Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:10][C:9]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:30]O>ClCCl.[Cl-].[NH4+]>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]2[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9](=[O:29])[CH2:10]2)=[CH:14][C:15]=1[OH:30]
Reactant: OO
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(Cl)c(B3OC(C)(C)C(C)(C)O3)c2)CC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(Cl)c(O)c2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
One an one-half (1.5 g, 3.56 mmol) of (4R)-tert-butyl-4-[4-chloro-3-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2yl))phenyl]-2-oxopyrrolidinecarboxylate was dissolved in 10 mL dichloromethane. To this solution, 3 equiv. of 35% hydrogen peroxide (10.68 mmol) was added dropwise. The reaction mixture was stirred overnight at room temperature. The mixture was diluted with saturated ammonium chloride aqueous solution and extracted with dichloromethane (3 times). The combined organic layers were dried over Na2SO4 and concentrated to dryness to provide tert-butyl (4R)-4-(4-chloro-3-hydroxyphenyl)-2-oxopyrrolidinecarboxylate (68a) as a clear oil (1.2 g, 95% yield). 1H-NMR (400 MHz, CD3OD): δ 2.63-2.69 (dd, J=17.2, 9.2 Hz, 1H), 2.80-2.87 (dd, J=17.2, 8.4 Hz, 1H), 3.47-3.54 (m, 1H), 3.61-3.66 (m, 1H), 4.12-4.11 (t, J=2.4 Hz, 1H), 7.24-7.22 (d, J=8.0 Hz, 1H), 6.82-6.82 (d, J=2.0 Hz, 1H), 6.73-6.75 (d, J=2.0 Hz, 1H); MS (ESI) m/z 334.01 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH:13]=O.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH2:13][NH:18][CH:15]1[CH2:17][CH2:16]1
Reactant: CC(=O)NCc1ccc(Cl)c(C=O)c1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)NCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A mixture of N-(4-chloro-3-formyl-benzyl)-acetamide (382 mg, 1.81 mmol) and cyclopropylamine (0.194 mL, 2.71 mmol) in MeOH (18 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (102 mg, 2.71 mmol) was added in portions. The mixture was stirred for 1 h, and the solvents were removed under reduced pressure. EtOAc (50 mL) was added, and the resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC(CH2Cl2/MeOH 95:5) yielded the title compound (371 mg, 81%). LC-MS: tR=0.53 min; ES+: 253.11.
Reaction SMILES: [N:1]1([C:8]2[N:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)C=[C:10]([N:17]3[CH2:20][CH:19](OS(C)(=O)=O)[CH2:18]3)[C:9]=2[CH3:26])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-:27].[Na+].C[N:30](C)C=O>>[Br:27][CH:19]1[CH2:20][N:17]([C:10]2[N:30]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:13]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:9]=2[CH3:26])[CH2:18]1
Reactant: Cc1c(N2CC(OS(C)(=O)=O)C2)cc(C2CC2)nc1N1CCCCCC1
Reactant: [Br-]
Reactant: CN(C)C=O
Agent: [Na+]
Product: Cc1c(N2CCCCCC2)nc(C2CC2)nc1N1CC(Br)C1
Temperature: 100 °C
Yield: 30 %

Procedure:
A mixture of methanesulfonic acid 1-(6-azepan-1-yl-2-cyclopropyl-5-methyl-pyridin-4-yl)-azetidin-3-yl ester 190 (0.4 g, 1 mmol) and sodium bromide (0.103 g, 1 mmol) in N,N-dimethylformamide (10 ml) is heated at 100° C. for 6 days. The mixture is then cooled and concentrated in vacuo. The mixture is diluted with dichloromethane and washed two times with water. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to afford 0.4 g of a crude mixture, which is purified by column chromatography (dichloromethane/methanol 98/2). 1-[6-(3-bromo-azetidin-1-yl)-2-cyclopropyl-5-methyl-pyrimidin-4-yl]-azepane 182 (0.11 g, 30%) is obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].NO.[CH3:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([C:20](OC)=[O:21])=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:24].C(O)(=O)C>CO.CN(C=O)C>[OH:3][NH:2][C:20]([C:14]1[CH:13]=[C:12]2[C:17]([C:18](=[O:19])[N:9]([CH3:8])[C:10](=[O:24])[NH:11]2)=[CH:16][CH:15]=1)=[O:21]
Reactant: COC(=O)c1ccc2c(=O)n(C)c(=O)[nH]c2c1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2cc(C(=O)NO)ccc2c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 19 %

