Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH2:18]([NH:25][C:26]1[S:27][CH:28]=[C:29]([CH2:31][C:32](O)=[O:33])[N:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26]1[S:27][CH:28]=[C:29]([CH2:31][C:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:6][CH:7]=2)=[O:33])[N:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: O=C(O)Cc1csc(NCc2ccccc2)n1
Product: CC(C)(C)OC(=O)NCCc1ccc(NC(=O)Cc2csc(NCc3ccccc3)n2)cc1

Procedure:
960 mg of t-butyl 2-(4-aminophenyl)ethylcarbamate and (2-benzylaminothiazol-4-yl)acetic acid were subjected to an amidation reaction to obtain 500 mg of t-butyl [2-[4-[2-(2-benzylaminothiazol-4-yl)acetylamino]phenyl]ethyl]carbamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH:5]([NH2:7])[CH3:6].N1C=CC=CC=1.Cl[C:18]([O:20][CH3:21])=[O:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:7][C:18](=[O:19])[O:20][CH3:21])[CH3:6])[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cl
Reactant: CC(N)c1cccc(Br)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)NC(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
To a solution of 23.8 g of 3-bromo-α-methylbenzylamine in toluene (120 ml), 14.1 g of pyridine was added at room temperature. To this solution, 18.6 g of methyl chloroformate was dropwise added under cooling with ice, followed by stirring at room temperature for 2 hours. The reaction solution was poured into a citric acid aqueous solution and extracted with ethyl acetate. The organic layer was washed with a citric acid aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 10.5 g of methyl N-[1-(3-bromophenyl)ethyl]carbamate as a colorless transparent viscous liquid.
Reaction SMILES: CS[C:3](=[N:12][C:13]#[N:14])[NH:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Br:11])[CH:10]=1.[C:15]1([S:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOCC>N1C=CC=CC=1>[Br:11][C:9]1[CH:10]=[C:5]([NH:4][C:3]([NH:12][C:13]#[N:14])=[N:24][CH2:23][CH2:22][S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[N:7][CH:8]=1
Reactant: NCCSc1ccccc1
Reactant: CSC(=NC#N)Nc1cncc(Br)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: N#CNC(=NCCSc1ccccc1)Nc1cncc(Br)c1

Procedure:
S-Methyl N-(5-bromo-3-pyridyl)-N'-cyanoisothiourea (650 mg) and 2-phenylthioethylamine (740 mg) in pyridine (0.5 ml) were heated to 50° C. for 5 hours. To the resulting clear solution was added ether (10 ml), and the desired pure compound was collected by filtration and washed with ether.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([Br:15])[C:12]([CH2:16]Br)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=O)C.C(N(CC)CC)C.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CC(C)=O.C(OCC)(=O)C>[Br:15][C:13]1[C:12]([CH2:16][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:4])[CH:14]=1
Reactant: COC(=O)c1cc(CBr)c(Br)cc1OC(C)=O
Reactant: C1COCCN1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(CN2CCOCC2)c(Br)cc1O
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(acetyloxy)-4-bromo-5-(bromomethyl)benzoate (may be prepared as described in Description 16; 741 mg, 2.03 mmol) in acetone (5 ml) was added triethylamine (0.56 ml, 4.05 mmol) and morpholine (0.23 ml, 2.63 mmol). The mixture was stirred for 1 hour, then the solvent was removed in vacuo to give a residue. The residue was redissolved in ethyl acetate (10 ml) and washed with water (10 ml). The organic layer was dried (MgSO4) and the solvent removed in vacuo to give oil. Purification by column chromatography (SiO2, 3:1-1:1 cyclohexane/ethyl acetate) gave the product as oil. 580 mg.
Reaction SMILES: Br[Si:2]([CH3:5])([CH3:4])[CH3:3].C[O:7][P:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:11])[O:9]C>>[CH3:3][Si:2]([O:7][P:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:11])[O:9][Si:2]([CH3:5])([CH3:4])[CH3:3])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)Br
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Product: C[Si](C)(C)OP(=O)(Cc1ccc(F)cc1)O[Si](C)(C)C
Temperature: 0 °C

