Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:26])=[C:5]([C:23]([OH:25])=[O:24])[C@@H:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][NH2:13])=[O:9].[C:27](OC(=O)C)(=[O:29])[CH3:28]>O>[C:27]([NH:13][CH2:12][CH2:11][O:10][C:8]([C:7]1[C@H:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:23]([OH:25])=[O:24])=[C:4]([CH3:26])[NH:3][C:2]=1[CH3:1])=[O:9])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCCN)=C(C)N1
Solvent: O
Product: CC(=O)NCCOC(=O)C1=C(C)NC(C)=C(C(=O)O)[C@H]1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
That is, 10 mg of the (4R)-1,4-dihydro-2,6-dimethyl3-(2-aminoethyl) oxycarbonyl-4-(3-nitrophenyl)pyridine-5-carboxylic acid obtained in Example 28 was dissolved in 2 ml of deionized water and 0.2 ml of acetic anhydride was added to the solution while stirring at room temperature. After stirring for continuous 30 minutes, the reaction mixture was extracted 3 times with 5 ml each of ethyl acetate and washed with 10 ml of saturated saline. The ethyl acetate layer was adsorbed on a preparatory TLC plate, developed with chloroform/methanol (7:1) to elute fractions showing UV absorption at Rf 0.22. The eluate was evaporated to dryness to obtain 3.7 mg of (4R)-3-(2-acetamidoethyl) oxycarbonyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) pyridine-5-carboxylic acid. The optical purity of this substance was determined by HPLC(mobile phase: 0.35% isopropanol/0.1M phosphaste buffer solution (pH 4.4), flow rate: 0.8 ml/minute) using an otical resolution column: CHIRAL AGP (4 mm×100 mm) manufactured by Daicel Chemical Industries Ltd. As a result, it revealed that the optical purity of the 4R form was 100% and the retention time was 14.3 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.Cl.Cl.[F:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C@H:25]2[CH2:29][CH2:28][CH2:27][NH:26]2)[CH:24]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:18][C:19]1[CH:24]=[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[CH:22]=[N:21][CH:20]=1
Reactant: Fc1cncc([C@H]2CCCN2)c1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1cnn2ccc(N3CCCC3c3cncc(F)c3)nc12
Temperature: 95 °C
Yield: 68.4 %

Procedure:
Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B; 0.50 g, 2.22 mmol), (R)-3-fluoro-5-(pyrrolidin-2-yl)pyridine dihydrochloride (0.53 g, 2.22 mmol) and diisopropylethylamine (1.46 mL, 8.86 mmol) were combined in isopropanol (2 mL) and heated at 95° C. for 70 hours. The crude product was purified by reverse phase chromatography, eluting with 0-50% acetonitrile/water to yield the title compound (540 mg, 68.6% yield). MS (apci) m/z=356.0 (M+H).
Reaction SMILES: [F:1][CH:2]1[CH:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31]C)=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][NH:4][CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C@H:2]1[C@H:7]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]2[N:23]4[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][OH:31])=[CH:27][C:22]4=[N:21][CH:20]=2)[CH:15]=[CH:14]3)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(OC5CCNCC5F)c4n3)cnc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: OCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CCNC[C@H]5F)c4n3)cnc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
To a flask containing 8-(-3-fluoropiperidin-4-yloxy)-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinoline (Prepared according to Example 20; 0.062 g, 0.14 mmol) was added CH2Cl2 (14 mL) and the solution was cooled to −78° C. BBr3 (1.0M in CH2Cl2, 0.71 ml, 0.71 mmol) was added dropwise and the reaction stirred at −78° C. for 1 hour, then slowly warmed to 0° C. over 2.0 hours, then warmed to ambient temperature and stirred for 0.5 hours. The reaction was quenched by the addition of a saturated aqueous NaHCO3 solution (15 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 and the combined organic phases were washed with brine and dried over Na2SO4. The mixture was filtered and concentrated in vacuo and purified via column chromatography (6% NH4OH in MeOH/CH2Cl2, 2% to 20% linear gradient) to afford 0.015 g (0.25%) of the title compound as a solid. MS APCI (+) m/z 423.2 [M+H]+ detected.
