Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[C:11]([O:14][C@@H:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([OH:18])=O)(=[O:13])[CH3:12].Cl.[C:26]1([C:32]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@@H:40]3[C@@H:36]([CH2:37][NH:38][CH2:39]3)[C@@:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][CH3:49])([OH:41])[CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:50]1([C:32]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:40]3[C@@H:36]([CH2:37][N:38]([C:16](=[O:18])[C@@H:15]([O:14][C:11](=[O:13])[CH3:12])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:39]3)[C@@:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[O:48][CH3:49])([OH:41])[CH2:34][CH2:33]2)[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: CC(=O)O[C@H](C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)[C@@H](OC(C)=O)c3ccccc3)C[C@H]21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.1 %

Procedure:
0.024 g of 1-hydroxybenzotriazole and 0.33 g of (S)-2-acetyloxy-2-phenylacetic acid are added to a suspension of 0.75 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride in 60 cm3 of dry methylene chloride, this solution is then cooled to +5° C. and a suspension of 0.4 g of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride in 20 cm3 of dry methylene chloride is rapidly added, followed by a solution of 0.63 cm3 of diisopropylethylamine in 20 cm3 of dry methylene chloride. The reaction mixture is stirred at +5° C. for 2 hours and at room temperature for 24 hours, diluted with 120 cm3 of methylene chloride, washed with 100 cm3 of water and then with 100 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2.5 cm, height 39 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting fractions of 60 cm3. Fractions 6 to 10 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.96 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[2-acetyloxy-2-phenyl-(S)-acetyl]-perhydroisoindol-4-ol are obtained in the form of a white foam.
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].O[O:11][S:12]([O-:14])=O.[K+].[CH3:16]C(C)=O>O>[CH3:16][S:12]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])(=[O:14])=[O:11]
Reactant: CSc1ccccc1O
Reactant: CC(C)=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
2-(Methylthio)phenol (1.08 g, 7.32 mmol) was dissolved in acetone (20 mL). Oxone® (9.4 g, 15 mmol) was separately dissolved in water (100 mL) and stirred at ambient temperature for 24 h. The acetone was concentrated, extracted with ether, dried over sodium sulfate, filtered, and concentrated to yield a waxy solid (1.2 g, 95%). 1H NMR (400 MHz, CDCl3): δ 8.85 (s, 1H), 7.69 (dd, J=8.4 Hz, J′=1.7 Hz, 1H), 7.54 (m, 1H), 7.05 (m, 2H), 3.12 (s, 3H); LCMS found for C7H9O3S (M+H)+: m/z=173.0.
Reaction SMILES: ClO.[CH2:3]([N:6]1[CH2:25][CH2:24][C@:13]23[C:14]4[C:15]5[O:23][C@H:12]2[C:11](=[O:26])[CH2:10][CH2:9][C@@:8]3([O:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:7]1[CH2:20][C:19]=4[CH:18]=[CH:17][C:16]=5[O:21][CH3:22])[CH:4]=C.C([O-])([O-])=O.[K+].[K+].C(I)C>O>[O:23]1[C@@H:12]2[C@@:13]34[CH2:24][CH2:25][N:6]([CH2:3][CH3:4])[C@@H:7]([C@:8]3([O:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:9][CH2:10][C:11]2=[O:26])[CH2:20][C:19]2=[C:14]4[C:15]1=[C:16]([O:21][CH3:22])[CH:17]=[CH:18]2
Reactant: C=CCN1CC[C@]23c4c5ccc(OC)c4O[C@H]2C(=O)CC[C@@]3(OCCCc2ccccc2)[C@H]1C5
Agent: O=C([O-])[O-]
Agent: OCl
Agent: [K+]
Solvent: CCI
Solvent: O
Product: CCN1CC[C@]23c4c5ccc(OC)c4O[C@H]2C(=O)CC[C@@]3(OCCCc2ccccc2)[C@H]1C5
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 4,5α-epoxy-3-methoxy-14β-[(3-phenylpropyl)oxy]morphinan-6-one hydrochloride (see Example 1) (4.0 g, 8.77 mmol), K2CO3 (8.0 g, 57.89 mmol), ethyl iodide (0.99 ml, 12.40 mmol) and 50 ml of water-free N,N-dimethylformamide was stirred for 5 h under N2 at 80° C. (bath temperature). After filtration from the inorganic residue, the filtrate was evaporated down and the residue (4.7 g of brown oil) was purified using column chromatography (silica gel; CH2Cl2/MeOH/conc. NH4OH: 8 l: (250/2/0.5)); 0.5 l: (250/3/0.5), (250/4/0.5), (250/6/0.5), (250/8/0.5), (250/10/0.5)). The evaporation residue (1.3 g of bright yellow oil) was crystallised out of MeOH. Yield: 1.2 g (30%) of compound 19. Fp. 95-101° C.; IR (KBr): 1719 (C═O) cm−1; 1H-NMR (DMSO-d6): δ 7.30-7.13 (m, 5 arom. H), 6.73 (d, J=8.2 Hz, 1 arom. H), 6.64 (d, J=8.2 Hz, 1 arom. H), 4.76 (s, 1H, C5—H), 3.78 (s, 3H, OCH3), 0.96 (t, 3H, N—CH2—CH3), J=7 Hz); MS (CI): m/z 448 (M++1).
Reaction SMILES: C(O[C:4]1[CH2:10][C:9](=[O:11])[NH:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)C.[C:16]([NH:24][NH2:25])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(O)=O>[C:17]1([C:16]2[N:5]3[C:4]([CH2:10][C:9](=[O:11])[NH:8][C:7]4[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=43)=[N:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CCOC1=Nc2ccccc2NC(=O)C1
Solvent: CC(=O)O
Product: O=C1Cc2nnc(-c3ccccc3)n2-c2ccccc2N1
Temperature: 120 °C

