Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2cnc(-c3ccccc3)nc2n(CC)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCN(C)CC2)c2cnc(-c3ccccc3)nc2n(CC)c1=O

Procedure:
To 0.9 g. (0.0025 mole) of 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (prepared by the method of Example 3, first paragraph) and 0.25 g. (0.0025 mole) of N-methyl piperazine in 40 ml. of ethanol was added 0.27 g. (0.0025 mole) of Na2CO3. The reaction mixture was refluxed for 3 hours after which time it was filtered and chilled in ice. The resulting precipitate was removed by filtration, and rinsed with diethyl ether, giving 0.7 g. of solid--m.p. 180°-185° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9]Br>C(O)C>[NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Nc1ncccc1O
Reactant: BrBr
Solvent: CCO
Product: Nc1ncc(Br)cc1O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
The 2-amino-5-bromo-3-pyridinol is prepared by dissolving 110.0 g of 2-amino-3-pyridinol in 250 ml of 95% ethanol. The solution is cooled to about 5° C. and at that temperature is treated with 160 g of liquid bromine during 2 hours. The mixture is stirred for 1 hour after the addition is completed and then concentrated to give 170.6 g of 2-amino-5-bromo-3-pyridinol.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=1)=[N:7]2.[NH2:36][NH2:37]>O1CCOCC1>[NH:36]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=1)=[N:7]2)[NH2:37]
Reactant: NN
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(Cl)c4cc3-c3ccccc3)cc2)CCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C

Procedure:
To a microwave vial was added tert-butyl {1-[4-(5-chloro-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-5) (4.05 g, 8.34 mmol), anhydrous hydrazine (5.24 mL, 167 mmol), and 1,4-dioxane (15 mL). The reaction mixture was then heated under microwave irradiation for 5 minutes at 100° C. (high absorption). The reaction mixture was permitted to cool to room temperature, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl {1-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-6) as an orange solid/foam. MS (M+H)+: observed=482.3, calculated=482.59.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[C:6]([OH:8])=O)(=[O:3])[CH3:2].[N+]([O-])(O)=O.[N+:21]([O:24][CH2:25][CH2:26][NH2:27])([O-:23])=[O:22]>>[N+:21]([O:24][CH2:25][CH2:26][NH:27][C:6](=[O:8])[C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)([O-:23])=[O:22]
Reactant: CC(=O)N[C@@H](COC1CCCCO1)C(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Product: CC(=O)N[C@H](COC1CCCCO1)C(=O)NCCO[N+](=O)[O-]
Yield: 29.8 %

Procedure:
The procedures of Example 1 were analogously repeated using 1.07 g of (2S)-2-acetylamino-3-(tetrahydropyran-2-yl)oxypropionic acid and 0.94 g of 2-nitrooxyethylamine nitrate to give 0.44 g of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33](Cl)=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH3:44])[CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([N:41]3[CH2:42][CH2:43][CH:38]([N:37]([CH3:44])[CH3:36])[CH2:39][CH2:40]3)=[O:34])[C@H:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C@H:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)C1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCC(N(C)C)CC1

Procedure:
cis-4-[2-(2-tert-Butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 20) was reacted 4-dimethylamino-piperidine (Aldrich) to give cis-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-dimethylamino-piperidin-1-yl)-methanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C33H41N6O2Cl2 [(M+H)+] 623.2663, observed 623.2665.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[S:11][CH:12]=2)[N:5]=[C:4]2[C:16]3[C:22]([Br:23])=[C:21]([O:24][CH3:25])[CH:20]=[CH:19][C:17]=3[O:18][C:3]=12.O=P(Cl)(Cl)[Cl:28]>>[Br:23][C:22]1[C:16]2[C:4]3[C:3]([O:18][C:17]=2[CH:19]=[CH:20][C:21]=1[O:24][CH3:25])=[C:2]([Cl:28])[CH:7]=[C:6]([C:8]1[N:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[S:11][CH:12]=1)[N:5]=3
Reactant: COc1ccc2oc3c(O)cc(-c4csc(C(C)C)n4)nc3c2c1Br
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2oc3c(Cl)cc(-c4csc(C(C)C)n4)nc3c2c1Br
Temperature: 110 °C
Yield: 16 %

