Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Cl)([O-:3])=[O:2].Cl.[CH2:16]([O:18][NH2:19])[CH3:17].C(N(CC)CC)C>CO>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:19][O:18][CH2:16][CH3:17])([O-:3])=[O:2]
Reactant: CCON
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCONc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A suspension of 10.0 g. (0.046 mole) of 2,6-dinitro-4-methylchlorobenzene in 100 ml. of methanol was prepared, and to the suspension there was added 7.6 g. (0.092 mole) of ethoxyamine hydrochloride, and 13.9 g. (0.138 mole) of triethylamine. The reaction mixture was stirred for about 30 minutes at room temperature and then heated and stirred for about 2-3 hours, checking samples from the mixture by NMR at half-hour intervals to follow the progress of the reaction. At this time an additional 16.7 g. (0.20 mole) of ethoxyamine hydrochloride was added, and the reaction mixture was stirred and refluxed for about 24 hours. An NMR spectrum of the reaction mixture indicated the presence of the desired product in about 70 percent yield. The reaction product mixture was poured over a mixture of ice and water, and the aqueous mixture filtered. The solid obtained was recrystallized from petroleum ether (b.p. 60°-71° C.) to yield 5.5 g. of product having a melting point of about 64°-66° C. The product was identified by its NMR spectrum as 2,6-dinitro-N-ethoxy-p-toluidine.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>>[CH3:28][C:26]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:27]=1
Reactant: Cc1ccc(Oc2ccc(O)cc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc(Oc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (278 mg, 1.56 mmol) was reacted with the product from Example 122b (336 mg, 1.56 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (226 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.34 (s, 3 H) 2.74 (s, 3 H) 6.56 (d, J=6.99 Hz, 1 H) 6.64-6.71 (m, 2 H) 6.75-6.81 (m, 2 H) 6.89 (d, J=8.46 Hz, 1 H) 7.26 (dd, J=8.46, 1.84 Hz, 1 H) 7.31 (s, 1 H) 7.76 (d, J=8.82 Hz, 1 H) 8.48 (d, J=6.99 Hz, 1 H) 8.95 (d, J=8.46 Hz, 1 H) 9.34 (s, 1 H) 10.91 (s, 1 H) 14.36 (s, 1 H); MS (ESI+) m/z 358 (M+H−TFA)+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:5]=2[N:6]=1.[Cl:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[Br:29]>>[Cl-:19].[NH2:1][C:2]1[N:6]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[Br:29])[C:5]2[C:7]([C:15]([F:18])([F:16])[F:17])=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:4]=2[N+:3]=1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[Br:29]
Reactant: Fc1ccc(OCCl)c(Br)c1
Reactant: Nc1nc2c(C(F)(F)F)cc(C(F)(F)F)cc2[nH]1
Product: Nc1n(COc2ccc(F)cc2Br)c2c(C(F)(F)F)cc(C(F)(F)F)cc2[n+]1COc1ccc(F)cc1Br
Product: [Cl-]

Procedure:
Following the procedure of Example 2 and replacing 2-aminobenzimidazole with 2-amino-5,7-bis-trifluoromethylbenzimidazole and replacing 2-bromo-4-chlorophenyl chloromethyl ether with 2-bromo-4-fluorophenyl chloromethyl ether, the title compound is obtained.
