Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:16]([N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21]C1)([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:22]1[CH2:23][CH2:24][N:19]([CH:16]([CH3:17])[CH3:18])[CH2:21]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)C3)ccc2[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a cold (0° C.) mixture of 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (10 g, 1.0 eq.), 1-isopropyl-piperidin-4-ol (intermediate 1, step 1, 7.32 g, 1.05 eq.) and triphenylphosphine (15.3 g, 1.2 eq.) in tetrahydrofuran (280 ml) was slowly added a solution of diisopropylazodicarboxylate (11.8 g, 1.2 eq.) in tetrahydrofuran (20 mL). The mixture was stirred 30 min at 0° C. and overnight at room temperature, was concentrated in vacuo, dissolved in methyltertiobutylether (310 mL), washed with sodium hydroxide aqueous solution (0.5N), brine, dried over Na2SO4, filtered and evaporated. The residue was purified on silica eluting with dichloromethane/methanol/ammoniac. One fraction was isolated and dried in vacuo, to yield 7.0 g (43%) of the desired product as white solid. MS (m/e): 331.5 (MH+, 100%)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1.[NH2:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:26][CH2:27][CH:28]([OH:31])[CH2:29][OH:30])=[O:22])[N:9]=1
Reactant: NCC(O)CO
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Solvent: CCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NCC(O)CO

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) and 2.4 g of (+/−) 3-amino-1,2-propanediol are heated at 60° C. for 2 h in 10 ml of ethanol. The crystals precipitating on cooling are filtered off and washed with ethanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2,3-dihydroxypropyl)acetamide remains as colorless crystals of m.p. 180-181° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>>[CH3:9][C:8]([C:4]1[CH:3]=[CH:2][C:1]([OH:7])=[CH:6][CH:5]=1)=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccccc1
Product: CC(=O)c1ccc(O)cc1

Procedure:
acylating phenol with acetic anhydride to produce 4-hydroxyacetophenone; and
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:14][CH2:15][CH2:16][OH:17])[C:6]1[CH:11]=[CH:10][C:9]([N:12]=O)=[CH:8][CH:7]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO.[Fe]>[OH:17][CH2:16][CH2:15][CH2:14][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: O=Nc1ccc(N(CCCO)CCCO)cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: Nc1ccc(N(CCCO)CCCO)cc1

Procedure:
Iron powder (6.72 g), N,N-bis(3-hydroxypropyl)-4-nitrosoaniline (10 g) and hydrochloric acid(20cm3) in methanol (120cm3) were refluxed for 2hrs. The resulting mixture was made alkaline with sodium carbonate, filtered and the solvent removed to leave N,N-bis(3-hydroxypropyl)-4-aminoaniline as a brown solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:19]([O:21]N1C(=O)CCC1=O)=O)[CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])[CH3:3].[NH2:29][C@H:30]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:55]([NH:57][C@H:58]([C:62]([OH:64])=[O:63])[C@@H:59]([CH3:61])[OH:60])=[O:56])[CH2:53][OH:54])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=[O:34])[CH2:31][OH:32].C(N(CC)CC)C>CN(C)C=O>[NH:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:19]([NH:29][C@H:30]([C:33]([NH:35][C@H:36]([C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:55]([NH:57][C@H:58]([C:62]([OH:64])=[O:63])[C@@H:59]([CH3:61])[OH:60])=[O:56])[CH2:53][OH:54])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])[CH2:37][C:38](=[O:40])[NH2:39])=[O:34])[CH2:31][OH:32])=[O:21])[CH2:10][S:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CSCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)O)[C@@H](C)O

Procedure:
5.3 g (13 mmols) of BOC-Cys(Bzl)-OSU and 7.4 g (10 mmols) of H-Ser-Asn-Leu-Ser-Thr-OH, 1.93TFA are dissolved in 75 ml of dimethylformamide. From a solution of 150 mmols of triethylamine in 100 ml of dimethylformamide, 18.1 ml (27.2 mmols) are added dropwise while stirring until the reaction mixture shows a pH of 6.4 on moist indicator paper. The solution is stirred for 3 days at room temperature, then evaporated to dryness in a high vacuum. The residue is stirred twice with 250 ml of ethyl acetate and three times with a mixture of 100 ml of ethyl acetate and 20 ml of 5% citric acid solution, filtered, and dried at 40°C under reduced pressure. Melting point: 184°-185°C; [α]D20 -13° (c = 2 in dimethylformamide); Rf6 = 0.45.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[OH-].[Na+].Br[CH2:9][CH2:10][CH2:11][Cl:12]>CC(C)=O>[Cl:12][CH2:11][CH2:10][CH2:9][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2]
Reactant: CCNCC
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCN(CC)CCCCl
Yield: 59.2 %

