Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:38][CH2:39][C:40]1[C:41]([OH:48])=[N:42][C:43]([CH3:47])=[CH:44][C:45]=1[CH3:46]>ClCCl>[OH:48][C:41]1[C:40]([CH2:39][NH:38][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([CH:8]([O:7][C:2]3[N:1]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:45]([CH3:46])[CH:44]=[C:43]([CH3:47])[N:42]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ncccn1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ncccn3)cc2)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 32.2 %

Procedure:
To a solution of 4-(1-(pyrimidin-2-yloxy)ethyl)benzoic acid (100 mg, 0.41 mmol), 1-hydroxybenzotriozole (83 mg, 0.61 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (118 mg, 0.61 mmol), triethylamine (0.2 mL) in dichloromethane (15 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (62 mg, 0.41 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-(pyrimidin-2-yloxy)ethyl)benzamide as a white solid (50 mg, 32%). LRMS (M+H+) m/z: 378.17. found 378. HPLC Purity (214 nm): 100%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.30 (d, J=4.8 Hz, 1H), 8.06-8.04 (m, 1H), 7.80-7.68 (m, 2H), 7.44-7.42 (m, 2H), 6.93-6.84 (m, 2H), 6.17 (q, J=6.6 Hz, 1H), 5.84 (s, 1H), 4.27 (d, J=4.8, 2H), 2.15 (s, 3H), 2.11 (s, 3H), 1.55 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12](Cl)=[O:13])=[CH:9][CH:8]=[C:7]([O:15][CH3:16])[CH:6]=2.[CH2:23]([C@H:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]>C(Cl)Cl.CN(C=O)C>[CH2:23]([C@H:25]([NH:32][C:12]([C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:15][CH3:16])=[CH:8][CH:9]=2)[N:4]=[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:2]=1[CH3:1])=[O:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]
Reactant: CC[C@H](N)c1ccccc1
Reactant: COc1ccc2c(C(=O)Cl)c(C)c(-c3ccccc3)nc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(C)c(-c2ccccc2)nc2cc(OC)ccc12)c1ccccc1
Reaction time: 12 h

Procedure:
Prepared as described in Ex. 1, starting from 1.27 g (4.09 mmol) of crude 3-methyl-7-methoxy-2-phenylquinoline-4-carbonylchloride, 0.55 g (4.09 mmol) of (S)-(−)-α-ethylbenzylamine and 1.71 ml (12.27 mmol) of TEA in 24 ml of dry CH2Cl2 and 1 ml of DMF to help solubility. The reaction mixture was stirred 12 hours at room temperture.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>>[CH2:23]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: NC(=O)C1CCNCC1
Reactant: CCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCCCCCN1CCC(C(N)=O)CC1
Yield: 101.2 %

Procedure:
Prepared from isonipecotamide (2.0 g, 15.6 mmol), 1-bromotridecane (4.0 mL, 15.6 mmol) and potassium carbonate (2.16 g, 15.6 mmol) of according to procedure used for Example 8 (Step A) to give 4.9 g of the title compound as a white solid.
Reaction SMILES: [CH:1]1([C:9]2[CH:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][C:10]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:28])=O>C(Cl)Cl.CN(C=O)C>[Cl:28][CH2:15][C:13]1[CH:12]=[CH:11][C:10]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])=[C:9]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:14]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2CCCCCCC2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C2CCCCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a stirred solution of 66.16F (0.130 g, 0.4 mmol) in DCM (2.00 mL) and DMF (0.03 mL) at 0° C. was added thionyl chloride (0.06 mL, 0.8 mmol). The reaction was stirred at room temperature for 2 hours. After which, the reaction was concentrated in vacuo and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.16G as a colorless oil (0.130 g, 95% yield).
Reaction SMILES: Br.[Br:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:10](=O)([O-])[O-:11].[K+].[K+]>O.C(OC)=O>[CH:10]([N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][Br:2])[CH2:5][CH2:6]1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: BrCC1CCNCC1
Agent: Br
Agent: [K+]
Solvent: O
Solvent: COC=O
Product: O=CN1CCC(CBr)CC1
Reaction time: 20 h

Procedure:
To a solution of 4-bromomethylpiperidin hydrobromide (12.8 g, 0.05 mole) in water (5 ml), methyl formate (25 ml) and potassium carbonate (10 g) were added and the mixture stirred for 20 hours. The solvent was decanted, and the residue was extracted with two 25 ml portions of ether. The combined organic phases were washed with water, dried and evaporated to give (A) as a colourless oil. The IR spectrum (chloroform) showed a strong band at 1650 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:19](OCC)(=[O:21])C>CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:14]([CH2:17][CH3:18])[CH2:15][O:16][C:19]3=[O:21])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CCC(CO)Nc1nc(-c2ccc(Br)cc2)cs1
Solvent: CCCCCC
Product: CCC1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Yield: 72 %

