Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.CC(C)([O-])C.[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CN(C=O)C>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1
Reactant: Cc1cc(N)c2c(-c3cccc(Br)c3)c(Br)sc2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(NS(=O)(=O)c2ccccc2)c2c(-c3cccc(Br)c3)c(Br)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a stirred solution of 2-bromo-3-(3-bromophenyl)-6-methylthieno[2,3-b]pyridin-4-amine (Description 49) (1 g, 2.51 mmol) in THF (10 mL) and DMF (5 mL) was added sodium tert-butoxide (0.603 g, 6.28 mmol) and benzenesulfonyl chloride (0.648 mL, 5.02 mmol). The reaction mixture stirred at RT under nitrogen for ca. 30 min. The reaction mixture was quenched with saturated ammonium chloride solution (ca. 30 mL) and extracted with DCM (25 mL×4). The combined organics were dried and concentrated. The residue was purified via normal phase chromatography eluted with a gradient of 0-50% ethyl acetate in DCM, to afford the title compound (1.12 g). LCMS (A) m/z: 539 [M+1]+, Rt 1.45 min (acidic).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[C:3]=1[O:10][CH3:11].N([O-])=[O:13].[Na+]>S(=O)(=O)(O)O>[OH:13][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[C:3]=1[O:10][CH3:11]
Reactant: O=N[O-]
Reactant: COc1c(N)ccnc1CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1c(O)ccnc1CO

Procedure:
4-Amino-2-hydroxymethyl-3-methoxypyridine is diazotised in dilute sulphuric acid with sodium nitrite and the diazonium compound is warmed to give 4-hydroxy-2-hydroxymethyl-3-methoxypyridine which may be demethylated with hydrobromic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:9]=[N:10][C:11]([S:14][CH2:15][CH3:16])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[I:31]I>C(OCC)C>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:9]=[N:10][C:11]([S:14][CH2:15][CH3:16])=[CH:12][C:13]=1[I:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: CCSc1ccc(NC(=O)OC(C)(C)C)cn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCSc1cc(I)c(NC(=O)OC(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
To (6-ethylsulfanylpyridin-3-yl)carbamic acid tert-butyl ester (27.6 g; 0.108 mol) and N,N,N′,N′-tetramethylethylenediamine (27 mL; 0.180 mol) in 300 mL diethyl ether at −78° C. was added dropwise n-butyllithium (100 mL of a 2.5 M solution in hexanes; 0.25 mol). The mixture was stirred mechanically for 15 minutes, warmed to 0° C.-5° C., stirred for 3 hours, cooled to −78° C. and iodine (60.6 g; 0.239 mol) in 300 mL of diethyl ether was added dropwise. The mixture was slowly warmed to room temperature, stirred overnight, and quenched with aqueous ammonium chloride and diethyl ether. The organic layer was washed with aqueous sodium metabisulfite, water, and brine, and dried over magnesium sulfate (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by CombiFlash chromatography using ethyl acetate and hexanes as the eluent. The product-rich fractions were concentrated in vacuo to provide (6-ethylsulfanyl-4-iodopyridin-3-yl)carbamic acid tert-butyl ester (27.7 g; 67%), MS (ES+) m/z 381 [M+H]+.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[Cl:6][CH2:7][C:8](=[O:32])[C@:9]1([OH:31])[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[C@@H:15]([F:29])[CH2:14]3)[CH2:11][C@@H:10]1[CH3:30].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[Cl:6][CH2:7][C:8](=[O:32])[C@:9]1([OH:31])[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[C@@H:15]([F:29])[CH2:14]3)[CH2:11][C@@H:10]1[CH3:30]
Reactant: C[C@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@@]1(O)C(=O)CCl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: CCC(=O)O
Product: C[C@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]2(C)[C@@]1(O)C(=O)CCl

