Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13]C#N)=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[CH2:13][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: N#CC[C@@H]1CCCN1c1ccc(Br)cc1
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)CC1CCCN1c1ccc(Br)cc1
Reaction time: 1 h
Yield: 105 %

Procedure:
(S)-2-(1-(4-bromophenyl)pyrrolidin-2-yl)acetonitrile: To a solution of 20A (2 g, 7.81 mmol) in methylene chloride (16 mL) at 0° C. was added TEA (2.177 mL, 15.62 mmol), and methanesulfonyl chloride (0.913 mL, 11.71 mmol). After 1 h, the reaction mixture was diluted with water and methylene chloride. The layers were extracted, and the organic layer was dried and concentrated to give 2.6 g of 1-(4-bromophenyl)-2-(methylsulfonylmethyl)pyrrolidine (8.17 mmol, 105% yield) as a brown oil that was used directly in the next step. To a solution of 1-(4-bromophenyl)-2-(methylsulfonylmethyl)pyrrolidine (2.6 g, 8.17 mmol) in DMSO (16 mL) was added NaCN (1.531 g, 31.2 mmol) and the resultant mixture was stirred at 50° C. overnight. The reaction mixture was diluted with EtOAc and water. The layers were extracted, and the organic layer was washed successively with water and brine. The organic layer was dried and concentrated, and the resulting material was purified via silica gel chromatography to give 20B (brown oil, 2.1 g, 7.92 mmol, 101% yield). Anal Calc'd for C12H13BrN2 264.03. found [M+H]=264.9, 266.9.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C@@H:11]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[C:20](=[O:33])[O:21][C:22]([CH2:29][CH:30]([CH3:32])[CH3:31])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH2:15]1)=[O:13]>>[CH2:29]([C:22]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]2[CH2:15][N:14]([C:12](=[O:13])[C@@H:11]([NH:10][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:19][CH2:18][C:17]=2[C:20](=[O:33])[O:21]1)[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)[C@@H](N)Cc1ccccc1)CC2
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)CC2

Procedure:
The procedure described for R06039-427 was employed to convert benzoyl chloride (6 mg, 0.041 mmol) to 5-((S)-2-amino-3-phenylpropanoyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (16 mg, 0.037 mmol) to provide N-((2S)-1-(3-isobutyl-1-oxo-3-phenyl-6,7-dihydrofuro[3,4-c]pyridin-5 (1H,3H,4H)-yl)-1-oxo-3-phenylpropan-2-yl)benzamide. The desired product was purified by column chromatography (4 g, SiO2, 0 to 100% dichloromethane/diethylether in hexanes) and isolated as a colorless oil (13 mg, 69%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.76-0.95 (m, 6H), 1.46-1.92 (m, 4H), 2.06-2.39 (m, 2H), 2.99-3.37 (m, 2H), 3.40-3.62 (m, 1H), 3.82-4.07 (m, 1H), 4.60 (d, J=19.59 Hz, 1H), 5.15-5.30 (m, 1H), 5.31-5.50 (m, 1H), 6.94-7.57 (m, 13H), 7.70-7.85 (m, 2H); MS m/z 523 (M+H)+, 521 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[C:5]([CH3:16])[CH:4]=[C:3]1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl[C:24]1C=CC(C(C2N(C)C(CC(OCC)=O)=CC=2C)=O)=CC=1>>[CH3:1][N:2]1[C:6]([C:7](=[O:15])[C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[C:5]([CH3:16])[CH:4]=[C:3]1[CH:17]([CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(F)cc2)n1C
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccc(F)cc2)n1C

Procedure:
The methylation procedure of Example 77A is repeated, except that an equivalent quantity of ethyl 1,4-dimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate (from Example 83) is methylated instead of the ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate used in Example 77A, to yield ethyl 1,4,α-trimethyl-5-(p-fluorobenzoyl)-pyrrole-2-acetate.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:8]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[C:10]3[N:15]=[CH:14][S:13][C:11]=3[N:12]=2)[CH2:3]1.[CH3:27][O:28][C:29]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1)=[O:30].CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([NH:16][C:9]2[C:10]3[N:15]=[CH:14][S:13][C:11]=3[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:35]([C:34]4[CH:38]=[CH:39][C:31]([C:29]([O:28][CH3:27])=[O:30])=[N:32][CH:33]=4)=[O:36])[CH2:3]3)[N:8]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COc1ccc(Nc2nc(N3CCC(N)C3)nc3scnc23)cc1OC
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)c4)c4ncsc4n3)C2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.4 %