Procedure:
In the same manner as described in step 4 of Example 1, replacing (2R)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}propan-1-ol with 2-[4-(4-bromo-phenyl)-thiazol-2-ylamino]-butan-1-ol, prepared in the previous step, and purification by flash chromatography using a solvent gradient of 10 to 20% ethyl acetate in hexane gave the title compound (155 mg, 72%) as a white solid; mp 148.5° C.; MS (ESI) m/z 353 [M+H]+. Anal. Calcd for C14H13BrN2O2S: C, 47.60; H, 3.71; N, 7.93. Found: C, 47.25; H, 3.64; N, 7.74. HRMS: calcd for C14H13BrN2O2S+H+, 352.99538; found (ESI, [M+H]+), 352.9939.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3([CH3:15])[C:11](=[CH:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[H-].[Na+].[CH3:20]I.O>C(COC)OC>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3([CH3:15])[C:11](=[CH:12][CH2:13][C:4]=2[CH:3]=1)[N:10]([CH3:20])[C:9](=[O:14])[CH2:8][CH2:7]3
Reactant: CC12CCC(=O)NC1=CCc1cc(F)ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1C(=O)CCC2(C)C1=CCc1cc(F)ccc12
Temperature: 25 °C
Yield: 56 %

Procedure:
8-fluoro 10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one (1.38 g; 6mmol) was added to a suspension of NaH (475 mg; 20 mmol) in glyme (15 ml). The mixture was refluxed for 1.5 hours and cooled quickly to room temperature. Methyl iodide (15 ml) was added and the mixture refluxed for 4 hours, then allowed to cool to room temperature. After addition of water, the mixture was concentrated to near dryness. The residue was partitioned between ethyl acetate and water. The organic layer was washed three times with water, dried over MgSO4 and concentrated under vacuum. Recrystallization from hexane afforded 737 mg (56% yield) of the subtitle compound. Melting point 110°-111° C.
Reaction SMILES: C(=O)(O)[O-].[Na+].O.[OH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[N:14]#[C:15]Br>C(Cl)Cl>[C:15]([N:11]1[CH2:12][CH2:13][CH:8]([OH:7])[CH2:9][CH2:10]1)#[N:14]
Reactant: OC1CCNCC1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#CN1CCC(O)CC1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A 5-liter, 3-neck flask was equipped with mechanical stirring, a reflux condenser, and a powder addition funnel. Sodium bicarbonate (840 g, 10 mmol) was added via the powder funnel while stirring, then water (ca. 300-400 mL) was gradually added while vigorously stirring to form a thick, uniform slurry. The flask was then placed in an ice bath, and a solution of 4-hydroxypiperidine (506 g, 5.00 mol) in CH2Cl2 (1.0 L) was added, and the contents were vigorously mixed while cooling. A solution of cyanogen bromide (640 g, 6.0 mol) in CH2Cl2 (600 mL) was added in a dropwise fashion over 2 h, and stirring was continued for an additional 30 min. The ice bath was removed, and the mechanical stirrer was replaced by a magnetic stirrer, and the reaction mixture was stirred for 16 h. The flask was once again placed under mechanical stirring, and sodium carbonate (100 g) was added in order to ensure complete neutralization. MgSO4 (500 g) was added, and vigorous stirring was continued for 15 min. The resulting suspension was filtered, rinsing with CH2Cl2 (2.0 L). A light amber, viscous oil was obtained upon solvent removal to give 1-cyano-4-hydroxypiperidine (574 g, 91% yield. 1H NMR (CDCl3) δ 3.80 (m, 1H), 3.39 (m, 2H), 3.05 (m, 2H), 1.87 (m, 2H), 1.70 (br s, 1H), 1.62 (m, 2H); MS m/z 212.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][C:18]=1[CH3:32]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:19][C:18]=2[CH3:32])=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: COC(=O)c1coc(-c2ccc(N)c(C)c2)n1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2C)nc1Cl
Yield: 50.3 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.12 g, 0.69 mmol), thionyl chloride (4 mL), methyl 4-amino-3-methylphenyl)-1,3-oxazole-4-carboxylate obtained in Example (109e) (0.23 g, 0.95 mmol) and pyridine (5 mL), to obtain 135 mg of the title compound as a light brown solid (50%).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:20]=[CH:19][C:12]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[S:21]1[CH2:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[S:21]1[CH2:22][CH:23]=[C:24]([C:2]2[C:3]([O:8][C:9]3[CH:20]=[CH:19][C:12]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:25][CH2:26]1
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
Reactant: CON(C)C(=O)c1ccc(Oc2nccnc2Cl)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CON(C)C(=O)c1ccc(Oc2nccnc2C2=CCSCC2)cc1
Temperature: 120 °C