Procedure:
A mixture of hydroxylamine hydrochloride (2.0 g, 29 mmol) in methanol (10 mL) was heated at 90° C. under a dry nitrogen atmosphere until homogeneous. To this heated solution was added a solution of potassium hydroxide (2.85 g, 50.8 mmol) in methanol (6 mL). A precipitate formed on mixing. After heating at 90° C. for 30 minutes, the mixture was cooled to rt and the solids were allowed to settle. The resulting solution was assumed to contain 1.7 M hydroxylamine.potassium salt and was carefully removed by syringe to exclude solids. An aliquot of the above solution (2.79 mL, 4.74 mmol) was added to a solution of methyl 3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (0.11 g, 0.47 mmol) in methanol (1 mL) and DMF (2 mL). After stirring for 4 h at rt, excess reagent was quenched by the addition of acetic acid (0.27 mL, 4.74 mmol). The mixture was concentrated to dryness and the residue was twice co-evaporated with toluene. The crude product was purified by preparative HPLC to afford N-hydroxy-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide (21 mg, 19%). LC-MS: (FA) ES+ 236; 1H NMR (400 MHz, DMSO) δ 10.87 (s, 2H), 7.95 (d, J=8.2 Hz, 1H), 7.56 (s, 1H), 7.48 (dd, J=8.2, 1.1 Hz, 1H), 3.25 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 88.1 %

Procedure:
To a stirred solution of 4-fluoronitrobenzene (5.0 g, 35.43 mmol) in DMF (40 mL) were added morpholine (4.7 mL, 53.15 mmol) and cesium carbonate (17.3 g, 53.15 mmol). The reaction mixture was stirred at 60° C. for 48 h, then water (50 mL) was added. The solid formed was filtered and washed with water (5×100 mL), then Et2O (3×50 mL) to give the title compound (6.5 g, 88%) as a yellow solid that was used without further purification. δH (DMSO-d6) 8.12-8.02 (2H, m), 7.09-7.00 (2H, m), 3.79-3.68 (4H, m), 4.46-3.37 (4H, m). LCMS (ES+) 208.9 (M+H)+, RT 2.49 minutes (Method 3).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][S:7][CH:6]=1)=[O:4].Cl[C:12]([F:17])([F:16])[C:13](Cl)=[O:14].[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>>[F:16][C:12]([F:17])([O:31][C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[CH:30][CH:29]=1)[C:13]([NH:10][C:9]1[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][CH:8]=1)=[O:14]
Reactant: O=C(Cl)C(F)(F)Cl
Reactant: COC(=O)c1cscc1N
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Product: O=C(O)c1cscc1NC(=O)C(F)(F)Oc1ccc(-c2ccc(F)cc2)cc1

Procedure:
In analogy to Example 58, the title compound was prepared using 4-amino-thiophene-3-carboxylic acid methyl ester, chlorodifluoroacetyl chloride and 4-fluoro-4′-hydroxybiphenyl. MS (m/e): 406.1 (M−H).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]1[CH2:23][S:24][C@@H:25]2[C@H:37]([NH:38][CH:39]=[O:40])[C:36](=[O:41])[N:26]2[C:27]=1[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29]>C(OCC)(=O)C>[Br-:20].[CH:39]([NH:38][C@@H:37]1[C:36](=[O:41])[N:26]2[C:27]([C:28]([O:30][CH2:31][C:32]([Cl:34])([Cl:33])[Cl:35])=[O:29])=[C:22]([CH2:21][P+:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:23][S:24][C@H:25]12)=[O:40]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CBr)CS[C@H]12
Solvent: CCOC(C)=O
Product: O=CN[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Product: [Br-]
Reaction time: 0.75 h
Yield: 74.1 %

