Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6](/[CH:31]=[CH:32]/[C:33]([O:35]C)=[O:34])[CH:7]=[C:8]([F:30])[C:9]=1[CH:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C:12]([CH3:24])([CH3:23])[N:11]1[CH2:25][C@H:26]([CH3:29])[CH2:27][F:28])=[CH:21][CH:20]=[CH:19][CH:18]=3.CO.Cl>C1COCC1.O>[F:30][C:8]1[CH:7]=[C:6](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])[CH:5]=[C:4]([F:3])[C:9]=1[CH:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C:12]([CH3:23])([CH3:24])[N:11]1[CH2:25][C@H:26]([CH3:29])[CH2:27][F:28])=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: COC(=O)/C=C/c1cc(F)c(C2c3[nH]c4ccccc4c3CC(C)(C)N2C[C@H](C)CF)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](CF)CN1C(c2c(F)cc(/C=C/C(=O)O)cc2F)c2[nH]c3ccccc3c2CC1(C)C
Temperature: 20 °C
Reaction time: 16 h
Yield: 0 %

Procedure:
Sodium hydroxide (184 mg, 4.61 mmol) was added to (E)-methyl 3-(3,5-difluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2, 3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1) (217 mg, 0.46 mol) in THF (1 ml)/methanol (1 ml). The resulting solution was stirred at 20° C. for 16 hours. The reaction was diluted with water (10 ml) and the pH was adjusted to 7 by the addition of 2N HCl. The solution was extracted with EtOAc (2×20 ml). The combined organics were dried over Na2SO4 and concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. The pure fractions were evaporated to give a crude material. The crude product was triturated using a diethyl ether/isohexane mixture to give the title product (53.0 mg, 25.2%) as a yellow solid. 1H NMR (400 MHz, DMSO, 27° C.) δ 0.54 (3H, d), 1.06 (3H, s), 1.34 (3H, s), 2.14 (1H, dd), 2.66 (1H, d), 2.83 (1H, d), 3.03 (1H, dd), 4.21 (1H, t), 4.33 (1H, t), 5.12 (1H, s), 6.73 (1H, d), 7.01 (2H, dtd), 7.14-7.28 (1H, m), 7.43 (1H, d), 7.54 (2H, s), 7.59 (1H, d), 10.50 (1H, s), 12.61 (1H, s), CO2H not observed. m/z: ES+ [M+H]+ 457 *Stereochemistry inferred to be (R) at the undefined centre by analogy with other examples, ie compound inferred to be: (E)-3-(3,5-difluoro-4-(1R)-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].CCN(C(C)C)C(C)C.[CH2:22]([NH:24][C:25]([N:27]1[N:31]=[CH:30][C:29]2([CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:28]1)=[NH:26])[CH3:23]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([S:9]([N:26]=[C:25]([N:27]2[N:31]=[CH:30][C:29]3([CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:28]2)[NH:24][CH2:22][CH3:23])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCNC(=N)N1CC2(C=N1)CCCC2
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=NS(=O)(=O)c1cccc(C#N)c1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 3.50 g 3-cyanobenzenesulfonyl chloride in 150 mL DCM were added 17.69 mL (6.0 equiv.) DiPEA and 4.00 g (1.0 equiv.) N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine. The reaction mixture was stirred overnight at room temperature and extracted with water. The organic phase was dried over Na2SO4 and evaporated, and the residue was purified by automated flash chromatography (EtOAc/PA 1:1) to give 3.54 g (57%) of a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.17 (t, J=8 Hz, 3H), 1.65-1.86 (m, 8H), 3.41-3.50 (m, 2H), 3.87 (br.s., 2H), 6.70-6.80 (br.s., 1H), 6.87 (s, 1H), 7.60 (t, J=8 Hz, 1H), 7.77 (d, J=8 Hz, 1H), 8.17 (d, J=8 Hz, 1H), 8.23 (br.s., 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:22](/[CH3:35])=[C:23](/[F:34])\[CH:24]=[CH:25]\[C:26](\[CH3:33])=[CH:27]\[C:28]([O:30]CC)=[O:29])[CH3:2].[OH-].[Na+]>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1/[C:22](/[CH3:35])=[C:23](/[F:34])\[CH:24]=[CH:25]\[C:26](\[CH3:33])=[CH:27]\[C:28]([OH:30])=[O:29])[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)O)C(c1ccccc1)=CC(C)(C)O2

