Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])/[CH:1]=[CH:2]/[CH:3]([OH:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(O)CCCCCCCC
Product: CCCCCCCCC(O)/C=C/[Sn](CCCC)(CCCC)CCCC
Temperature: 120 °C

Procedure:
To 0.07 g (0.42 mmol) of the titled product of Example 7 is added 0.15 g (0.5 mmol) of tri-n-butyltin hydride and 20 mg of azoisobutyronitrile (AIBN). The reaction mixture was heated to 120° C. for 2 hours. Afterwards, it was cooled to room temperature and pumped at high vacuum overnight. The crude reaction mixture was then heated to 90° C. and maintained at high vacuum for 2 additional hours. Upon cooling to room temperature, the crude product was used as is.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])=O.[NH2:13][S:14]([C:17]1[CH:18]=[C:19]([C:23](=[S:25])[NH2:24])[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]>>[CH2:11]([C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:24]=[C:23]([C:19]2[CH:18]=[C:17]([S:14]([NH2:13])(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=2)[S:25][CH:2]=1)[CH3:12]
Reactant: CCc1ccncc1C(=O)CBr
Reactant: NC(=S)c1cccc(S(N)(=O)=O)c1
Product: CCc1ccncc1-c1csc(-c2cccc(S(N)(=O)=O)c2)n1
Yield: 38.1 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-ethylpyridin-3-yl)ethanone hydrobromate (161 mg) and 3-(aminosulfonyl)benzenecarbothioamide (110 mg), the title compound (67 mg) was obtained as colorless powder crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]([C:21](O)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:16]1[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:22]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccccc1
Yield: 68.6 %

Procedure:
N-(2-(5-chloro-1H-Indol-3-yl)ethyl)biphenyl-2-carboxamide was prepared following Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), biphenyl-2-carboxylic acid (0.0943 g; 0.466 mmol), HATU (0.193 g; 0.508 mmol) and N,N-diisopropylethylamine (0.179 mL; 1.06 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.109 g (68%) of N-(2-(5-chloro-1H-Indol-3-yl)ethyl)biphenyl-2-carboxamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[N:24][NH2:25])[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:23])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[N:27]([O-])=O.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[Cl:23])[N:27]=[N:25][N:24]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccccc1-n1nnnc1-c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A solution of crude 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide (150 mg, 0.334 mmol) in acetic acid (0.5 mL) was treated with a solution of sodium nitrite (115 mg, 1.6 mmol) in water (0.5 mL) at 0° C. After 30 min, an additional 50 mg of sodium nitrite was added. After 10 min, 3 mL of 10% aqueous sodium hydroxide was added. The mixture was extracted with ethyl acetate and the organics dried over sodium sulfate and concentrated. The crude residue was purified by flash column chromatography to give 286 as a colorless solid (111 mg). 1H NMR (dmso-d6, 400 MHz) δ 8.00 (m, 1H), 7.98 (m, 1H), 7.85 (m, 1H), 7.56 (m, 1H), 7.46 (m, 1H), 7.26 (m, 2H), 7.13 (m, 1H), 4.27 (t, 2H), 3.11 (t, 2H). MS (ESI) 461.1
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]3[CH2:12][CH2:13][CH:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]([Cl:14])=[N:4][N:3]=1.[Zn](C(C)C)[CH:16]([CH3:18])[CH3:17]>O1CCOCC1>[CH:16]([C:2]1[C:11]2[CH:10]3[CH2:12][CH2:13][CH:7]([CH2:8][CH2:9]3)[C:6]=2[C:5]([Cl:14])=[N:4][N:3]=1)([CH3:18])[CH3:17]
Reactant: CC(C)[Zn]C(C)C
Reactant: Clc1nnc(Cl)c2c1C1CCC2CC1
Solvent: C1COCCO1
Product: CC(C)c1nnc(Cl)c2c1C1CCC2CC1

