Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([N+:11]([O-])=O)=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6]>C(O)C.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([NH2:11])=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6]
Reactant: O=Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(Cl)cc1C=O
Yield: 86.8 %

Procedure:
3,4-Dichloro-6-nitrobenzaldehyde (4.40 g, 20 mmol) was dissolved in 50% aqueous ethanol (200 ml) at 50°-60° C. and the solution was added to a solution of iron(II) sulfate heptahydrate (27.8 g, 100 mmol) in water (200 ml) at 90° C. Concentrated (25%) aqueous ammonia (50 ml) was added in several portions with intensive stirring while the temperature was kept close to the boiling point. The mixture was refluxed for 5-10 min. and cooled. The precipitate was filtered off and washed with ethanol. The filtrate was concentrated in vacuo until most of the ethanol was removed. The resulting precipitate was collected, washed with water and dried in vacuo at 40°-50° C. to give 3.3 g of 3,4-dichloro-6-aminobenzaldehyde.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:5][C:4]([C:11]([O:13]CC)=[O:12])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.CCO>O>[CH2:9]([O:8][C:6]([C:4]1([C:11]([OH:13])=[O:12])[CH2:3][C:2]([F:1])([F:16])[CH2:5]1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C1(C(=O)OCC)CC(F)(F)C1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)O)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl 3,3-difluorocyclobutane-1,1-dicarboxylate (161) (2.8 g, 12 mmol) was dissolved in ice cooled ethanolic potassium hydroxide solution (0.5 M, 11 mL) and water (2.2 mL). The mixture was stirred at room temperature overnight. An additional 0.5 eq was added to the solution at room temperature and the mixture was stirred at room temperature overnight. Water was added and most of the EtOH was removed under reduced pressure. The mixture was acidified with 2M HCl and extracted three times with ethyl acetate. The organic layer was dried with magnesium sulfate and concentrated to yield 1-(ethoxycarbonyl)-3,3-difluorocyclobutanecarboxylic acid (162). 1H NMR (400 MHz, CD2Cl2) δ 4.33-4.24 (m, 2H), 3.26-3.13 (m, 4H), 1.34-1.27 (m, 3H). MS m/z 209.2 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:12][C:13]3[CH:14]=[C:15]([C:19]4([C:25]#[N:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH:9]=2)[N:4]2[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:28][N:29]=[C:3]12.[CH3:36]C(C)([O-])C.[K+].IC>C1COCC1.CCOC(C)=O.O>[CH3:36][N:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([S:12][C:13]3[CH:14]=[C:15]([C:19]4([C:25]#[N:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH:9]=2)[N:4]2[C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:28][N:29]=[C:3]2[C:2]1=[O:1]
Reactant: CC(C)(C)[O-]
Reactant: N#CC1(c2cccc(Sc3ccc4c(c3)[nH]c(=O)c3nnc(-c5ccccc5)n34)c2)CCOCC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1c(=O)c2nnc(-c3ccccc3)n2c2ccc(Sc3cccc(C4(C#N)CCOCC4)c3)cc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