Procedure:
Following General Procedure G, a solution of ethyl (2E,4E,6E)-7-(7-ethoxy-2,2-dimethyl-4-phenyl-2H-chromen-6-yl)-6-fluoro-3-methyl-octa-2,4,6-trienoate (Compound 114, 147 mg, 0.31 mmol) was hydrolyzed with NaOH to yield a yellow oil after purification by column chromatography (silica gel, 100% hexane to 5% to 50% ethyl acetate in hexanes). The resulting oil was recrystallized from acetonitrile to produce the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:66]=[C:65]([CH:67]=[CH:68][C:69]([O:71][CH3:72])=[O:70])[CH:64]=[CH:63][C:4]=1[O:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:47]=[CH:46][C:45]([O:48][C:49](=[O:62])[C:50]2[CH:55]=[CH:54][C:53]([CH:56]=[CH:57][C:58]([O:60][CH3:61])=[O:59])=[CH:52][CH:51]=2)=[CH:44][C:14]=1[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:43])[C:31]1[CH:36]=[C:35]([N+:37]([O-])=O)[CH:34]=[C:33]([N+:40]([O-])=O)[CH:32]=1)=[O:16].[Cl-].[NH4+]>[Zn].CO.O>[CH3:1][O:2][C:3]1[CH:66]=[C:65]([CH:67]=[CH:68][C:69]([O:71][CH3:72])=[O:70])[CH:64]=[CH:63][C:4]=1[O:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:47]=[CH:46][C:45]([O:48][C:49](=[O:62])[C:50]2[CH:51]=[CH:52][C:53]([CH:56]=[CH:57][C:58]([O:60][CH3:61])=[O:59])=[CH:54][CH:55]=2)=[CH:44][C:14]=1[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:43])[C:31]1[CH:36]=[C:35]([NH2:37])[CH:34]=[C:33]([NH2:40])[CH:32]=1)=[O:16]
Reactant: COC(=O)C=Cc1ccc(C(=O)Oc2ccc(CCCCCCOOc3ccc(C=CC(=O)OC)cc3OC)c(C(=O)OCCCCCCCCCCCOC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC(=O)C=Cc1ccc(C(=O)Oc2ccc(CCCCCCOOc3ccc(C=CC(=O)OC)cc3OC)c(C(=O)OCCCCCCCCCCCOC(=O)c3cc(N)cc(N)c3)c2)cc1

Procedure:
0.997 g (1.00 mmol) 3,5-Dinitrobenzoic acid 11-[2-[6-[2-methoxy-4-(methoxycarbonylvinyl)phenoxy]oxyhexyl]-5-[4-(2-methoxycarbonylvinyl)benzoyloxy]benzoyloxy]undecyl ester and 0 g (4.00 mmol) of ammonium chloride were suspended in 15 ml of a mixture consisting of methanol:water 9:1. 1.31 g (20.0 mmol) of zinc was then added in one portions. After 0.5 hour at room temperature 20 ml of a mixture consisting of methanol:water 9:1 is added to the thick suspension. After a further 21 hours the reaction suspension was partitioned between dichloromethane and water. The resulting suspension was filtered, the organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water. The organic phase was then dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography of the residue on silica yield 3,5-Diaminobenzoic acid 11-[2-[6-[2-methoxy-4-(methoxycarbonylvinyl)phenoxy]oxyhexyl]-5-[4-(2-methoxycarbonylvinyl)benzoyloxy]benzoyloxy]undecyl ester.
Reaction SMILES: I.[NH2:2][C@@H:3]1[C:20](=[O:21])[N:5]2[C:6]([C:17]([O-:19])=[O:18])=[C:7]([CH2:10][N+:11]3([CH3:16])[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:8][S:9][C@H:4]12.[OH-].[Na+].C1C=CC2N(O)N=NC=2C=1.[CH3:34][O:35]/[N:36]=[C:37](\[C:44](O)=[O:45])/[C:38]1[N:42]=[C:41]([NH2:43])[S:40][CH:39]=1>O.O1CCCC1>[NH2:43][C:41]1[S:40][CH:39]=[C:38](/[C:37](=[N:36]/[O:35][CH3:34])/[C:44]([NH:2][CH:3]2[C:20](=[O:21])[N:5]3[C:6]([C:17]([O-:19])=[O:18])=[C:7]([CH2:10][N+:11]4([CH3:16])[CH2:15][CH2:14][CH2:13][CH2:12]4)[CH2:8][S:9][C@H:4]23)=[O:45])[N:42]=1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)CCCC1
Agent: I
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCCC3)CS[C@H]12)c1csc(N)n1

