Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34]5[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=5)[N:33]=[C:29]4[N:28]=[C:27]([CH3:42])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:45][O:46][C:47]([CH3:53])([CH3:52])[C:48]([NH:50][OH:51])=[O:49]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:45]/[O:46][C:47]([C:48](=[O:49])[NH:50][OH:51])([CH3:53])[CH3:52])/[C:8]([NH:10][CH:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34]5[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([OH:41])[CH:35]=5)[N:33]=[C:29]4[N:28]=[C:27]([CH3:42])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CC(C)(ON)C(=O)NO
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(-c3ccc(O)c(O)c3)nc2n1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)/C(=N\OC(C)(C)C(=O)NO)c4csc(N)n4)C3SC2)n2nc(-c3ccc(O)c(O)c3)nc2n1
Reaction time: 8 h

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(3,4-dihydroxyphenyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (1.3 g) and 0.44 g of 2-(aminooxy)-N-hydroxy-2-methylpropionamide hydrochloride are dissolved in 10 ml of dimethylacetamide. After standing overnight the mixture is evaporated in a vacuum. The residue is digested with 20 ml of water and the precipitate formed is filtered off under suction and dried. There are obtained 1.15 g of 6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(hydroxycarbamoyl)-1-methylethoxy]imino]acetamido]-3-[[[2-(3,4-dihydroxyphenyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH3:25][NH2:26].C(=O)(O)[O-].[Na+]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[C:2]([NH:26][CH3:25])=[N:3][CH:4]=[CH:5]3)(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Nc1ccc2c(Cl)nccc2c1)c1ccc(Cl)cc1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CNc1nccc2cc(NS(=O)(=O)c3ccc(Cl)cc3)ccc12
Yield: 52 %

Procedure:
1-Chloro-6-(4-chlorobenzenesulfonylamino)isoquinoline (50 mg, Synthetic Example 61b) and a 40% methylamine methanol solution (5.0 ml) were heated at 130° C. in a sealed tube for 18 hours. After cooling as it was, an aqueous saturated sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column, to give the title compound (28 mg, 52%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CC2CCC(C1)N2C(=O)OC(C)(C)C
Reaction time: 20 h

Procedure:
A reaction flask was charged with 3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester (0.260 g, 0.88 mmol) and Pd/C (0.026 g) in MeOH (4 mL). The reaction flask was evacuated and purged with hydrogen twice followed by stirring under a hydrogen atmosphere for 20 h. The reaction mixture was filtered through Celite, washed with MeOH, and concentrated to give the crude title compound as the major isomer (0.255 g, 97%; 1:3 α:β). Major isomer: 1H NMR (CDCl3) δ 4.17-4.15 (m, 2H), 4.13-4.06 (m, 2H), 2.32-2.26 (m, 1H), 2.13 (d, J=7.0 Hz, 2H), 1.95-1.90 (m, 2H), 1.67-1.61 (m, 2H), 1.59-1.54 (m, 2H), 1.43 (s, 9H), 1.42-1.27 (m, 2), 1.22 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3) δ 172.4, 153.3, 79.0, 60.2, 53.3, 41.3, 37.2, 28.4, 26.0, 14.2
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)[CH:13]([CH3:15])[CH3:14]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:16][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CC(C)COc1ccccc1B(O)O
Product: CC(C)COc1ccccc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-isobutoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-isobutoxyphenylboronic acid in a manner analogous to Example 2c (0.46 g, 70%). MS=302 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:10][CH:9]=[CH:8][C:7]=1[OH:25].Br[CH2:28][CH2:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33]>>[CH3:35][O:34][C:32](=[O:33])[C:31]([CH3:37])([CH3:36])[CH2:30][CH2:29][CH2:28][O:25][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:26]
Reactant: COC(=O)C(C)(C)CCCBr
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Product: COC(=O)/C=C/c1c(C#CCCCCOC2CCCCO2)cccc1OCCCC(C)(C)C(=O)OC
Yield: 92 %