7c (58 mg, 0.12 mmol) was dissolved in THF (1.2 μL) and cooled to 0° C. Potassium tert-butoxide (18 mg, 0.16 mmol) was added, followed by iodomethane (0.01 mL, 0.18 mmol), and the reaction was warmed to room temperature and stirred overnight. The reaction was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (20-100% EtOAc, followed by 10% MeOH in EtOAc) to give the desired product, 7d.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].C(OC)(OC)OC.[C:38]1(C)C=CC(S(O)(=O)=O)=C[CH:39]=1.O>CCOCC>[CH2:23]([O:22][CH2:21][C:20]([NH:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[C:38]([CH3:39])[N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5])=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccc(NC(=O)COCc2ccccc2)cc1C(=O)NC1CCC(=O)NC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: COC(OC)OC
Product: Cc1nc2ccc(NC(=O)COCc3ccccc3)cc2c(=O)n1C1CCC(=O)NC1=O
Yield: 118.9 %

Procedure:
A solution of 2-amino-5-(2-benzyloxy-acetylamino)-N-(2,6-dioxo-piperidin-3-yl)-benzamide (0.26 g, 0.6 mmol) and trimethyl orthoformate (2 mL) and p-toluene sulfonic acid (60 mg) in acetonotrile (10 mL) was heated to reflux for 21 hours. To the mixture, was added water (25 mL) and ether (25 mL). The suspension was filtered and washed with water (50 mL) and ethyl acetate (50 mL) to give 2-benzyloxy-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-yl]-acetamide as a white solid (180 mg, 72% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.87 min (99.3%); mp: 248-250° C.; 1H NMR (DMSO-d6) δ 2.14-2.16 (m, 1H, CHH), 2.62-2.87 (m, 3H, CH2, CHH), 4.15 (s, 2H, CH2), 4.64 (s, 2H, CH2), 5.49-5.50 (m, 1H, NCH), 7.31-7.41 (m, 5H, Ar), 7.68 (d, J=9 Hz, 1H, Ar), 8.06-8.10 (m, 1H, NH), 8.28 (s, 1H, CH), 8.55 (br, 1H, Ar), 10.24 (s, 1H, NH), 11.16 (s, 1H, NH); 11C NMR (DMSO-d6) δ 23.05, 31.48, 58 (br), 69.87, 72.92, 115.69, 122.15, 127.30, 128.16, 128.28, 128.34, 128.77, 137.98, 138.14, 144.06, 146.48, 160.10, 168.93, 170.43, 172.90; LCMS: MH=421; Anal Calcd for C22H20N4O5: C, 62.85; H, 4.79; N, 13.33. Found: C, 60.60; H, 4.29; N, 12.54.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:6]=[CH:5]2.C([Li])CCC.[C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=[O:31])#[N:27]>O1CCCC1>[OH:31][CH:30]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:12]([CH3:14])[CH3:13])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])[N:6]=[CH:5]2)[C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[C:26]#[N:27]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(I)ccc21
Reactant: N#Cc1ccccc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(C(O)c3ccccc3C#N)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
A solution of 5-iodo-1-[tris(1-methylethyl)silyl]-1H-indazole (1.8 g, 4.6 mmol) in tetrahydrofuran (9.2 mL) was cooled to −78° C., and n-butyllithium was added (1.6M in hexanes, 3.4 mL, 5.5 mmol). After 15 min., 2-cyanobenzaldehyde (0.78 g, 6.0 mmol) in 2.0 mL tetrahydrofuran was added quickly and the solution was allowed to warm to room temperature. The reaction mixture was quenched with an excess of saturated aqueous ammonium chloride solution, then partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted (2×100 mL ethyl acetate). The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. Column chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.17 g (9%) of 2-(hydroxy{1-[tris(1-methylethyl)silyl]-1H-indazol-5-yl}methyl)benzonitrile. 1H NMR (400 MHz, CDCl3): 8.20 (s, 1H), 7.95 (m, 1H), 7.69 (s, 1H), 7.51 (m, 3H), 7.23 (m, 1H), 7.09 (m, 1H), 6.50 (s, 1H), 1.77 (m, 3H), 1.06 (m, 18H); MS (EI) for C24H31N3OSi: 250 (M-SiiPr3).
