Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[N:32][C:31]([N:34]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[N:33]=[N:32][C:31]([N:34]5[CH2:39][CH2:38][N:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36][CH2:35]5)=[CH:30][CH:29]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: CCOC(=O)CN1CCN(c2ccc(Cl)nn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nn2)CC1

Procedure:
Compound 344 was prepared as a light yellow solid (TFA salt) from compound 4 and compound 345 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.65 (1 H, s), 9.33 (1 H, s), 8.63-8.68 (2 H, m), 8.15 (1 H, d, J=9.8 Hz), 7.94 (1 H, d, J=9.8 Hz), 5.46 (1 H, qt), 4.33 (2 H, q, J=7.1 Hz), 4.11 (2 H, s), 3.98 (4 H, br. s.), 3.46 (4 H, t, J=5.1 Hz), 2.45-2.59 (2 H, m), 2.13-2.31 (4H, m), 1.84-1.96 (2 H, m), 1.34 (3 H, t, J=7.2 Hz). LCMS-ESI (POS), M/Z, M+1: Found 502.3.
Reaction SMILES: C([NH:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][S:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:19])[CH3:12])(OC(C)(C)C)=O.Cl>C1COCC1.O1CCOCC1>[NH2:8][CH2:9][CH2:10][N:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][CH2:21][CH2:22][S:23][C:24]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:19])[CH3:12]
Reactant: CN(CCCCCC(=O)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN(CCN)CCCCCC(=O)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Boc-NH—(CH2)2—N(CH3)—(CH2)5—CONH—(CH2)2-STrt (62.8 mg, 0.11 mmol) was dissolved in THF (6 ml) and HCl in dioxane (130 μl, 4 M solution) was added. The reaction mixture was stirred for 12 h at RT. 200 μl HCl in dioxane was added and the solvent was removed in vacuo. The residue was purified by RP-HPLC to give H2N—(CH2)2—N(CH3)—(CH2)5—CONH—(CH2)2-STrt and not consumed starting material Boc-NH—(CH2)2—N(CH3)—(CH2)5—CONH—(CH2)2-STrt.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([C@H:27]2[C@@H:36]([C:37]([OH:39])=O)[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29](=[O:40])[N:28]2[CH3:41])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1>[CH2:5]([O:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:16]2[C:37](=[O:39])[C:36]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29](=[O:40])[N:28]([CH3:41])[C:27]=3[C:15]=2[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN1C(=O)c2ccccc2[C@H](C(=O)O)[C@@H]1c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: Cn1c2c(c3ccccc3c1=O)C(=O)c1cc(OCc3ccccc3)c(OCc3ccccc3)cc1-2
Reaction time: 0.5 h
Yield: 14.1 %

Procedure:
Thionyl chloride (8.1 mL) was added with stirring to the cis acid 12g (0.7 g, 2.1 mmol). The result was a yellowish-brown mixture that became orange within 15 min and after 30 min was red. After 4 h, the reaction mixture was diluted with benzene (25 mL) and evaporated to dryness. The brownish-red solid was recrystallized from methanol and passed through a short column (SiO2), eluting with chloroform, to give a brown solid (0.14 g, 24%): MP 198-200° C.; 1H NMR (DMSO-d6) δ8.43 (d, J=8.0 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 7.39 (m, 13H), 5.34 (s, 1H), 5.29 (s, 1H), 3.93 (s, 1H); CIMS m/z (relative intensity) 474 (MH+, 100). Anal. Calcd for C31H23NO4: C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=O)[C:19](=[O:22])[C:18]=2[O:23]CC)=[CH:4][CH:3]=1.[NH2:26][C@@H:27]([CH2:29][CH3:30])[CH3:28]>C1COCC1>[C@H:27]([NH:26][C:20]1[C:19](=[O:22])[C:18](=[O:23])[C:17]=1[NH:16][C:5]1[C:6]([OH:15])=[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])[C:2]([Cl:1])=[CH:3][CH:4]=1)([CH2:29][CH3:30])[CH3:28]
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Reactant: CC[C@@H](C)N
Solvent: C1CCOC1
Product: CC[C@@H](C)Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Temperature: 50 °C