Procedure:
Diethyl-amine (7.27 ml, 70 mmol), acetone (15 ml, 3 vol), 5M NaOH solution (16.8 ml, 1.2 eq.) and 1-bromo-3-chloropropane (16.5 g, 105 mmol, 1.5 eq.) were reacted together according to general procedure A to give the title compound (6.2 g, 59%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[NH4+].[Cl-]>[Zn].CO>[Cl:1][C:2]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1
Reactant: O=[N+]([O-])c1ccc(OCc2nccs2)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccc(OCc2nccs2)c(Cl)c1
Reaction time: 2 h
Yield: 77 %

Procedure:
3-Chloro-4-(thiazol-2-ylmethoxy)-phenylamine is prepared by added Zn dust (55.9 g, 856 mmol) to a mixture of 2-(2-chloro-4-nitro-phenoxymethyl)-thiazole (47.0 g, 190 mmol) in 5:1 MeOH:saturated aqueous NH4Cl solution (600 ml). After 2 h, the reaction mixture is filtered, and the filtrate concentrated. The resulting solid is triturated with water to give 3-chloro-4-(thiazol-2-ylmethoxy)-phenylamine (35.2 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([N:20]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[N:11]=[C:10]([NH:25][C@H:22]2[CH2:23][CH2:24][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:21]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)nc3ccccc23)C1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 2,4-dichloroquinazoline (0.940 g, 4.70 mmol) in dichloromethane (50 mL) was treated with (S)-(−)-1-boc-3-aminopyrrolidine (0.863 mL, 4.70 mmol) followed by triethylamine (2 mL, 14.20 mmol) and the solution was stirred at room temperature for 36 hours. The mixture was diluted with water (20 mL) and extracted with diethyl ether (2×20 mL). The combined organic extracts were dried (MgSO4) and concentrated to give the title compound as a pale brown solid which was used without further purification.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28](=[O:40])[C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21](OCCCC)=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].[NH2:43][C:44]1[NH:48][N:47]=[N:46][N:45]=1>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28](=[O:40])[C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([NH:43][C:44]4[NH:48][N:47]=[N:46][N:45]=4)=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nnn[nH]1
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N(C(=O)c1ccc(OC(F)(F)F)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)c2ccc(OC(F)(F)F)cc2)C2CCc3cc(C(=O)Nc4nnn[nH]4)ccc32)CC1

Procedure:
Butyl 1-{(trans-4-tert-butylcyclohexyl)[4-(trifluoromethoxy)benzoyl]amino}indane-5-carboxylate, enantiomer A (50 mg) or enantiomer B (70 mg), was saponified with aqueous LiOH and then coupled to 5-amino tetrazole following the procedure described (Step D., Example 1/2) to give 1-{(trans-4-tert-butylcyclohexyl)[4-(trifluoromethoxy)benzoyl]amino}-N-1H-tetrazol-5-ylindane-5-carboxamide. Enantiomer A: HPLC/MS: m/z=571.2 (M+1), Rt=2.65 min. 1H NMR (DMSO-d6): δ 12.34 (1H, br s), 7.95 (1H, s), 7.90 (1H, d, J=8.0 Hz), 7.52 (2H, d, J=8.0 Hz), 7.44 (2H, d, J=8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 5.05 (1H, m), 3.35 (1H, m), 3.15 (1H, m), 2.96 (1H, m), 2.55 (1H, m), 2.36 (1H, m), 2.12 (1H, m), 1.77 (6H, m), 0.99 (1H, m), 0.84 (1H, m), 0.79 (9H, s). Enantiomer B: HPLC/MS and 1H NMR (DMSO-d6) are identical to those of enantiomer A.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C.Cl>C(O)C.C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][NH2:11]
Reactant: CC(C)(C)OC(=O)NCCSSc1ccccn1
Agent: Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: NCCSSc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
tert-Butyl 2-(pyridin-2-yldisulfanyl)ethylcarbamate (1.06 g, 3.70 mmol) in 16 ml of EtAc was added 4.0 ml of HCl (conc.) at RT. The mixture was stirred at RT for 0.5 h, diluted with ethanol/toluene (6 ml, 1:1), evaporated and co-evaporated with ethanol/toluene (3×10 ml), crystallized with ethanol/EtAc/Hexane, filtered, and dried over a vacuum to afford 135 mg (88%) of the title compound. 1H NMR (CD3OD) 7.58 (m, 1H), 7.47 (m, 1H), 7.06 (m, 1H), 6.83 (m, 1H), 3.34 (m, 2H), 3.02 (m, 2H); 13C NMR 158.69, 149.07, 137.81, 122.48, 120.98, 39.52, 36.94; MS m/z+ 187.10 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Ag+2:5].[CH2:6]([S:11]([OH:14])(=[O:13])=[O:12])[S:7]([OH:10])(=[O:9])=[O:8].C(=O)=O>O>[CH2:6]([S:11]([O-:14])(=[O:13])=[O:12])[S:7]([O-:10])(=[O:9])=[O:8].[Ag+2:5]
Reactant: O=S(=O)(O)CS(=O)(=O)O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: O
Product: O=S(=O)([O-])CS(=O)(=O)[O-]
Yield: 123.7 %

