Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:13][CH2:12]3)[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=3[CH3:25])[C:6]=2[CH:5]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:3]=1.[B:32]1(B2OC(C)(C)C(C)(C)O2)[O:36]C(C)(C)C(C)(C)[O:33]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(=O)C.[K+].Cl>O1CCOCC1.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].O>[CH:11]1([C:8]2[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[C:16]=3[CH3:25])[C:6]3[CH:5]=[C:4]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:3]=[C:2]([B:32]([OH:36])[OH:33])[C:10]=3[N:9]=2)[CH2:13][CH2:12]1
Reactant: Cc1c(Cn2c(C3CC3)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(Cn2c(C3CC3)nc3c(B(O)O)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 95 °C
Yield: 20.9 %

Procedure:
A mixture of 4-(4-bromo-2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine (1.01 g, 2.043 mmol), bis(pinacolato)diboron (1.556 g, 6.13 mmol), Pd2(dba)3 (0.094 g, 0.102 mmol), X-Phos (0.097 g, 0.204 mmol) and potassium acetate (0.602 g, 6.13 mmol) in 1,4-Dioxane (20 mL) in a 40 mL scintillation vial was heated for 1 hr at 95° C. When cooled the reaction contents were poured into 1N HCl (10 ml) and H2O (10 mL) mixture, swirled and then extracted with EtOAc, dried over MgSO4 and concentrated in-vacuo. The residue was dissolved in MeOH and the material was purified by reverse phase chromatography eluting with a gradient 30% CH3CN to 60% CH3CN over 10 minutes. The fractions containing clean desired compound were combined and concentrated in-vacuo to provide the desired product (196 mg, 0.427 mmol, 20.89% yield) as a clear oil after drying in a vacuum oven at 50° C. The oil was triturated to provide an analytically pure off-white powder (2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid (115 mg, 0.250 mmol, 12.26% yield). m/e: 459.2, 460.3 [M+H]+; 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.67 (d, J=8.08 Hz, 1H), 7.50 (br. s., 1H), 7.28 (t, J=7.83 Hz, 1H), 7.08 (d, J=2.27 Hz, 1H), 6.73 (d, J=8.08 Hz, 1H), 5.90 (s, 2H), 3.72-3.92 (m, 4H), 3.10-3.23 (m, 4H), 2.21-2.42 (m, 1H), 1.22-1.37 (m, 4H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][CH2:34][NH2:35])[CH3:27]>C(N(CC)CC)C>[CH2:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][CH2:34][NH:35][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:27]
Reactant: CCN1CCC[C@H]1CCN
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Solvent: CCN(CC)CC
Product: CCN1CCC[C@H]1CCNc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 140 °C
Yield: 16.5 %

Procedure:
A mixture of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67, 0.1 g), 2-((S)-1-ethylpyrrolidin-2-yl)ethylamine (Intermediate 136, 0.5 g) and triethylamine (0.5 mL) was stirred and heated in a sealed tube at 140° C. overnight. After cooling, the mixture was concentrated under vacuum and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM (10%). The product was repurified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[2-((S)-1-ethylpyrrolidin-2-yl)ethylamino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.022 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][N:4]([CH3:9])[C:5](=[O:8])[CH2:6][OH:7].[OH-].[K+].Cl[C:15]1[S:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][N:19]=1>C(#N)C>[F:1][C:2]([F:10])([F:11])[CH2:3][N:4]([CH3:9])[C:5](=[O:8])[CH2:6][O:7][C:15]1[S:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][N:19]=1
Reactant: CN(CC(F)(F)F)C(=O)CO
Reactant: Clc1nnc(-c2ccccc2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CN(CC(F)(F)F)C(=O)COc1nnc(-c2ccccc2)s1
Reaction time: 15 h
Yield: 59.4 %

