Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:40]=2[CH3:41])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: Cc1ccncc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1ccncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K30) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (276 mg, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:12])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[F:20][C:21]1[CH:37]=[CH:36][C:24]([O:25][C:26]2[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1([NH:12][S:32]([C:29]2[CH:30]=[CH:31][C:26]([O:25][C:24]3[CH:36]=[CH:37][C:21]([F:20])=[CH:22][CH:23]=3)=[CH:27][CH:28]=2)(=[O:33])=[O:34])[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: CCOC(=O)C1(N)CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of 4-aminotetrahydropyran-4-carboxylic acid ethyl ester (7.00 grams, 0.0404 mole) in N,N-dimethylformamide (40 mL) was added triethylamine (5.94 mL, 0.043 mole). Solid 4-(4-fluorophenoxy)benzenesulfonyl chloride (12.165 grams, 0.0424 mole) was added in portions. The resulting mixture was stirred at room temperature for 16 hours and then most of the solvent was removed by evaporation under vacuum. The residue was partitioned between saturated sodium bicarbonate solution and dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent under vacuum provided crude 4-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid ethyl ester as an amber oil (21.05 grams). Flash chromatography on silica gel eluting with 25% ethyl acetate/hexane followed by 50% ethyl acetate/hexane provided 4-[4-(4-fluorophenoxy)benzenesulfonylamino]tetrahydropyran-4-carboxylic acid ethyl ester as an off-white crystalline solid (12.15 grams, 71%, mp 116-117° C.).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[N:4]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=2[CH3:18])[CH:5]=[CH:6][CH:7]=1.C(C([Sn])=C(CCCC)CCCC)CCC.[CH3:35][C:36]1[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=[C:38]([CH3:45])[C:37]=1[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH:52]=[CH2:53])[C:47]1=[O:54]>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>[CH3:35][C:36]1[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=[C:38]([CH3:45])[C:37]=1[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH:52]=[CH2:53])[C:47]1=[O:54].[CH3:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([CH3:14])[C:8]=1[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH2:48][CH2:47][OH:54])[C:3]1=[O:19]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(Br)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=Cc1cccn(-c2c(C)cc([N+](=O)[O-])cc2C)c1=O
Agent: CCCCC([Sn])=C(CCCC)CCCC
Product: Cc1cc([N+](=O)[O-])cc(C)c1-n1cccc(CCO)c1=O