Procedure:
To a stirred solution of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (1 g, 2.56 mmol) in THF (20 ml) was added (R)-(−)-2-aminobutane (0.52 ml, 5.12 mmol). The reaction mixture was heated at 50° C. for 7 hours. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. The EtOAc solution was washed with 1M HCl (aq) and brine. The EtOAc solution was dried (MgSO4) and concentrated in vacuo. The residue was crystallized from toluene to give a solid; [M+H]+ 418.2. 1H NMR (DMSO) 0.9 (3H, t, CH3), 1.2 (3H, d, CH3), 1.5 (2H, m), 3.0 (3H, s, CH3), 3.6 (3H, s, CH3), 4.0 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.3 (1H, d), 9.4 (1H, s), 10.1 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:19])[C:3]=1[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([CH3:31])=[CH2:30])[CH:23]=1)O>CCO.CC(O)=O.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][Si:9]([CH:10]([CH3:12])[CH3:11])([CH:13]([CH3:15])[CH3:14])[CH:16]([CH3:18])[CH3:17])[CH:5]=[C:4]([CH3:19])[C:3]=1[CH2:20][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH:29]([CH3:31])[CH3:30])[CH:23]=1
Reactant: C=C(C)c1cc(C(O)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)ccc1F
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1Cc1ccc(F)c(C(C)C)c1

Procedure:
A solution of 1-(2,6-dimethyl-4-triisopropylsilanyloxyphenyl)-1-(4′-fluoro-3′-isopropenylphenyl)methanol (1.2 g, 2.71 mmol) and Pd/C (0.1 g, 10%) in EtOH/HOAc (9:1, 10 mL) was stirred under a H2 atmosphere for 16 h. The reaction mixture was filtrated through a plug of Celite and concentrated to afford the crude 3,5-dimethyl-4-(4′-fluoro-3′-iso-propylbenzyl)triisopropylsilanoxybenzene that was used for the next step without further purification.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[C@@H:3]([CH3:5])[OH:4].FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Compound 1 from previous step (27.5 g, 65.084 mmol) was dissolved in dichloromethane (215 mL) and the solution was treated with trifluoroacetic acid (149.9 g) which was added within 5 minutes. The reaction mixture was stirred for additional 25 minutes at room temperature to complete the reaction. For work-up, the solution was diluted with dichloromethane (300 mL) and was treated slowly with half saturated aq. Na2CO3-solution (660 mL). The biphasic mixture was intensively stirred for 15 minutes and the phases were separated. The aqueous phase was extracted with dichloromethane (300 mL) and the organic phases were combined. The combined organic phase was washed with water (300 mL) and the solvent was evaporated under reduced pressure at 40-45° C. to obtain 21.72 g crude product, Thr-Leu-OBzl (100% crude yield) as foam. The crude product (compound 2) was sufficiently pure to use for the next step without additional purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8](O)=[O:9])[C:4](=[O:11])[O:3]1.C(N(S(F)(F)[F:19])CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([F:19])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Solvent: ClCCl
Product: CC1(C)OC(=O)[C@@H](CC(=O)F)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (100 mg, 0.6 mmol) in CH2Cl2 (2 mL) was added (diethylamino)sulfur trifluoride (DAST) (111 mg, 0.7 mmol) at 0° C. and the resulting solution was stirred at 0° C. for 1 h. More CH2Cl2 (10 mL) was added. The whole mixture was washed with cold water twice, dried over anhydrous Na2SO4, filtered and evaporated in vacuo to afford the title compound. 1H NMR (400 MHz, CDCl3): δ4.68-4.71 (m, 1H), 3.11-3.17 (m, 1H), 2.98-3.04 (m, 1H), 1.64 (s, 3H), 1.58 (s, 3H).
Reaction SMILES: Br[CH:2]([C:5](=O)[C:6]([CH3:9])([CH3:8])[CH3:7])[C:3]#[N:4].[NH2:11][C:12]([NH2:14])=[S:13]>>[NH2:14][C:12]1[S:13][C:2]([C:3]#[N:4])=[C:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[N:11]=1
Reactant: NC(N)=S
Reactant: CC(C)(C)C(=O)C(Br)C#N
Product: CC(C)(C)c1nc(N)sc1C#N
Yield: 66.3 %