Procedure:
Using the procedure of example 122, rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester (example 121) was alkylated with methyl 5-bromo-2,2-dimethylpentanoate giving the title compound, in 92% yield, as a colorless oil.
Reaction SMILES: C(=O)([O-])O.[K+].Br[CH2:7][C:8]1[O:9][C:10](=[O:14])[O:11][C:12]=1[CH3:13].[C:15]1([S:21]([NH:24][C:25]2[CH:26]=[C:27]([C@@H:31]([OH:51])[CH2:32][NH:33][C:34]([CH3:50])([CH3:49])[CH2:35][CH2:36][N:37]3[C:45]4[C:40](=[CH:41][C:42]([C:46]([OH:48])=[O:47])=[CH:43][CH:44]=4)[CH:39]=[CH:38]3)[CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[C:15]1([S:21]([NH:24][C:25]2[CH:26]=[C:27]([C@@H:31]([OH:51])[CH2:32][NH:33][C:34]([CH3:49])([CH3:50])[CH2:35][CH2:36][N:37]3[C:45]4[C:40](=[CH:41][C:42]([C:46]([O:48][CH2:7][C:8]5[O:9][C:10](=[O:14])[O:11][C:12]=5[CH3:13])=[O:47])=[CH:43][CH:44]=4)[CH:39]=[CH:38]3)[CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1oc(=O)oc1CBr
Reactant: CC(C)(CCn1ccc2cc(C(=O)O)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium hydrogen carbonate (331 mg, 3.30 mmol) and 4-bromomethyl-5-methyl-[1,3]dioxol-2-one (Chem. Pharm. Bull. 1984, vol. 32 (6), page 2241-2248) (505 mg, 2.36 mmol) are added to a solution of 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylic acid-hydrotrifluoroacetate (Example 6; 1.0 g, 1.57 mmol) in 10 ml DMF. Then the reaction mixture is stirred for 18 hours at RT. Then the solid is filtered off and the filtrate is freed from the solvent in vacuo. The residue is chromatographed on silica gel (DCM/methanol/ammonia=100:0:0→90:10:0.1).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])(=[O:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(F)(F)(F)F>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][Br:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCCCCCCS(=O)(=O)c1ccc(C)cc1
Agent: FC(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CC(=O)OCCCCCCS(=O)(=O)c1ccc(CBr)cc1
Yield: 71 %

Procedure:
2.0 g of 4-[(6-acetoxyhexyl)sulfonyl]toluene, 1.3 g of N-bromo-succinimide (NBS), 0.015 g of benzoyl peroxide (BPO) , and 20 mL of carbon tetrafluoride were added to a 250 mL round bottomed flask and heated with reflux for 12 hours in nitrogen. The mixture was allowed to cool down and then filtered. The filtrate was washed by deionized water repeatedly. The organic fraction was dried over anhydrous magnesium sulfate and then concentrated by a rotary evaporator. The concentrate was further purified by re-crystallization to produce a white solid. The yield was 71% with the following structure.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:11][C:12]([CH:14]1[CH2:18][C:17](F)([F:19])[CH2:16][NH:15]1)=[O:13])[CH:9]=[CH2:10]>O1CCCC1.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH2:8]([O:11][C:12]([C:14]1[NH:15][CH:16]=[C:17]([F:19])[CH:18]=1)=[O:13])[CH:9]=[CH2:10]
Reactant: C=CCOC(=O)C1CC(F)(F)CN1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1cc(F)c[nH]1
Temperature: 80 °C
Yield: 88.6 %

Procedure:
To a solution of 4,4-Difluoro-pyrrolidine-2-carboxylic acid allyl ester trifluoroacetic acid salt (Example 14d, 6.13 g, 20.08 mmol) in anhydrous tetrahydrofuran (300 mL) was added manganese(IV) dioxide and the reaction mixture was heated at 80° C. for 4 h. The mixture was filtered over Celite, and was washed with hot and then cold tetrahydrofuran. The filtrate was concentrated in vacuo to give a dark orange oil. The oil was dissolved in ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate solution. The solvent was removed in vacuo to give an orange oil, which was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 30% ethyl acetate in hexanes) to afford the desired product, 4-fluoro-1H-pyrrole-2-carboxylic acid allyl ester (3.01 g, 17.80 mmol, 88.7% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 4.77 (2H, d, J=5.7 Hz), 5.29 (1H, d, J=10.2 Hz), 5.38 (1H, d, J=15.9 Hz), 5.94-6.04 (1H, m), 6.64-6.65 (1H, m), 6.72-6.74 (1H, m), 8.91 (1H, bs).
Reaction SMILES: [OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:50])[CH3:49])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35]C(OC(C)(C)C)=O)[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1.C(N(C(C)C)CC)(C)C.[C:73](Cl)(=[O:78])[C:74]([CH3:77])([CH3:76])[CH3:75]>ClCCl>[OH:1][C@H:2]1[CH2:54][C@@:53]2([CH3:55])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:56][C:57](=[O:60])[CH2:58][CH3:59])[C:17](=[O:52])[CH:18]([O:20][C:21](=[O:51])[C@H:22]([CH:48]([CH3:49])[CH3:50])[NH:23][C:24](=[O:47])[C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30](=[O:46])[C@H:31]([CH3:45])[NH:32][C:33](=[O:44])[C@H:34]([CH3:43])[NH:35][C:73](=[O:78])[C:74]([CH3:77])([CH3:76])[CH3:75])[OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:63])[C:9]([C@@H:10]([CH3:61])[CH2:11]2)=[CH:8][C:7](=[O:62])[CH:6]=[CH:5]1
Reactant: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)C(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Temperature: 25 °C
Reaction time: 25 h