Procedure:
A mixture of 15C (1.2 g, 2.8 mmol) in POCl3 (10 mL) was heated to 110° C. and reacted for 30 min. TLC monitored the reaction. After the reaction completed, POCl3 in the reaction mixture was evaporated. The residue was added dropwise into ice-water. The precipitated solids were collected by filtration and purified by short column chromatography to give M15 (0.2 g, 16% yield).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4]1.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][CH:23]([F:26])[CH2:22][CH2:21]2)[C:17]2[CH:27]=[CH:28][C:29]([S:31](Cl)(=[O:33])=[O:32])=[CH:30][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:21][CH2:22][CH:23]([F:26])[CH2:24][CH2:25]2)[C:17]2[CH:27]=[CH:28][C:29]([S:31]([N:3]3[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4]3)(=[O:32])=[O:33])=[CH:30][C:16]=2[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)CC1
Reactant: O=Cc1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C=O)c3)ccc2n1CC1CCC(F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (0.19 g, 60%, 4.8 mmol) was added to a solution of 1H-pyrrole-3-carbaldehyde (0.13 g, 1.4 mmol) in THF (30 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature, stirred for 1 h and cooled to 0° C. 2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (0.37 g, 0.96 mmol) was added to the reaction mixture and stirred for 1 h. The reaction mixture was quenched with saturated NaHCO3 solution (30 mL) and the solvent was concentrated. Water (50 mL) was added to the residue and the product was extracted with DCM (workup). The solvent was concentrated and the product was purified by MPLC on silica gel using 50-80% EtOAc/heptane to provide the title compound as white solid. Yield: 0.25 g (57%); MS (ESI) (M+H)+=445.9.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1>CN(C=O)C.C(Cl)Cl>[O:21]1[CH2:22][CH2:23][CH:19]([S:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:20]1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: IC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(SC2CCOC2)cc1
Reaction time: 16 h
Yield: 85.6 %

Procedure:
To a suspension of methyl 4-sulfanylbenzoate (0.85 g, 5.05 mmol), potassium carbonate (1.39 g, 10.1 mmol) in DMF (10 mL) at room temperature was added 3-iodotetrahydrofuran (1.00 g, 5.05 mmol). The resulting suspension was stirred for 16 hours. The reaction mixture was diluted with DCM (25 mL), filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM (25 mL) and washed with water (3×15 mL) and saturated aqueous brine solution (1×15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield methyl 4-tetrahydrofuran-3-ylsulfanylbenzoate (1.03 g, 86%) as a yellow solid. ESI-MS m/z calc. 238.1. found 239.3 (M+1)+; Retention time: 1.47 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.91-7.83 (m, 2H), 7.48-7.39 (m, 2H), 4.16-4.08 (m, 2H), 3.91-3.72 (m, 5H), 3.55 (q, J=7.6 Hz, 1H), 2.49-2.35 (m, 1H), 1.86-1.74 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:28].[O:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:31]4[CH:32]=[CH:33][O:29][CH:30]=4)=[C:3]([F:28])[CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: OB(O)c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccoc2)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-3-fluorobenzenesulfonamide (E105) (100 mg, 0.21 mmol) and 3-furanylboronic acid (47 mg, 0.42 mmol) in DME (3 ml) was added potassium tert-butoxide (212 mg, 1.89 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The solvent was evaporated with the addition of a few drops of toluene and the residue passed through an SCX column eluting with methanol followed by 2M ammonia in methanol. The basic fractions were combined and the solvent evaporated. The crude product was purified by mass directed autoprep HPLC and the relevant fractions collected and solvent evaporated to afford the title compound (E116). MS (ES+) m/e 460 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:53]=[C:54]([C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([NH2:66])[CH:61]=2)[CH:55]=[CH:56][C:57]=1[O:58][CH3:59]>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:53]=[C:54]([C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([NH:66][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=2)[CH:55]=[CH:56][C:57]=1[O:58][CH3:59]
Reactant: COc1ccc(-c2cccc(N)c2)cc1OC
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1OC
Temperature: 25 °C
Yield: 64.2 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′,4′-Dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 64% yield: LCMS (ESI) m/z 432 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4]([OH:14])=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].Cl[S:16]([OH:19])(=[O:18])=[O:17]>>[C:1]([C:3]1[C:4]([OH:14])=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][C:9]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:8][CH:7]=2)#[N:2]
Reactant: O=S(=O)(O)Cl
Reactant: N#Cc1c(O)nc2ccccc2c1O
Product: N#Cc1c(O)nc2ccc(S(=O)(=O)O)cc2c1O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
280 parts of 3-cyano-2,4-dihydroxyquinoline were introduced into 1,000 parts of chlorosulfonic acid. This was followed by stirring at 80° C. for 5 hours, cooling down, pouring onto ice-water, filtering off with suction and washing with water. The crude product obtained after drying need not be purified for chlorination.
Reaction SMILES: [CH:1]1([NH:11][C:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[N:17][C:18]([Cl:25])=[CH:19][C:20]=3[CH3:24])[NH:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.IC.N1[CH2:29]CCN2CCCCCC=12>CN(C=O)C>[CH:1]1([NH:11][C:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[N:17][C:18]([Cl:25])=[CH:19][C:20]=3[CH3:24])[N:15]2[CH3:29])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(Cl)nc2[nH]n(C(=O)NC3CCCc4ccccc43)c(=O)c12
Reactant: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(Cl)nc2c1c(=O)n(C(=O)NC1CCCc3ccccc31)n2C