Procedure:
Using α-bromo-pivaloylacetonitrile and thiourea as the raw materials, the same operation as the Example 181(1) gave the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.C1C[O:16][CH2:15][CH2:14]1>C(OCC)C.O.[Zn+2].[Br-].[Br-].[Cl-].[Cl-].[Zn+2]>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:14][CH:15]=[O:16]
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [Br-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCOCC
Product: O=CC=Cc1ccccc1C(F)(F)F
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of 2-trifluoromethylbenzaldehyde (260 mg) in 5 mL THF was added 200 mg of ZnBr2. With stirring, 400 mg of α,α-bis(trimethylsilyl)-t-butylacetaldimine (7) was added, and stirring was continued overnight. The solution was cooled to 10° C., then hydrolyzed by the addition of a solution of ZnCl2 (200 mg) in diethyl ether/water (3 mL each), followed by stirring at room temperature for 1 h. The solids were removed by filtration through Celite and the filtrate extracted with diethyl ether (2×). The combined ether extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to provide the crude title compound as an oil. The product was purified via silica gel column chromatography to afford a white powder (130 mg): 1H NMR (CDCl3) δ 6.70 (dd, 1H, J=9.6, 4.5 Hz), 7.55 (t, 1H, J=4.5 Hz), 7.63 (t, 1H, J=4.5 Hz), 7.76 (d, 2H, J=4.8 Hz), 7.88 (br d, 1H, J=9.6 Hz), 9.77 (d, 1H, J=4.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[Cl:11].CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>CC(O)=O.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:19][CH:18]=[CH:17]2)=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(-n2cccc2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-amino-2-chlorobenzoic acid methyl ester (0.46 g) and 2,5-dimethoxytetrahydrofuran (0.33 mL) in AcOH (16 mL) was heated under reflux for 2 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The extract was washed with satd. NaHCO3 and brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/EtOAc 5/1) to yield 0.48 g of 2-chloro-4-(1-pyrrolyl)benzoic acid methyl ester. ESMS: m/z 236 (MH+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1CCCCC1>[O:11]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:6])[N:12]1[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1CCCCC1
Product: CCOC(=O)C(C)N1C(=O)c2ccccc2C1=O
Yield: 89 %

Procedure:
20.87 g (0.141 mol) of phthalic anhydride together with 16.5 g (0.141 mol) of ethyl aminopropionate in an open round-bottom flask at 120° C. for 5 h. 300 ml of cyclohexane are added, and the mixture is heated to reflux. The hot cyclohexane solution is decanted off from the remaining oil and completely concentrated. A slowly solidifying viscous oil is obtained (31 g, 89% yield).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH2:22].[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:22][CH2:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1ccccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.215 ml 2-(2-chloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 465 mg light yellow oil (97%). MS (ISP) 302.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:21]=[C:12]2[CH:13]=[CH:14][C:15]([C:17](OC)=[O:18])=[CH:16][N:11]2[N:10]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[N:21]=[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][OH:18])=[CH:16][N:11]2[N:10]=1
Reactant: COC(=O)c1ccc2nc(-c3c(C)cccc3C)nn2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1cccc(C)c1-c1nc2ccc(CO)cn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a solution of methyl 2-(2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate (0.35 g, 1.24 mmol) in DCM (20 mL), DiBAL-H (1 M solution in toluene, 4.98 mL, 4.98 mmol) is added drop wise at 0° C. The reaction mixture is warmed to room temperature and stirred for 2 hours. The reaction is quenched with aqueous NH4Cl solution and extracted with EtOAc (4×50 mL). The combined extracts are dried over sodium sulphate, filtered, and concentrated. The crude material is purified by silica gel chromatography (combiflash) eluting with 50% EtOAc in hexanes. The product is concentrated to give the title compound as a transparent liquid (0.18 g, 57%). LCMS m/z 254 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:3]1.[O:18]1[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19]1>>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[S:11][C:10]([NH:12][C:23]([C:20]3[CH:21]=[CH:22][O:18][CH:19]=3)=[O:24])=[N:9][C:8]=2[C:13]2[SH:14]=[CH:15][CH2:16][CH:17]=2)=[N:3]1
Reactant: Cn1nnc(-c2sc(N)nc2-c2cccs2)n1
Reactant: O=C(Cl)c1ccoc1
Product: Cn1nnc(-c2sc(NC(=O)c3ccoc3)nc2C2=CCC=[SH]2)n1