Procedure:
A total of 12.76 g (30 mmoles) of (6R,7R)-7-amino-3-(1-methyl-1-pyrrolidinio)methylceph-3-em-4-carboxylate monohydroiodide (prepared in Example 19) was suspended in 87 ml of water with good stirring at 20°-25° C. The slurry was cooled to 8°-10° C., and the pH was raised to 5.80 at 7° C. by dropwise addition of 13.0 ml (26 mmoles, 0.87 equivalents) of 2N sodium hydroxide solution over a period of 35 minutes. Next, 555 ml of tetrahydrofuran was added, and the pH of the resulting solution was increased to 6.8 at 10° C. by dropwise addition of 1.9 ml (3.8 mmoles, 0.13 equivalents) of 2N sodium hydroxide solution. The cooling bath was removed, and 29.5 g (92.7 mmoles, 1.5 equivalents) of the HOBT active ester of syn-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid was added in two equal portions of 14.75 g each over 30 minutes. Following each addition, the pH was readjusted to 6.5 every 5-10 minutes, by dropwise addition of 2N sodium hydroxide solution. In the remaining reaction time, the pH was readjusted to 6.5 by dropwise addition of 2N sodium hydroxide solution every 15 minutes (total 2N sodium hydroxide used was 28.6 ml (57.2 mmoles, 1.91 equivalents).
Reaction SMILES: C(NC1N=CC(C(C2C3C(=NC=CC=3)NC=2)=O)=CC=1)C(C)C.[CH:23]1([CH2:29][NH:30][C:31]2[N:36]=[CH:35][C:34]([C:37]([C:39]3[C:47]4[C:42](=[N:43][CH:44]=[CH:45][CH:46]=4)[NH:41][CH:40]=3)=O)=[CH:33][CH:32]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([CH2:29][NH:30][C:31]2[CH:32]=[CH:33][C:34]([CH2:37][C:39]3[C:47]4[C:42](=[N:43][CH:44]=[CH:45][CH:46]=4)[NH:41][CH:40]=3)=[CH:35][N:36]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(c1ccc(NCC2CCCCC2)nc1)c1c[nH]c2ncccc12
Agent: CC(C)CNc1ccc(C(=O)c2c[nH]c3ncccc23)cn1
Product: c1cnc2[nH]cc(Cc3ccc(NCC4CCCCC4)nc3)c2c1

Procedure:
was prepared following the protocol of Scheme 8, substituting (6-Isobutylamino-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-0025 with [6-(Cyclohexylmethyl-amino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-0031, (prepared as described in Example 5). MS (ESI) [M+H+]+=321.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28](O)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]4)=[C:4]([O:14][CH3:15])[CH:3]=3)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: COc1cc(N)ccc1N1CC[C@@H](O)C1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1N1CC[C@@H](O)C1