Procedure:
To a solution of 5-(3-aminopyrrolidin-1-yl)-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (80 mg, 0.22 mmol) and 6-(methoxycarbonyl)nicotinic acid (39 mg, 0.22 mmol) in dichloromethane (15 mL) was added the solution of 1-methyl-1H-imidazole (71 mg, 0.88 mmol) and EDCI (164 mg, 0.88 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 15 hours, the solid was collected by filtration and washed with MeOH to afford methyl 5-(1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)picolinate (90 mg, 80.3%) as a off-white solid. 1H NMR (300 MHz, DMSO): δ 9.57 (s, 1H), 9.07 (s, 1H), 8.99 (d, 1H, J=6.3 Hz), 8.79 (s, 1H), 8.36 (dd, 1H, J1=8.1 Hz, J2=2.1 Hz), 8.11 (d, 1H, J=8.1 Hz), 7.86 (s, 1H), 7.45 (s, 1H), 6.90 (d, 1H, J=8.7 Hz), 4.60-4.58 (m, 1H), 3.89 (s, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 3.64 (brs, 4H), 2.28-2.24 (m, 1H), 2.11-2.06 (m, 1H). LC-MS: 536 [M+H]+, tR=1.37 min. HPLC: 95.95% at 214 nm, 96.44% at 254 nm, tR=4.85 min.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([C:9](OCC)=[O:10])=[C:7]([C:14](OCC)=[O:15])[N:6]=[C:5]1[S:19][CH3:20])[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].[OH-].[Na+]>ClCCl.CCOCC.O>[CH2:1]([N:4]1[C:8]([CH2:9][OH:10])=[C:7]([CH2:14][OH:15])[N:6]=[C:5]1[S:19][CH3:20])[CH2:2][CH3:3]
Reactant: CCCn1c(SC)nc(C(=O)OCC)c1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CCCn1c(SC)nc(CO)c1CO
Reaction time: 3 h
Yield: 48 %

Procedure:
A solution of the above-identified diethyl 1-n-propyl-2-(methylthio)imidazole-4,5-dicarboxylate (23 mmol) in anhydrous dichloromethane (50 mL) was slowly (1 hour) added to a stirred suspension of lithium aluminum hydride (69 mmol) in anhydrous ether (140 mL) at 0.5° C. under nitrogen. The mixture was stirred at 0°-5° C. for 3 hours after the addition was completed, then at ambient temperature for 1 hour. The excess hydride was carefully decomposed by the slow sequential addition of water (2.6 mL), 15% sodium hydroxide solution (2.6 mL) and water (7.8 mL). The precipitate of inorganic salts was filtered and extracted continuously for 24 hours with tetrahydrofuran heated under reflux in a Soxhlet apparatus. The tetrahydrofuran solution was combined with the filtrate from the reaction mixture and reduced to dryness in vacuo. The solid residue was crystallized from acetone and identified as 1-n-propyl-2-(methylthio)-4,5-bis(hydroxymethyl)imidazole (48% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+].C(OCC)C.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[O:26]=[C:17]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)CCc1ccccc1)C(=O)O
Yield: 84.6 %

Procedure:
L-Leucine (7.87 g, 60 mmol) was dissolved in a solution of sodium hydroxide (4.8 g, 120 mmol) in water (40 ml, 1.5M). Diethyl ether (40 ml) was added. The mixture was cooled in an ice bath and while stirring rapidly, hydrocinnamoyl chloride (10.1 g, 8.92 ml, 60 mmol) was added dropwise over a period of 30 minutes. The ice bath was removed and the mixture was stirred at room temperature 2 hours, maintaining a slightly basic pH by periodic addition of small amounts of 1N sodium hydroxide solution. The layers were separated. The ether layer was reextracted with 1N sodium hydroxide solution. The combined aqueous layers were washed once with ether and then acidified with concentrated hydrochloric acid. The product was extracted into chloroform, dried over magnesium sulfate, and freed of solvent in vacuo leaving a white solid (13.36 g). This material was recrystallized from ethyl acetate (65 ml) to give 8.37 g of the title B compound (53%), m.p. 129°-130° C. [α]D =-41.3° (c=1.3, MeOH).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>CN(C=O)C>[CH2:17]([O:16][CH:15]([O:19][CH2:20][CH3:21])[CH2:14][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[CH3:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(CBr)OCC
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Temperature: 150 °C
Yield: 86.7 %