Procedure:
150 mg (0.17 mmol) of H-Ala-Ala-Pro-Val-O-MPP x TFA (Example 3) and 60 μl (0.34 mmol) of diisopropylethylamine are dissolved in 6 ml of dichloromethane, mixed with 20 μl (0.18 mmol) of pivaloyl chloride and stirred for 25 hours at room temperature. The residue that remains after removal of the solvent i.vac. is directly chromatographed. Gradient chromatography (24 g of silica gel 60, hexane→hexane/acetone 7:3) yields 102 mg (70%) of slightly contaminated N-(N-(N-(N-(2,2-dimethylpropionyl)-L -alanyl)-L-alanyl)-L-prolyl)-L-valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy-pregna-1,4-dien-21-yl] ester. A second chromatography (Lichroprep Si60A pre-packed column, hexane/dichloromethane 1:1→hexane/dichloromethane/methanol 30:60:10) yields 92 mg, 83 mg of crystalline compound consisting of dichloromethane/diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]([OH:21])=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.O=S(Cl)Cl.[CH3:26]O>>[CH3:26][O:20][C:19](=[O:21])[CH2:18][C:8]1[N:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reaction time: 2 h
Yield: 80 %

Procedure:
To a magnetically stirred solution of (6-methyl-2-p-tolyl-imidazo[1,2-a]pyridin-3-yl)-acetic acid 1a (5.0 g, 17.85 mmol) in methanol (MeOH) (25 mL) at 0° C. under Ar atmosphere was slowly added SOCl2 (2.60 mL, 35.7 mmol). The reaction mixture was stirred for 2 h and then concentrated in vacuo. Aqueous 10% Na2CO3 solution (100 mL) was added, and the aqueous phase was extracted with EtOAc (2×200 mL). The combined organic layers were washed with aqueous NaHCO3 solution, dried (MgSO4), and concentrated in vacuo to the provide the title compound (4.2 g, 80%) as yellow solids. 1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 2.40 (s, 3H), 3.76 (s, 3H), 4.03 (s, 2H), 7.07 (dd, J=1.7, 9.1 Hz, 1H), 7.28 (d, J=8.3 Hz, 2H), 7.55 (d, J=9.1 Hz, 1H), 7.70 (dd, J=1.8, 6.3 Hz, 2H), 7.85 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ 18.7, 21.5, 30.8, 52.7, 112.4, 117.0, 121.5, 122.2, 127.8, 128.5, 129.6, 131.6, 137.7, 144.2, 144.6, 170.3.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH3:27]S(O)(=O)=O>C(Cl)Cl>[C:1]1([C:7]2[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:27])=[O:23])[CH2:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CC=C(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Reactant: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1CC=C(c2c(-c3ccccc3)[nH]c3ccccc23)CC1
Yield: 71 %

Procedure:
A solution of 70.0 g (0.22 mol) of 4-(2-phenyl-1H-indol-3-yl)-3-cyclohexene-1-carboxylic acid (Example 1), 35.2 g (1.1 mol) of methanol, 350 mL of methylene dichloride, and 0.5 mL of methanesulfonic acid was heated under reflux for 21 h. The reaction mixture was cooled, washed with water, dried over sodium sulfate, concentrated in vacuo, and crystallized from ethyl acetate:hexane to give 51.8 g (71%) of methyl 4-(2-phenyl-1H-indol-3-yl)-3-cyclohexene-1-carboxylate in two crops: m.p. 175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O.C(O)(=O)C>O.[Fe]>[NH2:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(O)ccc1Cl
Temperature: 100 °C
Yield: 88.2 %