Procedure:
Bromotrimethylsilane (6.0 mL, 45.4 mmol) was added dropwise to (4-fluoro-benzyl)-phosphonic acid dimethyl ester (4.57 g, 20.95 mmol) and stirred in a reaction flask chilled to 0° C. The resulting solution was allowed to warm to ambient temperature and stirred for an additional hour, then concentrated by rotary evaporation to remove volatiles yielding crude (4-fluoro-benzyl) phosphonic acid bis(trimethylsilyl) ester which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=O)[C:12]([OH:14])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.CC1C=CC(S(NN)(=O)=O)=CC=1.C1COCC1.[BH4-].[Na+]>CO.CCO.O.Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)c1c[nH]c2cc(Br)ccc12
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)Cc1c[nH]c2cc(Br)ccc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 2.4 %

Procedure:
Step E (2): To a solution of 2-(6-bromo-1H-indol-3-yl)-2-oxoacetic acid (780 mg, 2.9 mmol) from Step E (1) in MeOH/EtOH (20.0 mL/5.0 mL) was added 4-methylbenzenesulfonohydrazide (1.1 g, 5.8 mmol). The mixture was heated at reflux for 5 h. The solvent was removed. 15 mL of THF and NaBH4 (658 mg, 17.4 mmol) were then added. The reaction mixture was stirred at 50° C. overnight and then at an additional 6 h at 80° C. The reaction mixture was diluted with H2O and 1.0 N HCl and washed with EtOAc. The aqueous layer was concentrated and the residue was purified using reverse phase Prep-HPLC to give 18 mg of the title compound. MS (ESI) (M−H)+=251.98/254.01. 1H-NMR (500 MHz, CD3OD) δ 7.52 (s, 1 H), 7.46 (d, J=8.55 Hz, 1 H), 7.19 (s, 1 H), 7.14 (dd, J=8.55, 1.53 Hz, 1 H), 3.73 (s, 2 H).
Reaction SMILES: [CH2:1]([N:8](C)[CH:9]1[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][N:11]2[C:17](=[O:26])[C:18]([OH:25])=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=[C:10]12)C1C=CC=CC=1.Cl>CO.[Pd]>[OH:25][C:18]1[C:17](=[O:26])[N:11]2[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][CH:9]([NH:8][CH3:1])[C:10]2=[N:20][C:19]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCN(C)CC2N(C)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC1CN(C)CCn2c1nc(C(=O)OC)c(O)c2=O

Procedure:
Compound of Step 1 was dissolved in MeOH and 6 N HCl (2.5 eq.) and stirred overnight under an H2 atmosphere in the presence of 10% Pd/C. The catalyst was then filtered off through celite, and the filtrate was concentrated under reduced pressure and triturated with diethyl ether to yield methyl 3-hydroxy-8-methyl-10-(methylamino)-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-d][1,4]diazepine-2-carboxylate as a yellow solid. MS (ES) C12H18N4O4 requires 282. Found: 283 (M+H+). The crude product was taken in dichloromethane and treated with triethylamine (2.5 eq.) and methyl chloro(oxo)acetate (1.2 eq.). After stirring one hour at room temperature, solvent was removed under reduced pressure and residue was taken in methanol and treated with an excess of dimethyl amine (2 M solution in methanol) at room temperature overnight. Volatiles were evaporated under reduced pressure to the title compound. MS (ES) C16H23N5O6 requires 381. Found: 382 (M+H+).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[OH:16][C:17]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][C:19](=O)[C:18]=1[N+:28]([O-:30])=[O:29].C(N(CC)CC)C>C(Cl)Cl>[N+:28]([C:18]1[C:19]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[N:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[C:17]=1[O:16][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:8])=[O:6])([O-:30])=[O:29]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1[nH]c2c(c(O)c1[N+](=O)[O-])CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)nc2c(c1OS(=O)(=O)C(F)(F)F)CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Trifluoromethanesulfonic anhydride (8.0 mL, 47 mmole) was added via a syringe to a cooled (0° C.) homogeneous mixture containing 5,6,7,8-tetrahydro-4-hydroxy-3-nitro-2 (1H) -quinolinone (4.0 g, 19 mmol) and triethylamine (6.6 mL, 47 mmole) in methylene chloride (200 mL). The reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was filtered through a layer of silica gel and the gel eluted with methylene chloride. The organic phase was evaporated under vacuum to provide 8.4 g of the desired product as a yellow oil.
Reaction SMILES: [NH3:1].CO.[NH2:4][C:5]1[C:6]2[C:31]([CH3:37])([C:32]([O:34]CC)=O)[C:30](=[O:38])[NH:29][C:7]=2[N:8]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[N:12]=2)[N:10]=1>>[NH2:4][C:5]1[C:6]2[C:31]([CH3:37])([C:32]([NH2:1])=[O:34])[C:30](=[O:38])[NH:29][C:7]=2[N:8]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][C:22]([F:27])([F:28])[C:23]([F:26])([F:25])[F:24])[N:12]=2)[N:10]=1
Reactant: CCOC(=O)C1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Reactant: N
Solvent: CO
Product: CC1(C(N)=O)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21

