Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:10][C@@H:11]2[C@@H:15]([OH:16])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[CH:5][CH:4]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:10][C@@H:11]2[C@@H:15]([O:16][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(O[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2OS(C)(=O)=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3-(bis(4-methoxyphenyl)(phenyl)methoxy)-4-hydroxypyrrolidine-1-carboxylate (3.50 g, 6.92 mmol) and DMAP (4.23 g, 34.61 mmol) in dichloromethane (60 mL) at 0° C. in an ice bath was added methanesulfonyl chloride (2.69 mL, 34.61 mmol) dropwise. The resulting mixture was stirred at ambient temperature for 1 hour, cooled to 0° C. in an ice bath and quenched with water (15 mL). The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution (60 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give (3S,4S)-tert-butyl 3-(bis(4-methoxyphenyl)(phenyl)methoxy)-4-(methylsulfonyloxy)pyrrolidine-1-carboxylate (4.01 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH3:23][N:24]([C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.C(Cl)CCl>CN(C=O)C>[CH3:23][N:24]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=1
Reactant: CN(c1ccncc1)c1ccc(N)cc1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(N(C)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (53 mg, 0.17 mmol) and 4-(N-methyl-N-pyridin-4-yl-amino)phenylamine (47 mg, 0.24 mmol) in DMF (3 mL), EDC (73 mg, 0.38 mmol) was added. The reaction mixture was stirred at room temperature overnight. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (28 mg). MS 500.2 and 502.2 (M+H, Cl pattern).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].[S:6](Cl)([CH3:9])(=[O:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[NH2:5][CH:3]([CH3:4])[CH2:2][NH:1][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(N)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(N)CNS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1,2-Diaminopropane (1.00 g, 13.5 mmol, 1.15 mL, 1.1 eq.) was placed in CH2Cl2 (30 mL) and cooled to 0° C. Mesyl chloride (1.40 g, 12.3 mmol, 0.95 mL, 1.0 eq.) was added over a period of five minutes followed by triethylamine (3.72 g, 36.9 mmol, 5.17 mL, 3.0 eq.). The reaction was stirred for 30 minutes and then concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-15% MeOH/CH2Cl2 as the eluting solvent to obtain N-(2-amino-propyl)-methanesulfonamide as a clear, colorless oil (504 mg, 27%). 1H-NMR (CDCl3, 400 MHz) δ 3.17-3.03 (m, 2H), 2.98 (s, 3H), 2.88-2.80 (m, 1H), 1.12 (d, 3H, J=6.3 Hz).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([Si:13]([C:18]#[CH:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12]>C(NC(C)C)(C)C.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.[Cu]I>[CH2:14]([Si:13]([C:11]#[C:12][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:15]
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: C#C[Si](CC)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Product: CC[Si](C#Cc1ccc2[nH]ccc2c1)(CC)CC
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
To a stirred solution of 5-iodoindole (0.50 g, 2.0 mmol) and (triethylsilyl)-acetylene (0.58 g, 4.0 mmol) in diisopropylamine (15 mL) was added Pd(PPh3)2Cl2 (0.07 g, 0.10 mmol) and CuI (0.04 g, 0.20 mmol) and the reaction mixture was stirred at r.t. for 16 h. The solvent was then removed in vacuo. EtOAc (15 mL) and water (15 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (2×20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 10% EtOAc/hexanes) gave the title compound (0.52 g, quantitative). δH (DMSO-d6) 11.30 (1H, br. s), 7.69 (1H, s), 7.45-7.41 (1H, m), 7.37 (1H, d, J 8.4 Hz), 7.15 (1H, dd, J 8.4 and 1.5 Hz), 6.48-6.40 (1H, m), 1.02 (9H, t, J 7.8 Hz), 0.65 (6H, q, J 7.9 Hz). MS (ES−) 254.0 (M−H)−.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:2]=1.[C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)(=[O:18])[NH2:17]>>[NH:8]([C:3]1[CH:2]=[CH:1][C:6]([NH:7][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:16]([NH2:17])=[O:18])=[CH:20][CH:21]=2)=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:16]([NH2:17])=[O:18])=[CH:20][CH:21]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccc(Nc2ccc(N)cc2)cc1
Reactant: NC(=O)c1ccc(C(=O)O)cc1
Product: NC(=O)c1ccc(C(=O)Nc2ccc(Nc3ccc(NC(=O)c4ccc(C(N)=O)cc4)cc3)cc2)cc1