Procedure:
A 100-mL round bottomed flask equipped with a magnetic stir bar was charged with 4-chloro-3-nitrophenol (6.0 g, 34.6 mmol) and acetic acid (60 mL). Iron powder (325 mesh) (19.31 g, 346 mmol) was added, and the mixture was heated at 100° C. for 30 min. The mixture was cooled to room temperature and diluted with water (40 mL). The mixture was then filtered through a pad of Celite and rinsed with water. The filtrate was then extracted with ethyl acetate, and the combined extracts were concentrated under reduced pressure. Heptane (ca. 100 mL) was added to the filtrate and then removed under reduced pressure in order to remove residual acetic acid and water. This was repeated. The residue was dissolved in acetonitrile and concentrated under reduced pressure. The resulting solid was suspended in heptane and concentrated under reduced pressure to afford 3-amino-4-chlorophenol (4.38 g, 88%) as a pale purple/amber solid. MS (ESI, pos. ion) m/z 144 [M+1].
Reaction SMILES: C(OC([NH:8][C@H:9]([C:12]([NH:14][C@@H:15]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:16]([OH:31])[CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[C:24]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:13])[CH2:10][SH:11])=O)(C)(C)C>FC(F)(F)C(O)=O>[C:27]([NH:26][C:24]([C@@H:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:18]1[CH2:17][C@@H:16]([OH:31])[C@@H:15]([NH:14][C:12](=[O:13])[C@H:9]([CH2:10][SH:11])[NH2:8])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:25])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CS
Yield: 85.4 %

Procedure:
A solution of 930 mg of 1-[3(S)-[[N-(tert.butoxycarbonyl)-L-cysteinyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide in 7 ml of trifluoroacetic acid was stirred at 20° C. for 1 hour. The mixture was then evaporated to dryness and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution. The organic phase was evaporated to give 650 mg of N-tert.butyl-1-[3(S)-[(L-cysteinyl)amino]-2(R)-hydroxy-4-phenylbutyl]-2(S)-piperidinecarboxamide as a colourless gum; MS: m/e [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([C:22]1[C:23](=[O:33])[N:24]([CH3:32])[C:25](=[O:31])[N:26]([CH3:30])[C:27]=1[CH2:28]Br)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH3:30][N:26]1[C:27]2=[CH:28][N:1]([C:2]3[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=3[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:22]2[C:23](=[O:33])[N:24]([CH3:32])[C:25]1=[O:31]
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Reactant: CCOC(=O)c1ccc(O)c(N)c1
Solvent: CCO
Product: CCOC(=O)c1ccc(O)c(-n2cc3c(c2-c2ccccc2)c(=O)n(C)c(=O)n3C)c1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
In a 100 mL round bottom flask ethyl 3-amino-4-hydroxybezoate (1.10 g, 6.07 mmol) and 4a (1.00 g, 2.98 mmol) were refluxed in ethanol (50 mL). After 2 h, the condenser was rearranged for distillation and ethanol (25 mL) was distilled off. The resulting solution was slowly poured into a vigorously stirred solution of ice cold water (200 mL) and citric acid (50 mg) giving a pink solid precipitate. The mixture was stirred for 10 min and then the solid was collected by filtration and rinsed with cold water to give 5h (1.23 g, 98.5%) after drying. The product was recrystallized from ethanol to give pale pink needles; m.p. 129.2-130° C. 1H NMR (600 MHz, CD2Cl2) δ 8.58 (s, 1H), 7.89 (dd, J=2.1, 8.7, 1H), 7.67 (d, J=2.1, 1H), 7.36-7.29 (m, 2H), 7.28-7.18 (m, 3H), 6.97 (d, J=8.7, 1H), 4.25 (q, J=7.1, 2H), 3.27 (s, 3H), 3.17 (s, 3H), 1.30 (t, J=7.1, 3H). 13C NMR (151 MHz, CD2Cl2) δ 165.40, 159.72, 156.82, 151.91, 136.06, 132.09, 130.86, 130.65, 129.49, 128.99, 128.83, 127.84, 125.70, 122.92, 117.65, 104.70, 103.11, 61.23, 32.02, 28.08, 14.24. MS (ES+) (m/z): [M+1]+ calculated for C23H22N3O5, 420.16. found 420.13.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][C:6]=1[C:7]#[N:8].Br[C:16]1[N:21]=[C:20]([CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:19]=[CH:18][CH:17]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(CC)(C)C>[N:23]1([CH2:22][C:20]2[N:21]=[C:16]([NH:1][C:2]3[S:3][C:4]([C:9]4[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=4)=[CH:5][C:6]=3[C:7]#[N:8])[CH:17]=[CH:18][CH:19]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: Brc1cccc(CN2CCOCC2)n1
Reactant: N#Cc1cc(-c2cccnc2)sc1N
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: N#Cc1cc(-c2cccnc2)sc1Nc1cccc(CN2CCOCC2)n1
Temperature: 100 °C