Procedure:
(R)-1-(4-Amino-2-methoxyphenyl)pyrrolidin-3-ol, preparation described in PCT application WO 2005/042541, was converted to the title compound (48 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (30 mg) following the procedure described in step C of Example 1. MS (ESI) 412 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Sn](Cl)Cl.N>Cl>[C:1]1([C:7]2[S:8][C:9]3[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc2nc(-c3ccccc3)sc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: N
Product: Nc1ccc2nc(-c3ccccc3)sc2c1
Temperature: 100 °C

Procedure:
2-Phenyl-6-nitrobenzothiazole (73.5 g, 0.286 mol) is added to tin dichloride (200.74 g, 0.89 mol) in 37% HCl (300 ml). The mixture is heated at 100° C. for 40 minutes. The resulting mixture is cooled and aqueous ammonia (pH=10) is added dropwise. The product is extracted with chloroform and the extracts are concentrated. The solid is recrystallized from isopropyl ether/hexane (2/1). Yield: 29.9 g (46%); Rf (9/1 chloroform/methanol): 0.68; m.p.: 199.8-201.1° C.; IR (KBr): 3450, 3305, 3190, 1619 cm−1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[N:9]2)=[C:4]([O:23][CH3:24])[CH:3]=1.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[CH3:22][O:21][N:19]([CH3:20])[C:17]([C:10]1[C:11](=[O:16])[C:12]([O:14][CH3:15])=[CH:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:3][C:4]=2[O:23][CH3:24])[N:9]=1)=[O:18]
Reactant: COc1cc(I)ccc1-n1cc(OC)c(=O)c(C(=O)N(C)OC)n1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(=O)N(C)OC)n1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A suspension of 1-(4-iodo-2-methoxyphenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (10.7 g, 24 mmol), pyrazole (1.63 g, 24 mmol), Cu2O (0.343 g, 2.4 mmol), salicylaldoxime (1.32 g, 9.6 mmol), and Cs2CO3 (15.6 g, 48 mmol) in CH3CN (100 mL) was refluxed for 4 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt/THF (1/0-0/1) to give the title compound (6.32 g, 68% yield) as a pale yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.39 (3H, s), 3.73 (3H, s), 3.91 (3H, s), 3.99 (3H, s), 6.53 (1H, dd, J=1.9, 2.3 Hz), 7.27 (1H, dd, J=2.3, 8.7 Hz), 7.58 (1H, d, J=8.7 Hz), 7.61 (1H, d, J=1.9 Hz), 7.77 (1H, d, J=1.5 Hz), 7.84 (1H, s), 7.98 (1H, d, J=2.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.NC1[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]2([OH:35])[CH2:32][C:31]([F:34])([F:33])[CH2:30]2)=[C:25]([O:38][CH3:39])[CH:24]=1.C1(O)C=CC=CC=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([C:21]4[CH:37]=[CH:36][C:26]([O:27][CH2:28][C:29]5([OH:35])[CH2:30][C:31]([F:34])([F:33])[CH2:32]5)=[C:25]([O:38][CH3:39])[CH:24]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(N)ccc1OCC1(O)CC(F)(F)C1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Solvent: CO
Solvent: Oc1ccccc1
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC1(O)CC(F)(F)C1
Temperature: 137.5 °C
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
A stirred mixture of (E)-methyl 5-(4-chlorophenyl)-3-((dimethylamino)methylene-amino)thiophene-2-carboxylate (33.9 g, 105 mmol) prepared in Example 1 Part E and 1-((4-amino-2-methoxy-phenoxy)methyl)-3,3-difluorocyclobutanol (27.2 g, 105 mmol) prepared in Part C and phenol (200 g) was heated at 135-140° C. for 45 min while the reaction being monitored by LC. The mixture was diluted with methanol (700 mL), stirred at RT for 15 min and allowed to stand at RT overnight. The precipitated product was isolated by filtration, washed with chilled methanol and dried under vacuum to yield 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (37 g, 73.3 mmol, 69.8% yield) as a white solid. Dilution of the mother liquor with Et2O and hexane precipitated more solid which was triturated with MeOH to yield 1.8 g of a second crop of the desired product. MP 198-199° C. 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1 H, s), 7.66 (2 H, d, J=8.56 Hz), 7.54 (1 H, s), 7.45 (2 H, d, J=8.56 Hz), 7.08 (1 H, d, J=8.56 Hz), 6.99 (1 H, d, J=2.27 Hz), 6.95 (1 H, dd, J=8.31, 2.27 Hz), 4.14 (2 H, s), 3.89 (3 H, s), 2.72-2.93 (4 H, m). 13C NMR (126 MHz, CDCl3) δ ppm 157.3, 156.7, 151.8, 150.4, 148.60 (1C, s), 148.0, 135.7, 131.4, 131.4, 129.4, 127.6, 123.1, 120.8, 119.4, 115.7, 117.6 (dd, J=282, 269. Hz), 111.4, 75.5, 64.6 (dd, J=18, 8 Hz), 56.0, 46.0 (t, J=22.89 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([O:13]CC)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:16][C@H:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22].Cl>>[NH2:1][C@H:2]([C:11]([NH:16][C@H:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCOC(=O)[C@@H](N)CCCCN
Agent: Cl
Product: CCOC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
Mal-Tyr-Lys-OEt was prepared with CT as the catalyst in a 100 ml beaker with Mal-Tyr-OEt employed as the electrophile and Lys-OEt.2 HCl employed as the nucleophile. After a short time, the product separated out as a white precipitate and was filtered off, washed with water and dried in a vacuum at 50° C. The conditions and results employed are compiled in the following table:
Reaction SMILES: C(OC([N:8]1[C:12](=[O:13])/[C:11](=[CH:14]\[OH:15])/[CH:10]2[CH2:16][C:17]3[C:22]([CH:9]12)=[CH:21][CH:20]=[CH:19][CH:18]=3)=O)(C)(C)C.FC(F)(F)C(O)=O.[Na]>ClCCl>[OH:15]/[CH:14]=[C:11]1/[CH:10]2[CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]2[NH:8][C:12]/1=[O:13]
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\O)C2Cc3ccccc3C21
Agent: [Na]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC2c3ccccc3CC2/C1=C/O
Reaction time: 1 h
Yield: 102 %