Procedure:
A solution of triphenylphosphine (1.06 g, 2 equiv.) in ethyl acetate (5 ml) was added to a stirred solution of 2,2,2-trichloroethyl 3-bromomethyl-7β-formamidoceph-3-em-4-carboxylate (0.91 g, 2 mmole) in ethyl acetate (5ml). The mixture was stirred at ca. 20° for 45 minutes and then warmed to 45° for 10 minutes. The precipitated solid was filtered off, washed with ethyl acetate and ether, and dried to give the title phosphonium salt (1.06 g, 74%), m.p. 151° to 153° (dec.), [α]D + 92° (C 1.0; CHCl3), λmax. (EtOH) 268.5 nm (ε 9,000) and 275 nm (ε 9,000), νmax. (CHBr3) 3430 (NHH), 1795 (azetidin-2-one), 1730 (CO2R), 1700 (CONH) and 1445 cm-1 (P+ -C6H5), 0.91 (1H,d, J 9Hz; NH), 4.25 (1H,dd, J 9 and 5 Hz; C7 --H), 4.67 (1H,d, J 5 Hz; C6 --H), 4.77 and 4.93 (2H, centres of two collapsed AB-quartets, JP-H 16 Hz; C3 --CH2P30 ), 5.25 and 5.45 (2H, AB-q, J 12 Hz; CH2CCl3)(Found: C, 46.9; H, 3.7; N, 3.7; P, 3.7; S, 3.9%; total halogen content, 3.9 equiv./mole compound. C29H25BrCl3N2O4PS (714.9) requires C, 48.7; H, 3.5; N, 3.9; P, 4.3; S, 4.5%; total halogen content 4 equiv./mole compound).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](=[O:17])SC2C=CC(C)=CC=2)=[CH:6][C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][N:3]=1.[CH:24]([C:26]1[CH:30]=[CH:29][O:28][C:27]=1B(O)O)=[O:25].C(Cl)(Cl)Cl.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH3:1][C:2]1[C:7]([C:8]([C:27]2[O:28][CH:29]=[CH:30][C:26]=2[CH:24]=[O:25])=[O:17])=[CH:6][C:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:4][N:3]=1
Reactant: O=Cc1ccoc1B(O)O
Reactant: Cc1ccc(SC(=O)c2cc(-c3ccccc3)cnc2C)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ncc(-c2ccccc2)cc1C(=O)c1occc1C=O
Temperature: 50 °C

Procedure:
To a mixture of S-(4-methylphenyl) 2-methyl-5-phenylpyridine-3-carbothioate (66 mg, 0.20 mmol), Cu(I) thiophene-2-carboxylate (59 mg, 0.31 mmol), 3-formylfuran-2-boronic acid (31 mg, 0.22 mmol), Pd2dba3.CHCl3 (2 mg, 0.002 mmol), and tri-2-furylphosphine (1.4 mg, 0.006 mmol) was added THF (2.5 mL). The reaction mixture was heated to 50° C. for 15 h, cooled to room temperature, diluted with EtOAc, and washed with 1 N HCl and brine. The organic layer was concentrated and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 10.60 (s, 1H); 8.91 (s, 1H); 8.02 (s, 1H); 7.40-7.61 (series of m, 6H); 7.05 (s, 1H); 2.66 (s, 3H). LRMS (ESI) calc'd for C18H13NO3 [M+H]+, 292.1. found 292.1.
Reaction SMILES: [CH3:1][CH:2]1[C:13]2[C:14]3[C:6](=[CH:7][N:8]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:9]=3[CH:10]=[CH:11][C:12]=2[O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(Cl)Cl.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[F:21][C:19]([F:20])([F:22])[S:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:24])=[O:25])[CH:7]=[C:6]3[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[C:13]=1[C:14]=23)(=[O:17])=[O:18]
Reactant: CC1c2c(OS(=O)(=O)C(F)(F)F)ccc3c2c(cn3S(=O)(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1NCCc2cn(S(=O)(=O)c3ccccc3)c3ccc(OS(=O)(=O)C(F)(F)F)c1c23
Reaction time: 1 h