Reaction SMILES: Br[C:2]1[C:3]([C:21]#[N:22])=[CH:4][C:5]([F:20])=[C:6]([NH:8][C@H:9]([CH2:13][C:14]2[CH:19]=[CH:18]C=CC=2)[C:10]([NH2:12])=[O:11])[CH:7]=1.Cl.[NH2:24][C:25]1[S:29][N:28]=[C:27]([CH3:30])[CH:26]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.O>[C:21]([C:3]1[C:2]([NH:24][C:25]2[S:29][N:28]=[C:27]([CH3:30])[CH:26]=2)=[CH:7][C:6]([NH:8][C@H:9]([CH2:13][CH:14]2[CH2:19][CH2:18]2)[C:10]([NH2:12])=[O:11])=[C:5]([F:20])[CH:4]=1)#[N:22]
Reactant: N#Cc1cc(F)c(N[C@H](Cc2ccccc2)C(N)=O)cc1Br
Reactant: Cc1cc(N)sn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(N[C@H](CC3CC3)C(N)=O)c(F)cc2C#N)sn1
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-phenylpropanamide (362 mg, 1.00 mmol), 5-amino-3-methylisothiazole hydrochloride (166 mg, 1.10 mmol), BINAP (70 mg, 0.112 mmol), Pd(OAc)2 (35 mg, 0.156 mmol) and K2CO3 (430 mg, 3.11 mmol) in dioxane (5 mL) was degassed with Ar, then was stirred at 120 C for 18 h. More Pd(OAc)2 (35 mg, 0.156 mmol) was added. The mixture was stirred at 120 C for another 18 h. Water and EtOAc were added. After being filtered, the filtrate was washed with water, dried over Na2SO4, concentrated in vacuo to give (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-3-cyclopropylpropanamide as a crude residue.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:10][O-:11].[Na+]>C1COCC1.CO>[C:4]1([CH:1]=[CH:2][C:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C[O-]
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Reaction of Aldehydes with Wang Resin-bound Acetophenones: Each packet of Acetophenone-Wang resin was transferred to a 250 mL PP bottle, to which a solution of NaOMe (51.2 mmol, 20 eq, 0.25 M) in 50% THF-MeOH (205 mL) and an aldehyde (51.2 mmol, 20 eq, 0.25 M) were added sequentially. After shaking at room temperature for 3 days, the packet was washed several times with MeOH (3×80 mL) and alternatively with DMF (80 mL) and MeOH (80 mL) for 3 cycles, followed by washes of DCM (2×80 mL) and MeOH (3×80 mL). The packet was air-dried overnight to afford a resin-bound Chalcone, that varied in color from yellow to dark red depending on the aldehyde used.
Reaction SMILES: B.CSC.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]([CH:23]3[CH2:28][CH2:27][N:26]([C:29]([C:31]4(O)[CH2:33][CH2:32]4)=[O:30])[CH2:25][CH2:24]3)=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1>C1COCC1>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14]([CH:23]3[CH2:28][CH2:27][N:26]([CH:29]([OH:30])[CH:31]4[CH2:33][CH2:32]4)[CH2:25][CH2:24]3)=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1
Reactant: O=C(N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1)C1(O)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OC(C1CC1)N1CCC(c2cc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Reaction time: 16 h
Yield: 23.1 %

Procedure:
Borane-methyl sulfide complex (1.68 mL, 2.0 M solution in THF) was added drop wise to stirred solution of the product of Step 1 (224 mg) in dry THF (5 mL) under nitrogen. After 16 h at room temperature, the solution was cooled, and excess borane was quenched with methanol. The solvent was evaporated to dryness, and the residue was dissolved in THF (5 mL). 2-(Dimethylamino)ethanol (0.67 mL) was added, and the reaction mixture was heated under reflux for 3 h, cooled, and evaporated to dryness. The residue was purified by preparative TLC (CH2Cl2—MeOH, 90:10) to give the title compound (50 mg). NMR (CD3OD): 0.54-0.59 (m, 2H, cyclopropyl),0.75-0.77 (m, 2H, cyclopropyl),1.85, 2.02, 2.32, 2.61 (4 m, 8H, piperidinyl),2.64-2.69 (m, 1H, CH),3.26-3.29 (d, 2H, CH2),6.20 (s, 1H, H-4),7.08-7.11 (m, 2H, H-2 & H-6 of 4-F-phenyl),7.24-7.26 (m, 2H, H-2 & H-6 of pyridinyl),7.33-7.37 (m, 2H, H-3 & H-5 of 4-F-phenyl),8.24-8.26 (m, 2H, H-3 & H-5 of pyridinyl)
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[NH:5][C:4]=2[CH:3]=1.[CH3:14][C:15]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][N:17](C(OC(C)(C)C)=O)[N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>CCOC(C)=O.O.COCCOC>[CH3:12][C:6]1([CH3:13])[NH:5][C:4]2[CH:3]=[C:2]([C:19]3[CH:18]=[N:17][NH:16][C:15]=3[CH3:14])[S:10][C:9]=2[C:8](=[O:11])[NH:7]1