Reaction SMILES: FC1C(=O)CCN(C2NN=CC=2[N+]([O-])=O)C1.[N:17]([CH:20]1[CH:26]([OH:27])[CH2:25][CH2:24][N:23]([C:28](OC(C)(C)C)=O)[CH2:22][CH2:21]1)=[N+:18]=[N-:19].ClC1[N:40]([CH2:41][CH:42]([F:44])[F:43])[N:39]=[CH:38][C:37]=1[N+:45]([O-:47])=[O:46]>>[N:17]([CH:20]1[CH2:21][CH2:22][N:23]([C:28]2[N:40]([CH2:41][CH:42]([F:44])[F:43])[N:39]=[CH:38][C:37]=2[N+:45]([O-:47])=[O:46])[CH2:24][CH2:25][CH:26]1[OH:27])=[N+:18]=[N-:19]
Reactant: O=[N+]([O-])c1cnn(CC(F)F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N=[N+]=[N-])CC1
Agent: O=C1CCN(c2[nH]ncc2[N+](=O)[O-])CC1F
Product: [N-]=[N+]=NC1CCN(c2c([N+](=O)[O-])cnn2CC(F)F)CCC1O

Procedure:
Following the procedure for Intermediate 48 starting from tert-butyl 4-azido-5-hydroxyazepane-1-carboxylate and 5-chloro-1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole gave 5-azido-1-(1-(2,2-difluoroethyl)-4-nitro-1H-pyrazol-5-yl)azepan-4-ol as a yellow gum (1.16 g, 50% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.14-8.09 (m, 1H), 6.11 (tt, J=27.8, 4.4 Hz, 1H), 4.50-4.39 (m, 2H), 3.83 (tt, J=8.8, 3.1 Hz, 1H), 3.67 (td, J=4.7, 3.6 Hz, 1H), 3.45-3.21 (m, 4H), 2.37 (d, J=2.9 Hz, 1H), 2.25-2.12 (m, 2H), 2.03-1.91 (m, 2H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=1)[CH2:15]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:19]=1)[CH2:15][N:31]=[N+:32]=[N-:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCC)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(CN=[N+]=[N-])cc(OCCCCCCCCCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
3,5-Didecoxybenzyl chloride (14.4 g, 32.8 mmol) was dissolved in DMF (50 mL) in a 250 mL RBF. Sodium azide (4.26 g, 65.6 mmol) and a magnetic stir bar were added to the RBF. The RBF was heated to just below boiling of the DMF using a heat gun. The reaction mixture was then stirred at room temperature until cool to the touch. Heating and cooling were repeated 3 times. Thin layer chromatography in hexanes showed the presence of a starting material. A heating mantel was used to gently heat the RBF. After 1 hour, thin layer chromatography showed no starting material present. The contents of the RBF were transferred to a separatory funnel. Ether (250 mL) and distilled H2O (250 mL) were added to the funnel. The aqueous layer was washed 2 times with ether (250 mL). The ether layers were combined and washed 2 times with saturated ammonium chloride solution (125 mL) and once with saturated sodium chloride solution (125 mL). The ether layer was then dried with magnesium sulfate, gravity filtered and concentrated using rotary evaporation. High vacuum was then used to remove trace amounts of the ether giving. There was a 13.6 g yield or a 93.1% yield of the derivative. The NMR characterization data for this derivative is as follows. 1NMR (300 MHz, CDCl3): 0.88 (t, J=6.6, 6H, CH2CH3), 1.27-1.43 (m, 28H, CH2(CH2)7), 1.76 (p, J=6.6, 4H, OCH2CH2), 3.92 (t, J=6.6, 4H, OCH2), 4.21 (s, 2H, ArCH2N3), 6.42-6.44 (m, 3H, ArH). 13C NMR (75 MHZ, CDCl3): 14.23, 22.79, 26.13, 29.31, 29.45, 29.49, 29.68, 29.71, 32.01, 55.01, 65.97, 68.19, 101.08, 106.52, 137.45, 160.68.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([N:8]2[CH2:19][CH2:18][C:11]3[N:12]=[C:13]([NH:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH2:9]2)[CH:7]=1.[N:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)=[C:22]=[O:23].CCCCCC>C1COCC1.O>[CH3:20][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:22]([NH:21][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[O:23])=[CH:7][C:6]=1[N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([NH:16][CH3:17])[N:14]=[CH:15][C:10]=2[CH2:9]1