Procedure:
A solution of 1,4-dichloro-5,6,7,8-tetrahydro-5,8-ethanophthalazine (Alfa Aesar) (0.109 g, 0.474 mmol), iPr2Zn (1 M in toluene, 0.50 mL, 0.50 mmol), PdCl2dppf CH2Cl2 (19.3 mg, 0.024 mmol) in dioxane (1.5 mL) was stirred at 80° C. for 2.5 hours, quenched with 1 N HCl, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (10% Et2O/CH2Cl2 to 5% MeOH/CH2Cl2) to give impure title compound as a tacky solid (34.9 mg). LC/MS (APCI) M/Z 237.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:31])[CH:7]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])C>C(O)C>[C:24]1([C:21]2[CH:20]=[CH:19][C:18]([O:17][CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:6]([OH:31])=[O:5])=[CH:23][CH:22]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=1
Reactant: CCCCCCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 ml of 2N sodium hydroxide solution are added to 27 g of α-[p-(1-cycloheptenyl)-phenoxy]-undecanoic acid ethyl ester in 150 ml of ethanol and the mixture is stirred for 2 hours at room temperature. The ethanol is removed in vacuo and the residue is partitioned between 2 N hydrochloric acid and ether. The organic phases are washed until neutral, dried over sodium sulphate and concentrated by evaporation in vacuo. Distillation of the residue at 0.04 mm gives α-[p-(1-cycloheptenyl)-phenoxy]-undecanoic acid, of melting point 79°-81° C (from n-hexane), in the fraction boiling at 185°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:5][CH:4]=1.[N+](=[CH2:18])=[N-]>CO.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[N:10]=[N:11][N:12]([CH3:18])[N:13]=2)=[CH:14][CH:15]=1
Reactant: C=[N+]=[N-]
Reactant: COc1ccc(CSc2nnn[nH]2)cc1
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(CSc2nnn(C)n2)cc1
Reaction time: 1 h

Procedure:
To a solution of 5-p-methoxybenzylthiotetrazole (7.00 g : 31.5 mMol.) in methanol (150 ml) is added under ice cooling a solution of diazomethane in ether (produced from 14 g of N-nitrosomethylurea), and the mixture is stirred for 1 hour and then concentrated. The residue is purified by Lobar column chromatography (toluene : ethyl acetate=5: 1) to give 5-p-methoxybenzylthio-2-methyltetrazole 4.86 g :
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:9][O:10][C:11]([C:13]#[C:14][C:15]([O:17][CH3:18])=[O:16])=[O:12]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[N:5]([C:13]([C:11]([O:10][CH3:9])=[O:12])=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:13]=2[C:11]([O:10][CH3:9])=[O:12])[N:4]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: COc1cccnn1
Solvent: CO
Product: COC(=O)c1c(C(=O)OC)c2ccc(OC)nn2c1C(=O)OC
Temperature: 0 °C

Procedure:
Commercially available 3-methoxypyridazine (3.00 g, 27.3 mmol) was dissolved in methanol (60 mL) and cooled to 0° C. Dimethylacetylene dicarboxylate (4.00 mL, 32.8 mmol, 1.2 eq) was added dropwise while the reaction was rapidly stirred. The mixture was maintained at −20° C. for two days. A pale yellow solid formed during this time that was recovered by filtration and washed with cold methanol (2 mL) to furnish an off white solid. MS m/z 323.1 (M+1).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:5]=2[C:6]=1[C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.C1CCCCC1.[N+:28]([O-:33])([N+]([O-])=O)=[O:29]>C(Cl)(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:4]2[O:3][C:2]([N+:28]([O-:33])=[O:29])=[C:6]([C:7]3[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=3)[C:5]=2[CH:17]=1
Reactant: O=C(O)Cc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: C1CCCCC1
Product: O=C(O)Cc1cccc(-c2c([N+](=O)[O-])oc3ccc(Cl)cc23)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3-(2-bromo-5-chloro-3-benzofuranyl)phenylacetic acid in chloroform with 1.5 equivalents of cyclohexane is treated with 1.5 equivalents of dinitrogen tetroxide and stirred for about 20 hours at room temperature. The mixture is washed with water, extracted with saturated sodium bicarbonate solution, then the aqueous extracts are acidified. The mixture is extracted with dichloromethane, which is dried and concentrated. The residue is recrystallized from a mixture of benzene and hexane to provide 3-(5-chloro-2-nitro-3-benzofuranyl)phenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[CH2:20]([OH:22])[CH3:21].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([O:22][CH2:20][CH3:21])[N:3]=1
Reactant: CCO
Reactant: CS(=O)c1nc(N)c(C#N)c(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCOc1nc(N)c(C#N)c(-c2ccco2)c1C#N
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a stirred suspension of 300 mg (1.10 mmol) 2-amino-4-furan-2-yl-6-methanesulfinyl-pyridine-3,5-dicarbonitrile in 15 ml dry DME were added 0.23 ml (3.86 mmol) ethanol and 0.25 ml (1.65 mmol) DBU and stirring continued for 2 hours at room temperature. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/4) followed by trituration in ether/hexane afforded 21 mg (8%) 2-amino-6-ethoxy-4-furan-2-yl-pyridine-3,5-dicarbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 254 (M+, 90), 226 (100), 198 (44), 143 (26).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:9])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[N:17]1.[CH2:25]([Sn:29](=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1>[CH2:25]([Sn:29]([CH2:30][CH2:31][CH2:32][CH3:33])([O:34][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:9])[CH3:10])=[CH:4][C:3]=1[N:16]1[N:17]=[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]2=[N:20]1)[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:9])[CH3:10])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[N:17]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](=O)CCCC
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(Oc1ccc(C(C)(C)CC(C)(C)C)cc1-n1nc2ccccc2n1)Oc1ccc(C(C)(C)CC(C)(C)C)cc1-n1nc2ccccc2n1
Temperature: 2.5 °C
Yield: 43.3 %