Procedure:
12 g (0.07 mol) of N-(2,2,2-trifluoroethyl)-N-methyl-hydroxyacetic acid amide and 4.5 g of potassium hydroxide powder were dispersed in 100 ml of acetonitrile at 0° C., and a solution of 12 g of 2-chloro-5-phenyl-1,3,4-thiadiazole in 50 ml of acetonitrile was added at 10° C. The mixture was stirred at 30° to 40° C. for 15 hours and concentrated, the concentrate was diluted with water and the mixture was filtered. The crystalline product was recrystallized from isopropanol. 12 g (63% of theory) of N-(2,2,2-trifluoroethyl)-N-methyl-5-phenyl-1,3,4-thiadiazol-2-yl-oxyacetic acid amide of melting point 123° C. were obtained.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([CH:70](OC)[O:71]C)[CH2:67][CH:68]=[CH2:69])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.ClCCl.O>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:67][CH:68]=[CH2:69])[CH:70]=[O:71])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:52])([CH3:54])[CH3:53])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: C=CC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C)C(OC)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C=CCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(C)(C)C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
50 mg (0.048 mmol) of N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N 1-[1(S)-(dimethoxymethyl)-3-butenyl]-L-leucinamide were dissolved in 4 ml of trifluoroacetic acid/dichloromethane (1:1) containing3 drops of water and the solution was stirred for 1 hour under nitrogen. The solution was evaporated to dryness under a vacuum and the residue was re-evaporated twice with toluene. The solid was triturated with 10 ml of diethyl ether to give 30 mg of 2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-pentenaldehyde; MS: m/e 831.5 [M+H]+.
Reaction SMILES: C(OC(N1CCN(S(C2C=CC=C(Br)C=2)(=O)=O)CC1)=O)(C)(C)C.C(OC([N:31]1[CH2:36][CH2:35][N:34]([S:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([N:46]3[C:50]4[N:51]=[C:52]([N:80]5[CH2:85][CH2:84][O:83][CH2:82][CH2:81]5)[N:53]=[C:54]([C:55]5[CH:56]=[N:57][C:58]([N:61](CC6C=CC(OC)=CC=6)CC6C=CC(OC)=CC=6)=[N:59][CH:60]=5)[C:49]=4[CH2:48][CH2:47]3)[CH:41]=2)(=[O:39])=[O:38])[CH2:33][CH2:32]1)=O)(C)(C)C>>[N:80]1([C:52]2[N:53]=[C:54]([C:55]3[CH:60]=[N:59][C:58]([NH2:61])=[N:57][CH:56]=3)[C:49]3[CH2:48][CH2:47][N:46]([C:42]4[CH:43]=[CH:44][CH:45]=[C:40]([S:37]([N:34]5[CH2:35][CH2:36][NH:31][CH2:32][CH2:33]5)(=[O:39])=[O:38])[CH:41]=4)[C:50]=3[N:51]=2)[CH2:85][CH2:84][O:83][CH2:82][CH2:81]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(S(=O)(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c3)cn2)cc1
Agent: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccc(Br)c2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccc(S(=O)(=O)N3CCNCC3)c2)cn1
Yield: 33 %