Reactant: CC1(C)NC(=O)c2sc(Br)cc2N1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A mixture of 6-bromo-2,2-dimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (522 mg, 2 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.85 g, 6.00 mmol), cesium carbonate (3.26 g, 10.0 mmol), 1,2-dimethoxyethane (20 mL) and water (5 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (163 mg, 0.20 mmol) was added, and the mixture was purged with argon again. The mixture was refluxed for 2 h. Then, sodium carbonate (636 mg, 6.00 mmol) was added. After 30 min, 8 M NaOH (1.5 mL, 12 mmol) was added. After 3 h, the mixture was cooled to room temperature, and poured into water (100 mL) and EtOAc (200 mL). The insoluble materials were filtered off, and the organic layer was collected from the filtrate. This organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residual oil was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc), then triturated with EtOAc, and the precipitate was collected by filtration to afford the title compound (312 mg, 60%) as a pale yellow solid:
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[O:11]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1NCCc2ccccc21
Product: O=C1NCCc2ccc(S(=O)(=O)Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To Chlorosulfonic acid (30 mL) is added 3,4-Dihydro-2H-isoquinolin-1-one (5 g, 34 mmol) at 0° C. After stirring at rt during 1 h, the mixture is heated at 50° C. during 16 h, then it is poured carefully into an ice bath and stirred at 0° C. during 30 min. The precipitate is filtered and dried in oven at 60° C. to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[N+:22]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>O.C(O)C.[Fe]>[NH2:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[NH:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1NC1CCN(Cc2ccccc2)CC1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)cc1NC1CCN(Cc2ccccc2)CC1
Yield: 67.1 %

Procedure:
A mixture of 20.75 g of the compound obtained in step A) and 10 g of iron powder in 19 ml of water and 19 ml of ethanol is brought to the reflux point. A solution of 37.5 ml of concentrated hydrochloric acid in 25 ml of water and 25 ml of ethanol is added dropwise to this mixture and reflux is maintained for 1 hour 30 minutes. After cooling, the reaction mixture is poured onto ice and then treated with a saturated solution of NaHCO3 and extracted with AcOEt. The extract is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/MeOH mixture (92/8; v/v) as the eluent. 12.71 g of the expected product are obtained after crystallization from isopropyl ether. M.p.=108° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([O:14][CH3:20])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CO
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(OC)c(OC)c1

Procedure:
3,4-Dimethoxyphenylacetic acid (3 g, 0.0153 mol) was dissolved in methanol (50 ml) and, thereafter, conc. sulfuric acid (0.05 ml) was added to the resulting solution, followed by heating at the reflux temperature for 2 h. Thereafter, the solvent was evaporated and the residue was neutralized with an aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic extract was dried with sodium sulfate, followed by evaporation of the solvent and drying under vacuum to yield the oil compound methyl 3,4-dimethoxyphenylacetate (3.2 g) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH3:3].[NH2:20][C:21]1[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]([CH2:33][CH2:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=2)[CH:22]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([CH2:34][CH2:33][C:23]2[NH:24][N:25]=[C:21]([NH:20][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([N:7]4[CH2:6][CH2:5][N:4]([CH:2]([CH3:1])[CH3:3])[CH2:9][CH2:8]4)=[CH:19][CH:18]=3)[CH:22]=2)[CH:36]=[C:37]([O:43][CH3:44])[CH:38]=1
Reactant: COC(=O)c1ccc(N2CCN(C(C)C)CC2)cc1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C(C)C)CC4)cc3)n[nH]2)cc(OC)c1