Procedure:
To a solution of 4-ethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Preparation 3(A) (5 g, 24 mmol) in glacial AcOH (75 mL) was added benzoic acid hydrazide (3.33 g, 24.5 mmol). The reaction mixture was heated to 120° C. for 2 hours and was cooled to room temperature. The solvent was removed in vacuo by azeotropic distillation with heptane (2×). The residue was dissolved in a minimum amount of methylene chloride and 50 mL ethyl acetate and the solution was poured slowly with stirring into a solution of 100 mL saturated NaHCO3/100 mL water. Ether (150 mL) was added and the mixture was stirred for 5 minutes. The precipitate was collected by filtration, was washed with water and the minimum amount of ether to give 5.89 g of 1-phenyl-4H,6H-2,3,6,10b-tetraaza-benzo[e]azulen-5-one. 1H NMR (CDCl3) δ 9.02 (br s, 1H), 7.48-7.36 (m, 6H), 7.10 (t, 1H), 6.95 (d, 1H), 4.23 (d, 1H), 3.60 (d, 1H); MS 277 (M+1).
Reaction SMILES: C(O[C:4](=[O:19])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[Cl:18][C:14]1[CH:13]=[C:12]([CH:5]([CH2:6][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]2)[C:4]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])[CH:17]=[CH:16][CH:15]=1
Reactant: CNC(N)=O
Reactant: CCOC(=O)C(CC1CCCC1)c1cccc(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1cccc(Cl)c1
Temperature: 100 °C
Yield: 8 %

Procedure:
A mixture of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid ethyl ester (1.70 g, 6.05 mmol) and methyl urea (673 mg, 9.08 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 17.3 mL, 12.1 mmol) was heated under reflux at 100° C. for 6 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 hexanes/ethyl acetate) afforded 1-[2-(3-chloro-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (149.1 mg, 8%) as a white solid: mp 52–55° C.; EI-HRMS m/e calcd for C16H21ClN2O2 (M+) 308.1292, found 308.1287. The methyl ester of the starting material was recovered from the reaction mixture due to transesterification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH2:12]=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:12][NH:8][CH2:7][CH2:6]2
Reactant: C=O
Reactant: COc1cccc(CCN)c1
Solvent: O
Product: COc1ccc2c(c1)CCNC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
A mixture of m-methoxyphenethylamine (25 g, 0.165 mol), 37% formaldehyde (12.7 mL) and water (12.7 mL) was stirred for 20 minutes. The reaction mixture was heated at 95°-100° C. for 1.5 hours, cooled, diluted with ice-water, and extracted with toluene (3x). The combined organic extracts were washed with saturated sodium chloride solution (2 ×30 mL), dried over magnesium sulfate, filtered and evaporated. The residual oil was heated with 6N hydrochloric acid (36 mL) for 3 hours, cooled, basified with 50% aqueous sodium hydroxide solution and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate and evaporated; the residue was converted to its hydrochloride salt with HCl (g) in isopropanol. The cream-colored crystalline hydrochloride salt was filtered and dried affording the title compound in 52% yield. m.p. 232°-234° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.C1COCC1.C([Li])CCC.[O:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1>CCOC(C)=O>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:37]4([OH:40])[CH2:38][CH2:39][O:34][CH2:35][CH2:36]4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C4(O)CCOCC4)cc3C)c(C)nc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
To a −78° C. solution of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.60 g, 1.53 mmol) and THF (10 mL) is added 1.56 M n-Bu-Li (1.03 mL, 1.61 mmol). After 30 minutes tetrahydro-pyran-4-one (0.21 mL, 2.29 mmol) is added over 5 minutes. The solution is stirred at −78° C. for 2 hours, warmed to ambient temperature, diluted with EtOAc (50 mL), washed with sat. NH4Cl (50 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-100% EtOAc/hexane gradient) furnish the title compound (0.38 g, 0.92 mmol, 60%). 1H NMR (CDCl3), δ 0.88 (t, J=7.5 Hz, 6H), 1.74-1.91 (m, 4H), 1.91-2.00 (m, 2H), 2.11 (s, 3H), 2.20-2.30 (m, 2H), 2.46 (s, 3H), 2.51 (s, 3H), 3.30-3.39 (m, 1H), 3.83-3.98 (m, 5H), 6.66 (s, 1H), 6.93 (s, 1H). LC/MS (m/z): calcd. for C23H31N3O2S (M+H)+: 414.3; found: 414.2.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[C:29]3[C:28]4[N:30]=[CH:31][CH:32]=[CH:33][C:27]=4[CH2:26][CH2:25][CH2:24][C:23]=3[NH:22][CH:21]=2)=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[C:29]3[C:28]4[N:30]=[CH:31][CH:32]=[CH:33][C:27]=4[CH2:26][CH2:25][CH2:24][C:23]=3[NH:22][CH:21]=2)=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=C(Nc1cccnc1OCCOC1CCCCO1)c1c[nH]c2c1-c1ncccc1CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C(Nc1cccnc1OCCO)c1c[nH]c2c1-c1ncccc1CCC2
Yield: 101.4 %