Procedure:
From 4-(3-bromo-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (prepared from 3-bromobenzenesulfonyl chloride and piperazine-1-carboxylic acid tert-butyl ester, 83 mg) instead of 1-(3-bromo-benzenesulfonyl)-4-ethyl-piperazine in Example 1-D-96, a crude product of 4-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzenesulfonyl]-piperazine-1-carboxylic acid tert-butyl ester was obtained, and then the PMB groups and BOC group were removed according to the above Deprotection method 1, to obtain the desired compound (D-132) as a yellow powder (32 mg, 33%).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:19].C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:7]([CH2:6][CH:2]=[O:1])[C:8](=[O:19])[CH:9]=[CH:10]2
Reactant: COc1ccc2c(ccc(=O)n2CC2OCCO2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(ccc(=O)n2CC=O)c1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
95 mg of 1-(1,3-dioxolan-2-ylmethyl)-6-methoxyquinolin-2(1H)-one was dissolved in 1.5 mL of 67% aqueous trifluoroacetic acid solution, and stirred at room temperature for 18 hours, at 40° C. for 6.5 hours, further at room temperature for 15 hours. After the reaction mixture was alkalized by adding aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (6-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Reactant: COc1ccc(C)cc1B(O)O
Product: COc1ccc(C)cc1-c1c(F)ccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 76.2 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (178 mg, 0.48 mmol) and 2-methoxy-5-methylphenylboronic acid (160 mg, 0.96 mmol) were reacted. After purification the title compound (134 mg, 76% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.98 (d, J=4.8 Hz, 1H), 8.50 (a dd, J=5.5, 9.3 Hz, 1H), 7.71 (t, J=9.1 Hz, 1H), 7.23 (m, 1H), 7.106(s, 1H), 7.02 (d, J=8.4 Hz, 1H), 3.60 (s, 3H), 2.95 (m, 1H), 2.28 (s, 3H), 0.67 (m, 4H). MS APCI, m/z=367.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]([CH3:22])([CH3:21])[C:19]#[CH:20].C(N(CC)CC)C>C1(C)C=CC=CC=1.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[C:20]#[C:19][C:18]([CH3:22])([CH3:21])[CH3:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1cc(Cl)ncc1NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a deoxygenated solution of (6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (23.3 g, 65.6 mmol), 3,3-dimethyl-but-1-yne (53.8 g, 0.656 mol), CuI (623 mg, 3.3 mmol) and triethylamine (13.3 g, 0.13 mol) in toluene (150 mL) and water (50 mL) was added Pd(PPh3)2Cl2 (2.30 g, 3.28 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 hours. The solid was filtered off and washed with ethyl acetate (200 mL×3). The filtrate was evaporated under reduced pressure to obtain a residue, which was purified by column (petroleum ether/ethyl acetate=10/1) to give [6-chloro-4-(3,3-dimethyl-but-1-ynyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (15.8 g, 78%). 1H NMR (300 MHz, CDCl3) δ 9.10 (br s, 1H), 7.21 (s, 1H), 6.98 (br s, 1H), 1.53 (s, 9H), 1.36 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1.[CH2:28]1[NH:33][CH2:32][CH2:31][N:30]2[CH2:34][CH2:35][CH2:36][CH:29]12>CS(C)=O>[CH2:28]1[CH:29]2[CH2:36][CH2:35][CH2:34][N:30]2[CH2:31][CH2:32][N:33]1[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1
Reactant: COc1cc(COc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: C1CC2CNCCN2C1
Solvent: CS(C)=O
Product: COc1cc(COc2cc(NC(=O)c3cnc(N4CCN5CCCC5C4)cn3)[nH]n2)cc(OC)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 37.4 %

Procedure:
5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (585 mg, 1.50 mmol) was added in one portion to 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine (379 mg, 3.00 mmol) in anhydrous dimethylsulfoxide (1.50 ml) at 25° C. The resulting solution was stirred at 100° C. for 18 h. The residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford impure product as a yellow solid. The impure material was then repurified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (269 mg, 37%) as a yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:3])[CH3:2].S(Cl)([Cl:22])(=O)=O.CCCCCC.C(OCC)(=O)C>ClCCl>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([Cl:22])[CH:9]=[C:8]1[C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)C(=O)c1cccn1CCOC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1cc(Cl)cn1CCOC(C)=O
Yield: 41 %

Procedure:
The resulting ethyl 1-(2-acetoxyethyl)pyrrole-2-glyoxalate prepared as in Preparation I (40.5 g, 0.16 mol.) is dissolved in anhydrous dichloromethane (900 ml.) and cooled to -70°. Recently distilled sulfuryl chloride (13.7 ml., 0.17 mol.) is added in a dropwise manner. When the addition is completed, the solution is allowed to come to room temperature spontaneously. After two hours at this temperature TLC (silica gel; hexane:ethyl acetate; 80:20) shows the absence of starting material. The solvent is removed in vacuo and the oily residue is dissolved in dichloromethane (300 ml.) and washed to neutrality with water. The organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. The residue, which weighed 63 g. is purified by column chromatography on silica gel (800 g.) using hexane ethyl acetate (90:10) as the eluting solvent. This procedure yields 19 g. (41% yield) of ethyl 1-(2-acetoxyethyl)4-chloropyrrole-2-glyoxalate (Formula V where Y is Cl) having the following physical constants:
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:14][CH:13]=2)=[N:7][CH:6]=1)C.CO.[OH-].[Na+]>C1COCC1>[C:31]([O:30][C:28]([N:19]([CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:35])=[O:3])=[CH:6][N:7]=2)=[CH:17][CH:16]=1)[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)c1ccc(Oc2ccc(CN(CCc3ccccc3)C(=O)OC(C)(C)C)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(Oc2ccc(C(=O)O)cn2)cc1
Reaction time: 24 h
Yield: 90.7 %