Procedure:
2-(2-Hydroxy-5-tert-octylphenyl)-2H-benzotriazole (64.6 g, 0.2 mol, TINUVIN® 329, CIBA), dibutyltin oxide (24.89 g, 0.1 mol) and toluene are charged to a laboratory reactor and the contents are heated to reflux and refluxed for seven hours. About half of the amount of toluene is removed by distillation. The reaction mass is cooled to 0-5° C. after the addition of 200 g of hexane. Any unreacted TINUVIN® 329 and dibutyltin oxide are removed by filtration. The solvent is then removed by distillation to yield the title compound (38 g, 43.3% yield) as a yellow resin whose structure is consistent with 1Hnmr analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:28](O)=[O:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[CH3:21])=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1cnccc1C(=O)O
Product: Cc1cnccc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3-methyl-4-pyridinecarboxylic acid as starting materials, MS (LC/MS): 422.0 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6][C:5]=2[N:4]=1.[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C=O)C>[N:16]([CH2:2][C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6][C:5]=2[N:4]=1)=[N+:17]=[N-:18]
Reactant: CC1(C)CCc2nc(CCl)[nH]c(=O)c2C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CCc2nc(CN=[N+]=[N-])[nH]c(=O)c2C1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 98.5 %

Procedure:
To a solution of 2-(chloromethyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one (150 mg, 0.66 mmol, reagent preparation 17) in DMF (3 mL) was added sodium azide (215 mg, 3.3 mmol). The resulting mixture was stirred at rt for 35 min. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with aqueous lithium chloride (10%), dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 2-(azidomethyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one (151 mg, 0.65 mmol, 98% yield) as a waxy yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.70 (br s, 1H), 4.41 (s, 2H), 2.66 (t, 2H), 2.33 (s, 2H), 1.58 (t, 3H), 1.00 (s, 6H); MS (EI) for C11H15N5O: 234 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]2[C:20]([CH3:25])=[N:21][CH2:22][CH2:23][O:24][C:3]=12.[BH3-]C#N.[Na+]>CCO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[C:4]2[CH:20]([CH3:25])[NH:21][CH2:22][CH2:23][O:24][C:3]=12
Reactant: CC1=NCCOc2c(F)cc3c(ccn3S(=O)(=O)c3ccccc3)c21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC1NCCOc2c(F)cc3c(ccn3S(=O)(=O)c3ccccc3)c21
Temperature: 50 °C
Yield: 11.9 %