Reaction SMILES: [CH2:1](N)C.Cl[C:5]1[C:14]([C:15]([C:17](=[CH:23][N:24](C)[CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([F:28])=[C:10]([F:27])[CH:11]=2)[N:6]=1>C(O)C>[CH2:21]([O:20][C:18]([C:17]1[C:15](=[O:16])[C:14]2[CH:13]=[C:12]3[CH:11]=[C:10]([F:27])[C:9]([F:28])=[CH:8][C:7]3=[N:6][C:5]=2[N:24]([CH2:25][CH3:1])[CH:23]=1)=[O:19])[CH3:22]
Reactant: CCN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Solvent: CCO
Product: CCOC(=O)c1cn(CC)c2nc3cc(F)c(F)cc3cc2c1=O
Reaction time: 0.67 h
Yield: 90.7 %

Procedure:
A solution, at about 2° C., of 14.6 g of ethylamine in 200 cm3 of ethanol is added in the course of 10 minutes, at between 2° and 5° C., with stirring, to a suspension of 20 g of ethyl 2-(2-chloro-6,7-difluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate in 200 cm3 of ethanol at about 2° C., the mixture is stirred for a further 40 minutes at between 2° and 5° C. and the temperature is then allowed to rise to about 20° C. in the course of 2 hours. After 24 hours at about 20° C., the insoluble matter is drained and washed with 2 times 30 cm3 of ethanol and 2 times 50 cm3 of diisopropyl ether. 16.35 g of 3-ethoxycarbonyl-1-ethyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthridine are obtained in the form of a beige solid melting at 290° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:11][OH:12])=[C:4]([F:20])[C:3]=1[NH:21][C:22]1[CH:26]=[C:25]([CH:27]2[CH2:29][CH2:28]2)[NH:24][N:23]=1.[C:30](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:27]1([C:25]2[NH:24][N:23]=[C:22]([N:21]3[C:3]4[C:4]([F:20])=[C:5]([NH:9][C@H:10]([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)[CH2:11][OH:12])[C:6]([F:8])=[CH:7][C:2]=4[N:1]=[CH:30]3)[CH:26]=2)[CH2:29][CH2:28]1
Reactant: CC(=O)O
Reactant: Nc1cc(F)c(N[C@@H](CO)c2ccc(F)cc2)c(F)c1Nc1cc(C2CC2)[nH]n1
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC[C@H](Nc1c(F)cc2ncn(-c3cc(C4CC4)[nH]n3)c2c1F)c1ccc(F)cc1

Procedure:
(R)-2-(4-Amino-3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2,6-difluorophenylamino)-2-(4-fluorophenyl)ethanol (Method 104, 0.230 g, 0.57 mmol) and formamidine acetate (0.119 g, 1.14 mmol) in EtOH (10 ml) was heated at reflux for 1 hour. Saturated sodium bicarbonate solution (5 ml) and EtOAc (15 ml) were added. The organic layer was separated, washed with brine (3 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by chromatography (Hex-EtOAc=1:1) to give the title compound as off white solid (0.070 g, 30%). 1H NMR (400 MHz) 12.83 (s, 1H), 8.20 (s, 1H), 7.34 (m, 3H), 7.07 (t, J=8.8 Hz, 2H), 6.14 (s, 1H), 5.14 (d, J=9.6 Hz, 1H), 4.97 (t, J=5.6 Hz, 1H), 4.62 (m, 1H), 3.64-3.74 (m, 2H), 1.97 (m, 1H), 1.00 (m, 2H), 0.76 (m, 2H). MS: Calcd.: 413; Found: [M+H]+ 414.
