Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(C(C)C)CC)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:70][N:71]1[CH:75]=[C:74]([C:76]2[CH:77]=[CH:78][C:79]3[N:80]([C:82]([SH:85])=[N:83][N:84]=3)[N:81]=2)[CH:73]=[N:72]1>CN(C=O)C.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]>[F:1][C:2]1[CH:3]=[C:4]([S:85][C:82]2[N:80]3[N:81]=[C:76]([C:74]4[CH:73]=[N:72][N:71]([CH3:70])[CH:75]=4)[CH:77]=[CH:78][C:79]3=[N:84][N:83]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3nnc(Sc4ccc([N+](=O)[O-])c(F)c4)n3n2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 24.2 %

Procedure:
A solution of trifluoro-methanesulfonic acid 3-fluoro-4-nitro-phenyl ester (1.51 g, 4.74 mmol), diisopropylethylamine (1.5 mL, 8.62 mmol) in DMF (14 mL) under nitrogen was degassed by bubbling in nitrogen for 10 min. Tris(dibenzylideneacetone)dipalladium (99 mg, 0.108 mmol, Strem catalyst) and Xantphos (125 mg, 0.215 mmol) were added together in one portion, followed by 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (1.0 g, 4.31 mmol). The reaction mixture was stirred at 100° C. for 3 h, then it was concentrated in vacuo. The residue was partitioned between saturated aqueous ammonium chloride and 10% methanol in dichloromethane. The aqueous layer was extracted with 10% methanol in dichloromethane, and the combined organic layers were directly adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-10% methanol/dichloromethane afforded 387 mg of 3-(3-fluoro-4-nitro-phenylsulfanyl)-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine as a yellow solid (24% yield): 1H NMR (DMSO-d6) δ 3.90 (s, 3H), 7.20 (dd, 1H), 7.59 (dd, 1H), 7.87 (d, 1H), 8.06 (m, 2H), 8.46 (s, 1H), 8.54 (d, 1H); MS (m/z) 372 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[CH:12][C:13]([OH:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([OH:15])=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(=CC(=O)O)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCC(CC(=O)O)CC1
Reaction time: 8 h
Yield: 41.2 %

Procedure:
To a solution of 2-(4-(ethoxycarbonyl)cyclohexylidene)acetic acid (6.0 g, 28.3 mmol) in EtOH (50 ml) was slowly added 10% Pd/C (306 mg). The solution was hydrogenated overnight. The catalyst was filtered off. The filtrate was concentrated in vacuo to afford 2.5 g of product as colorless oil (42%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.[N:38]1([C:46](=O)[CH2:47]Cl)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:46][CH2:47][O:37][C:36]2[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:3][C:2]=2[F:1])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: O=C(CCl)N1CCCCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCCCCC3)c(F)c2)c1
Yield: 31.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azocan-1-yl-2-chloroethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.9 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:26])[F:25])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([CH3:40])[C:37]([OH:39])=[O:38])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([CH:36]([CH3:40])[C:37]([OH:39])=[O:38])=[CH:34][CH:35]=3)=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:11]([C:24]([F:27])([F:25])[F:26])=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccccc2)cc1
Reactant: CC(C(=O)O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)O)c1ccc(COc2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3ccccc3)cc2)cc1

Procedure:
The title compound was prepared by treating 4-(2-benzyl-7-trifluoromethyl-2H-indazole-3-yl)-phenol (20 mg, 1 eq) with 2-(4-bromomethyl-phenyl)-propionic acid (39 mg, 3 eq) and potassium carbonate (37 mg, 5 eq) in DMF (2 mL) at 150° C. overnight. After cooling, water was added and the pH adjusted to 1 (aq. HCl, 2M) followed by extraction with dichloromethane. Purification by preparative HPLC gave the desired product in 45% yleld.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:9])[C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14].Cl>O>[CH3:1][O:2][C@H:3]([CH3:9])[C@H:4]([NH:5][C:13]([O:15][CH3:16])=[O:14])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)Cl
Reactant: CO[C@H](C)[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Reaction time: 12 h
Yield: 97 %