Reactant: CNc1ncc2c(n1)CCN(c1cc(N)ccc1C)C2
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CNc1ncc2c(n1)CCN(c1cc(NC(=O)Nc3cccc(C(F)(F)F)c3)ccc1C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.7 %

Procedure:
To a clear stirred solution of [6-(5-Amino-2-methyl-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-methyl-amine (75 mg, 0.278 mmol) in the THF (1.5 ml) was added 1-Isocyanato-3-trifluoromethylbenzene (57.3 mg, 0.306 mmol) all at once, and the reaction mixture was allowed to stirred for 3 hours at room temperature. After 3 hours, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was given a brine wash, dried over sodium sulphate and concentrated to dryness to get sticky mass which was given a hexane wash to get 83.4 mg of 1-[4-Methyl-3-(2-methylamino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea [43] [Yield 65.6%] as light brown colored solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:12](Cl)(=[O:14])[CH3:13]>ClCCl.N1C=CC=CC=1>[C:12]([O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[Br:1])(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc(O)c(Br)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To a solution of 3-bromo-4-hydroxy-benzoic acid (3.0 g, 13.83 mmol) in dichloromethane (100 mL) and pyridine (20 mL) was added acetyl chloride (1.1 mL, 15.20 mmol) and the resulting mixture was stirred at rt for 1 h. The reaction was quenched with water (50 mL) and acidified with HCl (1 N) to adjust pH=1˜2. The mixture was extracted with dichloromethane (3×100 mL) and concentrated to afford 4-acetoxy-3-bromo-benzoic acid (3.6 g, 100%). To a solution of 4-acetoxy-3-bromo-benzoic acid (3.60 g, 13.83 mmol) in dichloromethane (100 mL) at rt was added oxalyl chloride (1.8 mL, 20.75 mmol) and DMF (0.5 mL), sequentially. The resulting mixture was stirred at rt for 1 h. The mixture was concentrated to afford the acid chloride. To a solution of the freshly prepared acid chloride in dichloromethane (100 mL) were added 2′-hydroxyacetophenone (2.5 mL, 20.75 mmol) and triethylamine (3.9 mL, 27.66 mmol). This mixture was stirred at rt for 2 h. The reaction was quenched with water (100 mL) and extract with dichloromethane (3×150 mL). The combined organic layers were concentration to afford an oily residue, which was purified by column chromatography using 30% EtOAc in hexane to give the phenol ester (4.5 g, 86%). A solution of the phenol ester (4.0 g, 10.61 mmol) in THF (100 mL) was mixed with potassium t-butoxide (1.6 g, 14.32 mmol) and stirred at 60° C. for 1.5 h. This mixture was cooled to rt, diluted with water (100 mL) and acidified with HCl (1 N) to adjust pH=5˜6. The mixture was extract with dichloromethane (3×100 mL) and the combined organic layers were concentration to give a yellow solid residue. The residue was purified by column chromatography using 30% EtOAc in hexane to give the diketone (2.3 g, 58%). A solution of the diketone (1.50 g, 3.98 mmol) in AcOH (100 mL) and HCl (conc., 2 mL) was stirred at reflux for 16 h. This mixture was cooled to rt, diluted with water (100 mL), extracted with dichloromethane (3×100 mL) and concentrated. The residue was purified by column chromatography using 50% EtOAc in hexane to give the flavone acetate (0.4 g, 28%). A solution of the flavone acetate (0.53 g, 1.48 mmol) in MeOH (80 mL) and water (20 mL) was mixed with potassium carbonate (1.10 g, 8.00 mmol) and was stirred at rt for 1 h. The solid was filtered off, washed with water, hexanes, and dichloromethane sequentially to give 390 mg of product (83%) as a light yellow solid. MS (ES) m/z: 318.84+316.84 (two isotopes of M); Mp. 273.5-274.9° C.