Procedure:
In analogy to example 2, 50 mg (0.14 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydro-pyrazolo[3,4-b]pyridine-2-carboxylic acid (1,2,3,4-tetrahydronaphthalen-1-yl)amide were reacted with 23.85 mg (0.168 mmol) of iodomethane in DMF with 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU) at RT. Yield: 12 mg (23%), M+H+: 371.42.
Reaction SMILES: [Li+].[N:2]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:15]2[CH:31]=[CH:30][C:18]([O:19][CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([O-:27])=O)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:32]1[CH2:35][CH2:34][CH2:33]1>>[N:32]1([C:25]([C:24]2[CH:28]=[CH:29][C:21]([CH2:20][O:19][C:18]3[CH:17]=[CH:16][C:15]([C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[CH2:7][N:2]4[CH2:3][CH2:4][CH2:5][CH2:6]4)=[O:14])=[CH:31][CH:30]=3)=[CH:22][CH:23]=2)=[O:27])[CH2:35][CH2:34][CH2:33]1
Reactant: O=C([O-])c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1
Reactant: C1CNC1
Agent: [Li+]
Product: O=C(c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1)N1CCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure D from 4-[4-(2-(S)-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenoxymethyl]-benzoic acid lithium salt and azetidine. MS (ES+) 448.2
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:16]=1)[CH:12]=[O:13])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:16]=1)[CH:12]=[O:13]
Reactant: COCCCc1cc(C=O)cc(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCCCc1cc(O)cc(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{[tert-butyl(dimethyl)silyl]oxy}-5-(3-methoxypropyl)benzaldehyde from the previous step (1 eq.) in THF (0.2 M) was added tetrabutylammonium fluoride (1.0 M THF solution, 1.1 eq.). The resulting reaction mixture was then stirred at RT for 30 min. The reaction was quenched sat. aq. NH4Cl and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Further purification of the crude product thus obtained by way of column chromatography (SiO2, Hex→3:2 (v/v) Hex:EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Sn](CCCC)(CCCC)CCCC)[N:3]=1.Cl[C:22]1[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][N:23]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:22]2[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cccnc1-c1cccc(Cl)n1
Yield: 71.9 %

Procedure:
To a degassed solution of 2-chloro-6-tributylstannylpyridine (prepared according to S. Choppin et al. in Org. Lett., 2000, 2, 803-5) (600 mg, 1.49 mmol) and 2-chloro-3-cyanopyridine (412 mg, 2.98 mmol) in THF was added tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) and the mixture heated at reflux for 96 hours. The solvent was removed under reduced pressure and the crude product chromatographed on silica, on a gradient of dichloromethane to 2% methanol in dichloromethane, to afford 6′-chloro-2,2′-bipyridinyl-3-carbonitrile as a white solid (231 mg): δH (400 MHz, d6-DMSO) 7.71-7.74 (2H, m), 8.11 (1H, t, J 7.8), 8.20-8.23 (1H, m), 8.48 (1H, dd, J 1.8, 8.0), 8.97 (1H, dd, J 1.8, 4.9); m/z (ES+) 216, 218 (M++H).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH2:32])[CH2:11][C:12]([CH3:31])([CH3:30])[CH2:13][C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][CH:18]([C:26]([O:28]C)=O)[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4].[CH3:36][NH2:37]>CN(C)C=O>[CH2:1]([NH:5][C:6](=[O:35])[C@H:7]([CH3:34])[CH2:8][C@H:9]([OH:33])[C@@H:10]([NH2:32])[CH2:11][C:12]([CH3:30])([CH3:31])[CH2:13][C:14]([N:16]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:19][CH:18]([C:26]([NH:37][CH3:36])=[O:28])[CH2:17]1)=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CN
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(C(=O)OC)Sc2ccccc21
Solvent: CN(C)C=O
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@@H](N)CC(C)(C)CC(=O)N1CC(C(=O)NC)Sc2ccccc21
Reaction time: 26 h

