Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)=[S:4].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>ClC(Cl)C.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[S:4]
Reactant: Nc1ccccc1
Reactant: CNC(=S)C1(c2cccnc2)CCCCC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: CNC(=S)C1(c2cccnc2)CCCCC1=Nc1ccccc1
Temperature: 25 °C

Procedure:
A stirred suspension of (±)-N-methyl-2-oxo-1-(3-pyridyl)cyclohexanecarbothioamide (2.5 g) and aniline (3.72 g) in anhydrous dichloroethane (30 ml) under an argon atmosphere was treated dropwise at 25° C. with titanium tetrachloride (0.8 ml). The reaction mixture was stirred at 25° C. until completion of the reaction (as judged by TLC analysis), and then it was poured into a solution of sodium bicarbonate (16.8 g) in water (100 ml) and stirred for 15 minutes. The mixture was filtered through a pad of celite and the aqueous layer was extracted with dichloromethane (3×75 ml). The combined organic solution was washed with aqueous sodium bicarbonate solution (100 ml; 10% w/w), with water (50 ml) and with saturated brine (100 ml), and then it was dried over sodium sulphate and concentrated in vacuo, to give N-methyl-2-phenylimino-1-(3-pyridyl)cyclohexanecarbothioamide in the form of a crude oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[N:11]([CH2:18][C:19]([O:21]C(C)C)=[O:20])[C:10]1=[O:25].[N+:26]([O-])([OH:28])=[O:27]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:26]([O-:28])=[O:27])=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[N:13]([CH3:16])[C:12](=[O:17])[N:11]([CH2:18][C:19]([OH:21])=[O:20])[C:10]1=[O:25]
Reactant: O=[N+]([O-])O
Reactant: CC(C)OC(=O)Cn1c(=O)n(C)c(=O)n(-c2ccc(F)cc2Cl)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(=O)n(CC(=O)O)c(=O)n(-c2cc([N+](=O)[O-])c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of isopropyl 3-(2-chloro-4-fluorophenyl)-tetrahydro-5-methyl-2,4,6-trioxo-s-triazine-1(2H)-acetate (48.7 g, 0.0508 mol) in concentrated sulfuric acid is cooled to 0° C., treated with 90% nitric acid (2.6 mL), stirred at room temperature overnight, treated with 90% nitric acid (1.0 mL), stirred for 4 hours, treated with 90% nitric acid (2.0 mL), stirred at room temperature overnight, treated with 90% nitric acid (1.0 mL), stirred for 1 hour and poured onto ice. The resultant aqueous solution is filtered to obtain a solid. A solution of the solid in ether is dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title product as a yellow foam which is identified by NMR spectral analyses.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[O:5][C:4](=[O:26])[CH:3]=1.[C:27]([C:31]1[CH:36]=[C:35]([CH2:37][OH:38])[C:34]([CH3:39])=[CH:33][C:32]=1[S:40]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:27]([C:31]1[CH:36]=[C:35]([CH2:37][OH:38])[C:34]([CH3:39])=[CH:33][C:32]=1[S:40][C:3]1[C:4](=[O:26])[O:5][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[CH2:7][C:2]=1[OH:1])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1C=C(O)CC(CCc2cccc(O)c2)(CCc2cccc(O)c2)O1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3cccc(O)c3)(CCc3cccc(O)c3)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The compound was synthesized following General Method 9 and using 172 mg (0.5 mmol) of 4-hydroxy-6,6-bis-[2-(3-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example XX), 179 mg (0.5 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF), 270 mg (2.0 mmol) of K2CO3, and 2 mL of DMF. The reaction was worked up as described and chromatographed on silica get eluting with (1:1 CH2Cl2 :EtOAc+2% MeOH), to yield the title compound, m.p. 92-94° C. 1H NMR (DMSO-d6) δ 1.48 (s, 9 H), 1.80 (s, 3 H), 2,07 (m, 4 H), 2.6 (m, 4 H), 3.0 (s, 2 H), 4.35 (s, 2 H), 6.6 (m, 6 H), 6.65 (s, 1 H), 7.05 (t, 2 H), 7.25 (s, 1 H), 9.25 (s, 2 H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)=[N:5][N:4]=1.[CH2:24]([NH:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:24]([N:28]([CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)=[N:5][N:4]=1)[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]
Reactant: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2ccccc2C1=O
Reactant: CCCCNCCCC
Solvent: CN(C)C=O
Product: CCCCN(CCCC)Cc1nnc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)o1
Yield: 85.2 %