Procedure:
To a mixture of O-methyl-L-threonine (3.0 g, 22.55 mmol), NaOH (0.902 g, 22.55 mmol) in H2O (15 mL) was added ClCO2Me (1.74 mL, 22.55 mmol) dropwise at 0° C. The mixture was allowed to stir for 12 h and acidified to pH 1 using 1N HCl. The aqueous phase was extracted with EtOAc and (2×250 mL) and 10% MeOH in CH2Cl2 (250 mL) and the combined organic phases were concentrated under in vacuo to afford a colorless oil (4.18 g, 97%) which was of sufficient purity for use in subsequent steps. 1H NMR (400 MHz, CDCl3) δ 4.19 (s, 1H), 3.92-3.97 (m, 1H), 3.66 (s, 3H), 1.17 (d, J=7.7 Hz, 3H). LC-MS: Anal. Calcd. for C7H13NO5: 191; found: 190 (M−H)−.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Br:13][CH2:14][CH2:15][CH2:16]Br>CC#N>[Br:13][CH2:14][CH2:15][CH2:16][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: BrCCCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OCCCBr
Temperature: 25 °C

Procedure:
To a solution of N-hydroxyphthalimide (2.0 g) and 1,3-dibromopropane (2.49 ml) in 50 ml of dry CH3CN was added diisorpopylethylamine (4.27 ml). The mixture was stirred at room temperature. After 4 hours the volatiles were removed in vacuo. The residue was triturated with Et2O to provide 2.53 g of while solid, homogeneous by TLC.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([OH:13])=[C:7]([O:14][CH3:15])[C:6]=1[CH3:16])(=[O:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[C:26]([CH2:34][CH3:35])=[N:27][O:28][C:29]=2[C:30]=1[CH2:31][CH2:32][CH3:33]>>[C:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]3[C:26]([CH2:34][CH3:35])=[N:27][O:28][C:29]=3[C:30]=2[CH2:31][CH2:32][CH3:33])=[C:7]([O:14][CH3:15])[C:6]=1[CH3:16])(=[O:3])[CH3:2]
Reactant: COc1cc(OC(C)=O)c(C)c(OC)c1O
Reactant: CCCc1c(OCCCBr)ccc2c(CC)noc12
Product: CCCc1c(OCCCOc2c(OC)cc(OC(C)=O)c(C)c2OC)ccc2c(CC)noc12
Yield: 39.1 %

Procedure:
The procedure from Example 76 Step C was followed using methyl-3,5-dimethoxy-4-hydroxyphenyl acetate (108 mg) and 3-bromo-1-(3-(Ethyl)-7-(propyl)-6-benz-[4,5]-isoxazoloxy)propane (156 mg) to afford a colorless oil (88 mg). NMR (CDCl3); δ 7.41 (d,2H), 6.99 (d,2H), 6.45 (s,2H), 3.76 (s,6H), 3.71 (s,3H), 3.55 (s,3H), 1.43 (t,3H), 0.92 (t,3H).
Reaction SMILES: [CH:1]([N:4]([CH2:42][CH2:43][NH:44]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:15][CH:14]([S:16][C:17]3[C@H:18]([CH3:41])[C@@H:19]4[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:20]4[C:21]=3[C:22]([O:24]CC3C=CC([N+]([O-])=O)=CC=3)=[O:23])[CH2:13]2)[S:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2]>O1CCCC1>[NH2:44][CH2:43][CH2:42][N:4]([CH:1]([CH3:3])[CH3:2])[C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:13][CH:14]([S:16][C:17]3[C@H:18]([CH3:41])[C@@H:19]4[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:20]4[C:21]=3[C:22]([OH:24])=[O:23])[CH2:15]2)[S:10][CH:11]=1)=[O:6]
Reactant: CC(C)N(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Solvent: C1CCOC1
Product: CC(C)N(CCN)C(=O)c1csc(N2CC(SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)C2)n1
Reaction time: 2 h
Yield: 27.6 %