Procedure:
6-Fluoro-1-methyl-8-(phenylsulfonyl)-3,8-dihydro-4H-[1,4]oxazepino[6,7-e]indole (Intermediate 31, 0.010 g, 0.028 mmol) was dissolved in EtOH (2 mL) and NaCNBH3 (3.5 mg, 0.056 mmol) was added. The reaction mixture was heated at 50° C. for 1 hour. The reaction was quenched by addition of water and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (1.2 mg). MS m/z 361 [M+H]+.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=34)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:36][CH3:37])[CH:12]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[C:13]([O:36][CH3:37])[CH:12]=2)[CH2:6]1
Reactant: CN(C)C1CNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 85 °C
Yield: 71.7 %

Procedure:
N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 227 mg, 1.31 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]-pyridin-3-ylpyrimidin-2-amine (Intermediate 155, 415 mg, 1.09 mmol) and DIPEA (0.755 mL, 4.36 mmol) in DMA (3.2 mL) and the mixture was heated at 85° C. for 1 h. The mixture was part-purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Clean fractions were combined and concentrated in vacuo. Further purification by FCC, eluting with 0-7% CH3OH in CH2Cl2 gave the title compound (360 mg, 72%) as an orange solid; 1H NMR: 2.15 (6H, s), 3.12-3.19 (1H, m), 3.74-3.78 (2H, m), 3.95 (3H, s), 4.04-4.09 (2H, m), 6.29 (1H, s), 7.08 (1H, td), 7.28 (1H, d), 7.36-7.41 (1H, m), 8.26 (1H, s), 8.35 (1H, d), 8.45-8.49 (2H, m), 8.78 (1H, s), 8.80 (1H, d); m/z: ES+ MH+ 461.33.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([CH3:10])[S:8][CH:9]=1)[CH2:3][NH2:4].[C:11]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=O)[CH3:25])=[CH:19][CH:18]=1)([O:13][CH3:14])=[O:12]>>[C:11]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH:24]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([CH3:10])[S:8][CH:9]=2)[CH3:25])=[CH:21][CH:22]=1)([O:13][CH3:14])=[O:12]
Reactant: Cc1nc(C(O)CN)cs1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Product: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C)n2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-hydroxy-2-(2-methyl-thiazol-4-yl)ethanamine with 1-(4-carbomethoxymethoxyphenyl)propan-2-one followed by purification of the base on a silica gel column using ethyl acetate/methanol =9:1 as eluant.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=1.[F:23][C:24]1([F:45])[CH2:44][CH2:43][C:27]2([C:35]3([N:39]=[C:38]([NH2:40])[C:37]([CH3:41])=[N:36]3)[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([NH2:42])[CH:33]=3)[CH2:28]2)[CH2:26][CH2:25]1.Cl>C(Cl)Cl.CN(C=O)C>[NH2:40][C:38]1[C:37]([CH3:41])=[N:36][C:35]2([C:34]3[C:29](=[CH:30][CH:31]=[C:32]([NH:42][C:20]([C:17]4[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][N:18]=4)=[O:22])[CH:33]=3)[CH2:28][C:27]32[CH2:26][CH2:25][C:24]([F:45])([F:23])[CH2:44][CH2:43]3)[N:39]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC1=NC2(N=C1N)c1cc(N)ccc1CC21CCC(F)(F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1=NC2(N=C1N)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1CC21CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 17.2 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (36 mg, 0.19 mmol) was added to a suspension of 5-chloropicolinic acid (27 mg, 0.17 mmol) in DCM (0.5 mL). The obtained orange solution was stirred for 5 min and then added dropwise over 2 min to an ice-cooled solution of 4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″,6′-diamine (Example 28d Step 1, 46 mg, 0.14 mmol) and 2M aq. HCl (0.072 mL, 0.14 mmol) in DMF (0.5 mL). The mixture was stirred at 0° C. for 10 min and was then allowed to reach r.t. overnight. The solvent was evaporated. The crude was purified using preparative chromatography to give the title compound (11 mg, 17% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.23 (d, 1 H), 1.51 (d, 2 H), 1.66-1.98 (m, 5 H), 2.18 (s, 3 H), 2.99 (d, 1 H), 3.08 (d, 1 H), 6.63 (br. s., 1 H), 7.23-7.29 (m, 2 H), 7.62 (d, 1 H), 8.10 (d, 1 H), 8.18 (dd, 1 H), 8.74 (s, 1 H), 10.50 (s, 1 H); MS (APCI+) m/z 458.1 [M+H]+.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16]C(=O)C)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1>Cl>[O:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)NCc1ccc(CN2CCOCC2)cc1
Agent: Cl
Product: NCc1ccc(CN2CCOCC2)cc1
Yield: 84.6 %