Yield: 5.4 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(4-propan-2-ylpiperazin-1-yl)benzamide was prepared as for Example 94, but starting from methyl 4-(4-propan-2-yl-piperizin-1-yl)benzoate (263 mg, 0.84 mmol), tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (244 mg, 0.7 mmol) and 1M NaHMDS (1.13 ml, 1.13 mmol) in THF (5 ml). The crude product was purified by reverse phase prep. HPLC (basic) using a 38-58% gradient of acetonitrile in water containing 1% 0.880 ammonia. The clean fractions were taken and evaporated to afford the title compound as a white solid (18 mg, 5%); 1H NMR (399.9 MHz, DMSO-d6) δ 1.02 (6H, d), 2.55-2.61 (4H, m), 2.65-2.76 (1H, m), 2.89 (2H, s), 3.2-3.28 (4H, s), 3.31 (2H, s), 3.72 (6H, s), 6.33 (1H, t), 6.42 (2H, d), 6.45 (1H, s), 6.95 (2H, d), 7.90 (2H, d), 10.29 (1H, s), 12.07 (1H, s)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@@H:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:20]([O:19][C:17](=[O:18])[CH:13]([NH:12][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:14]([CH3:15])[CH3:16])([CH3:22])([CH3:21])[CH3:23]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(NS(=O)(=O)c1ccc(Br)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask was added 4-Bromo-benzenesulfonyl chloride (24.37 g, 95.4 mmol, 1 equiv), anhydrous methylene chloride (350 mL), and H-D-Val-OtBu (20 g, 95.4 mmol, 1 equiv.). The mixture was cool to 0° C. followed by the addition of Hunig's base (38.2 mL, 219 mmol, 2.3 equiv.). The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature and stirred overnight. Starting material was consumed as determined by TLC. The reaction mixture was then diluted with methylene chloride (200 mL) and washed with H2O (500 mL), brine (250 mL). The organic layer was dried over anhydrous MgSO4, evaporated under vacuum to yield 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid tert-butyl ester in quantitative yield (35.0 g).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[OH:7][CH:8]([C:19]1[S:33][C:22]2[C:23]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:24][N:25]([CH3:28])[C:26](=[O:27])[C:21]=2[CH:20]=1)[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>ClCCl>[CH3:28][N:25]1[C:26](=[O:27])[C:21]2[CH:20]=[C:19]([C:8]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][CH:10]=3)=[O:7])[S:33][C:22]=2[C:23]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:24]1
Reactant: CC(C)Cc1nn(C)c(=O)c2cc(C(O)c3cccc4ccccc34)sc12
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)Cc1nn(C)c(=O)c2cc(C(=O)c3cccc4ccccc34)sc12
Reaction time: 1 h
Yield: 35.2 %

Procedure:
Potassium permanganate (0.335 g) and 18 crown-6 (10 mg) were added to a solution of 2-[1-hydroxy-1-(1-naphthalenyl)methyl]-5-methyl-7-(2methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one (example 7, 0.40 g) in dichloromethane (30 ml) at room temperature. After 1 hour, further potassium permanganate (0.30 g) was added and stirring was continued for a further hour. The mixture was filtered, diluted with dichloromethane (70 ml), washed twice with water then with brine, then dried, filtered and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate:isohexane (1:2), to give the title compound (0.14 g). This was purified further by preparative normal-phase HPLC with gradient ethyl acetate/isohexane elution.
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:16])=[CH:11][N:10]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C.O.C(OCC)(=O)C>[CH2:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([OH:40])([C:32]([F:33])([F:34])[F:35])[C:36]([F:37])([F:38])[F:39])=[CH:29][CH:30]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][N:10]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)Nc1ccc(C(=O)N2CCNCC2)cn1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCNC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cn1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
1-Butyl-3-(5-(piperazine-1-carbonyl)pyridin-2-yl)urea (45 mg, 0.147 mmol), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (55 mg, 0.162 mmol), potassium carbonate (61 mg, 0.442 mmol) and sodium iodide (4 mg, 0.029 mmol) were stirred together in acetonitrile (1.5 mL) at reflux for 2 hours. After this time the mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated, dried and concentrated under reduced pressure. The residue was purified by silica chromatography eluting with 5% methanol in dichloromethane to give the title compound (29 mg).
