([N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:31])[CH3:30]
Reactant: CCCCCCN(C(=O)Nc1ncc(SCC(=O)OCC)s1)c1cccc(NC(C)=O)c1
Agent: CC(=O)Nc1cccc(N)c1
Agent: CCCCCC=O
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CCCCCCN(C(=O)Nc1ncc(SCC(=O)O)s1)c1cccc(NC(C)=O)c1

Procedure:
The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-hexyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-aminophenyl)-acetamide, hexanal and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.