Procedure:
tert-Butyl 6-methyl-1-(phenylsulfonyl)-7-{[(trifluoromethyl)sulfonyl]oxy}-1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate, Intermediate 16 (12.6 mg, 0.022 mmol) was dissolved in a 50/50 mixture of DCM/TFA (1 mL) and left at room temperature for one hour. The evaporated crude product was purified by preparative HPLC (ACE C8 5 mm, water containing 0.1% TFA —CH3CN) to give 7.2 mg of the title compound as a light brown oil. MS m/z 474 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=CC=CC=2)[CH:3]=[CH:2]1.Br[C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:24])[CH:21]=3)[NH:16][C:15]=2[C:14]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[C:13]2[NH:31][C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=3[C:12]=12>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:13]1[C:14]([O:25][CH2:26][CH2:27][N:28]([CH3:30])[CH3:29])=[C:15]3[NH:16][C:17]4[CH:18]=[CH:19][C:20]([Cl:24])=[CH:21][C:22]=4[C:23]3=[C:11]([N:1]3[CH2:9][CH2:4][CH2:3][CH2:2]3)[C:12]2=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(C)CCOc1c2[nH]c3ccc(Cl)cc3c2c(Br)c2c1[nH]c1ccc(Cl)cc12
Product: CN(C)CCOc1c2[nH]c3ccc(Cl)cc3c2c(N2CCCC2)c2c1[nH]c1ccc(Cl)cc12

Procedure:
The title compound was prepared in a manner analogous to Example 126 except the starting indole is 2-(12-bromo-2,10-dichloro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine. 1H-NMR (400 MHz, CDCl3) δ ppm 10.14 (br s, 2H), 8.11 (s, 2H), 7.37-7.28 (m, 4H), 4.34 (t, J=4.4 Hz, 2H), 3.67-3.55 (m, 4H), 2.72 (t, J=4.4 Hz, 2H), 2.53 (s, 6H), 2.45-2.33 (m, 4H); MS (ESI) m/z 479.1 (M−H)−; MS (ESI) m/z 481.1 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][CH:24]([N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[C:25]#[CH:26].C(N(CC)CC)C>C(#N)C.[Cu](I)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>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:26]#[C:25][CH:24]([N:27]3[C:35](=[O:36])[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:37])[CH3:23])=[CH:18][CH:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(C)N1C(=O)c2ccccc2C1=O
Reactant: Brc1ccc(Oc2ccc(OCc3ccccc3)nc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C#Cc1ccc(Oc2ccc(OCc3ccccc3)nc2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Benzyloxy-5-(4-bromophenoxy)pyridine (826 mg, 2.32 mmol) and 2-(1-methylprop-2-ynyl)isoindole-1,3-dione (693 mg, 3.48 mmol) were dissolved in anhydrous acetonitrile under argon and admixed with triethylamine (2.78 ml, 19.94 mmol), copper iodide (22.1 mg, 0.116 mmol) and bis(triphenylphosphine)palladium(II) chloride (81.4 mg, 0.116 mmol). The reaction mixture was stirred at 100° C. in a microwave reactor for 30 min. A further 0.75 equivalent of the reactants were added and the stirring was continued at 100° C. for a further 60 min. The batch was concentrated, admixed with ethyl acetate and water and filtered, and the organic phase was separated off and concentrated. The crude product was further reacted without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:17](=O)[C:18]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[C:20]([O:21][CH3:22])[CH:19]=1>>[CH3:22][O:21][C:20]1[CH:19]=[C:18]([C:17]2[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]3[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[CH:3][C:2]=3[N:1]=2)[CH:27]=[CH:26][C:23]=1[O:24][CH3:25]
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Reactant: COc1ccc(C=O)cc1OC
Product: COc1ccc(-c2nc3cnc4ccccc4c3n2CC(C)C)cc1OC