Procedure:
A solution of 3-[1-hydroxy-meth-(Z)-ylidene]-2-oxo-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester D1 (0.400 g, 1.32 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (2 mL) at 0° C. The solution was stirred for 1 h. A saturated solution of sodium hydrogenocarbonate was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with a saturated solution of sodium hydrogenocarbonate, dried and concentrated in vacuo to give 3-[1-Hydroxy-meth-(Z)-ylidene]-3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one C1 (White solid, 271 mg, quant.). C12H11NO2; MW: 201.23; LCMS (method A) RT 1.18 min; ES: 256 (MH++MeCN), 224 (MNa+), 202 (MH+); IR: 3264, 1678 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 10.00 (1H, s), 7.16-7.38 (4H, m), 7.13 (1H, d), 4.94 (1H, d), 3.68-3.82 (1H, m), 3.31 (2H, dd), 3.01 (1H, dd) ppm.
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.[Cl:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:19])([CH3:18])[C:15](Cl)=[O:16])=[CH:11][CH:10]=1.CCl>>[Cl:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:18])([CH3:19])[C:15]([P:1](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:16])=[CH:11][CH:10]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Reactant: COP(OC)OC
Agent: CCl
Product: COP(=O)(OC)C(=O)C(C)(C)Oc1ccc(Cl)cc1
Temperature: 0 °C
Yield: 72.1 %