Procedure:
A solution of 3,4,5,6-tetrahydro-3,10-diaza-benzo[e]azulene-1-carboxylic acid {2-[2-(tetrahydropyran-2-yloxy)-ethoxy]-pyridin-3-yl}amide (850 mg) and p-toluenesulfonic acid monohydrate (700 mg) in methanol (30 mL) is refluxed for 1 h. The solvent is removed and the residue is extracted with DCM and washed with NaHCO3 (aq.). The organic layer is dried and solvent removed to give 700 mg of 3,4,5,6-tetrahydro-3,10-diazabenzo[e]azulene-1-carboxylic acid [2-(2-hydroxy-ethoxy)pyridin-3-yl]amide.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.BrCC1CCCCO1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2([C:37]3[C:33]4=[N:34][O:35][N:36]=[C:32]4[CH:31]=[CH:30][C:29]=3[O:28][CH2:27]2)[C:19]1=[O:38]>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]3([C:37]4[C:33]5=[N:34][O:35][N:36]=[C:32]5[CH:31]=[CH:30][C:29]=4[O:28][CH2:27]3)[C:19]2=[O:38])[CH:5]=1
Reactant: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Reactant: BrCc1cccnc1
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2cccnc2)c2ccccc2C12COc1ccc3nonc3c12

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 3-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(pyridin-3-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one was obtained (47%) as a colorless solid: mp 230-232° C.; 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 8.59 (d, J=2.7 Hz, 1H), 7.88-7.82 (m, 2H), 7.39-7.16 (m, 4H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 5.35-5.24 (m, 2H), 4.99 (d, J=9.3 Hz, 1H), 4.84 (d, J=15.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.1, 162.9, 149.4, 148.8, 148.3, 144.8, 141.7, 135.1, 130.8, 129.8, 129.7, 123.9, 121.8, 119.4, 109.6, 106.9, 81.9, 57.2, 42.0; MS (ES+) m/z 371.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[OH:22].[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>C(OCC)(OCC)OCC.CCCCCC>[F:20][C:19]1[C:2]2[N:1]=[CH:23][O:22][C:3]=2[C:4]2[NH:8][C:7](=[O:9])[N:6]([C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])[C:5]=2[C:18]=1[F:21]
Reactant: Nc1c(F)c(F)c2c([nH]c(=O)n2-c2ccc(I)cc2F)c1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Product: O=c1[nH]c2c3ocnc3c(F)c(F)c2n1-c1ccc(I)cc1F
Temperature: 120 °C
Yield: 535.3 %