Procedure:
92 mg of 5(S)-Amino-4(S)-hydroxy-2(R),7,7-trimethyl-8-[2(R,S)-methoxycarbonyl-3,4-dihydro-2H-1,4-benzothiazin-4-ylcarbonyl]-octanoic acid (N-butyl)amide (Example 18)) are dissolved in 3 ml of a 5N methylamine solution in dimethylformamide and the solution is left to stand at room temperature for 26 h. After purification of the concentrated crude product by means of FC (mobile phase T) over 50 g of silica gel, the title compound is obtained as a diastereomer mixture: Rf (T)=0.26/0.31; FAB-MS: (M+H)+ =507.
Reaction SMILES: [NH2:1][C@H:2]([CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)[C:3]([N:5]1[CH2:10][C@@H:9]([CH3:11])[N:8]([C:12](=[O:24])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:7][C@@H:6]1[CH2:25][CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[NH:30])=[O:4].N[C@@H:44]([C:56](O)=[O:57])CC1C=C2C(C=CC=C2)=CC=1>>[NH:28]([CH2:27][CH2:26][CH2:25][C@H:6]1[CH2:7][N:8]([C:12](=[O:24])[CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C@H:9]([CH3:11])[CH2:10][N:5]1[C:3](=[O:4])[C@H:2]([NH:1][C:56](=[O:57])[CH3:44])[CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)[C:29]([NH2:31])=[NH:30]
Reactant: C[C@@H]1CN(C(=O)[C@H](N)Cc2ccc3ccccc3c2)[C@@H](CCCNC(=N)N)CN1C(=O)Cc1ccc2ccccc2c1
Reactant: N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Product: CC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)N1C[C@@H](C)N(C(=O)Cc2ccc3ccccc3c2)C[C@@H]1CCCNC(=N)N

Procedure:
The following compound was synthesized by the method of Scheme 6. The compound of Example 38 was treated by the method of Example 36 to introduce an acetyl group at the amino group of the D-2-Nal residue. It was tested as described above with the results shown. The mass was analyzed as 607.7 (M+H).
Reaction SMILES: [OH:1][C@H:2]([C@H:21]1[O:26][CH2:25][CH2:24][N:23]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][N:31]([CH3:36])[C:30]3=[O:37])[C:22]1=[O:38])[C:3]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:8][CH:7]=1)=[O:4].Cl.O1CCOCC1>>[NH2:11][CH2:10][C:9]1[CH:19]=[CH:20][C:6]([NH:5][C:3](=[O:4])[C@H:2]([OH:1])[C@H:21]2[O:26][CH2:25][CH2:24][N:23]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[CH2:32][N:31]([CH3:36])[C:30]4=[O:37])[C:22]2=[O:38])=[CH:7][CH:8]=1
Reactant: CN1Cc2ccc(N3CCO[C@H]([C@@H](O)C(=O)Nc4ccc(CNC(=O)OC(C)(C)C)cc4)C3=O)cc2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1Cc2ccc(N3CCO[C@H]([C@@H](O)C(=O)Nc4ccc(CN)cc4)C3=O)cc2C1=O
Reaction time: 3 h
Yield: 89 %

Procedure:
To round bottom flask charged with the compound 71-2 (50 mg) at rt was added 4 N HCl/dioxane (3 mL). The resulting solution was stirred for 3 h, concentrated under reduced pressure, and placed under high vacuum. The crude product was dissolved in MeOH and Et2O and the resultant solid was collected and dried to afford EXAMPLE 71 (36 mg) as an off-white solid. LC-MS: M+H=425 (free base).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:40][C:30]([C:27]1[CH:28]=[CH:29][C:24]([C:6]2[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=4)[N:15]=3)=[CH:8][CH:7]=2)=[CH:25][CH:26]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 62.1 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with benzylamine (available from Aldrich Chemical Company, Inc.; 66 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4′-benzylcarbamoyl-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (73 mg, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.23 (br s, 1H), 9.15 (t, J=6.0 Hz, 1H), 8.48 (s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 1.8 Hz, 1H), 8.10 (dd, J=8.5, 2.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.34 (d, J=4.3 Hz, 4H), 7.21-7.29 (m, 1H), 4.52 (d, J=6.0 Hz, 2H).