Procedure:
A three-necked round-bottomed flask fitted with an efficient stirrer and a reflux condenser was charged with potassium phthalimide (150 g, 0.81 mol) and 2-bromo-1,1-diethoxy-ethane (196 g, 1.0 mol) and DMF (500 mL). The stirrer was started and the mixture was heated for about 3-4 h in an oil bath maintained at 150° C. The solvent DMF was removed under reduced pressure. The residue was purified by column chromatography to afford pure 2-(2,2-diethoxyethyl)isoindoline-1,3-dione (185 g, yield 87%). 1H NMR (400 MHz, MeOD): 1.16 (t, 6H), 3.48-3.60 (m, 2H), 3.68-3.75 (m, 2H), 3.76-3.89 (d, 2H), 4.89 (t, 1H), 7.68-7.75 (m, 2H), 7.85-7.96 (m, 2H). MS (E/Z): 264 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]([F:15])([F:14])[F:13])([O-])=O.C([O-])=O.[NH4+]>C1COCC1.CO>[F:13][C:12]([F:14])([F:15])[CH2:11][NH:10][C:5]1[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1NCC(F)(F)F
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccccc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (2-nitro-phenyl)-(2,2,2-trifluoro-ethyl)-amin (2.16 g, 9.8 mmol) in THF (6 mL) and MeOH (24 mL) at 0° C. was added ammonium formate (2.47 g, 39.2 mmol). The resulting mixture was purged with nitrogen, then 10% Pd/C (57 mg) was added. The ice bath was removed and the reaction mixture was stirred at room temperature for 5 h. The resulting mixture was filtered over CELITE®, washing with EtOAc. Removal of the solvent in vacuo yield N-(2,2,2-trifluoro-ethyl)-benzene-1,2-diamine, which was used in the next step without further purification. MS 191 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])[NH2:11].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH:8]([C:5]1[N:6]=[CH:7][C:2]([C:16]2[CH:17]=[CH:18][C:13]([C:10]([NH2:11])=[O:12])=[CH:14][CH:15]=2)=[CH:3][CH:4]=1)=[O:9]
Reactant: O=Cc1ccc(Br)cn1
Reactant: NC(=O)c1ccc(B(O)O)cc1
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: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(-c2ccc(C=O)nc2)cc1
Temperature: 77.5 °C
Yield: 62.3 %

Procedure:
To a solution of 5-bromo picolinaldehyde (0.7 g, 3.76 mmol) in toluene (100 mL) and ethanol (75 mL) was added (4-carbamoylphenyl)boronic acid (1.24 g, 7.52 mmol), 2M sodium carbonate (2.8 g, 26.32 mmol, 6 mL water), Pd(PPh3)4 (0.217 g, 0.188 mmol) under argon. The resulting mixture was heated at 75-80° C., for 6 h. The contents were cooled to room temperature, diluted with ethyl acetate (150 mL) and washed with bicarbonate solution (2×100 mL) and brine solution (2×100 mL). The organic layer was dried over sodium sulphate and distilled off to obtain the crude product. The crude product was purified by flash chromatography (100-200μ; 35% ethyl acetate in hexane) to afford 4-(6-formylpyridin-3-yl)benzamide (0.53 g, 62% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.03 (s, 1H), 9.20 (s, 1H), 8.39 (d, 1H), 8.07 (s, 1H), 8.03 (d, 3H), 7.93 (d, 2H), 7.44 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][NH:10][C:8]([C:5]1[N:6]=[N:7][C:2]([N:28]2[CH2:29][CH2:30][CH:25]([CH2:24][CH2:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH3:16])[CH2:26][CH2:27]2)=[CH:3][CH:4]=1)=[O:9]
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Reactant: Cc1ccccc1CCC1CCNCC1
Product: Cc1ccccc1CCC1CCN(c2ccc(C(=O)NCCC(C)C)nn2)CC1

Procedure:
The title compound was prepared in the same manner as described for Example 16 from 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide and 4-[2-(2-methylphenyl)ethyl]piperidine. MS (+ESI) m/z 395 (MH+).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41](=[O:50])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1>C1COCC1.ClCCl>[Br:1][CH:42]([C:43]1[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=1)[C:41]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[Cl:34])=[O:50]
Reactant: [Br-]
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccccc1Cl
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1ccccc1Cl)C(Br)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
29.54 g of phenyltrimethylammonium tribromide are added to a solution of 20.83 g of 1-(2-chlorophenyl)-2-(4-chlorophenyl)ethanone in THF. The homogeneous solution is stirred at room temperature for 1 hour 15 minutes. The reaction medium is filtered and concentrated to dryness. The crude reaction product is taken up in dichloromethane and washed successively with water, with aqueous Na2CO3 solution and then with water. The organic phase is dried over Na2SO4, filtered and concentrated to dryness by distilling off the solvent under reduced pressure. The product is obtained in the form of an oil that crystallizes slowly. The crystals are washed with a minimum amount of ethanol to give the expected product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: NCCO
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CO
Product: OCCNCc1ccc(Cl)nc1