Procedure:
Analogously to Example 12, 200 mg of 21-chloro-6α-fluoro-17α-hydroxy-16β-methyl-pregn-4-ene-3,20-dione propionate (see Example 10) are treated with 250 mg of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 8 ml of dioxan and further processed to yield 21-chloro-6α-fluoro-17α-hydroxy-16β-methyl-pregna-1,4-diene-3,20-dione propionate; melting point 216°-219° C. (from methylene chloride/ether).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH3:15][NH:16][C:17]([CH2:19][NH:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:15][NH:16][C:17]1[S:2][C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[N:20][CH:19]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CNC(=O)CNC(=O)c1cccnc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CNc1cnc(-c2cccnc2)s1
Temperature: 25 °C
Yield: 23 %

Procedure:
A suspension of phosphorus pentasulfide (1.73 g, 7.8 mmol) and N-methylcarbamoylmethyl-nicotinamide (1 g, 5 mmol) in dry toluene (10 mL) was stirred at reflux under nitrogen for 16 h. The mixture was cooled to room temperature and then dry pyridine (4 mL) was added. The mixture was stirred at reflux under nitrogen for 8 h, then it was cooled to room temperature and the organic layer was removed. The dark residue was treated with hot saturated aqueous sodium bicarbonate (Na2CO3, 40 mL) and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate (MgSO4), and purified by silica gel chromatography (1% methanol in dichloromethane) to yield a brown amorphous solid (0.22 g, 22%): mp 141-146° C.; 1H NMR (300 MHz, CDCl3) δ 8.97 (d, J=2.4 Hz, 1H), 8.53 (dd, J=5.0, 1.8 Hz, 1H), 8.06 (ddd, J=7.2, 3.3, 0.6 Hz, 1H), 7.31 (ddd, J=5.5, 4.7, 0.5 Hz, 1H), 6.96 (s, 1H), 2.97 (d, J=5.0 Hz, 3H); ESIMS m/z 192 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17]([C:26]#[C:27][C:28]([O:30]CC)=[O:29])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17]([C:26]#[C:27][C:28]([OH:30])=[O:29])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C#Cc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C#Cc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.8 %

Procedure:
A mixture of ester 7.3 (68 mg, 0.157 mmol) and 1N LiOH (2 ml) in 6 ml MeOH/THF (1:2) was stirred at rt for 24 h, concentrated, and partitioned between Et2O and H2O. The organic phase was extracted with 0.1 N NaOH (2×), and the combined aqueous extracts were acidified with conc. HCl, and extracted with EtOAc (3×). The combined organic extracts were washed with H2O, brine, and dried (Na2SO4) to afford 64 mg (100%) of acid 7.4. HRMS (ESI) calc'd for C25H25N2O3 401.1865, found 401.1855 (M+H+); 1H NMR (300 MHz, CDCl3) δ 7.48–7.37 (m, 5H), 7.26 (d, J=8.8, 2H), 7.08 (d, J=8.8, 2H), 6.51 (s, 1H), 5.13 (s, 2H), 4.15–4.06 (m, 1H), 2.05–1.97 (m, 2H), 1.90–1.87 (m, 4H), 1.28–1.23 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)#[N:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(Cl)Cl>[CH2:14]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[C:3]([C:1]#[N:2])=[C:4]1[C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[O:21])=[CH:18][CH:17]=1)[CH3:15]
Reactant: CCn1c(-c2ccc(C(=O)O)cc2)c(C#N)c2ccc(OC)cc21
Reactant: C1COCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1c(-c2ccc(C(=O)N3CCOCC3)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (50 mg, 0.16 mmol) is suspended in CH2Cl2 (2.2 mL) and catalytic DMF (2 μL). Oxalyl chloride (22 μL, 0.25 mmol) is added. The reaction mixture is stirred at room temperature for 1 hour, at which time full dissolution occurred. This reaction mixture is pipetted dropwise into a vigorously stirring solution of morpholine (1.0 mL) in CH2Cl2 (5 ml). After addition is complete, the reaction mixture is washed with aqueous HCl solution. The organic layer is dried and concentrated. Purification by silica column (1:1 CH2Cl2/EtOAc) yields 1-ethyl-6-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile (56 mg, 90%) as a white solid.
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.[O:26]1CCOCC1.O>[N+]([O-])([O-])=O.[Ag+].C(Cl)Cl>[CH3:23][N:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][C:17](=[O:18])[N:12]([C:9]2[CH:10]=[CH:11][C:6]3[S:5][N:4]=[C:3]([CH:2]=[O:26])[C:7]=3[CH:8]=2)[C:13]1=[O:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Br)Br)c3c2)c1=O
Reactant: C1COCCO1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-[3-(dibromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.500 g, 0.00100 mol) in a dioxane/water mixture (5:2) is treated with silver nitrate (0.340 g, 0.00200 mol), refluxed for 90 minutes, cooled to room temperature, stirred for 18 hrs, refluxed for three hrs, cooled, and filtered through a pad of diatomaceous earth. The resultant filtrate is concentrated in vacuo to obtain an aqueous mixture. The aqueous mixture is extracted with methylene chloride. The organic extract is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a solid. Column chromatography of the solid using silica gel and methylene chloride gives the title product as a solid (0.240 g, mp 193-194.5° C.).
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[O:23]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24]1>>[CH2:18]([C:13]1[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH:25]3[CH2:26][CH2:27][O:23][CH2:24]3)=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)OC)cn1
Reactant: NC1CCOC1
Product: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)NC2CCOC2)cn1
Yield: 70 %