Procedure:
Silver carbonate (20 g, 0.0725 moles) was added to methanedisulfonic acid (25.55 g 50% solution in water) and diluted in 25 mL of distilled water while stirring. The silver carbonate dissolved with effervescence of carbon dioxide. After the reaction was complete, any remaining insoluble material was removed by filtration and the filtrate was stripped of water was removed under vacuum to give 25.3 g of pure silver methanedisulfonate.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][O:7]C(C)(C)[O:5][CH2:4][CH:3]1[NH:11][C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([S:19](=[O:33])(=[O:32])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[CH:15][CH:14]=1.C(O)C>O>[OH:1][CH:2]([CH2:8][OH:7])[CH:3]([NH:11][C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([S:19](=[O:32])(=[O:33])[NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:30])([F:31])[F:29])[CH:22]=2)=[CH:15][CH:14]=1)[CH2:4][OH:5]
Reactant: CC1(C)OCC(O)C(NC(=O)c2ccc(S(=O)(=O)Nc3ccc(F)c(C(F)(F)F)c3)cc2)CO1
Solvent: CCO
Solvent: O
Product: O=C(NC(CO)C(O)CO)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
2 g (3.95 mmol) of 4-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]-benzoic acid-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-amide as well as 2 ml of cation exchanger in H. form are added to a solution of 10 ml of ethanol and 5 ml of distilled water and warmed for 90 minutes on the water bath. It is filtered from the exchanger, rewashed with distilled water, evaporated to dryness in a vacuum, and again taken up in water and by freeze-drying of this solution, 1.55 g=84.2% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: O1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=4)=[N:12][O:13][C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22](C(C)(C)C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3]C1.[CH3:40][OH:41]>>[O:41]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:29][CH2:30][CH2:31][O:32][C:33]4[N:38]=[CH:37][C:36]([Br:39])=[CH:35][N:34]=4)=[N:12][O:13][C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:10]([CH3:11])([CH3:8])[CH2:14][OH:13])(=[O:17])=[O:18])=[CH:9][C:4]=2[O:3][CH2:40]1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2onc(OCCOc3ncc(Br)cn3)c2-c2ccc3c(c2)OCO3)cc1
Reactant: CO
Product: CC(C)(CO)c1ccccc1S(=O)(=O)Nc1onc(OCCOc2ncc(Br)cn2)c1-c1ccc2c(c1)OCO2
Reaction time: 48 h

Procedure:
Amycolata autotrophica ATCC35203 maintained on a quarter strength ATCC172 agar slope was inoculated as a loopful of spores into a 300 ml Erlenmeyer flasks each containing 50 ml of MY inoculum medium. This was allowed to incubate for 2 days at 28° C., 200 rpm on an Infors Multitron™ Shaker with 1 ″ throw. Two mLs of this inoculum was then transferred to each of twenty 300 ml Erlenmeyer flask containing 50 ml of MY production medium and incubated under the same conditions for a further 24 hours. At this point 5 mg of N-(4-(1,3-benzodioxol-5-yl)-3-{2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy}-5-isoxazolyl)-4-(tert-butyl)benzene-sulfonamide (Example 2) dissolved in 0.5 mL of methanol was added to each of the flasks and the fermentation allowed to continue under the same conditions for a further 144 hours. Each flask was then extracted with 200 mls of ethyl acetate and the combined ethyl acetate solubles concentrated to dryness to give a gum solid.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=2)=[CH:4][CH:3]=1.CO>O1CCCC1.[Pt].[C]>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc(Oc2ccc(Br)cc2)nc1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cnc(Oc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
Under an argon atmosphere, to a solution of 2-(4-bromophenoxy)-5-nitropyrimidine (400 mg) in tetrahydrofuran (20 mL)/methanol (20 mL) was added 3% platinum-carbon (200 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered through Celite® to give the titled compound (363 mg) having the following physical data.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([NH2:15])(=[O:14])[CH:12]=[CH2:13].S(=O)(=O)(O)O>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH:12]([CH3:13])[C:11]([NH2:15])=[O:14]
Reactant: C=CC(N)=O
Reactant: Sc1nc2ccccc2s1
Agent: O=S(=O)(O)O
Product: CC(Sc1nc2ccccc2s1)C(N)=O
Temperature: 0 °C