Procedure:
Following the general method of Example 195, Step B, 3-amino-4-(isobutylamino)quinoline was reacted with veratraldehyde to provide 2-(3,4-dimethoxyphenyl)-1-isobutyl-1H-imidazo[4,5-c]quinoline, melting point 192°-199° C. Analysis: Calculated for C20H23N3O2 : % C, 73.1; % H, 6.4; % N, 11.6. Found: % C, 72.7; % H, 6.3; % N, 11.4.
Reaction SMILES: ClC1N=C(N2CC[O:14][CH2:13]C2)C2C=CSC=2N=1.[NH2:17][C:18]1(C(OC)=O)[CH2:22][CH:21]=[CH:20][S:19]1.ClS([N:31]=[C:32]=[O:33])(=O)=O>>[NH:17]1[C:18]2[S:19][CH:20]=[CH:21][C:22]=2[C:13](=[O:14])[NH:31][C:32]1=[O:33]
Reactant: COC(=O)C1(N)CC=CS1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Clc1nc(N2CCOCC2)c2ccsc2n1
Product: O=c1[nH]c(=O)c2ccsc2[nH]1

Procedure:
Scheme 6 shows the synthesis of 4-(2-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine 18 starting by cyclization of methyl 2-amino-thiophenecarboxylate 15 (95 g) with chlorosulfonyl isocyanate at low temperature remains (−60° C. to −55° C.) to give thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 16. Phosphorous oxychloride was added slowly to a cold solution of thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 16 and N,N-dimethylaniline (0.75 equiv.) in acetonitrile while maintaining the temperature below 25° C. The mixture was then heated to 80-85° C. and stirred for 24 hours to afford dichlorothieno[2,3-d]pyrimidine 17. Morpholine (2.2 equiv.) was added to a solution of 2,4-dichlorothieno[2,3-d]pyrimidine 17 in methanol and stirred at ambient temperature for 1 h to give 18.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1>>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:22])[C:13]1[CH:18]=[C:17]([N+:1]([O-:4])=[O:2])[C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1
Reactant: COc1cc(C(=O)c2ccccc2F)ccc1O
Reactant: O=[N+]([O-])O
Product: COc1cc(C(=O)c2ccccc2F)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
7.8 ml of 65 percent nitric acid are added dropwise at 20° within 20 minutes to 29.4 g of 2'-fluoro-4-hydroxy-3-methoxybenzophenone (dissolved in 450 ml of acetic acid). After stirring for 1.5 hours, the reaction mixture is poured into 2 l of ice-water and the precipitate formed is filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from methanol. There is obtained 2'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone of m.p. 127°-129°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:15][C:16](N(OC)C)=[O:17])=[CH:10][CH:9]=1.CC(N=P(N=P(N(C)C)(N(C)C)N(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)(C)C>C1COCC1.[I-].[Zn+2].[I-]>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:15][C:16]([C:5]2[CH:4]=[CH:3][N:2]=[N:1][CH:6]=2)=[O:17])=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Reactant: c1ccnnc1
Agent: CN(C)P(=NP(=NC(C)(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C)(N(C)C)N(C)C
Agent: [I-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Cc1ccccc1[C@H](CC(=O)c1ccnnc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 2.5 %