Reaction SMILES: [N:1]1C=CC=CC=1.[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:1])(=[O:16])=[O:15]
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1Br
Reaction time: 8 h

Procedure:
The resin-bound secondary amine resin (from C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) followed by 2-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole) and shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH:15]([C:22]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:27][C:23]=1[C:24](O)=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClC1C=C(C=CC=1C)NC1C=C(C(O)=O)C(NC2C=CC(C)=C(Cl)C=2)=CC=1C(O)=O>>[CH:38]1[CH:39]=[C:40]2[C:31]([C:29]3[C:28]([NH:34][C:35]2=[CH:36][CH:37]=1)=[CH:27][C:23]1[C:24]([C:21]2[C:16]([NH:15][C:22]=1[CH:30]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:25])=[O:32]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)c(Cl)c3)cc2C(=O)O)cc1Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 85 °C

Procedure:
380 parts of polyphosphoric acid, containing 85.0% P2O5, are introduced into a pressure vessel. Then 68.5 parts of 2,5-dianilinoterephthalic acid and 7.6 parts of 2,5-di(3-chloro-4-methylanilino)terephthalic acid are introduced with stirring at from 80 to 90° C. and the mixture is heated at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction mixture is then introduced into a second pressure vessel where it is hydrolyzed under pressure and with stirring with a mixture of 1712 parts of 30% phosphoric acid at 140° C. During this hydrolysis the temperature rises to 155° C. The mixture is stirred at 155° C. for 0.5 hour. Then it is cooled to 60° C. and the mixed crystal pigment is filtered off with suction, washed to neutrality with water and dried at 80° C.
Reaction SMILES: CC(C)(OC(N1CC2C=C(C3C=CC=CC=3)C=CC=2NCC1)=O)C.[ClH:25].[NH:26]1[CH:30]=[C:29]([CH2:31][N:32]2[C:38]3[CH:39]=[CH:40][C:41]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:42][C:37]=3[CH2:36][N:35](C(C3C4C(=CC=CC=4)C=CC=3)=O)[CH2:34][CH2:33]2)[N:28]=[CH:27]1.C1(C(N2C3C=CC=CC=3CNCC2)=O)C2C(=CC=CC=2)C=CC=1.C(C1N=CNC=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].[OH-].[NH4+]>C(Cl)Cl.C(O)(=O)C>[ClH:25].[NH:26]1[CH:30]=[C:29]([CH2:31][N:32]2[C:38]3[CH:39]=[CH:40][C:41]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][C:37]=3[CH2:36][NH:35][CH2:34][CH2:33]2)[N:28]=[CH:27]1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccccc3)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCNc2ccc(-c3ccccc3)cc2C1
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(-c2ccc3c(c2)CNCCN3Cc2c[nH]cn2)cc1
Reaction time: 4 h

Procedure:
A solution of 2,3,4,5-tetrahydro-4-[(1,1-dimethylethoxy)-carbonyl]-7-phenyl-1H-1,4-benzodiazepine (prepared from Compound B of Example 12 as described for Compound A of Example 4, 0.20 g) and 4-formyl imidazole (0.52 g, 5.6 mmol) in CH2Cl2 (10 mL) and acetic acid (2 mL) was stirred for 40 min. Sodium triacetoxyborohydride (0.9 g, 6 mmol) was added and stirring was continued for 4 hrs. Sodium bicarbonate (sat., 5 mL) and ammonium hydroxide (conc, 5 mL) were added and the mixture was stirred for another 3 hrs. The aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with 1N NaOH (2×10 mL) and conc. NH4OH (10 mL), dried (Na2SO4) and evaporated. The residual solid was stirred in MeOH (5 mL) and aqueous HCl in dioxane (4M, 10 mL) overnight. The solvent was evaporated and the residue was triturated with CHCl3 to give a solid (0.35 g) which was purified by preparative HPLC (methanolwater gradient with 0.1% TFA) and converted to the HCl salt by lyophilization from 1M HCl (5 mL) to provide Example 89 (0.12 g, 57%) as an off white solid.