Procedure:
Compound 754 was prepared according to the procedure described in Scheme IV from 4,4′-diaminodiphenylamine and 4-carbamoylbenzoic acid. [M+H]+ calcd for C28H23N5O4: 494.18; found 494.00.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>FC(F)(F)C(O)=O>[F:12][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4](=[CH:3][C:2]=1[F:1])[NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(F)c(F)cc2[nH]c1=O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cc(F)c(F)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 55 °C
Reaction time: 20 h
Yield: 68.1 %

Procedure:
To a suspension of 6,7-difluoro-1,4-dihydro-2,3-quinoxalinedione (837 mg, 4.23 mmol) in trifluoracetic acid (30 mL) was added KNO3 (512 mg, 5.07 mmol). The mixture was stirred at 55° C. for 20 h at the end of this time, 256 mg (2.50 mmol) of KNO3 was added and the reaction mixture was stirred at 55° C. for 20 h, then another 256 mg (2.50 mmol) of KNO3 was added and the mixture was stirred at 55° C. for 20 h. The reaction mixture was then rota-evaporated to dryness. To the residual solid was added ice-cold water (about 15 mL), the solid was collected by vacuum filtration, washed with ice-cold water (5×5 mL), and dried at 40° C. under 1 mm Hg for 14 h, giving 700 mg (68%) of the title compound as a yellow powder. Mp 288°-90° C. (dec.). IR (KBr) 3424, 3226, 1752, 1717, 1554, 1356, 1304 cm-1. 1H NMR (DMSO-d6): 12.249 (s, 1H), 11.864 (bs, 1H), 7.330 (dd, 1H, J=10.5, 7.8 Hz). Analysis for C8H3F2N3O4, calcd: C, 39.50, H, 1.24, N, 17.29; found: C, 39.42, H, 1.26, N, 17.08.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1>O1CCCC1>[Cl:1][CH2:2][CH2:3][C:4]([N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)CCNC2
Solvent: C1CCOC1
Product: O=C(CCCl)N1CCc2ccccc2C1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A solution of 3-chloropropanoyl chloride (10.5 g) in tetrahydrofuran (400 mL) was cooled down to 6° C. followed by the addition of a solution of 3,4-dihydro-1H-isoquinoline (10.0 g). The resulting mixture was stirred at 10° C. for 30 min, filtered and concentrated in vacuo. The residue was subjected to a standard aqueous work up procedure followed by purification by flash chromatography on silicagel (eluent: ethyl acetate/heptane 1:1) to give the product as a colourless oil (10 g).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:13][N:12]=1>C(N(CC)CC)C.[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:17]1([C:15]2[C:14]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:13][N:12]=[C:11]([C:7]#[C:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:9])=[O:8])[N:16]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: C#CCCCCC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(O)CCCCC#Cc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 3.4 %

Procedure:
88 mg (0.7 mmol) of 6-heptynoic acid, 6 mg (0.07 eq.) of copper(I) iodide and 14 mg (0.04 eq.) of bis(triphenylphosphine)palladium(II) chloride were added to a solution of 114 mg (0.5 mmol) of 2-chloro-4,5-diphenylpyrimidine in 5 ml of triethylamine, and the mixture was stirred at 50° C. for 1 hour. The residue after evaporation was purified by preparative HPLC (method A). 6 mg (3%) of the desired product were obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH:22]3[CH2:24][CH2:23]3)[CH2:20][CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[CH:22]1([N:21]2[C:14]3[N:15]([C:16](=[O:18])[N:17]=[C:12]([O:1][CH2:2][C:3]4[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=4)[C:6]#[N:7])[CH:13]=3)[CH2:19][CH2:20]2)[CH2:24][CH2:23]1
Reactant: N#Cc1cccc(CO)c1
Reactant: O=c1nc(Cl)cc2n1CCN2C1CC1
Product: N#Cc1cccc(COc2cc3n(c(=O)n2)CCN3C2CC2)c1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 3-(hydroxymethyl)benzonitrile and 7-chloro-1-cyclopropyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:10][O-:11].[Na+].O>C(#N)C>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Br)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1nc(Cl)ccc1Br
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a solution of 3-bromo-2,6-dichloropyridine (3.00 g, 13.2 mmol) in acetonitrile (20 mL) was added sodium methoxide (methanol solution, 4.83 mol/L, 3.0 mL) dropwise at 0° C. The mixture was stirred at room temperature over night. To the mixture was added 30 mL of water, and the organic was evaporated. The resulting suspension was filtered, and the pad was washed with water for several times. The pad was dried under reduce pressure to give title compound (2.74 g, 93.2%) as white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[C:28]([CH3:35])[CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:28]([CH3:35])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1ccc(B(O)O)c(C)c1
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C)c1