Procedure:
0.66 g (2 mmol) of 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 75° overnight with 1.2 g (9.3 mmol) of dibutylamine and 10 ml of N,N-dimethylformamide. After evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 0.72 g (85%) of 3-(5-dibutylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 211°-213°.
Reaction SMILES: [Na].CO.[OH:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CS(C)=O>[CH2:22]([O:21][C:19]([CH:18]([O:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=1)[CH3:24])=[O:20])[CH3:23]
Reactant: Cc1ccc(-n2cnc(O)n2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(C)cc2)n1
Yield: 28.7 %

Procedure:
The process was carried out as described in Example 8, starting with 1.1 g of sodium, 20 ml of methanol, 150 ml of dimethylsulfoxide, 8.5 g of 3-hydroxy-1-(4-methylphenyl)-1,2,4-1H-triazole and 8.7 g of ethyl 2-bromopropionate. A yield of 3.8 g of the desired product, m.p. 69°-71°, was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][N:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[CH2:25]([Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[C:28]#[CH:29])[CH3:26].C(N(CC)CC)C>C(#N)C.[Cu]I>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([NH:12][CH2:11][C:8]3[N:6]4[N:7]=[C:2]([C:26]#[C:25][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[CH:14][CH:15]=[N:16]2)=[N:21][CH:20]=1
Reactant: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Reactant: C#C[Si](CC)(CC)CC
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[Si](C#Cc1ccc2nnc(CNc3ccnc4cc(OC)cnc34)n2n1)(CC)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an argon flushed pressure vial (15 mL) was added copper (I)iodide (0.0070 g, 0.037 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.012 g, 0.015 mmol), N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (0.050 g, 0.15 mmol), and triethyl(ethynyl)silane (0.13 ml, 0.73 mmol) in acetonitrile (2 mL) followed by triethylamine (0.61 ml, 4.4 mmol). The vial was sealed and stirred at room temperature overnight The solution was concentrated and purified by MPLC (eluted with 0-10% (90:10:1 DCM:MeOH:NH4OH)) to yield the product as a light yellow solid. MS m/z=446.1 [M+1]+. Calc'd for C23H27N7OSi: 445.2.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:17])[C:11]=3[C:10]3=[N:18][O:19][C:20]([CH3:21])=[C:9]3[C:8]2=[O:22])[CH:4]=[CH:3]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](O)=[O:33].CCN(CC)CC.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:12]1[C:11]2[C:10]3[C:9](=[C:20]([CH3:21])[O:19][N:18]=3)[C:8](=[O:22])[N:7]([CH:5]3[CH2:6][CH:2]([NH:1][C:32](=[O:33])[CH2:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])[CH:3]=[CH:4]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: Cc1onc2c1c(=O)n(C1C=CC(N)C1)c1cccc(Cl)c21
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)NC1C=CC(n2c(=O)c3c(C)onc3c3c(Cl)cccc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a stirred solution of 5-(4-amino-cyclopent-2-enyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (97 mg, 0.31 mmol) in CH2Cl2 (4 mL) was added 2-methoxy phenyl acetic acid (66.3 mg, 0.40 mmol), Et3N (0.11 ml, 0.40 mmol) and EDCI (77 mg, 0.40 mmol) and stirred at r.t. for 18 hours. The mixture was diluted with CH2Cl2, washed (brine), dried (Na2SO4), filtered and concentrated. Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave the title compound (59 mg, 41%). Mass Spectrum (FIA) (m/z) 464.2 (M+1) Anal. Calc. For C25H22ClN3O4. Theoretical: C, 64.73, H, 4.78, N, 9.06%. Found. C, 64.78, H, 4.91, N, 8.83%.
Reaction SMILES: Cl.Cl.[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4].[CH3:37][C:38]1([CH3:41])[CH2:40][O:39]1.CCN(C(C)C)C(C)C>CC#N>[CH2:3]([C:5]1[N:9]([C:10]2[N:18]=[C:17]3[C:13]([N:14]=[C:15]([C:20]4([OH:26])[CH2:25][CH2:24][CH2:23][N:22]([CH2:37][C:38]([OH:39])([CH3:41])[CH3:40])[CH2:21]4)[N:16]3[CH3:19])=[C:12]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[N:11]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH3:4]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCNC3)n(C)c2n1
Reactant: CC1(C)CO1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCCN(CC(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23.4 %