Procedure:
Prepared from 5-(2-methyl-2H-tetrazol-5-yl)-4-thiophen-2-yl-thiazol-2-ylamine and furan-3-carbonyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[NH:33]1[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][OH:40])[CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:40][CH2:39][CH:35]1[CH2:36][CH2:37][CH2:38][N:33]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:31])([F:32])[F:30])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:34]1
Reactant: OCC1CCCNC1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCCC(CO)C3)ccc21
Yield: 79.4 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(3-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]amide (72 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (75 mg), 3-piperidinemethanol (20 mg), HBTU (73 mg), and DIEA (42 uL), with a modification of General Procedure F where DIEA was slowly added to the reaction mixture as the last reagent. LC/MS: m/z 563.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.41 (bs, 1H), 8.53-8.40 (m, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.87-7.60 (m, 2H), 7.50 (d, 1H), 7.36 (d, 1H), 4.73-4.50 (m, 1H), 4.43-4.01 (m, 3H), 3.82 (d, 1H), 3.67 (s, 3H), 3.31-3.16 (m, 2H), 3.06-2.87 (m, 1H), 2.86-2.34 (m, 1H), 1.82-1.41 (m, 3H), 1.40-1.10 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:29][CH2:28][C:27]([NH:33][CH3:34])([C:30](N)=[O:31])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1.[CH3:35][OH:36]>>[CH3:35][O:36][C:30]([C:27]1([NH:33][CH3:34])[CH2:28][CH2:29][N:24]([C:13]2[N:12]=[CH:11][N:10]=[C:9]3[C:14]=2[N:15]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[N:8]3[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:25][CH2:26]1)=[O:31]
Reactant: CNC1(C(N)=O)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reactant: CO
Product: CNC1(C(=O)OC)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 60 °C

Procedure:
1-[9-(4-Chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-methylaminopiperidine-4-carboxylic acid amide 7A-87 (Example 164; 53 mg, 0.093 mmol) and Amberlyst 15 (0.8 g) in methanol (5 ml) was sealed in a tube and then heated to 60° C. for 20 h. The resin was removed by filtration and washed with 2:1 methanol/triethylamine and then 10% NH4OH in methanol. The combined organic layers were concentrated and then purified on a Biotage™ Flash 12S column using 0–2–4% methanol in methylene chloride as eluant to give title compound 21A-1 as a light brown solid (26 mg, 55%): +ESI MS (M+1) 511.1; 1H NMR (400 MHz, CD2Cl2) δ 8.28 (s, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.44–7.32 (m, 5H), 7.21 (d, J=8.7 Hz, 2H), 5.55 (v br s, 1H), 4.65 (v br s, 2H), 4.13 (v br s, 2H), 3.71 (s, 3H), 2.28 (s, 3H), 2.07 (ddd, J=13.7, 9.6, 3.7 Hz, 2H), 1.79 (dt, J=13.7, 3.9 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([N-]C(C)C)(C)C.[Li+].[B:17](OC)([O:20]C)[O:18]C>O>[F:1][C:2]1[C:3]([F:8])=[CH:4][CH:5]=[CH:6][C:7]=1[B:17]([OH:20])[OH:18]
Reactant: Fc1ccccc1F
Reactant: COB(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Product: OB(O)c1cccc(F)c1F
Temperature: 25 °C