Procedure:
p-Nitrobenzyl (1R,5S,6S)-2-[1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)ethyl]-carbamoyl}-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (610 mg, 0.74 mmol) (obtained as described in Example 65(1)) in a mixture of tetrahydrofuran (30 ml) and distilled water (30 ml) was subjected to catalytic hydrogenation in the presence of 7.5% palladium on charcoal (610 mg) in a water bath (35° C.) for 2 hours. After checking the completion of the reaction, ethyl acetate and distilled water were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the aqueous layer was separated and concentrated under reduced pressure. The residue was purified by chromatography on a Cosmosil column (eluant: distilled water→2% acetonitrile in distilled water→4% acetonitrile in distilled water→6% acetonitrile in distilled water→8% acetonitrile in distilled water→10% acetonitrile in distilled water→12% acetonitrile in distilled water→14% acetonitrile in distilled water→16% acetonitrile in distilled water→18% acetonitrile in distilled water) and the eluate was lyophilized to afford the desired compound (1R,5S,6S)-2-(1-{4-[N-(2-aminoethyl)-N-isopropyl-carbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid (104 mg, yield 28%) as a white solid.
Reaction SMILES: CN(C(ON1N=NC2[CH:12]=[CH:13][CH:14]=[N:15]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[N:32]1[N:33]([C:41]2[N:62]=[CH:61][CH:60]=[CH:59][C:42]=2[C:43]([NH:45][CH:46]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:47]([OH:51])[C:48]([OH:50])=O)=[O:44])[CH:34]=[C:35]2[C:40]=1[CH:39]=[CH:38][CH:37]=[CH:36]2.C1(N)CC1>ClCCl>[CH:14]1([NH:15][C:48](=[O:50])[CH:47]([OH:51])[CH:46]([NH:45][C:43](=[O:44])[C:42]2[CH:59]=[CH:60][CH:61]=[N:62][C:41]=2[N:33]2[CH:34]=[C:35]3[C:40]([CH:39]=[CH:38][CH:37]=[CH:36]3)=[N:32]2)[CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:12][CH2:13]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc2ccccc2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-n1cc2ccccc2n1
Reaction time: 0.08 h
Yield: 62.2 %

Procedure:
HATU (201 mg, 0.528 mmol) and Et3N (0.127 ml, 0.913 mmol) were successively added to a suspension of 3-[2-(2H-indazol-2-yl)nicotinamido]-2-hydroxy-4-phenylbutanoic acid (200 mg, 0.480 mmol) and cyclopropylamine (0.034 ml, 0.48 mmol) in dichloromethane (50 ml) at 5° C., and the mixture was stirred for 5 minutes. A pH of 10 was adjusted by adding Et3N (0.1 ml, 0.720 mmol), stirring was continued for 1 hour at 5° C. and then overnight at room temperature. The reaction mixture was then concentrated under reduced pressure and poured into 50 ml of water. The precipitate formed was filtered off with suction and dried in vacuo to give 136 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14](O)=[O:15])=[C:12](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].[OH-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([CH2:14][OH:15])=[C:12](/[CH:17]=[CH:18]/[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1c(-c2ccc(F)c(F)c2)noc1/C=C/c1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: OCc1c(-c2ccc(F)c(F)c2)noc1/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of 3-(3,4-difluoro-phenyl)-5-([E]-styryl)-isoxazole-4-carboxylic acid (18 g, 55.0 mmol) and triethylamine (7.7 mL, 55.0 mmol) in THF (450 mL) was added at room temperature a solution of ethyl chloroformate (5.35 mL, 55.0 mmol) in THF (52 mL). After 1 h triethylamine hydrochloride salt was filtered off and washed with a small amount of THF. The solution was added to a solution of sodium borohydride (5.42 g, 138 mmol) in water (52 mL). The mixture was stirred overnight at room temperature. Sodium hydroxide solution (1 N, 180 mL) was added. Extraction with tert-butylmethylether and chromatography (silica, dichloromethane) afforded the title compound (12.6 g, 73%) as a light green solid. MS: m/e=314.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: C1CCNC1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCCC3)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and pyrrolidine according to conditions described in general procedure C. Mp: 205-207° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.81 (s, 4 H), 3.06 s, 2 H), 3.27 (s, 4 H), 3.41 (s, 2 H), 3.77 (s, 4 H), 6.27-6.19 (m, 1 H), 7.03-7.06 (m, 1 H), 7.27 (d, J=9.1 Hz, 1H), 7.42-7.46 (m, 1H), 7.51 (s, 1 H), 7.57-7.639 (m, 3 H), 7.86 (d, J=8.4 Hz, 1 H), 8.00 (d, J=8.3 Hz, 1 H), 8.23-8.25 (m, 1 H), 10.47 (s, 1 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=4)=[CH:17][CH:16]=3)=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].CN1C2C(=CC=C(C(O)=O)C=2)C(CC2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=C1>>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:7]2[C:6]3[C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][CH:8]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc2[nH]cc(Cc3ccc(OCc4ccc5ccccc5n4)cc3)c12
Agent: Cn1cc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c2ccc(C(=O)O)cc21
Product: O=C(O)c1cccc2[nH]cc(Cc3ccc(OCc4ccc5ccccc5n4)cc3)c12