Procedure:
As described in example 8, 6-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (200 mg, 0.57 mmol), and tetrahydrofuran-3-amine instead of isopropylamine, was converted to the title compound (140 mg, 70%) which was obtained as a light red solid after purification by chromatography (silica, dichloromethane:methanol 100:0 to 94:6). MS: m/e=328.4 [M+H]+.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:5]([C:29]([O:31][CH3:32])=[O:30])[CH:4]=1.C1CCN2C(=NCCC2)CC1.[CH3:44][O:45][C:46]1[C:47]([CH3:54])=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH:49]=O>C(#N)C>[CH3:32][O:31][C:29](=[O:30])[C:5]1[CH:4]=[C:3]([Br:2])[CH:28]=[CH:27][C:6]=1[CH:7]=[CH:49][C:48]1[CH:51]=[CH:52][CH:53]=[C:46]([O:45][CH3:44])[C:47]=1[CH3:54]
Reactant: COC(=O)c1cc(Br)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cccc(C=O)c1C
Agent: [Br-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc(Br)ccc1C=Cc1cccc(OC)c1C
Yield: 83.6 %

Procedure:
To a stirred mixture of (4-bromo-2-methoxycarbonylbenzyl)-triphenylphosphonium bromide (4) (34.2 g; 60.0 mmol), DBU (1,8-diazabicyclo(5.4.0) undec-5-ene; 20.1 g; 132 mmol), and 3-methoxy-2-methylbenzaldehyde (7.21 g; 48.0 mmol) in acetonitrile were heated at reflux temperature for 2 hours. The mixture was cooled and the solvent was evaporated. The residue was partitioned between water and ethyl acetate and the organic phase was washed with 0.1 N HCl, water, and brine. The solution was dried over MgSO4, filtered, and evaporated. The residue was crystallized from ethyl acetate and hexane to yield compound 5 (14.5 g; 84%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=2)=[CH:16][CH:15]=1.O>CN(C=O)C>[N:1]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=3)=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: c1ccc2[nH]nnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(Cn3nnc4ccccc43)cc2)no1
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
To a mixture of benzotriazole (13 mg, 0.11 mmol) in DMF (1 mL) was added NaH (60% dispersion; 5 mg, 0.125 mmol). The mixture was stirred for 20 min and then a solution of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at room temperature overnight. H2O was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed three times with H2O/brine, dried (Na2SO4), evaporated, and purified by chromatography (10-25% acetone/CH2Cl2) to give 3-(4-benzotriazol-1-ylmethyl-phenyl)-isoxazole-5-carboxylic acid amide (12 mg, 35%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (br. s., 1H) 8.06 (d, J=8.2 Hz, 1H) 7.98 (br. s., 1H) 7.81-7.91 (m, 3H) 7.49-7.59 (m, 2H) 7.34-7.48 (m, 3H) 6.06 (s, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH:11]2[CH:10]([O:21]2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 55 %