Procedure:
A mixture of 5-amino-6,7-difluoro-1-(2-fluoro-4-iodo-phenyl)-4-hydroxy-1,3-dihydro-benzoimidazol-2-one (I-13a: 550 mg, 1.3 mmol) in triethyl orthoformate (5 mL) and p-toluene sulfonic acid (20 mg, 0.13 mmol) were taken in a flask and the flask was heated to reflux at 120° C. for 30 minutes. The reaction was monitored by TLC (70% ethyl acetate in hexane). The reaction mixture was concentrated under reduced pressure and the concentrate was triturated with diethyl ether and filtered. The residue was washed with diethyl ether and dried under reduced pressure to afford 300 mg of the product (54.5% yield). H1NMR (DMSO-d6, 300 MHz): δ 12.50 (s, 1H), 8.87 (s, 1H), 7.97 (dd, 1H), 7.78 (d, 1H), 7.50 (t, 1H). LCMS: 92.2%, m/z=431.9 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C.Cl.[CH3:37][NH:38][O:39][CH3:40]>C(#N)C>[CH3:40][O:39][N:38]([CH3:37])[C:11](=[O:13])[CH:10]([CH3:14])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C(C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-[(tert-Butoxycarbonyl)amino]-2-methylpropanoic acid (2.0 g, 9.9 mmol) was dissolved in acetonitrile (50 mL). To this solution was added HOBT (1.6 g, 11.85 mmol) and EDC (2.0 g, 10.4 mmol). The reaction was stirred at room temperature for 2 hr, and then treated with triethylamine (2.8 mL, 20 mmol) and N,O-dimethylhydroxyamine hydrochloride (2.0 g, 20 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate (3×). The combined organic extract was washed sequentially with 0.5N hydrochloric acid, 1N aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on a Biotage® system (silica, 40-100% ethyl acetate in hexanes) to yield tert-butyl {3-[methoxy(methyl)amino]-2-methyl-3-oxopropyl}carbamate as white solid. MS (M+1−Boc): 147.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15]CC)=O)[NH:7][C:6]2=[O:18])#[N:2].[NH2:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C1COCC1>[NH2:24][C:23]1[CH:22]=[C:21]([CH2:20][NH:19][C:13]([C:8]2[NH:7][C:6](=[O:18])[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=3)[N:9]=2)=[O:15])[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1nc2ccc(C#N)cc2c(=O)[nH]1
Reactant: NCc1cccc(N)c1
Solvent: C1CCOC1
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(N)c3)[nH]c(=O)c2c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
A suspension of ethyl 6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxylate obtained in Reference Example 51 (1.00 g, 4.11 mmol) and 3-(aminomethyl)aniline (0.753 g, 6.17 mmol) in THF (15 mL) was stirred at 80° C. for 15 hr. The reaction mixture was cooled to room temperature, IPE was added, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate-IPE to give the title compound as a white powder (899 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](Cl)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:24]([CH2:23][Cl:22])=[N:13][N:12]=[C:10]3[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1ccccc1C1=CCc2nnc(CCl)n2-c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 18.2 g of 7-chloro-5-(2-fluorophenyl)-2-hydrazino-3H-1-benzazepine in 220 ml of glacial acetic acid is treated dropwise at 15° with 5.1 ml of chloroacetyl chloride. The mixture is stirred at room temperature for a further 2 hours. The mixture is treated with 7.5 g of sodium acetate, stirred at room temperature for 2 hours. and at boiling under reflux for 20 minutes, then evaporated in vacuo and the residue is partitioned between chloroform and water. The organic phase is washed with sodium hydrogen carbonate solution and water and evaporated. The crude product obtained is chromatographed on silica gel while eluting with chloroform/ethanol (98.5:1.5) and there is obtained 8-chloro-1-(chloromethyl)-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine as white crystals of melting point 180° (decomposition).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7](OS(C)(=O)=O)[NH:6][C:5]2[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[N:22][C:4]1=2)[CH3:2].Cl.[O:26]([NH2:28])[CH3:27].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[N:28][O:26][CH3:27])[NH:6][C:5]2[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[N:22][C:4]1=2)[CH3:2]
Reactant: CON
Reactant: CCN1c2ncccc2C(OS(C)(=O)=O)Nc2c(C)cc(C)nc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1c2ncccc2C(=NOC)Nc2c(C)cc(C)nc21
Yield: 31.4 %