Procedure:
A 2 M solution of ammonia in MeOH (28.6 mL, 57.3 mmol) was added to ethyl 4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate, as prepared by the procedure described in Example 158, (220 mg, 0.441 mmol) and the resultant mixture heated at 50° C. for 16 hours. The reaction mixture was concentrated in vacuo and the residue purified by silica gel column chromatography using a DCM/MeOH (with 0.5% NH4OH) gradient. Chiral separation by SFC using a Chiralpak AD column provided both enantiomers of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 11.27 (1H, s), 9.02 (1H, dd, J=8.06, 1.62 Hz), 8.64 (1H, dd, J=4.50, 1.63 Hz), 7.45 (1H, s), 7.38 (1H, dd, J=8.07, 4.49 Hz), 7.19 (1H, s), 6.82 (2H, s), 4.88 (2H, t, J=6.80 Hz), 3.04-2.90 (2H, m), 1.57 (3H, s). m/z=471.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.Br[C:11]1[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=[C:15]([Br:17])[CH:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:17][C:15]1[CH:16]=[C:11]([NH:8][C:6]2[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([CH3:1])[N:7]=2)[C:12](=[O:19])[N:13]([CH3:18])[CH:14]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cc1cc(N)nc(C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Br)cn(C)c2=O)nc(C)n1
Temperature: 90 °C
Yield: 70.1 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (150 mL), 2,6-dimethylpyrimidin-4-amine (2.5 g, 20.3 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (5.4 g, 20.3 mmol), Pd2(dba)3 (1.86 mg, 2.03 mmol), XantPhos (2.3 g, 4.06 mmol), and cesium carbonate (13.2 g, 40.6 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 2.5 h. After this time the reaction was filtered and the filtrate was evaporated in vacuo. The resulting residue was recrystallized from ethyl acetate to afford 173a as a yellow solid (4.4 g, 40%). MS-ESI: [M+H]+ 309.0.
Reaction SMILES: Cl.Cl[C:3]1[NH:4][C:5](=[O:14])[C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][OH:22].CC([O-])(C)C.[K+]>CS(C)=O>[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][O:22][C:3]1[NH:4][C:5](=[O:14])[C:6]2[C:12]([CH3:13])=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1
Reactant: OCCCOc1ccccc1Cl
Reactant: Cc1ccnc2nc(Cl)[nH]c(=O)c12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccnc2nc(OCCCOc3ccccc3Cl)[nH]c(=O)c12

Procedure:
In analogy to the procedure described in example 97.3, 2-chloro-5-methyl-3H-pyrido[2,3-d]pyrimidin-4-one hydrochloride was reacted with 3-(2-chloro-phenoxy)-propan-1-ol [60222-56-2] in DMSO in the presence of molecular sieves and potassium tert-butylate to give the title compound as off-white crystals. MS: m/e=346.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[NH2:29]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:29][C:28]3[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:26]([CH3:25])[CH:27]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COc1ccc(N)cc1C
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Solvent: CCOCC
Product: COc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc1C
Temperature: 165 °C