Procedure:
A finely powdered mixture of 16.8 g of 2-mercaptobenzothiazole and 7.5 g of acrylic amide is added at 45°-50° in the course of 1 hour to 100 ml 70% sulfuric acid, with stirring. After a further hour at 45°-50°, the rection mixture is poured into ice water. The precipitate is filtered off, washed with water and dried. The obtained 2-(benzthiazol-2-ylthio)-propionic acid amide is recrystallized from ethylacetate and melts at 144°-145°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10].OO>C(O)(=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][N:1]=[C:2]3[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=23)=[CH:12][CH:13]=1
Reactant: Cc1cccc(C(=O)c2ccc(Cl)cc2)c1N
Agent: OO
Solvent: CC(=O)O
Product: Cc1cccc2c(-c3ccc(Cl)cc3)onc12
Temperature: 0 °C
Yield: 33.6 %

Procedure:
A solution of 49 g (0.2 mole) of (2-amino-3-methylphenyl)(4-chlorophenyl)methanone, 1 liter of glacial acetic acid and 200 ml of 30% hydrogen peroxide was let stand at ambient temperature over the weekend. The mixture was heated on a steam bath for 1 hr and poured into 2.5 liters of ice water. The solid which precipitated was collected by filtration, washed with water, and recrystallized from 2-propanol and then from cyclohexane to yield 16.4 g (34%) of crystals, m.p. 134°-136° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Li][CH2:12][CH2:13][CH2:14]C.CCCCCC.CC(C)=O>C1COCC1>[CH3:12][C:13]1([CH3:14])[C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[O:6]1
Reactant: O=C(O)c1ccccc1Br
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC1(C)OC(=O)c2ccccc21
Temperature: -78 °C
Reaction time: 0.3 h
Yield: 40 %

Procedure:
To a solution of 2-bromobenzoic acid (500 mg, 2.49 mmol) in THF (12.0 ml) cooled at −78° C. was added 2.5M n-BuLi/Hexane (2.0 ml). After stirring for 18 minutes, acetone (0.91 ml, 12.4 mmol) was added. The reaction was allowed to warm to room temperature after 5 minutes at −78° C., and then quenched into 10% HCl aqueous solution (50 ml). The acidic solution was rapidly stirred for 1 hour, and then extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3, brine, dried with anhydrous Na2SO4, and rotary evaporated to give a mixture. Gradient chromatography of the mixture through silica gel column eluted with 20% to 30% EtOAc in hexane afforded 3,3-dimethyl-2-benzofuran-1(3H)-one as a white solid (161 mg, 40%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.CN(C)[CH:22]=[O:23]>C1COCC1>[F:13][C:14]1[N:15]=[CH:16][CH:17]=[CH:18][C:19]=1[CH:22]=[O:23]
Reactant: Fc1ccccn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cccnc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 45.9 %