Procedure:
To prepare the compound of the Formula (Ia), 3-bromopyridin-2(1H)-one (III) is reacted with 1-fluoro-2,5-dimethyl-4-nitrobenzene (IV) to give 3-bromo-1-(2,6-dimethyl-4-nitrophenyl)pyridin-2(1H)-one (V). Then, (V) is converted with tributylvinyl tin and tetrakis(triphenylphosphine)palladium into 1-(2,6-dimethyl-4-nitrophenyl)-3-vinylpyridin-2(1H)-one (VI). Hydroboration and oxidation of (VI) produces 1-(2,6-dimethyl-4-nitrophenyl)-3-(2-hydroxyethyl)pyridin-2(1H)-one (VII). In order to protect the hydroxy group, (VII) is reacted with tert-butyl(chloro)diphenylsilane in the presence of a base, giving 3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-1-(2,6-dimethyl-4-nitrophenyl)pyridin-2(1H)-one (VIII). The reduction of the nitro group in (VIII) leads to 1-(4-amino-2,6-dimethylphenyl)-3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)pyridin-2(1H)-one (IX). Then follows the reaction of (IX) with (S)-epoxyphthalimide (X) to give 2-[(2R)-3-({4-[3-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}amino)-2-hydroxypropyl]-1H-isoindole-1,3(2H)-dione (XI). Ring closure to the oxazolidinone and cleaving off the phthalimide group produces starting from (XI) 1-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2,6-dimethylphenyl}-3-(2-{[tert-butyl-(diphenyl)silyl]oxy}ethyl)pyridin-2(1H)-one (XII), which is reacted with 5-chlorothiophene-2-carbonyl chloride (XIII) to give N-[((5S)-3-{4-[3-(2-{[tert-butyl-(diphenyl)silyl]oxy}ethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]-5-chlorothiophene-2-carboxamide (XIV). Cleaving off the protective group in (XIV) produces 5-chloro-N-[((5S)-3-{4-[3-(2-hydroxyethyl)-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]thiophene-2-carboxamide (IIa), which is reacted with trans-4-aminohexanol (XV) to give 5-chloro-N-{[(5S)-3-{4-[3-{2-[(trans-4-hydroxycyclohexyl)amino]ethyl}-2-oxopyridin-1(2H)-yl]-3,5-dimethylphenyl}-2-oxo-1,3-oxazolidin-5-yl]methyl}thiophene-2-carboxamide (Ia).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:39])[NH:7][C@@H:8]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]2[C:18]3[CH:31]=[CH:30][S:29][C:19]=3[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:22]=2)[CH2:13][C@H:12]1[C:32](O)=[O:33])=[O:10])([CH3:4])([CH3:3])[CH3:2].[NH2:40][C@@H:41]([CH2:50][CH2:51][CH3:52])[CH:42]([OH:49])[C:43]([NH:45][CH:46]1[CH2:48][CH2:47]1)=[O:44].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[C:1]([NH:5][C:6](=[O:39])[NH:7][C@@H:8]([C:35]([CH3:37])([CH3:38])[CH3:36])[C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]2[C:18]3[CH:31]=[CH:30][S:29][C:19]=3[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:22]=2)[CH2:13][C@H:12]1[C:32]([NH:40][C@@H:41]([CH2:50][CH2:51][CH3:52])[CH:42]([OH:49])[C:43]([NH:45][CH:46]1[CH2:47][CH2:48]1)=[O:44])=[O:33])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC[C@H](N)C(O)C(=O)NC1CC1
Reactant: CC(C)(C)NC(=O)N[C@H](C(=O)N1C[C@H](Oc2nc(-c3ccccn3)nc3sccc23)C[C@H]1C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2nc(-c3ccccn3)nc3sccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)C(O)C(=O)NC1CC1

Procedure:
(2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yloxy)pyrrolidine-2-carboxylic acid (60) (1 mmol) was coupled with (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide (1 mmol, as prepared in Reference A) in the presence of O (7 azabenzotriazol 1 yl) 1,1,3,3 tetramethyl-uronium hexafluorophosphate (HATU) (1.2 mmol) and diisopropylethylamine (4 mmol) in dichloromethane and N,N-dimethylformamide to give (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-4-(2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yloxy)pyrrolidine-2-carboxamide (61) as a crude solid after aqueous/organic extractive work up.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][N:20]=1.O>CN(C=O)C.CCOC(C)=O>[Cl:18][C:19]1[CH:24]=[C:23]([O:25][C:2]2[C:3]([CH3:11])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: Cc1nc([N+](=O)[O-])ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Temperature: 100 °C
Yield: 54.7 %

Procedure:
A solution of 3-bromo-2-methyl-6-nitropyridine (25.59 g, 118 mmol), K2CO3 (48.9 g, 354 mmol) and 2-chloro-4-hydroxy-pyridine (30.6 g, 236 mmol) in DMF (160 mL) was sparged with Ar, heated at 100° C. overnight, then cooled to RT. The mixture was treated with water and EtOAc, the solids removed via filtration through diatomaceous earth and washed with water, EtOAc, then DCM. The aqueous filtrate was extracted with EtOAc (2×) and the organic extracts were combined with the organic filtrates, washed with water, then brine, dried over Na2SO4 and concentrated to dryness. The residue was treated with MTBE, sonicated and the resulting solid collected via filtration to afford 3-((2-chloropyridin-4-yl)oxy)-2-methyl-6-nitropyridine (17.16 g, 55%). 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J=5.7 Hz, 1H), 8.25 (d, J=8.7 Hz, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.3 Hz, 1H), 7.16 (dd, J=5.7, 2.3 Hz, 1H), 2.46 (s, 3H); MS (ESI) m/z: 266.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([NH2:24])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].CO[CH:33]1[CH2:37][CH2:36][CH:35](OC)O1.O>C(O)(=O)C>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([N:24]1[CH:33]=[CH:37][CH:36]=[CH:35]1)=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1CCC(OC)O1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(N)cc12
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-n3cccc3)cc12
Yield: 66.3 %