Procedure:
This compound was prepared from the methyl ester (example 12, part i) by the method described in Example 10, part iii, m.p. 209°-211° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].[CH:11]1C=CC=CC=1.C=O.Cl.N1CCCCC1>O.C(O)(=O)C>[C:1]([C:3](=[CH2:11])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]
Reactant: c1ccccc1
Reactant: CC(C)(C)OC(=O)CC#N
Agent: C=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: O
Product: C=C(C#N)C(=O)OC(C)(C)C

Procedure:
41.6 g of phosphorus pentachloride was dispersed in 150 ml of ether and then, while stirring and cooling in an ice-water bath, there was added dropwise, from a dropping funnel, a solution of 17 g of cyanoacetic acid dissolved in 50 ml of ether. Directly after the completion of the dropwise addition, the ether and phosphorus oxychloride were driven off with an evaporator and 150 ml of tetrahydrofuran added to the residue. While stirring at 50° C., 15.6 g of t-butanol was added dropwise. Following the dropwise addition, the reaction was continued for 8 hours, after which the t-butyl cyanoacetate was obtained by distillation. A suspension of 19.8 g of the t-butyl cyanoacetate obtained, 110 ml of benzene, 4.2 g of paraformaldehyde, 1 g of piperidine hydrochloride and 1 g of glacial acetic acid was heated and water eliminated while refluxing. After water no longer was given off, the benzene was distilled off. The residue was cooled, after which it was dissolved in acetone and reprecipitated in water. The resinous material was collected by decanting, then redissolved in acetone and subjected to thermal decomposition and distillation under reduced pressure. t-Butyl α-cyanoacrylate was obtained. 5 g of the t-butyl α-cyanoacrylate obtained and 100 mg of azobisisobutyronitrile were dissolved in 50 ml of tetrahydrofuran, and polymerization carried out at 60° C. Poly-t-butyl α-cyanoacrylate was obtained. The molecular weight of the polymer obtained determined by gel permeation chromatography (GPC) was, by polystyrene conversion, a number average molecular weight of 32,000 and a weight average molecular weight of 98,000. The polymer obtained was irradiated with an electron beam, and the value of the main chain scission efficiency Gs calculated from the number average molecular weight determined by GPC was 3.8.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:4]=1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:39]1[CH2:43]OC[CH2:40]1.C(I)CC>CN(C=O)C>[CH2:1]([C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:4]=1[CH:23]([CH2:40][CH2:39][CH3:43])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)Cc1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OCC)c1c(CC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a solution of ethyl [2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.491 g; 1.25 mmol) in dry DMF (5 mL) at −10° C. was added a 1N solution of LHMDS in THF (1.38 mL; 1.38 mmol) and 1-propyliodide (0.183 mL; 1.88 mmol). The reaction mixture was allowed to warm up to room temperature and the stirring was carried on for 3 h. The reaction mixture was quenched by addition of a saturated solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to afford 0.322 g (59%) of the title compound as a light yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccccn2)C[C@H](C)N3C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Methyl 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 22)(700 mg, 1.685 mmol) was dissolved in MeOH (10 ml) and sodium hydroxide solution (2M, 1.68 ml, 3.37 mmol) was added. After 6.5 h a further 2 equivalents of sodium hydroxide (2M, 1.685 ml) was added and reaction mixture stirred overnight. The was concentrated and the residue was diluted with water. Hydrochloric acid (2N, 1 ml) was added forming a precipitate which was isolated by filtration and dried to give 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (500 mg, 1.245 mmol, 73.9% yield) as a pinky solid. The aqueous phase was extracted EtOAc (×3) and the combined organic phases were dried over MgSO4 then concentrated in vacuo to give a further batch of 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (140 mg, 0.349 mmol, 20.70% yield) as a yellow foam. LCMS (HpH, 2 min), Rt=0.62 min, MH+=402.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:23])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:23]
Reactant: CC=CCC1Cc2ccc(OC3CCCC3)cc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=CCC1Cc2ccc(OC3CCCC3)cc2C1=O
Reaction time: 1 h
Yield: 73 %

Procedure:
An ozone stream (1.5 g ozone/hour) was conducted for 60 minutes while stirring through a solution, cooled to -70°, of 8.1 g of (RS)-2-(2-buten-1-yl)-6-cyclopentoxy-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 3.29 ml of dimethyl sulfide, the mixture was stirred at room temperature for 21 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 75 ml of dichoromethane and, after the addition of 12.5 ml of water and 12.5 ml of trifluoroacetic acid, stirred at room temperature for 5 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 5.63 g (73%) of (RS)-2-(2-oxoethyl)-6-cyclopentoxy-1-indanone were obtained as an orange oil.