Procedure:
An amount of 10.6 g (86 mmol) of trimethyl phosphite was added dropwise to 20.0 g (86 mmol) of p-chlorophenoxyisobutyryl chloride cooled to 0° C. As varification of the reaction, evolution of methyl chloride could be observed. Distillation under reduced pressure gave 19.0 g (62 mmol) of dimethyl p-chlorophenoxyisobutyrylphosphonate as an almost colorless oil.
Reaction SMILES: O.[OH-].[Li+].C([O:6][P:7]([CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[O:8])C>O.C(O)C>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][CH2:18][CH2:17][CH2:16][P:7]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])(=[O:6])[OH:8])=[CH:26][CH:25]=1
Reactant: CCOC(OCC)P(=O)(CCCNCc1ccc(Cl)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(OCC)P(=O)(O)CCCNCc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 0.36 g of lithium hydroxide monohydrate in 7 ml of water is added to a solution of 1.61 g of 3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid ethyl ester in 3 ml of ethanol, and the mixture is heated at 60° for 24 hours. The mixture is then cooled to room temperature and the solvent is removed under reduced pressure. The evaporation residue is taken up in water and neutralised with phosphoric acid. A white precipitate forms and is filtered off, and the filtrate is concentrated to dryness by evaporation. The white residue is dried under reduced pressure and crystallised from toluene/diethyl ether. Filtration with suction and drying yield 3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid having a melting point of 177°-179°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=3)=[O:18])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)=[O:18])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: O=C(CN1CCN(c2ccc(CO)c(Cl)c2)CC1)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cccc(C(=O)CN2CCN(c3ccc(CO)c(Cl)c3)CC2)c1

Procedure:
A solution of 2-[4-[3-chloro-4-(hydroxymethyl)phenyl]-1-piperazinyl]-1(3-nitrophenyl)ethanone (1.5 g, 3.8 m mole) in 100 ml of tetrahydrofuran was catalytically reduced at 25° over 0.5 g of Raney-Nickel with an average of three atmospheres of hydrogen. When the theoretical amount of hydrogen had been absorbed, the mixture was filtered and the filtrate was evaporated at reduced pressure to give a yellow solid which was recrystallized from acetonitrile to afford 0.95 g (69%), mp 174.5°-180° (Table 1). Prepared in the like manner were Cpd. 37 (Table 2) and 26 (Table 1).
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]/[C@H:17]([C:31](N1[C@@H](C(C)C)C(C2C=CC=CC=2)(C2C=CC=CC=2)SC1=O)=[O:32])[C@@:18]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:54][C@@H:55]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([O:67][CH2:68][C:69]#[C:70][CH3:71])=[CH:63][CH:62]=1)[C:56]([O:58][CH3:59])=[O:57]>ClCCl>[CH2:68]([O:67][C:64]1[CH:63]=[CH:62][C:61]([CH2:60][C@H:55]([NH:54][C:31]([C@@H:17](/[CH:16]=[CH:15]/[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C@@:18]([OH:30])([CH2:26][CH2:27][O:28][CH3:29])[C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[O:32])[C:56]([O:58][CH3:59])=[O:57])=[CH:66][CH:65]=1)[C:69]#[C:70][CH3:71]
Reactant: CC#CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Reactant: CCCCCCCSCCCCCC/C=C/[C@H](C(=O)N1C(=O)SC(c2ccccc2)(c2ccccc2)[C@@H]1C(C)C)[C@@](O)(CCOC)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCSCCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Temperature: 50 °C
Reaction time: 120 h
Yield: 80 %

Procedure:
tert-Butyl (E)-(2S,3S)-11-heptylsulfanyl-2-hydroxy-3-((S)-4-isopropyl-2-oxo-5,5-diphenyl-thiazolidine-3-carbonyl)-2-(2-methoxy-ethyl)-undec-4-enoate (No. 6804239; 68.3 mg, 0.0889 mmol) and methyl (S)-2-amino-3-(4-but-2-ynyloxy-phenyl)-propionate (33.0 mg, 0.133 mmol) were dissolved in dichloromethane. The solvent was distilled off under reduced pressure. The resulting mixture was stirred at 50° C. for 5 days, cooled to room temperature, and then extracted by adding ethyl acetate and water. The organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, and then filtered. The solvent was distilled out of the filtrate under reduced pressure. The residue was purified with SP1 (SiO2 cartridge, 25% ethyl acetate/n-hexane, Rf=0.1) to obtain tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-heptylsulfanyl-2-hydroxy-2-(2-methoxy-ethyl)-undec-4-enoate (No. 6804240; 50.9 mg, 80% yield)