Procedure:
This compound was made in a manner analogous to that set forth in Step A of Example 2, using 8.5 grams (0.060 mole) of (6-chloro-3-pyridyl)formaldehyde (known compound), 4.4 grams (0.072 mole) of 2-aminoethan-1-ol, 4.9 grams (0.048 mole) of triethylamine, 14.4 grams (0.119 mole) of magnesium sulfate, and 13.6 grams (0.360 mole) of sodium borohydride in 150 mL of methanol. The yield of the subject compound was about 11.3 grams, which included an impurity of about 10% by weight. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:26][NH:25][C:8]2=[N:9][C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=[C:7]2[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].O=[CH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]([O:4][CH:5]1[CH2:26][N:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:8]2=[N:9][C:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:12]=[C:7]2[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CNc2nc(-c3ccccc3)c(-c3ccccc3)nc2C1OC(C)=O
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)CCCCCCN1CC(OC(C)=O)C(OC(C)=O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of rac-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine-7,8-diyl diacetate (Intermediate I) (69 mg, 0.171 mmol) in DCE (3 ml) was added ethyl 7-oxoheptanoate (88 mg, 0.513 mmol) followed by sodium triacetoxyborohydride (109 mg, 0.513 mmol). The reaction was left to stir overnight at room temperature under an atmosphere of nitrogen. To the reaction mixture was added further ethyl 7-oxoheptanoate (88 mg, 0.513 mmol) followed by sodium triacetoxyborohydride (109 mg, 0.513 mmol). The reaction mixture was left to stir at RT under an atmosphere of nitrogen for 4 days. The mixture was diluted with water and extracted with EtOAc (3×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-70% EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(P(=O)(OCC)OCC)#N.CN1CCOCC1.[NH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]1[C:44]2[CH:45]=[C:46]([S:49]([NH:52][CH2:53][C:54]3[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=3)(=[O:51])=[O:50])[CH:47]=[CH:48][C:43]=2[S:42][N:41]=1>C(Cl)Cl.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([NH:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]3[C:44]4[CH:45]=[C:46]([S:49](=[O:50])(=[O:51])[NH:52][CH2:53][C:54]5[CH:55]=[CH:56][C:57]([O:60][CH3:61])=[CH:58][CH:59]=5)[CH:47]=[CH:48][C:43]=4[S:42][N:41]=3)=[O:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: COc1ccc(CNS(=O)(=O)c2ccc3snc(NCCCN)c3c2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(CNS(=O)(=O)c2ccc3snc(NCCCNC(=O)c4ccc(-c5ccc(OC)cc5)cc4)c3c2)cc1
Reaction time: 0.25 h
Yield: 21.1 %

Procedure:
To a solution of 4′-methoxybiphenyl-4-carboxylic acid (34 mg, 0.1 mmol) in methylene chloride (1 mL), diethyl cyanophosphonate (23 μL, 0.2 mmol) and 4-methylmorpholine (34 μL, 0.3 mmol) were added at room temperature and allowed to stir for 15 min. A solution of 3-(3-aminopropylamino)-N-(4-methoxybenzyl)benzo[d]isothiazole-5-sulfonamide (57 mg, 0.1 mmol) in methylene chloride (1 mL) was then added and the resulting reaction mixture was allowed to stir for 7 h. Upon diluting the reaction mixture with methylene chloride (20 mL) and 10% HCl aqueous solution, a precipitate was observed, filtered and air-dried to provide 4′-methoxy-N-(3-(5-(N-(4-methoxybenzyl)sulfamoyl)-benzo[d]isothiazol-3-ylamino)propyl)biphenyl-4-carboxamide (13 mg). 1H NMR (300 MHz, DMSO-d6): 9.01 (br s, 1H), 8.58 (t, 1H), 8.47 (d, 1H), 7.88-7.91 (m, 3H), 7.70 (d, 2H), 7.66 (d, 2H), 7.50 (dd, 1H), 7.34 (d, 1H), 7.13 (d, 2H), 7.03 (d, 2H), 6.78 (d, 2H), 3.88 (d, 2H), 3.80 (s, 3H), 3.67 (s, 3H), 3.42-3.48 (m, 2H), 3.31 (m, 2H), 2.00-2.09 ppm (m, 2H). MW=616 confirmed by LC-MS, tr=13.65 min (Method Y) MH+=617.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[OH-].[Na+].C(Cl)Cl.[Cl:17][C:18]([Cl:23])([CH3:22])[C:19](Cl)=[O:20]>O>[Cl:17][C:18]([Cl:23])([CH3:22])[C:19]([N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]1[CH3:1])=[O:20]
Reactant: CC(Cl)(Cl)C(=O)Cl
Reactant: CC1NCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1c2ccccc2CCN1C(=O)C(C)(Cl)Cl