Procedure:
Combine 6-{4-[(tert-Butoxycarbonyl-phenethyl-amino)-methyl]-phenoxy}-nicotinic acid ethyl ester (0.333 g, 0.72 mmol), MeOH (5 mL), THF (5 mL), and 2.5N NaOH (aq) (2 mL). After the reaction refluxes under a Nitrogen atmosphere for 24 hours, concentrate under reduced pressure. Add 2.5N HCl (aq) (2 mL), Ethyl acetate, and wash with water, brine, and then dry over Na2SO4. Concentrate the organic mixture under reduced pressure to afford 293.0 mg (91% yield) of title compound as a white foam: 1H NMR (500 MHz, CDCl3); 1.4 (9H, s), 2.6-2.8 (2H, m), 3.2-3.4 (2H, m), 4.2-4.4 (2H, m), 4.3-4.4 (2H, m), 6.9 (1H, d), 7.0-7.3 (9H, m), 8.3 (1H, d), 8.8 (1H, s); MS m/z 349 (M−100, Boc).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][N:22]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=2)=[CH:15][CH:14]=1.[C:33]([NH:38][C:39](=[O:44])[O:40][CH:41]([CH3:43])[CH3:42])(=[O:37])/[CH:34]=[CH:35]/[CH3:36]>C(#N)C>[CH3:36][CH:35]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][N:22]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=2)=[CH:15][CH:14]=1)[CH2:34][C:33]([NH:38][C:39]([O:40][CH:41]([CH3:42])[CH3:43])=[O:44])=[O:37]
Reactant: C/C=C/C(=O)NC(=O)OC(C)C
Reactant: CC(C)(C)OC(=O)CCn1cnc(-c2ccc(N)cc2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(CC(=O)NC(=O)OC(C)C)Nc1ccc(-c2cn(CCC(=O)OC(C)(C)C)cn2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
DBU (954 mg, 944 μl, 6.26 mmol) was added to a stirred solution of 1,1-dimethylethyl 3-[4-(4-aminophenyl)-1H-imidazol-1-yl]propanoate (for a preparation see Intermediate 96) (1.8 g, 6.26 mmol) and 1-methylethyl (2E)-2-butenoylcarbamate (for a preparation see Intermediate 49) (1.34 g, 7.83 mmol) in acetonitrile (25 mL). The reaction mixture was stirred at 50° C. for 48 h then was cooled to room temperature and most of the solvent was removed in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 5% MeOH in AcOEt) gave 1,1-dimethylethyl 3-[4-(4-{[1-methyl-3-({[(1-methylethyl)oxy]carbonyl}amino)-3-oxopropyl]amino}phenyl)-1H-imidazol-1-yl]propanoate (1.53 g, 3.34 mmol, 53%) as an orange oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:18])[C:9](=[O:10])[CH2:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.CC(C)([O-])C.[K+].[CH3:25][N:26]=[C:27]=[S:28]>CN(C)C=O>[OH:10][C:9]1[C:4]([CH2:3][O:2][CH3:1])([CH3:18])[O:5][C:6]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=2[C:8]=1[C:27](=[S:28])[NH:26][CH3:25]
Reactant: CN=C=S
Reactant: COCC1(C)Oc2ccc([N+](=O)[O-])cc2CC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=S)C1=C(O)C(C)(COC)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
To a mixture of 5 g of 3,4-dihydro-2-methoxymethyl-2-methyl-6-nitro-2H-1-benzopyran-3-one and 60 ml of dried N,N-dimethylformamide was added 2.5 g of potassium tertiary butoxide under nitrogen stream with stirring under ice-cooling and the mixture was stirred for 5 minutes. Then, 1.7 ml of methyl isothiocyanate in 3 ml of N,N-dimethylformamide was added to the mixture and it was stirred at 5° C. for 18 hours. Ice water was added to the mixture and it was washed with ether. A water layer was acidified to be hydrochloric acid and extracted with ether. After an organic layer was washed with water and dried, the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, hexane:AcOEt=3:1) to obtain 5.1 g of 3-hydroxy-2-methoxymethyl-N,2-dimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide with a melting point of 139°-141° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.[CH2:21]([NH:23][CH3:24])[CH3:22]>>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]([CH2:21][CH3:22])[CH3:24])[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: CCNC
Product: CCN(C)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C#N