Procedure:
A mixture of 4-(3-chloropyrazin-2-yloxy)-N-methoxy-N-methylbenzamide (1.4 g, 4.77 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.132 g, 5.01 mmol), potassium carbonate (1.976 g, 14.30 mmol), and bis(tri-tert-butylphosphine)palladium(0) (0.244 g, 0.477 mmol) in p-dioxane/H2O (10:1, 11 ml) was heated to 120° C. in 4 h, cooled, taken up in H2O, extracted with EtOAc (3×), dried over MgSO4, concentrated and purified by ISCO (50% EtOAc/hexanes) to give the titled compound. MS [M+1]: 358.1.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:19])=[C:9]([CH:18]=1)[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11].C(N(CC)CC)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>C1COCC1>[Cl:19][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH:3][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:18][C:9]=1[C:10]([NH:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)=[O:11]
Reactant: CC(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a suspension of 5-(aminomethyl)-2-chloro-N-(1H-imidazol-2-yl)benzamide dihydrochloride (50 mg, 0.154 mmol, 1.0 equiv) in THF (0.77 mL), add triethylamine (80 μL, 0.57 mmol, 3.7 equiv) and isobutyryl chloride (16.3 μL, 0.154 mmol, 1.0 equiv), and stir the reaction mixture for 1 h at room temperature. Concentrate the reaction mixture under reduced pressure, triturate the crude solids with a mixture of water (10 mL), hexanes (10 mL), and diethyl ether (10 mL), isolate the white solid by filtration and dry in a 40° C. vacuum oven to give the title compound (19 mg, 38% yield): 1H NMR (DMSO-d6, 400 MHz): δ 11.74 (br s, 2H), 8.30 (t, 1H, J=6.0 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.36 (d, 1H, J=2.0 Hz), 7.26 (dd, 1H, J=8.0, 2.0 Hz), 6.73 (br s, 2H), 4.22 (d, 2H, J=5.9 Hz), 2.37 (septet, 1H, J=6.6 Hz), 0.97 (d, 6H, J=6.8 Hz). MS (m/z) (35Cl/37Cl) 321/323 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][O:22][CH:23]([C:27]2[C:35]3[C:31](=[CH:32][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:34]=3)[CH:30]=[C:29]([Cl:44])[CH:28]=2)[C:24](O)=[O:25])([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:45][NH:46][CH3:47].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O>[Cl:44][C:29]1[CH:28]=[C:27]([CH:23]([O:22][CH2:21][C:11]2([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[C:24]([N:46]([CH3:47])[CH3:45])=[O:25])[C:35]2[C:31](=[CH:32][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:34]=2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reactant: CNC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 1 h

Procedure:
To a solution of 2-((1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methoxy)-2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)acetic acid (25 mg, 0.039 mmol) and dimethylamine (40% in water, 0.024 mL) in dimethylformamide (1 mL) at 0° C. was added PyBOP® (24.08 mg, 0.046 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was quenched by addition of water and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (50%→85% ethyl acetate/n-hexane) gave 21 mg (81%) as a foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.31 (dd, J=8.5, 5.5 Hz, 2H), 7.09 (d, J=1.8 Hz, 1H), 6.99 (dd, J=8.6, 8.5 Hz, 2H), 5.66 (d, J=10.7 Hz, 1H), 5.62 (d, J=10.7 Hz, 1H), 3.70 (m, 2H), 3.57 (m, 3H), 3.44 (d, J=8.9 Hz, 1H), 3.05 (m, 2H), 2.88 (s, 3H), 2.80 (s, 3H), 2.13 (m, 2H), 1.91 (m, 2H), 1.42 (s, 9H), 0.91 (t, J=8.3 Hz, 2H), −0.04 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 169.0, 161.5 (d, J=245 Hz), 155.0, 145.8, 138.7, 129.0 (d, J=7.7 Hz), 128.3, 125.9, 122.7, 122.5, 119.2, 115.2 (d, J=21 Hz), 82.1, 79.4, 78.4, 75.7, 67.7,41.4, 40.1 (br), 36.8, 36.1, 32.1, 28.6, 17.9, −1.3. Mass spec.: 675.38 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7](=[O:18])[CH:6]3[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[CH3:23]C(C)([O-])C.[Na+].IC>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:7](=[O:18])[C:6]3([CH3:23])[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCOCC1
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: CC12COCCN1c1nc(Cl)ncc1N(C1CCOCC1)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.7 %