Procedure:
A solution of 5,11-dihydro-11-ethyl-6-methanesulfonyloxy-2,4-dimethyl-6H-dipyrido[3,2-b:2',3'-e] [1,4]diazepine (0.3 g, 0.75 mmol), methoxylamine hydrochloride (0.15 g, 1.8 mmol) and diisopropylethylamine (0.3 g, 2 mmol) in methylene chloride was stirred at room temperature for 4 days. The organic phase was washed with water, dried, and filtered. The solution was concentrated in vacuo and the residue was chromatographed over silica with 20% ethyl acetate/hexane to give 0.07 g of the title compound, m.p. 164°-166° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].O=[C:28](N1C=CN=C1)[N:29]1C=CN=C1.CN>ClCCl.O>[CH3:28][NH:29][C:22]([C:21]1[CH:20]=[CH:19][C:18]([N:16]2[CH:15]=[C:12]3[C:11]([CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:14][CH2:13]3)=[N:17]2)=[CH:26][CH:25]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(=O)O)cc3)nc2CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1ccc(-n2cc3c(n2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[6-{[(1,1-dimethylethyl)oxy]carbonyl}-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzoic acid (may be prepared as described in Description 23) (185 mg, 0.52 mmol) in dichloromethane (10 ml) was added 1,1′-(oxomethanediyl)bis-1H-imidazole (168 mg, 1.04 mmol) and the reaction stirred at room temperature, under argon, overnight. Methylamine (64 mg, 2.07 mmol) was added and stirring continued, under argon, at room temperature for 4 hours. The resulting crude mixture was diluted with water, and extracted with dichloromethane (×2). The combined organic fractions were washed with water (×1), dried over magnesium sulphate and solvent evaporated in vacuo to afford the title compound (D24). MS (ES+) m/e 371 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.O(CC)[C:10]([S-:12])=[S:11].[K+].CN1CCCC1=O.C(O)(=O)C>O>[S:12]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][N:6]=2)[NH:1][C:10]1=[S:11]
Reactant: CCOC(=S)[S-]
Reactant: Nc1nccnc1Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CC(=O)O
Product: S=c1[nH]c2nccnc2s1
Temperature: 150 °C
Yield: 66.7 %

Procedure:
To a mixture of 2-amino-3-chloropyrazine (5 g, 38.6 mmol) and potassium ethyl xanthate (9.28 g, 57.9 mmol) was added 1-methyl-2-pyrrolidinone (68 mL) and the solution was heated (150° C., 16 h). The suspension was cooled (rt) and treated with glacial acetic acid (10 mL) and H2O (1500 mL). The suspension was filtered and the resulting solid was suspended and sonicated in ethanol:H2O (1:1, 500 mL). The suspension was filtered and the solid was washed with H2O, dried (calcium sulfate) in vacuo to yield the title compound as a solid (4.36 g, 67%). MS (ESI): mass calculated for C5H3N3S2, 168.98; m/z found, 170.00 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 14.69 (s, 1H), 8.42 (d, J=2.8, 1H), 8.39 (d, J=2.8, 1H).
Reaction SMILES: [CH:1]1([Si:6]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16](O)(C)C.C[Si](C)(C)Cl>[O-]CC.[Na+]>[CH:11]([O:10][Si:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)([O:13][CH2:14][CH3:15])[O:7][CH2:8][CH3:9])([CH3:16])[CH3:12]
Reactant: CC(C)O
Reactant: CCO[Si](OCC)(OCC)C1CCCC1
Agent: CC[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CCO[Si](OCC)(OC(C)C)C1CCCC1
Yield: 46.1 %

Procedure:
In a 500 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 19.6 g (0.0841 mole) of cyclopentyl triethoxysilane, 98.0 g (1.63 mole) of isopropyl alcohol and 198.7 mg (2.92 m mole) of sodium ethoxide, which were then reacted with each other at room temperature for 2 hours under stirring. Then, trimethylchlorosilane was added to neutralize the alkali. Then, 9.56 g (0.0388 mole) of isopropoxy cyclopentyl diethoxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. Tile yield was 46%.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)=[C:2]=[O:3].Cl.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]3[CH:32]=[C:31]4[C:26]([CH2:27][CH2:28][NH:29][CH2:30]4)=[CH:25][CH:24]=3)[N:20]=[C:19]([NH2:33])[N:18]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C>O1CCCC1>[NH2:33][C:19]1[N:20]=[C:21]([C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][N:29]([C:2]([NH:1][CH:4]4[CH2:8][CH2:7][CH2:6][CH2:5]4)=[O:3])[CH2:30]3)=[CH:25][CH:24]=2)[CH:22]=[C:17]([N:14]2[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]2)[N:18]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C=NC1CCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC3CCCC3)CC4)nc(N)n2)CC1
Reaction time: 0.5 h

Procedure:
Isocyanatocyclopentane (0.030 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (10 mg, 0.02 mmol) and triethylamine (16 μL, 0.12 mmol) in tetrahydrofuran (0.3 mL). After 30 minutes, the mixture was purified by RP-LCMS (pH=10) to afford the desired products. Analytic LCMS (M+H)+: m/z=436.5.