Reaction SMILES: [OH:1][CH:2]([C:14]1[CH:15]=[C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])[O:17][CH:18]=1)[CH2:3][CH:4]=[C:5]([CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH:6]=[O:7]>C1C=CC=CC=1>[OH:7][CH:6]1[O:1][CH:2]([C:14]2[CH:15]=[C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])[O:17][CH:18]=2)[CH2:3][CH:4]=[C:5]1[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12]
Reactant: CC(C)=CCCC(C=O)=CCC(O)c1coc([Si](C)(C)C)c1
Solvent: c1ccccc1
Product: CC(C)=CCCC1=CCC(c2coc([Si](C)(C)C)c2)OC1O

Procedure:
5-Hydroxy-2-(4-methyl-3-pentenyl)-5-(2-trimethylsilyl-4-furyl)-2-pentenal (0.88 g, 0.274 mmol) was dissolved in 27 ml anhydrous benzene, placed in a quartz tube and deoxygenated by saturating with oxygen-free nitrogen for one hour. The solution was irradiated at 254 nm for three hours, cooled and concentrated to give a brown-yellow gum. This material was purified by flash chromatography (silica, 15 to 30% ethyl acetate/hexane). First eluted was the desired acetal followed by starting aldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([N:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:21][CH2:22][CH3:23])[CH:19]=1)[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:9])=[O:6].O.N([O-])=O.[Na+].[N-:33]=[N+:34]=[N-].[Na+]>C(O)(=O)C.CCOC(C)=O>[N:1]([C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([N:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:21][CH2:22][CH3:23])[CH:19]=1)[C:5]([NH:7][C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH3:9])=[O:6])=[N+:33]=[N-:34]
Reactant: CCCN(c1cc(N)cc(C(=O)N[C@H](C)c2ccc(F)cc2)c1)S(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCN(c1cc(N=[N+]=[N-])cc(C(=O)N[C@H](C)c2ccc(F)cc2)c1)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a solution of 0.2 g (0.5 mmol) 3-amino-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide (Intermediate XXI) in 4 mL acetic acid was added 1 mL water followed by 0.038 g (0.55 mmol) sodium nitrite. After 2 minutes 0.035 g (0.055 mmol) sodium azide was added resulting in gas evolution. The reaction mixture was stirred for 30 minutes then diluted with 75 mL EtOAc, washed with 50 mL water, 50 mL 4M NaOH, 50 mL brine, dried over MgSO4, filtered, and concentrated. Purification by automated flash chromatography (40 g silica gel cartridge, 20-100% EtOAc/hexanes over 20 min) afforded 3-azido-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide. 1H NMR (CDCl3, 400 MHz) δ 7.45 (br t, J=1.47 Hz, 1H), 7.36 (m, 3H), 7.11 (t, J=2.01 Hz, 1H), 7.06 (m, 2H), 6.31 (br d, J=7.32 Hz, 1H), 5.28 (quint, J=7.14 Hz, 1H), 3.64 (t, J=7.15 Hz, 2H), 2.89 (s, 3H), 1.61 (d, J=6.96 Hz, 3H), 1.5 (m, 2H), 0.91 (t, J=7.33 Hz, 3H). LCMS [M+H]+=420.1
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([Cl:10])=[N:4][CH:3]=1.O.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[C:7]([CH:8]=[N:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:5]([Cl:10])=[N:4][CH:3]=1
Reactant: O=Cc1cc(Cl)ncc1Br
Reactant: CC(C)(C)N
Solvent: O
Product: CC(C)(C)N=Cc1cc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 107.1 %

Procedure:
To a mixture of 5-bromo-2-chloroisonicotinaldehyde (1.047 g, 4.749 mmol) and Water (2.0 mL, 110 mmol) was added tert-butylamine (2.0 mL, 19 mmol). The reaction mixture was stirred at room temperature for 20 hours, and then excess tert-butylamine was removed by rotary evaporation. The resulting residue was partitioned between ethyl acetate and water, and the organic layer dried with brine and MgSO4, filtered, and evaporated in vacuo to yield 1.401 g (87%) of N-((5-bromo-2-chloropyridin-4-yl)methylene)-2-methylpropan-2-amine. 1H NMR (400 MHz, DMSO) δ 8.72 (s, 1H), 8.43 (s, 1H), 7.78 (s, 1H), 1.28 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:12]([CH3:21])[CH:13](O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[NH2:11])=[O:5])[CH3:2].O=S(Cl)Cl.CCN(CC)CC>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[CH:12]([CH3:21])[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C(C)C(O)c2ccccc2)c1N