Procedure:
The title compound was prepared in analogy to example 27 step C from 2,6-dichloro-4-phenyl-quinoline-3-carbonitrile (prepared as described in example 27 step B) and ethyl-methyl-amine. Yellow solid. MS (ESI): 322.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C@@H:11]1[C@@H:15]([CH3:16])[O:14]C(C)(C)[O:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>C(#N)C>[CH2:1]([NH:8][C:9](=[O:10])[C@@H:11]([OH:12])[C@H:15]([OH:14])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1OC(C)(C)O[C@@H]1C(=O)NCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: C[C@@H](O)[C@H](O)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A flask was charged with 4.23 g (17.0 mmol) (4S,5R)-2,2,5-trimethyl-[1,3]dioxolane-4-carboxylic acid benzylamide, 30 mL acetonitrile, and 17 mL 0.5 M aqueous hydrochloric acid solution. This mixture was stirred overnight at room temperature. The solution was made neutral by the addition of 1 M aqueous sodium hydroxide solution. The solvent was removed under reduced pressure, and the crude residue was dried in a vacuum oven. The dry, crude material was purified by column chromatography (20:1 dichloromethane/methanol) to give 3.03 g (85%) of the title compound as a white solid. MS (APCI) (m+1)/z 210.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].O[C:17]1[CH:49]=[CH:48][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]2=[O:47])=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:9]1(=[O:10])[N:5]([O:4][CH2:3][CH2:2][O:1][C:17]2[CH:49]=[CH:48][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]3=[O:47])=[CH:19][CH:18]=2)[C:6](=[O:15])[C:7]2=[CH:14][CH:13]=[CH:12][CH:11]=[C:8]12
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1c2ccccc2C(=O)N1OCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Yield: 80.8 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 2.0 g of N-(2-hydroxyethoxy)phthalimide [prepared as described in step (a) above], 4.4 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 2.53 g of triphenylphosphine and 1.68 g of diethyl azodicarboxylate, 5.00 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:11]2[CH2:12][C:8]3([CH2:9][CH2:10]2)[CH:4]([CH2:5][CH2:6][C:7]3=[O:13])[C:3]1=[CH2:14].C(O)=O>CCCCC>[CH3:14][C:3]1[C:2]([CH3:1])([CH3:15])[CH:11]2[CH2:12][C:8]3([CH2:9][CH2:10]2)[C:4]=1[CH2:5][CH2:6][C:7]3=[O:13]
Reactant: C=C1C2CCC(=O)C23CCC(C3)C1(C)C
Solvent: CCCCC
Solvent: O=CO
Product: CC1=C2CCC(=O)C23CCC(C3)C1(C)C

Procedure:
350 mg of 7,7-dimethyl-6-methylene-tricyclo[6.2.1.01,5 ]undecan-2-one (see example 1) were heated at 40° for 5 days in the presence of 20 ml of 98% formic acid. After the usual treatments of extraction, washing, drying and evaporation, there were isolated 330 mg of crude material (purity 90%). The pure compound was obtained after cristallization in n-pentane.