Procedure:
A reaction vessel was chrged with 2 g 1-methyl-1,2,3,4-tetrahydroisoquinoline, 10 ml 10% sodium hydroxide and 50 ml methylene chloride. With this mixture stirred, 3 ml 2,2-dichloropropionyl chloride was added dropwise to the mixture. The mixture was stirred for 20 minutes, then water was added. The organic extract was dried with magnesium sulfate, stripped of solvent and subjected to Kugelrohr distillation (170° C. @ 0.25 mm Hg) to provide 2.7 g of a yellow oil product having the elemental analysis reported in Table I.
Reaction SMILES: [Cl:1][C:2](=[C:7](Cl)[C:8]([F:11])([F:10])[F:9])[C:3]([F:6])([F:5])[F:4].C1(C)C=CC=CC=1.[CH2:20]([OH:23])[CH2:21][OH:22].[H-].[Na+]>O>[Cl:1][CH:2]([C:7]1([O:23][CH2:20][CH2:21][O:22]1)[C:8]([F:11])([F:10])[F:9])[C:3]([F:6])([F:5])[F:4]
Reactant: FC(F)(F)C(Cl)=C(Cl)C(F)(F)F
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)C(Cl)C1(C(F)(F)F)OCCO1
Temperature: 40 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
233 g of 2,3-dichloro-1,1,1,4,4,4-hexafluorobut-2-ene were added dropwise to 400 ml of toluene, 80 g of ethylene glycol and 80 g of 60% strength sodium hydride in mineral oil at room temperature. The reaction mixture was stirred at 40° C. for 5 hours and water was then added. The organic phase was separated off, the aqueous phase was extracted with methyl t-butyl ether and the combined organic phases were dried over sodium sulfate. After removal of the solvent and subsequent distillation in vacuo, 180 g of 2-chloro-1,1,1,4,4,4-hexafluoro-3,3-ethylenedioxybutane (boiling point: 48° C./16 mbar) were obtained.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:56])[CH:48]([CH:50]3[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]3)[CH3:49])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:56])[CH:48]([CH:50]3[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]3)[CH3:49])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: CC(C(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C1CCCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)C1CCCNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
N-(3-{1-Perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)-3-piperidylpropanamide was 4 mL of 4.0 N HCl in 1,4-dioxane. The reaction mixture was stirred at room temperature overnight. After neutralization with a saturated aqueous solution of NaHCO3, the crude reaction mixture was evaporated to dryness and purified by preparative HPLC (0.106 g, 38% yield over 2 steps): 1H NMR (CD3OD) δ 8.73 (br s, 1H), 8.35 (br s, 1H), 8.17 (t, 1H), 8.1 (dd, 1H), 7.7–7.6 (m, 3H), 7.5 (t, 1H), 2.8 (t, 2H), 2.66 (t, 2H), 2.58 (br s, 4H), 1.65 (m, 4H), 1.5 (m, 2H); ES-MS (m/z) 416 [M+H]+.
Reaction SMILES: FC1C=CC(F)=CC=1C[P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].Br[CH2:19][C:20]1[CH:25]=[C:24]([Cl:26])[N:23]=[CH:22][N:21]=1>>[CH2:7]([O:6][P:5]([CH2:19][C:20]1[CH:25]=[C:24]([Cl:26])[N:23]=[CH:22][N:21]=1)(=[O:12])[O:9][CH2:10][CH3:11])[CH3:8]
Reactant: Clc1cc(CBr)ncn1
Reactant: CCOP(=O)(Cc1cc(F)ccc1F)OCC
Product: CCOP(=O)(Cc1cc(Cl)ncn1)OCC

Procedure:
Prepared according to the same procedure as diethyl 2,5-difluorobenzylphosphonate, starting with 4-(bromomethyl)-6-chloropyrimidine. 1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.68 (dd, J=2.3, 1.1 Hz, 1H), 4.21-3.88 (m, 4H), 3.74-3.45 (m, 2H), 1.20 (t, J=7.0 Hz, 6H), Mass spec.: 265.1 (MH)+.