Procedure:
22.1 A solution of 19.6 g N-Boc-pyrroline in 200 ml CH2Cl2 was cooled to −10° C. and was treated in two portions with 30 g meta-chloroperbenzoic acid. The mixture was stirred for 17 h, slowly warming up to room temperature. Then, the white precipitate was filtered off and washed with dichloromethane. The filtrate was washed with 5% aq. NaHSO3, sat. aq. NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc 65:35) to give 11.8 g 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester as a light yellow oil. MS 186.1 ([M+H]+)
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([OH:24])=O)=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25][N:26]1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C1(C(NO)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[NH:1]([C:8]1[N:17]=[CH:16][C:15]2[CH2:14][CH2:13][C:12]3[C:18]([C:22]([NH:26][OH:25])=[O:24])=[N:19][N:20]([CH3:21])[C:11]=3[C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nc(C(=O)O)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: ONC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)NO)c2c1-c1nc(Nc3ccccc3)ncc1CC2
Yield: 66.1 %

Procedure:
To a solution of 260 mg (0.81 mmol) of 8-anilino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid in 50 mL of anhydrous dimethylformamide 111 mg of N-hydroxybenzotriazole (0.81 mmol), 0.16 mL of N-methylmorpholine, 205 mg (1.07 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 585 mg (2.13 mmol) of triphenylmethylhydroxylamine were added consecutively. After 48 hours at room temperature the solvent was removed under reduced pressure and the residue taken up with dichoromethane and washed with water. The organic layer was then dried over sodium sulfate and evaporated. The crude was treated with 10 mL of a mixture dichloromethanetrifluoroacetic acid and after 4 hours the volatiles were removed in vacuo. The residue was redissolved with dichoromethane and washed with aqueous NaHCO3 and the product purified by chromatography on a silica gel column, eluted with CH2Cl2-CH3COCH3 4/1, to give 180 mg (66% yield) of the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][CH:9]=[N:8]1)C.[CH3:15][NH2:16]>C(O)C>[CH3:15][NH:16][C:4](=[O:3])[CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH:11]=[CH:10][CH:9]=[N:8]1
Reactant: CN
Reactant: CCOC(=O)CCn1ncccc1=O
Solvent: CCO
Product: CNC(=O)CCn1ncccc1=O
Temperature: 40 °C
Reaction time: 30 h
Yield: 82 %

Procedure:
Next a mixture of 1.96 g (0.01 mole) of ethyl-3-(3-oxo-2-pyridazinyl)propionate and 20 ml of methylamine (30% ethanol solution was stirred at 40° C. for 30 hours and distilled to give white crystals. Recrystallization from ethanol gave 1.6 g (82% yield of N-methyl-3-(3-oxo-2-pyridazinyl)propionamide, m.p. 94°-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[Cl:27]Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:11]=[CH:10][C:9]=2[Cl:27])=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(-n2nccc2-c2ccc(Cl)cc2)cc1
Reactant: ClCl
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(-n2ncc(Cl)c2-c2ccc(Cl)cc2)cc1
Yield: 75 %

Procedure:
A 100 mL three-necked round-bottomed flask equipped with reflux condenser, gas dispersion tube and provisions for magnetic stirring was charged with 4-[5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide (500 mg, 1.2 mmol) and 50 mL of glacial acetic acid. The solution was stirred at room temperature and treated with a stream of chlorine gas for a period of 15 minutes. The solution was then stirred at room temperature for 1.25 hours and then diluted with 100 mL of water. The solution was then extracted three times with ether and the combined ethereal phase washed with brine, dried over anhyd. MgSO4, filtered, and concentrated in vacuo to give a white solid that was recrystallized from ether/petroleum ether to provide 400 mg, 75% of 4-[5-(4-chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide, 1H nmr CDCl3 /300 MHz) 8.06 (s, 1H), 7.81 (d, J=8.4 Hz, 2H) 7.53 (d, J=8.4 Hz 2H), 7.43 (brs, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[Li]CCCC.[B:17](OCCCC)([O:23]CCCC)[O:18]CCCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([B:17]([OH:23])[OH:18])=[CH:8][C:7]=2[CH:11]=1
Reactant: COc1ccc2occc2c1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2oc(B(O)O)cc2c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
5-Methoxybenzofuran (5.3 g, 35.8 mmol) was dissolved in anhydrous THF (120 mL) and cooled to −30° C. The solution was treated with n-BuLi (18 mL, 45 mmol, 2.5 M in hexanes) over 30 min, maintaining the internal temperature at −30° C. during the addition to give a yellow solution. After 1 h at −30° C., tributyl borate (12.2 mL, 45.1 mmol) was added over 10 min and the solution became pale yellow. The resulting solution was allowed to warm slowly to 14° C. over 12 h, then was quenched with 6 M HCl (50 mL) and extracted with EtOAc (150 mL). The organics were washed with water, then brine and dried over MgSO4. After filtration, the organic solution was concentrated and the boronic acid precipitated by the addition of hexanes. The solid was filtered and washed with hexanes to give an off-white solid (3.95 g, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][C:17]([OH:19])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.C([N:22](CC)CC)C.ClC(OCC(C)C)=O.N.Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][C:17](=[O:19])[NH2:22])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)CC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reaction time: 0.17 h
Yield: 14 %