Reaction SMILES: CO.C(C1C=C[C:8]([N:11]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[C:13]([OH:32])[C:12]2=[O:33])=CC=1)=O.[CH2:34]([OH:37])[CH2:35][OH:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[O:36]1[CH2:35][CH2:34][O:37][CH:8]1[N:11]1[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:14]([C:22](=[O:31])[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[C:13]([OH:32])[C:12]1=[O:33]
Reactant: OCCO
Reactant: COc1ccc(C(=O)C2=C(O)C(=O)N(c3ccc(C=O)cc3)C2c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)C2=C(O)C(=O)N(C3OCCO3)C2c2ccccc2)cc1
Yield: 10 %

Procedure:
The 0.1M methanol solution of 1-(4-formylphenyl)-3-hydroxy-4-(4-methoxybenzoyl)-5-phenyl-1,5-dihydropyrrol-2-one (1 mL, 0.1 mmol) was concentrated under reduced pressure. Toluene (1 mL), ethylene glycol (0.033 mL, 0.6 mmol) and p-toluenesulfonic acid monohydrate (3.8 mg, 0.02 mmol) was added to the residue. The mixture was heated under azeotropic dehydration for 3 hr. Water (100 mL) was added to the mixture, which was then extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added ethyl acetate, and the precipitate was collected by filtration and dried to give 1-(1,3-dioxolan-2-yl)-3-hydroxy-4-(4-methoxybenzoyl)-5-phenyl-1,5-dihydro-pyrrol-2-one (3.8 mg, 8%) as pale yellow crystals.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:26][N:19]1[CH2:18][CH2:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)([C:22]#[N:23])[CH2:21][CH2:20]1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Product: CN1CCC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CC1
Yield: 76 %

Procedure:
The title compound (80 mg, 76%) was prepared from 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile, formaldehyde and sodium triacetoxyborohydride similarly to the procedure used for example 54. 1H NMR (400 MHz, CD3OD) δ 1.81-1.85 (m, 4H), 1.97-2.15 (m, 6H), 2.37 (s, 3H), 2.45 (t, 2H), 2.58-2.62 (m, 4H), 2.68 (t, 2H), 2.99 (d, 2H), 4.04 (t, 2H), 6.96 (d, 2H), 7.42 (d, 2H). LRMS APCI+ m/z 328 [MH]+. Microanalysis: Found: C, 73.01; H, 8.94; N, 12.81%. C20H29N3O requires C, 73.36; H, 8.93; N, 12.83%.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[C:7](=[NH:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Br:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCCC1.O.C(OCC)(=O)C>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:13][CH2:14]2)/[C:7](=[N:15]/[C:21](=[O:22])[C:20]2[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:19]=2[Br:18])/[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(C(C)(C)C)cc(=N)n1CC1CC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2Br)n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of Example 3E (3.52 g, 17 mmol) in tetrahydrofuran (20 mL) was added sodium hydroxide (2.72 g, 68 mmol) in water (5.00 mL), followed by addition of a solution of 2-bromo-5-(trifluoromethyl)benzoyl chloride (3.85 g, 17 mmol) in tetrahydrofuran (5 mL) dropwise at 0° C. The mixture was stirred at room temperature for 1 hour then diluted with water (20 mL) and ethyl acetate (30 mL). The layers were separated and the organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, eluted with a gradient of 15-100% hexane in solvent B, solvent B: 10:1:0.5 ethyl acetate:methanol:triethylamine) to afford the title compound (6.3 g, 93%). 1H NMR (300 MHz, DMSO-D6) δ ppm 0.41-0.52 (m, 4H) 1.13-1.27 (m, 1H) 1.40 (s, 9H) 3.94 (s, 3H) 4.20 (d, J=6.74 Hz, 2H) 6.83 (s, 1H) 7.54 (dd, J=8.53, 2.18 Hz, 1H) 7.77-7.82 (m, 2H); MS (ESI) m/z 458 [M+H]+.