Procedure:
N-(4-Morpholinomethylphenylmethyl)acetamide hydrochloride (28.4 g) was dissolved in 4N hydrochloric acid (114 ml) and the mixture was refluxed under heating for 3 hr 15 min. The solvent was evaporated and ethyl acetate was added. The resulting crystals were collected by filtration. The obtained crystals were dissolved in water (40 ml) and potassium carbonate was added to saturation, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and, after drying, the solvent was evaporated under reduced pressure to give the objective 4-(morpholinomethyl)phenylmethylamine (17.4 g), melting point 47-49° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:13][C:14]([F:34])([F:33])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([N:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][C:14]([F:13])([F:33])[F:34])=[CH:17][CH:18]=1)[S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-:32])=[O:31])=[O:8])=[O:5]
Reactant: O=[N+]([O-])c1ccccc1SNc1ccc(OC(F)(F)F)cc1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)N(Sc1ccccc1[N+](=O)[O-])c1ccc(OC(F)(F)F)cc1)c1ccccc1Cl
Temperature: -5 °C
Reaction time: 96 h

Procedure:
A solution of 50 g of 2-chlorobenzoyl isocyanate in 50 ml of dry toluene was added to a stirred solution of 60 g of N-[4-(trifluoromethoxy)phenyl]-2-nitrobenzenesulphenamide in 100 ml of the same solvent. The reaction was slightly exothermic, reaching a maximum temperature of 35° C. After 4 days at room temperature, the reaction mixture was cooled to -5° C. and the crystalline cake of product was broken up under cold toluene, filtered, washed with toluene followed by cold light petroleum (b.p. 40°-60° C.) and dried at 40° C. under reduced pressure, to give 1, as pale yellow crystals, m.p. 155°-158° C. (with decomposition).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([NH:10][C:11]1[N:12]=[C:13](C2N=CNN=2)[C:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH:18]=[CH:17][C:15]=2[N:16]=1)(=[O:9])[CH3:8]>O1CCOCC1>[C:7]([NH:10][C:11]1[N:12]=[C:13]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH:18]=[CH:17][C:15]=2[N:16]=1)(=[O:9])[CH3:8]
Reactant: COc1ccc(-c2ccc3nc(NC(C)=O)nc(-c4nc[nH]n4)c3n2)cc1OC
Reactant: C1CNCCN1
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3nc(NC(C)=O)nc(N4CCNCC4)c3n2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Piperazine (258 mg; 3 mmole) was added to a stirred suspension of 2-acetamido-6-(3,4-dimethoxyphenyl)-4-(1,2,4-triazolyl)pyrido[3,2-d]pyrimidine (586 mg; 1.5 mmole) in dioxane (50 ml). The mixture was stirred at room temperature for 24 hours and the volatiles were removed under reduced pressure, yielding 2-acetamido-4-(N-piperazinyl)-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine as a crude residue. The latter was dissolved in DMF and m-tolyl isocyanate (0.66 ml, 5 mmole) was added. After 18 hours at room temperature, the solvent was removed and the residue was suspended in a mixture of CH2Cl2 (20 ml) and sodium ethoxide 0.2 N (20 ml). The suspension was stirred during 16 hours and neutralized with 5-6 N HCl in isopropyl alcohol. The crude residue was purified by silica gel column chromatography, the mobile phase consisting of a CH3OH/CH2Cl2 mixture in a ratio gradually ranging from 2:98 to 5:95, thus resulting in the pure title compound (350 mg, yield 43%) which was characterized by its mass spectrum as follows: MS (m/z): 542 ([M+H]+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH2:19][C:18]=3[CH:24]=2)=[CH:4][CH:3]=1.[OH:25]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH2:19][C:18]=3[CH:24]=2)=[O:25])=[CH:6][CH:7]=1
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)COC(=O)N3)cc1
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methyl-phenylmercapto)-butoxy]-4H-3,1-benzoxazin-2-one and hydrogen peroxide.