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cnn2c1NC(c1ccccc1)C2C
Reaction time: 1.5 h

Procedure:
Compound 2 (0.80 g, 2.8 mmol) was dissolved in CH2Cl2. SOCl2 (0.61 mL, 8.3 mmol) was added dropwise. After 90 minutes, the solution was concentrated to give a yellow solid. After pumping on high vacuum for 5 minutes, the solid was dissolved in CHCl3. Et3N (2.7 mL, 19.5 mmol) was added dropwise and the reaction mixture stirred for 1 hour. The reaction was quenched with water and diluted with AcOEt. The solution was washed with sat. NH4Cl, sat. NaHCO3, brine, and then dried (MgSO4). Flash chromatography (20% AcOEt/hexane) gave both the syn (0.10 g, 14%) and anti (0.62 g, 82%) isomers 3. Anti isomer 1H NMR (400 MHz, CDCl3) δ 1.23 (t, J=7.0 Hz, 3H), 1.80 (d, J=6.6 Hz, 3H), 4.10-4.20 (m, 2H), 4.25-4.35 (m, 1H), 4.38 (brs, 1H), 5.10 (d, J=9.8 Hz, 1H), 7.17-7.25 (m, 5H), 7.59 (s, 1H). Syn isomer 1H NMR (400 MHz, CDCl3) δ 1.28 (d, J=7.0 Hz, 3H), 7.38 (t, J=7.4 Hz, 3H), 4.25-4.35 (m, 2H), 7.43-7.52 (m, 1H), 5.17 (brs, 1H), 5.23 (d, J=9.8 Hz, 1H), 7.37-7.45 (m, 5H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[C:17]([Cl:18])=[C:16]([O:19][CH3:20])[CH:15]=[C:14]([O:21][CH3:22])[C:13]=3[Cl:23])[CH:8]=2)[N:3]=1.[NH2:24][C@H:25]1[C@H:29]([OH:30])[CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]1.C1CCN2C(=NCCC2)CC1>C(#N)C.CCOC(C)=O>[Cl:18][C:17]1[C:16]([O:19][CH3:20])=[CH:15][C:14]([O:21][CH3:22])=[C:13]([Cl:23])[C:12]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:24][C@H:25]1[C@H:29]([OH:30])[CH2:28][C@@H:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]1)[N:11]=[CH:10]2
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(Cl)ncc3c2)c1Cl
Reactant: COC(=O)C1C[C@@H](N)[C@H](O)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](O)[C@H](Nc2ncc3cc(-c4c(Cl)c(OC)cc(OC)c4Cl)ccc3n2)C1
Temperature: 65 °C
Yield: 67.8 %

Procedure:
2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline (0.576 g, 1.558 mmol), methyl (3R,4R)-3-amino-4-hydroxycyclopentane-1-carboxylate (0.372 g, 2.337 mmol) were taken up in acetonitrile (3 ml) and DBU (0.470 ml, 3.12 mmol) was added. The reaction was purged with N2 for 5 minutes then heated to 65° C. overnight. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified via flash chromatography (0-100% Hex/EtOAc; 12 g column), and (1S,3R,4R)-methyl 3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-4-hydroxycyclopentanecarboxylate (0.520 g, 1.056 mmol, 67.8% yield) was recovered. MS (ES+) C23H23Cl2N3O5 requires: 492, found: 493 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:17][C@@H:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[C:23]([O:22][C:20]([NH:19][C@H:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:17][C@H:16]([CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=1)[C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCc2ccccc2)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a solution of 610 mg (1.10 mmol) of di-tert-butyl (4R)-4-{[5-(benzyloxy)pyridin-2-yl]methyl}-N-(tert-butoxycarbonyl)-L-glutamate in methanol (35 mL) was added a 10% palladium on charcoal catalyst (29 mg), and the resulting suspension was stirred overnight under an atmosphere of hydrogen at room temperature. The catalyst was removed by filtration, and the filtrate was evaporated to give 500 mg of the pure target compound as colorless foam (98% yield).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)=[CH:10][C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)=[N:8]2)=[CH:4][CH:3]=1.[N:33]1([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[C:42]([O:41][C:39]([N:33]1[CH2:38][CH2:37][N:36]([CH2:16][CH2:15][CH2:14][C:11]2[C:12](=[O:13])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:32][CH:31]=3)[N:8]=[C:9]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=3)[CH:10]=2)[CH2:35][CH2:34]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CCCN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 37.4 %

Procedure:
Following the procedure of Example 1(10), 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a brown oil (yield: 37.4%).