Procedure:
2-Amino-5-pyridin-3-ylthiophene-3-carbonitrile (76 mg, 0.38 mmol), 4-[(6-bromopyridin-2-yl)methyl]morpholine (Example 45, Step 1) (97 mg, 0.38 mmol), dibenyzlideneacetone bis(triphenylphosphine) (17.29 mg, 0.02 mmol), 2-dicylohexylphosphino-2′,4′,6′-triisopropyl-1,1-biphenyl (45.0 mg, 0.09 mmol), and potassium carbonate (57.4 mg, 0.42 mmol) were dissolved in tert-amyl alcohol (3.8 ml) and the mixture was bubbled with nitrogen for 5 min. The reaction was then heated to 100° C. overnight. The mixture was diluted with ethyl acetate and water and extracted with ethyl acetate (3×50 mL). The combined organics were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane/methanol to afford the title compound as a solid.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:26]=[CH:25][C:17]([O:18]C(C)C(OC)=O)=[CH:16][CH:15]=1)[C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1.Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl>[CH3:1][N:2]([C:14]1[CH:26]=[CH:25][C:17]([O:18][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:16][CH:15]=1)[C:3]1[N:4]=[N:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COC(=O)C(C)Oc1ccc(N(C)c2nnc3cc(Cl)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(N(C)c2nnc3cc(Cl)ccc3n2)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 55.8 %

Procedure:
A mixture of 4-[N-methyl-N-(7-chloro-1,2,4-benzotriazin-3-yl)amino]phenol (1.5 g; Example 6 part (a)), ethyl 2-bromo-2-methylpropionate (1.23 g), anhydrous potassium carbonate (0.87 g) and dimethylformamide (15 ml) was heated, with stirring, at a temperature of 100° C. for a period of 3 days. The cooled solution was poured into dichloromethane and the mixture was washed with water. The aqueous phase was dried (over anhydrous magnesium sulfate) and the solvent was removed by distillation under reduced pressure to give an oil. The crude product was purified by chromatography over silica gel (eluent dichloromethane) to give the title compound (0.9 g) as a red oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:14](=O)[CH3:15])[C:9]([O:11]CC)=O)(=[O:3])[CH3:2].Cl.[C:21](=[NH:26])([NH2:25])[CH2:22][CH2:23][CH3:24].C[O-].[Na+].CO>CO>[C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][C:8]1[C:9](=[O:11])[NH:26][C:21]([CH2:22][CH2:23][CH3:24])=[N:25][C:14]=1[CH3:15])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc(C(C)=O)c1)C(C)=O
Reactant: CCCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1nc(C)c(Cc2cccc(C(C)=O)c2)c(=O)[nH]1
Reaction time: 12 h
Yield: 78 %

Procedure:
To a solution of ethyl 2-(3-acetylbenzyl)-3-oxobutanoate (2.39 g) and butanimidamide hydrochloride (1.68 g) in methanol (20 mL) was added 28% sodium methoxide-methanol solution (5.27 mL), and the mixture was stirred for 12 hr. The reaction mixture was concentrated, and the residue was dissolved in water and diethyl ether. The aqueous layer was separated, and weakly acidified with 1 M hydrochloric acid. The precipitate was collected by filtration and dried under reduced pressure to give the title compound (2.02 g, 78%) as a colorless solid.