Procedure:
A mixture of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-3-ol dihydrochloride (150 mg, 0.28 mmol), 2,2-dimethyloxirane (100 μL, 1.12 mmol) and DIPEA (192 μL, 1.12 mmol) in MeCN (4 mL) was stirred at r.t. for 20 h then heated at 70° C. for 24 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient acetonitrile 5-30%) affording 746 (35 mg, 23%). LCMS (method I): RT 2.57 min, [M+H]+ 535.2. 1H NMR (DMSO, 400 MHz): δ 8.03-7.98 (1 H, m), 7.65-7.61 (1 H, m), 7.28-7.21 (2 H, m), 5.46 (1 H, s), 4.45-4.05 (5 H, m), 3.96 (3 H, s), 3.77-3.76 (4 H, m), 3.30-3.22 (2 H, m), 3.07-2.99 (1 H, m), 2.91-2.83 (1 H, m), 2.70-2.60 (1 H, m), 2.45-2.35 (1 H, m), 2.26 (2 H, s), 2.15-2.00 (1 H, m), 1.96-1.69 (3 H, m), 1.32 (3 H, t, J=7.43 Hz), 1.01 (6 H, d, J=15.78 Hz)
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:65][S:62]([CH:59]6[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A solution of 17-[2-(4-isopropylthiazole-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid 46 (560 mg, 0.867 mmol) prepared according to Example 4, and carbonyldiimidazole (308 mg, 1.90 mmol) in dry THF (10 mL) was stirred at reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (400 mg, 3.301 mmol) and DBU (286 mg, 1.881 mmol) were added. This solution was heated at 50° C. for 15 h. Then, the reaction mixture was cooled down at room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and HCl 1 N, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) afforded 314 mg of an off-white solid which was further washed with water, then isopropylether, and dried in the vacuum oven to deliver 282 mg (40%) of the pure title product 47 as a white powder: m/z=750 (M+H)+. 1H NMR (CDCl3): 0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, 1H), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, 1H), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J=13 Hz, 1H), 5.04 (t, J=11 Hz, 1H), 5.37 (m, 1H), 5.66 (m, 1H), 6.21 (s, 1H), 7.02 (s, 1H), 7.22 (d, J=10 Hz, 1H), 7.45 (s, 1H), 7.99 (d, J=10 Hz, 1H), 10.82 (broad s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](F)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:18]=[CH:19][CH:20]=1>O1CCCC1>[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:11][CH2:10][CH2:9][CH2:8][CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CN1CCC(CCCO)CC1
Reactant: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2[N+](=O)[O-])CC1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.45 g of 3-(1-methylpiperidin-4-yl)propan-l-ol in 40 ml of tetrahydrofuran are added 360 mg of sodium hydride. The white suspension formed is stirred for 15 minutes at 65° C., cooled and mixed with 1.45 g of 4-[(3-bromophenyl)amino]-7-fluoro-6-nitroquinazoline, whereupon the mixture suddenly turns dark red. The reaction mixture is stirred first for 10 minutes at ambient temperature, then for 45 minutes at 65° C. As the reaction is not yet complete, a further 150 mg of sodium hydride are added and the mixture is stirred for a further 45 minutes at 65° C. The solvent is distilled off using a rotary evaporator and the brown residue is stirred with 50 ml of ice water. The aqueous phase is extracted with methylene chloride. The combined extracts are washed with water, dried over sodium sulfate and concentrated by evaporation. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol/concentrated ammonia solution (90:10:0.05). Yield: 1.30 g of (65% of theory); Rf value: 0.28 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1); mass spectrum (ESI+): m/z=500, 502 [M+H]+.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]3[CH:15]=[CH:16][C:17](=[O:20])[NH:18][N:19]=3)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].Br.Cl[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24]>>[CH2:1]([N:4]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]3[CH:15]=[CH:16][C:17](=[O:20])[NH:18][N:19]=3)[CH:11]=2)[CH2:6]1)[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[CH2:2][CH3:3]
Reactant: CC(C)COC(=O)Cl
Reactant: CCCNC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Agent: Br
Product: CCCN(C(=O)OCC(C)C)C1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1

Procedure:
2-Propylamino-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide and isobutyl chloroformate were treated in the same manner as in Example 51 to obtain 2-(N-propyl-N-isobutoxycarbonylamino)-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10][C:9]=1[N+:27]([O-:29])=[O:28])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[S:33][CH:34]=[CH:35][N:36]=1>>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)=[CH:10][C:9]=1[N+:27]([O-:29])=[O:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Reactant: Brc1nccs1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nccs2)cc1[N+](=O)[O-]
Yield: 26.2 %