Procedure:
To a solution of pyridazine (250 mg, 3.12 mmol) and (R)-3-(4-bromophenyl)-N-methoxy-N-methyl-3-o-tolylpropanamide (1.81 g, 4.99 mmol) in THF (10 mL) was added zinc iodide (996 mg, 3.12 mmol). The suspension was stirred for 10 min. at ambient temperature. The reaction mixture was cooled to −78° C., then N′″-(1,1-dimethylethyl)-N,N′,N″-tris[tris(dimethyl-amino)phosphoranylidene]-phosphorimidic triamide solution (“Schwesinger P4 base”; 1 M in hexane 4.68 mL, 4.68 mmol) was added. The reaction mixture was allowed to reach room temperature over 16 h, then partitioned between sat, aq. ammonium chloride solution and dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound 30 mg, 3%), while the most of the starting material was recovered (1.51 g, 83%). Light yellow gum, MS: 381.1 [M+H]+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[CH:26]([C:29]1[CH:34]=[CH:33][C:32]([NH:35]N)=[CH:31][CH:30]=1)([CH3:28])[CH3:27]>>[CH:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:31][CH:30]=1)([CH3:28])[CH3:27]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: CC(C)c1ccc(NN)cc1
Product: CC(C)c1ccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (4-isopropyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=441.0 (M+H)+
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[NH2:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]2[C:55]([NH:56][C:57]([NH:59][C:60]3[CH:65]=[CH:64][C:63]([O:66][C:67]4[CH:72]=[CH:71][N:70]=[CH:69][CH:68]=4)=[CH:62][CH:61]=3)=[O:58])=[CH:54][C:53]([C:73]([CH3:76])([CH3:75])[CH3:74])=[N:52]2)=[CH:47][CH:46]=1>C1COCC1.C(#N)C>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10](=[O:12])[NH:43][CH2:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]2[C:55]([NH:56][C:57]([NH:59][C:60]3[CH:65]=[CH:64][C:63]([O:66][C:67]4[CH:68]=[CH:69][N:70]=[CH:71][CH:72]=4)=[CH:62][CH:61]=3)=[O:58])=[CH:54][C:53]([C:73]([CH3:76])([CH3:75])[CH3:74])=[N:52]2)=[CH:47][CH:46]=1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(CN)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC(=O)NCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
To a solution of N-Boc-glycine (260 mg, 1.48 mmol), EDCI (283 mg, 148 mmol) and HOBT (200 mg, 1.48 mmol) in THF/acetonitrile (50:50, 5 mL) was added N,N-diisopropylethylamine (380 mg, 2.96 mmol), and the resulting reaction mixture was stirred at room temperature for 1 h. Then, 1-[2-(4-aminomethyl-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea (450 mg, 0.99 mmol) was added to the solution and the reaction mixture was stirred at 50° C. for 18 h. The reaction mixture was cooled to room temperature, concentrated at reduced pressure, and the residue was dissolved in EtOAc (20 mL). The solution was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by preparative TLC (50:50 hexanes/EtOAc) to give 65 mg (11%) of the desired product. 1H-NMR (DMSO-d6) 8.68 (s, 1H), 8.42 (d, J=6.3 Hz, 2H), 7.98 (s, 1H), 7.82 (b, 1H), 7.61 (d, J=6.9 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.08 (d, J=6.6 Hz, 2H), 6.80 (d, J=6.3 Hz, 2H), 6.46 (s, 1H), 4.48 (d, J=6.0 Hz, 2H), 3.78 (d, J=5.7 Hz, 2H), 1.35 (s, 9H), 1.30 (s, 9H); MS LC-MS [M+H]+=614, RT=2.89 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]#[N:12])=[N:2]1.[CH2:13](N)[CH2:14][NH2:15].C(=S)=S.C(Cl)(Cl)[Cl:21]>>[ClH:21].[NH:12]1[CH2:13][CH2:14][N:15]=[C:11]1[CH2:10][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]=1
Reactant: ClC(Cl)Cl
Reactant: N#CCc1noc2ccccc12
Reactant: NCCN
Solvent: S=C=S
Product: Cl
Product: c1ccc2c(CC3=NCCN3)noc2c1
Reaction time: 8 h

Procedure:
A mixture of 1,2-benzisoxazole-3-acetonitrile (1.6 g), ethylenediamine (0.7 g) and carbon disulfide (0.2 ml) was heated at 130° to 150°C for 0.5 hour and then allowed to stand at room temperature overnight. to the reaction mixture was added chloroform and the insoluble substance was filtered off. The filtrate was subjected to silica gel column chromatography and eluted with 10 to 20 % methanol-chloroform. The eluates were collected and treated with ethanolic hydrochloric acid to give the hydrochloride. The product was treated with charcoal and then recrystallized from ethanol to give the desired compound (0.4 g). m.p. 223° to 228°C.