Procedure:
A solution of tert-butyl(6-amino-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.41 g, 1 mmol) and 2,5-dimethoxytetrahydrofuran (0.19 ml, 1.5 mmol) in acetic acid (10 ml) was stirred at 80° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(1H-pyrrol-1-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.31 g, 67.4%) as crystals.
Reaction SMILES: B(C1CCCCC1)C1CCCCC1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17].[Zn](CC)CC.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1>>[CH3:14][C:15]([CH3:19])([CH3:18])[CH:16]=[CH:17][C@@H:31]([C:30]1[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:35])[F:36])=[CH:34][CH:33]=1)[OH:32]
Reactant: C#CC(C)(C)C
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: B(C1CCCCC1)C1CCCCC1
Agent: CC[Zn]CC
Product: CC(C)(C)C=C[C@H](O)c1ccc(C(F)(F)F)cc1
Yield: 89 %

Procedure:
The product was prepared by General procedure S using 98 mg (0.55 mmol) Cy2BH, 68 μL (0.55 mmol) 3,3-dimethyl-1-butyne, 0.55 mL (1.1 mmol, 2.0 M in hexanes) Et2Zn, 4.8 mg (0.02 mmol) (−)-MIB, and 68 μL (0.50 mmol) p-trifluoromethylbenzaldehyde. The crude product was purified by column chromatography (5% ethyl acetate in hexanes) to afford the title compound as a white solid in 89% yield (115 mg, 0.45 mmol). m.p.: 30-32° C.; [α]D20=−10.0 (c=0.27, CHCl3, 95% ee); 1H NMR (CDCl3, 500 MHz): δ 0.98 (s, 9H), 2.03 (br s, 1H), 5.15 (d, 1H, J=7.0 Hz), 5.47 (dd, 1H, J=15.5, 7.2 Hz), 5.78 (d, 1H, J=15.6 Hz), 7.43 (d, 2H, J=8.0 Hz), and 7.55 (d, 2H, J=8.0 Hz) ppm; 13C{1H} NMR (CDCl3, 125 MHz): δ 29.3, 33.0, 74.9, 123.1, 125.28, 125.31, 125.34, 126.4, 126.7, 129.4, 129.7, 144.6, and 147.3 ppm; IR (film): 3335, 3025, 2962, 2905, 2868, 1661, 162.0, 1477, 1463, 1414, 1364, and 1327 cm−1; HRMS-CI m/z 239.1247 [(M−F)+; calcd for C14H17F2O: 239.1247].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].O>O1CCCC1.CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: NCCCCCCO
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CNC(=O)OCc1ccccc1)NCCCCCCO
Temperature: 23 °C
Reaction time: 12 h

Procedure:
A solution of 31.5 g of the N-hydroxysuccinimide ester of N-benzyloxycarbonylglycine [J. Am. Chem. Soc., 86, 1839, (1964)] in 100 ml of tetrahydrofuran is reacted dropwise with 12 g of 6-amino-1-hexanol in 50 ml of 50% methanol in tetrahydrofuran. The reaction is stirred for 12 hours at 23° C. and poured into water. The resulting precipitate is washed thoroughly with water, filtered, and dried to provide crude N-(benzyloxycarbonylglycyl)-6-amino-1-hexanol. The pure compound recrystallized from ethyl acetate has a melting point of 104°-5° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:13][C:12]([C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[N:11]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:13][C:12]([C:26]([F:32])([F:31])[C:27]([F:28])([F:29])[F:30])=[N:11]1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(N3CCNCC3)s2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.4 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[5-(piperazin-1-yl)-thiophen-2-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.07 mmol) prepared in Step 1, triethylamine (47.0 uL, 0.34 mmol) and methanesulfonyl chloride (11.6 mg, 0.10 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][C:31]([O:33]CC)=[O:32])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].[OH-].[Li+].CO.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][C:31]([OH:33])=[O:32])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: CCOC(=O)C[C@@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CC(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 63 %