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (1189 mg, 0.5 mmol) and 4-methoxy-2-methylphenylboronic acid (166 mg, 1.0 mmol) to afford after chromatographic purification the title compound (105 mg, 50%). 1H NMR (CDCl3, 300 MHz) δ 7.04 (d, 1H, J=8.5 Hz), 6.65-6.79 (m, 4H), 3.75-4.22 (m, 2H), 3.74 (s, 3H), 3.58-3.68 (m, 1H), 3.18-3.42 (m, 4H), 2.76-3.16 (m, 3H), 2.17 (s, 3H), 1.70-1.84 (m, 2H), 1.40 (s, 9H) ppm. MS-ApCI: 421 [M+H+].
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:16][N:17]([CH3:21])[C:18](=[S:20])[S-:19].C[NH2+]C>C(=S)=S>[CH3:16][N:17]([CH3:21])[C:18](=[S:19])[S:20][CH:9]([CH2:10][N+:11]([O-:13])=[O:12])[C:8]1[CH:14]=[CH:15][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: CN(C)C(=S)[S-]
Reactant: CC(=O)Oc1ccc(C=C[N+](=O)[O-])cc1
Agent: C[NH2+]C
Solvent: S=C=S
Product: CC(=O)Oc1ccc(C(C[N+](=O)[O-])SC(=S)N(C)C)cc1

Procedure:
As in Example 17, reaction of 4-acetoxy-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave 4-acetoxy-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 116° - 118° C. after recrystallization without heating from acetone-methanol solution.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1.[N-:46]=[C:47]=[O:48].[K+]>O.C(O)(=O)C>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][C:47]([NH2:46])=[O:48])[CH:3]=[C:4]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[CH:10]=2)[CH:5]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc(O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: [N-]=C=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NC(N)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 35 °C
Yield: 33.8 %