Procedure:
A mixture of 0.113 g (0.29 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.40 g (2.90 mmol) of 3-methyl-4-methoxyaniline was heated, with stirring, in a 165° C. oil bath. The resulting solution was heated for 5 minutes and cooled to room temperature. Ether (1 mL) was added. The crystals that developed were filtered and washed with 2 mL of ether; wt 0.109 g. The solid was purified to remove dark colors by silica gel chromatography, eluting with chloroform and then ethyl acetate. The ethyl acetate eluent was concentrated to 3 mL volume. On cooling, pure crystals of product separated; wt 0.060 g; mp 218°-220° C.
Reaction SMILES: O.O.[Na+:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1.[OH-].[Na+].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O.[Cl-].[Na+].O>[Na+:3].[CH3:17][S:18]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([O-:14])(=[O:12])=[O:13])=[CH:7][CH:6]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Oc1ccc(S(=O)(=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
4-Hydroxybenzenesulfonic acid sodium salt dihydrate (11.6 g, 50.0 mmol) and sodium hydroxide (2.00 g, 50.0 mmol) were dissolved in distilled water (50 mL) and the solution cooled to 0° C. Methane sulfonyl chloride (4.25 mL, 55.0 mmol) was added dropwise with stirring and the mixture then allowed to warm to room temp. and left for 2 h. Brine (20 mL) was added and the solution left to stand for 1 h with the formation of white crystalline solid. The solids were filtered, recrystallised (brine), and dried under vacuum to give the title compound as a white crystalline solid (7.81 g, 57%),
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[S:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][C:2]2[CH:3]=[C:4]([C:11]3[N:12]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[S:14][CH:15]=3)[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[O:31])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccc([N+](=O)[O-])c(N)c2)cs1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc(-c3csc(NC(=O)OC(C)(C)C)n3)ccc2[N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of compound 150 (390 mg, 1.28 mmol) in pyridine was added 4-methoxybenzoyl chloride (181 mg, 1.06 mmol) and 4-(N,N-dimethylamino)pyridine (13 mg, 0.11 mmol). The mixture was stirred for 16 h and partitioned between EtOAc and H2O. The organic layer was washed with brine and some compound was collected by filtration. The filtrate was dried over MgSO4, filtered and concentrated in vacuo and then crystallized from a mixture of EtOAc/Hexanes. The two crops were combined affording the title compound 151 (358 mg, 72% yield). 1H NMR: (400 MHz, CD3OD) δ(ppm): 11.73 (s, 1H), 10.71 (s, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.95 (d, J=9.0 Hz, 2H), 7.86 (d, J=0.8 Hz, 1H), 7.83 (dd, J=8.6, 2.0 Hz, 1H), 7.10 (d, J=9.0 Hz, 2H), 3.85 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH:11][S:12]([C:15]1[C:20]2=[N:21][S:22][N:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13].O[Li].O.Cl>C1COCC1.O>[N:23]1[S:22][N:21]=[C:20]2[C:15]([S:12]([NH:11][C:5]3[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=3[C:3]([OH:24])=[O:2])(=[O:13])=[O:14])=[CH:16][CH:17]=[CH:18][C:19]=12
Reactant: COC(=O)c1ccc(C)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)O)c(NS(=O)(=O)c2cccc3nsnc23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
A solution of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-methylbenzoic acid methyl ester (1.22 g, 3.36 mmol) in 3:1 THF/water (10 mL) was treated with LiOH.H2O (1.41 g, 33.6 mmol) and was stirred at rt for 16 h. The mixture was acidified with 1 N HCl, and the resulting precipitate was collected by filtration, washing with water. Drying in air provided the title acid as a tan solid (0.89 g, 2.5 mmol, 74%). 1H NMR (500 MHz, CDCl3): 11.16 (s, 1H), 8.38 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.84 (d, J=8.1, 1H), 7.71 (dd, J=8.8, 7.1, 1H), 7.56 (br s, 1H), 6.83 (br d, J=8.4, 1H), 2.32 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([N:16]=[N+]=[N-])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([NH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])C[C@H]1C(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](N)C[C@H]1C(=O)O
Yield: 67 %

Procedure:
The trans azido acid 8b (3.0 g., 11.7 mmol) was hydrogenated as for the synthesis of 6, to give 1.8 g (67% yield) after crystlalization from ethanol, m.p.=228°-229° C. (decomp.). 1H NMR (CDCl3) δ1.42/1.47 (2s, 9H), 2.29 (m, 1H), 2.45 (m, 1H), 3.58 (m, 1H), 3.80 (m, 1H), 3.99 (m, 1H), 4.24 (m, 1H). Anal. (C10H18N2O4.0.5H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:14]([N:15]([CH3:17])[CH3:16])=[CH:13][C:5]([CH:6](O)CS(C)(=O)=O)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].C[O-].[Na+].[NH:24]([CH2:31][CH2:32][C:33]#[N:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O>[NH:24]([CH:31]=[C:32]([CH2:6][C:5]1[CH:13]=[C:14]([N:15]([CH3:16])[CH3:17])[C:2]([Cl:1])=[C:3]([N:18]([CH3:19])[CH3:20])[CH:4]=1)[C:33]#[N:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#CCCNc1ccccc1
Reactant: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C)c1Cl