Procedure:
To a 20 mL vial containing 2-chloro-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (0.0907 g, 0.279 mmol) was added DMSO (0.5 mL); placed in a dry ice-acetone bath and then added sodium tert-butoxide (0.030 g, 0.307 mmol) followed by DMSO (0.5 mL) and iodomethane (0.019 ml, 0.307 mmol). The dry ice-acetone bath was removed and the mixture was allowed to warm up to room temperature and stirred for 16 h. The reaction was diluted with 10 mL of water and vigorously stirred at room temperature. Collected rust/orange solids by vacuum filtration, washed with additional water and dried under high vacuum affording 2-chloro-6a-methyl-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (46.0 mg, 48.4% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (d, J=0.76 Hz, 3H) 2.48-2.72 (m, 2H) 3.17-3.34 (m, 1H) 3.41-3.77 (m, 5H) 3.94-4.19 (m, 6H) 4.61 (tt, J=12.38, 4.29 Hz, 1 H) 7.98-8.14 (m, 1H). MS [M+H] found 339.3.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1Br.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)#[CH:33]>ClCCCl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1[C:33]#[C:32][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)n1nc(-c2nc(C#Cc3ccccc3)c(N)nc2-c2ccccc2)ccc1=O

Procedure:
In the presence of copper(I) iodide (5 mg) and dichlorobis(triphenylphosphine)palladium(II) (18 mg), triethylamine (0.0794 ml) was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (200 mg) and ethynylbenzene (0.0626 ml) in 1,2-dichloroethane (2 ml) at 60° C. The mixture was refluxed for 2 hours. The mixture was cooled to give a precipitate. The precipitate was collected by filtration and suspended in MeOH to give 6-[5-amino-3-phenyl-6-(phenylethynyl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (104 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:4].[CH3:15][N:16]1[C:20]([CH3:21])=[CH:19][C:18]([C:22](Cl)=[O:23])=[N:17]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:22]([C:18]1[CH:19]=[C:20]([CH3:21])[N:16]([CH3:15])[N:17]=1)=[O:23])(=[O:13])=[O:12])=[O:4]
Reactant: Cc1cc(C(=O)Cl)nn1C
Reactant: COC(=O)c1ccccc1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)c1cc(C)n(C)n1
Yield: 68.5 %

Procedure:
10.8 g of 2-methoxycarbonylphenylsulfonamide, 8.6 g of 1,5-dimethylpyrazole-3-carbonyl chloride and 13.8 g of potassium carbonate in 200 ml of absolute acetone are refluxed for 8 h. The solvent is removed by distillation and then the residue is taken up in water and the pH is adjusted to 2. The precipitate is filtered off with suction and washed with H2O until neutral. The residue is stirred with ether, filtered off with suction and dried under reduced pressure. 11.6 g of N-(2-methoxycarbonylphenylsulfonyl)-1,5-dimethylpyrazole-3-carboxamide with a melting point of 176°-177° C. are obtained (active ingredient Example No. 40).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19]O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (0.25 g), 2-(tert-butoxycarbonylamino)ethanol (0.33 g) and triphenylphosphine (0.59 g) in tetra hydrofuran (2 mL) was added diethyl azodicarboxylate (40% toluene solution, 1.34 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was directly purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-3/1) to give 4-[2-(tert-butoxycarbonylamino)ethoxy]benzaldehyde (0.41 g). The title compound was prepared in a similar manner to that described in Reference Example 45 using this material instead of 4-isobutylbenzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Brc1cnc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cccc(Cn2ccc3ncc(Br)cc32)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-bromo-1H-pyrrolo[3,2-b]pyridine (400 mg, 2.030 mmol) and sodium hydride (60% in mineral oil) (89 mg, 2.233 mmol) in 4 mL N,N-dimethylformamide was stirred at ambient temperature for 10 minutes and 1-(bromomethyl)-3-fluorobenzene (384 mg, 2.030 mmol) was added. The mixture was heated at 100° C. for 3 hours. The mixture was cooled to ambient temperature, diluted with 100 mL of ethyl acetate and washed successively with water and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on Analogix IntelliFlash280 eluting with 10 to 70% ethyl acetate/hexanes to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:36])[CH2:32][C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:36])[CH2:32][C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)CC(=O)O
Product: CCOC(=O)CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (>98%). MS: m/e=473(M+H+).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].N(OC(C)(C)C)=O.N[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>[Cu](F)F.N1C=CC=CC=1>[O:1]([N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: Nc1ccccc1
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1Oc1ccccc1
Yield: 55237.1 %

Procedure:
The procedure of Example 1 is repeated using 5.79 g (0.021 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 5.05 g (49 mmol) of tert-butyl nitrite, 12.6 mg (0.125 mmol) of copper(II) fluoride, 120 mL of pyridine and 3.91 g (42 mmol) of aniline at 70° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 4.10 g of the title compound as a yellowish oil in 55.3% yield. The structure is confirmed by mass spectrographic analysis. MS [M+1]354.