Procedure:
A solution of n-butyllithium (77 mL, 2.5 M in hexane, 0.19 mol) was added to a solution of N,N-diisopropylamine (27 mL, 0.19 mol) in dry THF (400 mL) under an atmosphere of nitrogen at −78° C. After the addition, the mixture was warmed to 0° C. for 15 minutes and then cooled again to −78° C. 2-Fluoropyridine (15.0 mL, 0.174 mol) was added dropwise to the mixture and stirred at −78° C. After 45 minutes, a pale yellow precipitate formed. N,N-Dimethylformamide (27 mL, 0.35 mol) was added slowly via syringe maintaining temperature below −55° C. After ten minutes, the cooling bath was removed and the mixture slowly warmed to room temperature. The reaction was quenched with NH4Cl/H2O and then 4 M HCl to adjust the pH ˜7. NaHCO3/H2O was then added to adjust the pH 9-10, and then extracted three times with Et2O. The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated to a yellow oil. The residue was purified by chromatography on silica gel, eluting with 25% EtOAc/hexane to provide 2-fluoronicotinaldehyde as a pale yellow oil (10.0 g, 45%). 1H NMR (CDCl3) δ 10.33 (s, 1H), 8.49 (m, 1H), 8.32 (m, 1H), 7.40 (m, 1H). LC/MS: 126 (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:38])/[C:6](/[NH:17][C:18](=[O:37])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])=[CH:21][C:20]=1[Cl:36])=[CH:7]/[C:8]1[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=1[CH3:16]>CO.O1CCCC1>[Cl:36][C:20]1[CH:21]=[C:22]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[O:26])[CH:23]=[CH:24][C:19]=1[C:18]([NH:17]/[C:6](=[CH:7]\[C:8]1[S:12][C:11]([CH:13]([CH3:14])[CH3:15])=[N:10][C:9]=1[CH3:16])/[C:5]([OH:38])=[O:4])=[O:37]
Reactant: COC(=O)/C(=C/c1sc(C(C)C)nc1C)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(C)C)sc1/C=C(\NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
An aqueous 1N solution of sodium hydroxide (1 mL, 1 mmol) was added to a solution of (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[2-(1-methylethyl)-4-methylthiazol-5-yl)]propenoic acid methyl ester (Example 233; 65 mg, 0.123 mmol) in methanol/tetrahydrofuran (1:1; 2 mL). The solution was stirred at room temperature for 18 h, then at 50° C. for 6 h and finally at room temperature for 16 h. The reaction mixture was evaporated to dryness and after the addition of water the solution was acidified with 1N hydrochloric acid solution. The gelatinous colorless solid that precipitated was recovered by filtration and washed thoroughly with water. It was re-suspended in water and lyophilized. The obtained tacky material was dissolved in methanol (0.25 mL) and treated to constant turbidity with water. The resulting off-white solid was filtered off, washed with water/methanol (9:1) and dried in vacuo (45° C., 66 h) to give (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-[2-(1-methylethyl)-4-methylthiazol-5-yl]propenoic acid (41 mg, 65% yield) as an off-white powder.
Reaction SMILES: C(OC([NH:11][CH:12]([CH3:23])[C:13]([N:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1([CH3:22])[CH3:21])=[O:14])=O)C1C=CC=CC=1.[H][H]>[Pd]>[NH2:11][CH:12]([CH3:23])[C:13]([N:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1([CH3:22])[CH3:21])=[O:14]
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)N1CC(=O)NC1(C)C
Reactant: [H][H]
Agent: [Pd]
Product: CC(N)C(=O)N1CC(=O)NC1(C)C

Procedure:
An ethanolic solution of 1-[2-(benzyloxycarbonylamino)propanoyl]-2,2-dimethyl-4-imidazolidinone (4.9 g) containing 1 g of 5% palladium on charcoal was stirred at room temperature while hydrogen was bubbled into the solution for 1 hour. Removal of the catalyst, evaporation of the solvent, and trituration of the residue with ethyl acetate afforded the title compound as a white powder m.p. 156° C. (decomp).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15](Cl)(=[O:26])[O:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=1.[OH-].[Na+]>C(Cl)Cl>[Cl:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([Cl:25])[CH:21]=1)[CH2:17][O:16][C:15]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
A reaction mixture comprising tert-butyl 4-aminopiperidine-1-carboxylate (1 g, 4.99 mmol), 3,5-dichlorobenzyl carbonochloridate (1.196 g, 4.99 mmol) and sodium hydroxide (250 ml, 499 mmol) in DCM (16.64 ml) was stirred at room temperature for 18 hours. The reaction mixture separated and the organic portion dried over MgSO4, filtered and concentrated under reduced pressure. No further purification was carried out and the material was taken crude to the next step.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][C:4]([O:6]CC)=O.[CH3:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=1[CH2:16][C:17]#[N:18].[Na]>C(O)C>[CH3:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:15]=1[CH:16]([C:17]#[N:18])[C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Cc1ccc(CC#N)c(C)c1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCC(=O)C(C#N)c1ccc(C)cc1C
Yield: 78 %

Procedure:
This material was prepared using 130.65 g (0.750 mol) of diethyl succinate, 72.60 g (0.500 mol of 2,4-dimethylbenzyl cyanide, 14.95 g (0.65 mol) of sodium, and 168 ml of dry ethanol using the procedure described in Part A of Example I. The product was obtained as a dark red oil, 106.5 g (78% yield).