Procedure:
A mixture of 15.7 g. of 4-chloro-3,5-bis(dimethylamino)-α-[(methylsulfonyl)methyl]benzyl alcohol, 2.8 g. of sodium methylate and 7.1 g. of β-anilinopropionitrile in 31 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 5 hours at 50° C. The mixture was poured into 200 ml. of water, the precipitated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated in vacuo. By purification of the residue over aluminum oxide with benzene and recrystallization from ethyl actate/petroleum ether, there was obtained α-(anilinomethylene)-4-chloro-3,5-bis(dimethylamino)hydrocinnamonitrile, having a melting point of 168° C.
Reaction SMILES: [Br:1][C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[CH2:4][C:5]1[O:6][C:7]([CH3:38])=[C:8]([CH3:37])[C:9]=1[C:10]([C:12]1[CH:31]=[CH:30][C:15]([O:16][S:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22]([OH:29])[CH:21]=2)(=[O:19])=[O:18])=[C:14]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:13]=1)=[O:11].[I-].[Mg+2].[I-].[C:46](OC(=O)C)(=[O:48])[CH3:47]>CCOCC>[C:46]([O:29][C:22]1[CH:21]=[C:20]([S:17]([O:16][C:15]2[CH:30]=[CH:31][C:12]([C:10]([C:9]3[C:8]([CH3:37])=[C:7]([CH3:38])[O:6][C:5]=3[CH2:4][C:3]3[CH:39]=[CH:40][CH:41]=[CH:42][C:2]=3[Br:1])=[O:11])=[CH:13][C:14]=2[CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)(=[O:19])=[O:18])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25])(=[O:48])[CH3:47]
Reactant: Cc1oc(Cc2ccccc2Br)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Reactant: CC(=O)OC(C)=O
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(C(=O)c3c(Cc4ccccc4Br)oc(C)c3C)cc2C2CCCC2)ccc1C(=O)O
Yield: 25 %

Procedure:
The title compound was prepared according to the procedure in Example 22 using 4-{4-[2-(2-bromo-benzyl)-4,5-dimethyl-furan-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoic acid (0.318 g, 0.487 mmol), magnesium iodide (0.132 g, 0.475 mmol) and acetic anhydride (3.8 mL) in ether. Purification on 2% H3PO4 /MeOH treated silica gel, eluting with a 30% EtOAc/pet ether gave 0.083 g (25%) of the title compound as a solid, mp 79° C. 1H NMR (DMSO-d6) δ 1.27-1.33 (m, 2 H), 1.51-1.54 (m, 2 H), 1.63-1.73 (m, 4 H), 1.79 (s, 3 H), 2.17 (s, 3 H), 2.24 (s, 3 H), 2.93 (quintet, 1 H), 3.91 (s, 2 H), 7.13-7.17 (m, 2 H), 7.21 (d, 1 H), 7.30 (dt, 1 H), 7.51 (dd, 1 H), 7.55 (dd, 1 H), 7.60 (d, 1 H), 7.85 (d, 1 H), 7.90 (dd, 1 H), 8.14 (d, 1 H)13.8 (br s, 1 H). mass spectrum (-ESI) m/z 693/695 (M-H). Anal. Calcd. for C34H31BrO9S: C, 58.71; H, 4.49; N, 0.00. Found: C, 58.04; H, 4.52; N, 0.04.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCc3ccccc3)CC2)cc1

Procedure:
4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid ethyl ester (3.0 g, 6.9 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.0 g (72%); off white powder; mp 208° C.; MS: 404.5 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[C:10]=1[N+:17]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pt]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[C:10]=1[NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1OCc1ccccc1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1c(F)cc(F)cc1OCc1ccccc1

Procedure:
2-Benzyloxy-4,6-difluoronitrobenzene (1.0 g, 3.77 mmol) is reduced in EtOAc (18 mL) and 100 mg of 5% platinum on carbon under a hydrogen balloon for 6 h. The mixture is filtered through Celite and solvent removed under reduced pressure. The residue is purified by column chromatography to give a yellow liquid as the title compound.