Reaction SMILES: Cl[C:2]([CH3:9])([CH3:8])[CH:3]([N:6]=[O:7])[CH2:4][CH3:5].Cl.Cl.Cl.[NH2:13][CH2:14][CH:15]([O:25][NH:26][C:27]([CH3:36])([C:29](=[N:34][OH:35])[CH2:30][CH2:31][CH2:32][CH3:33])[CH3:28])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[N+:22]([O-:24])=[O:23].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:8][C:2]([CH3:9])([NH:13][CH2:14][CH:15]([CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[N+:22]([O-:24])=[O:23])[O:25][NH:26][C:27]([CH3:28])([CH3:36])[C:29](=[N:34][OH:35])[CH2:30][CH2:31][CH2:32][CH3:33])[C:3](=[N:6][OH:7])[CH2:4][CH3:5]
Reactant: CCC(N=O)C(C)(C)Cl
Reactant: CCCCC(=NO)C(C)(C)NOC(CN)Cn1ccnc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(=NO)C(C)(C)NOC(CNC(C)(C)C(CC)=NO)Cn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-Chloro-4-methyl-3-nitrosopentane (0.52 g, 3.5 mmol, Example 27(A)) was added to a mixture of the hydrochloride title product of step B above (0.62 g, 1.5 mmol) and diisopropylethylamine (0.45 g, 3.5 mmol) in acetonitrile (10 mL), and the mixture was stirred at room temperature for 12 hrs. Acetonitrile was removed on a rotary evaporator and the thick oil obtained was basified with potassium carbonate solution. The light green oil obtained was extracted with ethyl acetate and dried (Na2SO4). Ethyl acetate was removed on a rotary evaporator and the oil obtained was purified by column chromatography (silica gel, ethyl acetate:hexane, 6:4). Fractions containing the product were collected and evaporated to give a colorless oil, which was dried under vacuum to afford a foamy solid. The solid obtained was dissolved in acetonitrile and left at room temperature for 2 hrs. The solid that formed was filtered and recrystallized from acetonitrile. Yield: 0.32 g (47%). mp. 153°-154° C. 1HNMR (DMSO): ε 0.86, 0.96, 1.11, and 1.35 [m, 22H, C(CH3)2, CH2CH3 and CH2CH2CH2CH3)], 2.15 (m, 4H, CH2CH2CH2CH3 and CH2CH3), 2.30 (m, 2H, HNCH2CHOH), 3.80 (m, 1H, CHO), 4.5 (m, 2H, CHOHCH2N<), 7.14 and 7.56 (s, 2H, imiH), 10.35 (s, 1H, NOH), and 10.37 (s, 1H, NOH). MS:(M+H)+ =456 Anal. Calcd. for C20H37N7O5 : C, 52.71; H, 8.19; N, 21.53. Found: C, 52.94; H, 8.26; N, 21.63.
Reaction SMILES: [H-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][SH:9].Cl[C:11]1[CH:16]=[CH:15][N+:14]([O-:17])=[C:13]([CH3:18])[C:12]=1[CH3:19]>O1CCOCC1.O>[CH3:18][C:13]1[C:12]([CH3:19])=[C:11]([S:9][CH2:8][C:4]2[O:3][CH:7]=[CH:6][CH:5]=2)[CH:16]=[CH:15][N+:14]=1[O-:17]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: SCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(SCc2ccco2)cc[n+]([O-])c1C
Reaction time: 0.25 h
Yield: 79.9 %

Procedure:
6 g (60% strength) of NaH are added in portions to 50 ml of dry dioxane, the mixture is stirred for 15 minutes, 11.7 g (0.11 mol) of 2-furylmethylmercaptan are metered in over a period of 20 minutes and the mixture is stirred again for 30 minutes until the evolution of gas has ended. A solution of 14.4 g (0.1 mol) of 4-chloro-2,3-dimethylpyridine N-oxide in 100 ml of dioxane is then added dropwise in the course of 20 minutes, and the reaction mixture is stirred at RT for 1 h, subsequently at 70° C. for 1 h and then at 100° C. for another 1 h. When the reaction has ended, the mixture is allowed to cool and is diluted with 500 ml of water and extracted 4 times with 300 ml of ethyl acetate each time. The combined organic phases are washed with water, dried over magnesium sulfate and concentrated and the residue is crystallized by addition of diisopropyl ether. 18.8 g (80% of theory) of 2,3-dimethyl-4-(2-furylmethylthio)-pyridine N-oxide of m.p. 111-112° C. are obtained.