Procedure:
Prepared from (2-nitro-4-tributylstannanyl-phenyl)-carbamic acid tert.-butyl ester (Example D2) (1.0 g, 1.9 mmol) and 2-bromothiazole (0.56 mL, 6.27 mmol) according to the general procedure E. Obtained as a yellow solid (160 mg).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]([C:12]([NH:14][C@H:15]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=2)[CH3:16])=[O:13])[NH:3]1.[F:27][C:28]1[CH:37]=[CH:36][C:31]([O:32][CH2:33][CH:34]=O)=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:27][C:28]1[CH:37]=[CH:36][C:31]([O:32][CH2:33][CH2:34][N:3]2[C@@H:4]([C:12]([NH:14][C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=3)[CH3:16])=[O:13])[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]2)=[CH:30][CH:29]=1
Reactant: O=CCOc1ccc(F)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2CCOc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a mixture of methyl 4-[(1S)-1-[[(3R)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]amino]ethyl]benzoate hydrochloride (800 mg, 2.13 mmol) and 2-(4-fluorophenoxy)acetaldehyde (493 mg, 3.2 mmol) in 1,2-dichloroethane (10.7 mL), add sodium triacetoxyborohydride (633 mg, 2.99 mmol) and stir the mixture at room temperature overnight. Add saturated aqueous NaHCO3 (25 mL), and extract the aqueous layer with ethyl acetate (2×25 mL). Wash the combined organic layers with saturated aqueous NaCl (25 mL), dry the organic phase over MgSO4, filter, and concentrate the filtrate under reduced pressure. Subject the resulting crude material to flash chromatography on silica gel using a 0% to 60% EtOAc/hexanes gradient. Consolidate the fractions containing the product, and concentrate them under reduced pressure to furnish the title compound as a colorless foam (550 mg, 54% yield). Mass spectrum (m/z): 477 ([M+H]+).
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[H-].[Na+].[CH3:11]I>C1COCC1.O>[CH3:11][O:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CI
Reactant: OCC1CC=CCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1CC=CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Cyclohexene-1-methanol (8.92 mmol, 1.00 g) and NaH (17.8 mmol, 428 mg) were mixed in THF (30 mL) at rt, and the THF solution was stirred for 1 h at rt. MeI (17.8 mmol, 1.10 mL) was added slowly into the above THF solution. After stirring for 16 h at rt, the solution was diluted with water (30 ml), and then was extracted with diethyl ether (2×30 mL). The organic layer was dried over Na2SO4, was concentrated by rotory evaporation, and then was distilled to generate the final product 17 as a colorless liquid (460 mg, 41%). 1H-NMR (500 MHz) δ 5.68 (m, 2H), 3.36 (s, 3H), 3.28 (dd, J=6.5 Hz, J=4 Hz), 2.06-2.14 (m, 3H), 1.92 (m, 1H), 1.83 (m, 1H), 1.75 (m, 1H), 1.29 (m, 1H). 13C-NMR (100 MHz) δ 127.2, 126.1, 78.0, 58.9, 34.0, 28.6, 25.8, 24.7. LC-MS (APCI): Peak time=1.59 min, m/z calcd for C8H15O [M+H]+ 127.11, found 127.10.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(c3ccc(N)cc3C#N)CC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCNCC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 41.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 151 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.66 g) and 5-amino-2-[4-(4-tert-butoxycarbonylpiperazin-1-yl)piperidin-1-yl]benzonitrile (1.0 g), the title compound (0.54 g) was obtained, melting point: 226° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH3:24][N:25]1[C:31](=[O:32])[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[N:28]([CH2:37][C:38]#[CH:39])[C:27](=[O:40])[CH2:26]1.C(OCC)(=O)C.O.C#C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:39]#[C:38][CH2:37][N:28]3[C:29]4[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31](=[O:32])[N:25]([CH3:24])[CH2:26][C:27]3=[O:40])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCN1C(=O)CN(C)C(=O)c2ccccc21
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Agent: C#C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nnc2n1-c1ccc(C#CCN3C(=O)CN(C)C(=O)c4ccccc43)cc1C(c1ccccc1F)=NC2

Procedure:
Coupling of 6-(2-Fluorophenyl)-8-iodo-1-methyl-4H[1,2,4]triazolo[4,3-a] [1,4]benzodiazepine with 3,4-dihydro-4-methyl-1-(2-propynyl)-1H-1,4-benzodiazepine 2,5-dione as described in example 17 gave after chromatography and crystallization from ethyl acetate colorless crystals with m.p. 179°-182° C. The crystals of the title compound contained according to analytical and nmr-data 0.16 mol of ethyl acetate and 0.66 mol of water. The preparation of the required acetylene is described in Example 54.