Procedure:
Prepared analogously to Example 19b from 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-4-[(2S)-2-(ethoxycarbonylmethyl)pyrrolidin-1-ylcarbonyl]benzamide and lithium hydroxide in tetrahydrofuran. Yield: 63%; Rf value: 0.32 (Reversed phase RP 8: methanol/5% sodium chloride solution=6:4); C23H22Cl2N4O4 (489.357); mass spectrum: (M−H)-=487/489/451 (chlorine isotope).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=O.N1CCCCC1>C1C=CC=CC=1>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: O=Cc1cccs1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: O=C1Nc2ccccc2C1=Cc1cccs1
Yield: 55 %

Procedure:
A mixture of oxindole (16.5 g, 0.12 mole), thiophene-2-carboxaldehyde (19.1 g, 0.17 mole) and piperidine (1 ml) in 200 ml of benzene is heated at reflux temperature for 4 hours, during which time water is separated by means of a Dean-Stark trap. Solvent is removed in vacuo and the residue is crystallized twice from ethanol to give 15 g of the product: m.p. 208.5°-210°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=O)[C:26]([C:32]3[CH:33]=[N:34][N:35]([CH2:38][C:39]4([O:47][CH3:48])[CH2:44][CH2:43][CH2:42][C:41]([CH3:46])([CH3:45])[CH2:40]4)[C:36]=3[CH3:37])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:49][S:50]([NH2:53])(=[O:52])=[O:51].Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[CH:24]=[CH:25][C:26]([C:32]3[CH:33]=[N:34][N:35]([CH2:38][C:39]4([O:47][CH3:48])[CH2:44][CH2:43][CH2:42][C:41]([CH3:45])([CH3:46])[CH2:40]4)[C:36]=3[CH3:37])=[C:27]([C:29](=[O:31])[NH:53][S:50]([CH3:49])(=[O:52])=[O:51])[N:28]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CS(N)(=O)=O
Reactant: COC1(Cn2ncc(-c3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)c2C)CCCC(C)(C)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC1(Cn2ncc(-c3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)NS(C)(=O)=O)c2C)CCCC(C)(C)C1

Procedure:
A solution of EXAMPLE 157E (0.051 g), methanesulfonamide (0.015 g), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride.HCl (0.037 g) and 4-dimethylaminopyridine (0.019 g) were stirred together in dichloromethane (1 mL) at room temperature overnight. The reaction mixture was loaded onto silica gel and eluted using a gradient of 0.5% to 3.25% methanol/dichloromethane to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 12.84 (s, 1H), 11.81 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.56-7.41 (m, 3H), 7.41-7.32 (m, 2H), 7.29 (s, 1H), 7.00 (d, 1H), 4.96 (s, 2H), 4.00 (d, 2H), 3.93 (t, 2H), 3.16 (s, 3H), 3.11 (s, 3H), 3.03 (t, 2H), 2.13 (s, 3H), 1.71 (d, 1H), 1.58-1.00 (m, 7H), 0.96 (s, 3H), 0.84 (s, 3H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[S:7]([C:10]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8]>ClCCl>[C:1]([NH:5][S:7]([C:10]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: COC(=O)c1ccc(C(=O)OC)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
At 5° C., 59.1 g (0.81 mol) of tert-butylamine were added dropwise to a solution of 118.3 g (0.4 mol) of crude dimethyl chlorosulfonylterephthalate (from Example A1) in 500 ml of dichloromethane, and the mixture was stirred at room temperature for another 1 h. The reaction solution was washed with water, dried and concentrated. Trituration of the crude product with heptane gave 106.7 g (81% of theory) of dimethyl tert-butylsulfamoylterephthalate of m.p. 132-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:27]([O-])=O)[CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH:10]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH:10]=1)[NH2:27]
Reactant: COc1ccc(Cc2cc(Sc3c(Cl)cc([N+](=O)[O-])cc3Cl)ccc2OC)cn1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(Cc2cc(Sc3c(Cl)cc(N)cc3Cl)ccc2OC)cn1