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:46])(=[O:45])[N:26]([CH2:36][CH2:37][O:38]C4CCCCO4)[CH2:27][CH2:28][O:29]C4CCCCO4)[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O.C([O-])(O)=O.[Na+]>C1COCC1>[OH:29][CH2:28][CH2:27][N:26]([CH2:36][CH2:37][OH:38])[S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:23][CH2:22]2)(=[O:46])=[O:45]
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)N(CCOC4CCCCO4)CCOC4CCCCO4)C4(CC4)C3)ncnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(N(CCO)CCO)N1CCN(c2ncnc3[nH]ccc23)CC12CC2

Procedure:
4-(4-{Bis-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-sulfamoyl}-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 17) was treated with a mixture of TFA (0.5 mL), H2O (0.2 mL) and THF (0.2 mL) at 40° C. for 1 h. The crude reaction mixture was neutralised using sat. NaHCO3 and then extracted with EtOAc (3×10 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: Cl.[CH3:2]OCN.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32])[CH2:11][O:12][C:13]1[C:17]([C:18]([OH:20])=O)=[CH:16][N:15]([CH3:21])[N:14]=1.O.[OH:40][N:41]1[C:45]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O.C(N(CC)CC)C>[CH3:2][O:40][N:41]([CH3:45])[C:18]([C:17]1[C:13]([O:12][CH2:11][C:10]2[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:30][C:31]=3[CH3:32])=[C:8]([O:7][CH3:6])[CH:9]=2)=[N:14][N:15]([CH3:21])[CH:16]=1)=[O:20]
Reactant: COCN
Reactant: On1nnc2ccccc21
Reactant: COc1cc(COc2nn(C)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(C)cc2C(=O)N(C)OC)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A mixture of methoxymethylamine hydrochloride (0.85 g), triethylamine (1.3 mL) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 30 min. To the reaction mixture were added 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxylic acid (3.45 g), 1-hydroxy-1H-1,2,3-benzotriazole monohydrate (1.22 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.60 g), and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give N-methoxy-N-methyl-3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carboxamide (3.63 g, yield 96%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 138-139° C.
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[CH2:2]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(Cl)Cl>CC#N>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30](=[O:35])[CH2:29][N:7]1[CH2:8][CH:1]2[O:9][CH:5]([CH2:4][N:3]([CH2:10][CH2:11][CH2:12][NH:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:2]2)[CH2:6]1
Reactant: N#Cc1ccc(NCCCN2CC3CNCC(C2)O3)cc1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)C(=O)CN1CC2CN(CCCNc3ccc(C#N)cc3)CC(C1)O2
Yield: 75.4 %

Procedure:
A mixture of 4-{[3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino}benzonitrile (Preparation C; 5.73 g, 0.02 mol), K2CO3 (11.05 g, 0.08 mol) in MeCN (300 mL) was treated with 1-chloropinacolone (4.44 g, 0.032 mol). The mixture was stirred at 50° C. overnight before DCM was added and the mixture filtered. The filter cake was then washed with a mixture of DCM and MeCN before the solvent was evaporated from the filtrate. The resulting residue was purified by chromatography on silica, eluting with a gradient of ethyl acetate:methanol:ammoniacal methanol (95:5:0 to 95:0:5), to give the title compound (5.8 g, 73.9%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5].[CH2:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[C:20]1([C:26]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)Cl)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:1][N:2]=[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([O-:6])=[O:5])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1.[CH2:13]([NH+:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]
Reactant: CCN(CC)CC
Reactant: O=C(O)C(=NO)c1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC[NH+](CC)CC
Product: O=C([O-])C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Yield: 84 %

Procedure:
2-Hydroxyimino-2-phenylacetic acid (syn isomer) (4.13 g, 25.0 mmole), triethylamine (8.7 ml, 62.5 mmole) and triphenylchloromethane (10.40 g, 37.5 mmole) were reacted together as described in Preparation 2(a) to give triethylammonium 2-triphenylmethoxyimino-2-phenylacetate (syn isomer) as a white solid (10.625 g, 21 mmole, 84%) m.p. 166 to 175 (dec), λmax 260 nm, inflexions at 264 and 292 nm (ε15,000; 14,400 and 2,300 respectively).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]2[CH2:21][C:20]3[CH:22]=[C:23](/[CH:26]=[CH:27]/[C:28]([O:30]C(C)(C)C)=[O:29])[CH:24]=[N:25][C:19]=3[NH:18][C:17](=[O:35])[CH2:16]2)=[CH:12][CH:11]=1.[Cl:38]CCl>>[ClH:38].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[CH2:21][C:20]3[CH:22]=[C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])[CH:24]=[N:25][C:19]=3[NH:18][C:17](=[O:35])[CH2:16]2)=[CH:36][CH:37]=1
Reactant: ClCCl
Reactant: COc1ccc(CN2CC(=O)Nc3ncc(/C=C/C(=O)OC(C)(C)C)cc3C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2CC(=O)Nc3ncc(/C=C/C(=O)O)cc3C2)cc1
Product: Cl
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a suspension of (E)-tert-butyl 3-(4(4-methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylate (112 mg, 0.27 mmol) in dichloromethane (1 mL) at room temperature. The reaction mixture was then stirred for 1 hour and concentrated to dryness. The resulting residue was suspended in a solution of hydrochloric acid in dioxane 4N (2 mL). After 10 minutes stirring at room temperature, the precipitate was filtered and washed with diethyl ether to afford the title product as a pale yellow solid (110 mg, quantitative).
Reaction SMILES: Cl.[CH:2]1[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][NH:4][N:3]=1.[CH2:11]([N:13]=[C:14]=[S:15])[CH3:12].C(N(C(C)C)CC)(C)C>CO.O>[CH2:11]([NH:13][C:14]([N:3]1[N:4]=[CH:5][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:2]1)=[S:15])[CH3:12]
Reactant: CCN=C=S
Reactant: C1=NNCC12CCCC2
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=S)N1CC2(C=N1)CCCC2
Temperature: 30 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
2,3-Diaza-spiro[4.4]non-1-ene hydrochloride (15.4 g, 95.9 mmol; isolated from reaction of 2,3-diaza-spiro[4.4]non-2-ene, synthesized as described in WO 2008/034863, with HCl in isopropanol/toluene) was taken up in a mixture of 70 mL methanol and 30 mL water. Ethyl isothiocyanate (10.09 g, 115.1 mmol) was added using an addition funnel, and the funnel was rinsed with 40 mL methanol. At 30° C., diisopropylethylamine (14.8 g, 114.5 mmol) was added dropwise over a period of 10 minutes, and the addition funnel was rinsed with 7 mL water. After stirring the reaction mixture for 1 hour at 30° C., the mixture was cooled to 10° C. over a period of 1 hour and subsequently stirred at this temperature for another 2 hours. The precipitate was isolated by filtration, washed twice with 20 mL of a cold 3:1 mixture of methanol and water and dried at 50° C. under reduced pressure to give 16.8 g (83%) of 2,3-diaza-spiro[4.4]non-3-ene-2-carbothioic acid ethylamide as a white to off-white solid. 1H NMR identical to spectrum obtained from material prepared on small scale (vide supra).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH2:18][CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O>>[CH2:18]([N:13]1[C:12]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[F:28])=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)[CH3:19]
Reactant: CCn1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccccc1F
Product: CCn1nc2c(c1-c1ccccc1F)CCNCC2
Yield: 94.1 %

Procedure:
The title compound (121 mg) was prepared according to Example 263 using 205 mg of 2-ethyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 193, Step A) and 97 mg of 2-fluorophenylboronic acid. MS (ESI): exact mass calculated for C15H18FN3, 259.15. found, m/z 260.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.61-7.55 (m, 1H), 7.39-7.30 (m, 3H), 4.01-3.91 (m, 2H), 3.43-3.41 (m, 2H), 3.18-3.16 (m, 2H), 2.79-2.73 (m, 2H), 1.28 (t, J=9.0 Hz, 3H).