Procedure:
To a suspension of (S)-2-(1-((5-(3-amino-5-hydroxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) in 403 μl water and 208 μl acetic acid was added potassium isocyanate (10 mg, 0.12 mmol) The mixture was heated 35° C. overnight. The reaction was poured into water and extracted twice with ethyl acetate. The organics were combined and washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 18 mg (33% yield) of the title compound.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[F:15][C:16]1[CH:53]=[CH:52][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([N:30]3[CH2:39][CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH2:41][CH2:42][N:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)[CH:36]=4)[CH:31]3[C:49](O)=[O:50])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.[O:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1[O:60][NH2:61]>CN(C=O)C>[O:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1[O:60][NH:61][C:49]([CH:31]1[C:32]2[C:37](=[CH:36][C:35]([O:40][CH2:41][CH2:42][N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)=[CH:34][CH:33]=2)[CH2:38][CH2:39][N:30]1[S:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:53][CH:52]=2)=[CH:22][CH:23]=1)(=[O:28])=[O:29])=[O:50]
Reactant: O=C(O)C1c2ccc(OCCN3CCOCC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)C1c2ccc(OCCN3CCOCC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 40 mg (0.264 mmol) of HOBt and 51 mg (0.264 mmol) of EDC in 2 ml of DMF was added dropwise to a solution of 98 mg (0.176 mmol) of 2-[4-(4-fluoro-phenoxy)benzenesulfonyl]-6-(2-morpholin-4-ylethoxy)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid and 46 mg (0.325 mmol) of O-(tetrahydropyran-2-yl)hydroxylamine in 3 ml of DMF at 0° C., and the mixture was stirred at room temperature. After standing overnight, it was poured onto H2O and extracted with ethyl acetate. The organic phase was dried with MgSO4 and concentrated. The residue was chromatographed on silica gel (dichloromethane→dichloromethane/methanol 99:1), the title compound being isolated as a colorless solid. Yield: 80%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]([CH3:41])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:26]([O:25][CH3:24])=[N:27][CH:28]=[C:29]([CH3:41])[CH:30]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1ncc(C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ncc(C)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)ccc1C
Temperature: 80 °C
Yield: 76.2 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (0.1 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (98 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (35 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol) and the reaction mixture was heated to 80° C. overnight. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The aqueous layer was back extracted with ethyl acetate (5 mL). The organics were dried over sodium sulfate and evaporated. The resulting crude material was purified by silica gel chromatography (eluting with 0-30% ethyl acetate in hexanes) to yield the product (95 mg, 76%). ESI-MS m/z calc. 415.48. found 416.1 (M+1)+. Retention time 1.92 minutes.
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3](Cl)=[O:4].[Cl:26][CH2:27][CH2:28][OH:29]>>[F:1][C:2]([F:25])([C:6]([F:23])([F:24])[C:7]([F:21])([F:22])[C:8]([F:19])([F:20])[C:9]([F:17])([F:18])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([O:29][CH2:28][CH2:27][Cl:26])=[O:4]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OCCCl
Product: O=C(OCCCl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-Chloroethyl perfluorooctanoate was prepared by adding 162 g (0.375 mol) of perfluorooctanoyl chloride to 32.2 g (0.40 mol) of 2-chloroethanol cooled at 0° C., stirring the resulting mixture at 0° for 2 h, and then stirring for about 2.5 days at 25°. Fractionation of the resulting solution gave 152.6 g (85% yield) of the chloroethyl ester, b.p. 84°-88° at 1.3 kpa (10 mm), 98% pure by GC. IR (CCl4): 2960 (sat'd CH), 1790 (C--O), 1300-1100 cm31 1 (CF, C-O). NMR (CCl4): 1H 4.59 (t, JHH 5.5 Hz, 2H, CH2) and 3.70 ppm (t, JHH 5.5 Hz, 2H, CH2); 19F -81.6 (t of t, JFF 10, 4 Hz, 3F, CF4), -119.0 (t of t, JFF 12, 6 Hz, 2, F, CF2C=O), -122.4 (m, 4F, CF2), -123.3 (m, 4F, CF2), and -126.8 ppm (m, 2F, CF2).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.I.[NH2:37][C:38]1[C:39]([C:46]([NH:48][C:49](=[NH:52])SC)=[O:47])=[N:40][C:41]([Cl:45])=[C:42]([NH2:44])[N:43]=1>C(O)C>[C:23]([O:22][C:20]([NH:19][C@H:15]([CH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([NH2:52])=[N:48][C:46]([C:39]2[C:38]([NH2:37])=[N:43][C:42]([NH2:44])=[C:41]([Cl:45])[N:40]=2)=[O:47])=[CH:7][CH:8]=1)[C:16]([OH:18])=[O:17])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCc1ccc(CCCCN)cc1)C(=O)O
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CCCc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1)C(=O)O
Temperature: 65 °C
Yield: 74.7 %

Procedure:
The compound 280 (0.077 g, 0.211 mmol) was mixed with ethanol (5 mL). The mixture was heated at 65° C. for 15 min to achieve complete dissolution. To the clear solution were sequentially added diisopropylethylamine (0.184 mL, 1.056 mmol) and 1-(3,5-diamino-6-chloropyrazinoyl)-2-methylisothiourea hydriodide (0.99 g, 0.254 mmol). The mixture was heated at 65° C. for an additional three hours. It was then concentrated under vacuum. The residue was chromatographed over silica gel, eluting with a mixture of concentrated ammonium hydroxide (0-2.2%), methanol (0-22%) and dichloromethane (100-75.8%) to afford the product 290 (0.091 g, 75%) as a yellow solid. 1H NMR (300 MHz, CD6OD): δ 1.44 (s, 9H), 1.58-1.84 (m, 8H), 2.54-2.68 (m, 4H), 3.34-3.42 (m, 2H), 4.02 (m, 1H), 7.08 (s, 4H). m/z (APCI) 577 [C26H37ClN8O5+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]([C:13]([OH:15])=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4].COC1C=CC2N=CC=C([C@H](O)[C@@H]3N4C[C@H](C=C)C(CC4)C3)C=2C=1.O>CO>[CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:7]([C:13]([OH:15])=[O:14])=[C:8]([CH3:12])[NH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Solvent: CO
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
To a solution of 5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (700 g, 2.1 mol) in methanol (14 L) was added Quinidine (617 g, 1.90 mol). The mixture was stirred at 90° C. under reflux until Quinidine was completely dissolved. The stirring was continued for 3 hours. 4.5 L water was added. The stirring was continued for 0.5 hour. The mixture was cooled down slowly. A solid was precipitated out and was filtered. The filter cake was treated with hydrochloric acid to produce (R)-5-(methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (130 g) in a yield of 18.6%.