Procedure:
3,5-Dichloro-4-(4'-methoxy-3'-(6-methoxy-3-pyridylmethyl)phenylthio)-nitrobenzene (28.60 g) and iron powder (35 g) were stirred with heating in glacial acetic acid (250 ml) at 90° for 40 minutes. The mixture was cooled, filtered, then evaporated to dryness and the resulting gum redissolved in chloroform, washed with water (twice), dried over anhydrous magnesium sulphate and evaporated to give the crude product as a light brown gum (27.17 g). This gum was chromatographed on silica gel using ethyl acetate-petroleum spirit (60-80°, gradient elution) as eluant. 3,5-Dichloro-4-(4'-methoxy-3'-(6-methoxy-3-pyridylmethyl)phenylthio) aniline was isolated as a pale yellow solid (21.29 g, 79%), m.p. 114-115°.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>CCO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][C:3]=1[F:9]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Br)c(F)c1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(Br)c(F)c1)C(=O)OCC
Yield: 83.9 %

Procedure:
A solution of 4-bromo-3-fluoroaniline (56.6 g, 297.87 mmol) and 1,3-diethyl 2-(ethoxymethylidene)propanedioate (72.45 g, 335.06 mmol) in EtOH (560 mL) was stirred at 80° C. for 4 h. The reaction mixture was allowed to cool, the solids collected by filtration and dried in an oven to afford the desired material (90 g, 84%) as an off-white solid which was used without further purification. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.26 (6H, q), 4.14 (2H, q), 4.22 (2H, q), 7.18-7.25 (1H, m), 7.57 (1H, dd), 7.64-7.7 (1H, m), 8.33 (1H, d), 10.62 (1H, d). Mass Spectrum: m/z (ES+)[M+H]+=360.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23]C(C)(C)C)=[O:22])[CH:16]=3)[CH2:10][C:9]=2[CH:8]=[N:7][CH:6]=1)=[O:4]>C(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]2[C:14]=1[CH2:13][CH2:12][N:11]([C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[C:21]([OH:23])=[O:22])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)OC(C)(C)C)c1)C2
Solvent: O=CO
Product: COC(=O)c1cncc2c1CCN(c1cccc(C(=O)O)c1)C2
Temperature: 30 °C
Yield: 65.7 %

Procedure:
A mixture of 7-(3-tert-Butoxycarbonyl-phenyl)-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carboxylic acid methyl ester (6.9 g, 0.0188 mol) and 98% formic acid (30 mL) was heated at 50° C. for 4 hr and at 30° C. overnight. HPLC analysis showed the reaction was not complete. It was heated at 50° C. for an additional 1.5 hr. The reaction mixture was concentrated under reduced pressure. Diluted with dichloromethane (200 mL) and cooled to 0° C. To the mixture (liquid and solid) was added saturated sodium bicarbonate until to get a pH=5-6 at 0° C. The solid was collected, washed with water (50 mL), dichloromethane (50 mL) and air dried. The solid was triturated with acetone (50 mL) for 30 min. The yellow-green solid was collected and dried in a drying pistol with refluxing acetone overnight to give the title compound (3.86 g, 66%). 1H NMR 300 MHz (d6-DMSO), δ 13 (brs, 1H), 8.8 (s, 1H), 8.65 (s, 1H), 7.5 (m, 4H), 4.5 (s, 2H), 3.8 (s, 3H), 3.6 (t, 2H), 3.2 (t, 2H).