Procedure:
To a solution of 8-bromo-5-carboxymethyl-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (100 mg, 0.308 mmol)in DMF (2 mL)in the presence of triethylamine (64 μL, 0.461 mmol) was added isobutyl chloroformate (44 μL, 0.338 mmol) at -20° C. After being stirred for 10 min, aqueous 28% ammonia (94 μL, 1.538 mmol) was added at -20° C. The stirring was continued for 30 min at room temperature and 0.1N hydrochloric acid (20 mL) was added. The precipitates formed were collected by filtration, washed with water, and again suspended in aqueous sodium bicarbonate. The suspension was adjusted to pH 7.0 by addition of 1N hydrochloric acid and extracted with 2:1 ethyl acetate/THF. The organic layer was washed with brine, dried over magnesium chloride, and concentrated. The residual solids were rinsed with dichloromethane to give 14 mg of the title compound (14%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ12.10 (bs, 1H), 7.66 (s, 1H), 7.29 (s, 1H), 7.17 (s, 2H), 5.04~5.10 (m, 1H), 2.80 (dm, 1H, J=18 Hz), 2.58 (dm, 1H, J=14 Hz), 2.41 (m, 1H, J=14 Hz), 1.85~2.00 (m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:10]3[O:11][CH2:12][CH2:13][NH:14][C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.Cl[C:18]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:19]=1[CH3:34]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH3:34][C:19]1[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:21][C:22]2[C:27]([C:18]=1[N:14]1[C:9]3[CH:8]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:16]=[CH:15][C:10]=3[O:11][CH2:12][CH2:13]1)=[CH:26][CH:25]=[CH:24][N:23]=2
Reactant: c1cc2c(cc1N1CCOCC1)NCCO2
Reactant: Cc1c(-c2ccccn2)nc2ncccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2ncccc2c1N1CCOc2ccc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by using 6-morpholino-3,4-dihydro-2H-benzo-[b][1,4]oxazine (68 mg, 0.31 mmol), 4-chloro-3-methyl-2-(pyridin-2-yl)-1,8-naphthyridine (79 mg, 0.31 mmol), XPhos precatalyst (23 mg, 0.031 mmol) in toluene (5 mL) for 2 h at 100° C. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 4-(3-methyl-2-(2-pyridinyl)-1,8-naphthyridin-4-yl)-6-(4-morpholinyl)-3,4-dihydro-2H-1,4-benzoxazine. 1H NMR (400 MHz, chloroform-d) δ ppm 9.10 (1H, dd, J=4.1, 2.0 Hz), 8.71 (1H, ddd, J=4.8, 1.9, 1.0 Hz), 8.16-8.24 (2H, m), 7.92 (1H, td, J=7.7, 1.8 Hz), 7.37-7.45 (2H, m), 6.89 (1H, d, J=8.8 Hz), 6.31 (1H, dd, J=8.8, 2.7 Hz), 5.60 (1H, d, J=2.7 Hz), 4.42-4.52 (2H, m), 3.80-3.87 (1H, m), 3.62-3.76 (5H, m), 2.68-2.80 (4H, m), 2.53 (3H, s). Mass Spectrum (ESI) m/e=440.0 (M+1).