Procedure:
10 g of trimeric 2,3-difluorophenylboronic anhydride are prepared according to Example 1 from 1,2-difluorobenzene, lithium diisopropylamide and trimethyl borate. The anhydride is dissolved in 200 ml of boiling water. The hot solution is filtered, and the filtrate is allowed to cool slowly to room temperature. The solid is separated off and dried to give 2,3-difluorophenylboronic acid having a melting point of 89° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[NH:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@H:10]([CH3:18])[N:9]2[C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Br)cc2)N1
Solvent: ClCCl
Product: C[C@H]1Cc2ccccc2[C@@H](c2ccc(Br)cc2)N1C(=O)Nc1ccc(F)cc1
Reaction time: 4 h

Procedure:
To a solution of (1R,3S)-1-(4-bromophenyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline (48.5 mg, 160 μmol) in CH2Cl2 (1.0 mL) at RT was added 1-fluoro-4-isocyanatobenzene (28.9 μL, 249 μmol). The reaction was stirred 4 h and directly purified by reverse phase HPLC to give (1R,3S)-1-(4-bromophenyl)-N-(4-fluorophenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide as a white solid. MS (ESI pos. ion) m/z: 439, 441 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1.[OH:18]OS([O-])=O.[K+]>ClCCl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:17][C:12]3=[N:13][CH:14]=[CH:15][N:16]=[C:11]3[CH:10]=2)=[CH:7][CH:8]=1)=[O:18]
Reactant: CSc1ccc(-c2cc3nccnc3[nH]2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2cc3nccnc3[nH]2)cc1

Procedure:
A stirred suspension of 6-(4-methylthiophenyl)-5H-pyrrolo[2,3-b]pyrazine [0.2362 g, Example 1(ah)] in dichloromethane (20 mL) was treated with TBA oxone (2.545 g). After 2 hours the resulting orange solution was evaporated. The residue was subjected to flash chromatography eluting with a mixture of methanol and dichloromethane (1:1, v/v) to give the title compound as a white solid. MS: 258 (MH+). 1H NMR [(CD3)2SO]: δ 12.66 (1H, s); 8.41 (1H, s); 8.24 (3H, m); 7.82 (2H, d, J=8.7 Hz); 7.33 (1H, s); 2.81 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([OH:20])[C:10]([C@@H:12]([OH:19])[C@H:13]([OH:18])[C:14]([CH2:16][OH:17])=[O:15])=O.[BH3-]C#N.[Na+]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C@:14]3([CH2:16][OH:17])[O:15][C@:10]2([C@H:12]([C@@H:13]3[OH:18])[OH:19])[CH2:9][OH:20])=[CH:4][CH:3]=1
Reactant: O=C(CO)[C@@H](O)[C@H](O)C(=O)CO
Reactant: Nc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: OC[C@]12O[C@](CO)([C@@H](O)[C@@H]1O)N2c1ccc(F)cc1
Reaction time: 8 h
Yield: 6.7 %

Procedure:
A solution of 4-fluoroaniline (30 g, 0.27 mol) and 15.46 mL of HOAC in 100 mL of MEOH was added to 5-keto-D-fructose (57.7 g, 0.324 mol) in 350 mL of MEOH. To this suspension was added 32 g of NaCNBH3 (0.5 mol). The tan mixture was heated at reflux. After reacting overnight, the solution was cooled, the MeOH was largely evaporated and the residue was dissolved in ca. 200 ml. of water and treated with ca. 500 mL of Dowex 50W-X8 cation exchange resin. After stirring for 2 h, the resin and solution were added to a column with a bed of 150 mL more resin, and the supernatant was eluted. The resin was then washed with another ca. 500 mL of water. The column was then eluted with 1N NH4OH, and the water of the fractions containing the products was removed under reduced pressure. The residue was purified on two Waters Prep 500.HPLC columns (hexane/iPrOH/NH4OH, 65:34:1) to give fractions highly enriched in all three stereoisomers. The fastest eluting material was recrystallized from iPrOH/hexane to give 4.9 g white needles (7%) of the mannitol isomer (Formula XVII). Both C-13 and H-1 NMR are consistent with the assigned structure. M.p. 198° C. (browning), 205°-207° C.; (melting with decomposition).