Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([O:29][C:30]2[CH:31]=[C:32](CN)[CH:33]=[CH:34][CH:35]=2)[CH2:24]1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([O:29][CH:25]5[CH2:26][CH2:27][CH2:28][N:23]([CH3:22])[CH2:24]5)[CH:35]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Reactant: CN1CCCC(Oc2cccc(CN)c2)C1
Solvent: CO
Product: CN1CCCC(Oc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)C1
Temperature: 120 °C

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (180 mg, 0.558 mmol) and 1-{3-[(1-methylpiperidin-3-yl)oxy]phenyl}methanamine (135 mg, 0.613 mmol) were dissolved in MeOH (2 ml). The reaction was heated in a microwave at 120° C. for 15 minutes, MeOH added, the resulting precipitate filtered and washed with MeOH to yield the title compound as a white solid. Yield: 140 mg (54%). 1H NMR (400 MHz, d6-DMSO) δ 8.66 (s, 1H), 7.92-7.87 (m, 3H), 7.57 (m, 2H), 7.25 (t, 1H, J=8.0 Hz), 6.94 (m, 1H), 6.89 (m, 2H), 5.18 (s, 2H), 4.36 (m, 1H J=4.3 Hz), 3.30 (d, 1H, J=9.6 Hz), 2.81 (d, 1H, J=10.7 Hz), 2.15 (s, 3H), 2.04-1.88 (m, 3H), 1.73-1.67 (m, 1H), 1.57-1.45 (m, 1H), 1.36-1.25 (m, 1H). MS (ESI+) 465.93 (M+1H+).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[C:11]1([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:17]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:24]=[CH:23][CH:22]=[C:19]([CH:20]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:18]=1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(-c2ccccc2)c1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-phenylbenzaldehyde in an analogous manner to that described in Example 1 to give 9-(3-biphenylyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from ethanol gave a pale yellow crystalline solid of melting point 227-229° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl.C(N(CC)CC)C.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41](=O)[NH:40][N:39]=2)=[CH:33][CH:32]=1.CN(C)C(=O)N(C)C.N>O.ClCCl>[CH3:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[NH:23][C:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:38]([CH2:37][C:34]2[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=2)=[N:39][N:40]=1
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Reactant: Cc1cccc(N)c1
Agent: Cl
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CN(C)C(=O)N(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(Nc2nnc(Cc3ccncc3)c3ccccc23)c1
Temperature: 200 °C

Procedure:
A mixture of 2.39 g (16.8 mmol) phosphorus pentoxide, 2.31 g (16.8 mmol) triethylamine hydrochloride, and 1.82 ml (16.8 mmol) m-toluidine is heated and stirred in a nitrogen atmosphere at 200° C. until a homogeneous melt has formed. To the melt, 1 g (4.2 mmol) 4-(4-pyridylmethyl)-1(2H)-phthalazinone is added and the reaction mixture stirred for a further 3.5 h at 205° C. After cooling to about 170° C., 4 ml tetramethylurea is added to the reaction mixture, followed by 2 ml water at about 110° C. The mixture is stirred for a further 30 min while cooling to RT and then distributed between dichloromethane and a mixture of 20 ml water and 5 ml conc. ammonia. The organic phase dried over sodium sulfate is concentrated by evaporation and the residue purified on silica gel by flash chromatography using acetate and acetate/methanol (99:1 and 19:1). Title compound is obtained after crystallization of the product-containing fractions from acetonitrile and subsequent recrystallzation from acetate; m.p. 141-143° C.; ESI-MS: (M+H)+=327.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[C:9](=[O:20])[S:8][C:5]2=[N:6][CH:7]=1.Cl[CH2:22][C:23](=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([CH2:22][C:23]([CH3:24])=[O:25])[CH2:18][CH2:19]3)=[O:13])[C:9](=[O:20])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Cn1c(=O)sc2ncc(Cl)cc21)N1CCNCC1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CN1CCN(C(=O)Cn2c(=O)sc3ncc(Cl)cc32)CC1
Temperature: 80 °C
Yield: 47.7 %

Procedure:
A mixture of 6-chloro-2-oxo-1-(1-piperazinyl)carbonylmethyl-1,2-dihydrothiazolo[5,4-b]pyridine (0.80 g), chloroacetone (0.24 g), and potassium carbonate (0.35 g) in dry N,N-dimethylformamide (2.4 ml) was heated at 80° C. for 30 min. The mixture was poured into an ice-water, and the precipitates obtained were extracted with chloroform. The chloroform layer was washed with water, dried over magnesium sulfate, and evaporated to give crude crystals (0.85 g). The crude crystals were recrystallized from a mixture of chloroform and ethyl acetate to give 6-chloro-2-oxo-1-[(4-acetonyl-1-piperazinyl)carbonylmethyl]-1,2-dihydrothiazolo[5,4-b]pyridine (0.45 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1ccc(CO)c([N+](=O)[O-])c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1ccc(C=O)c([N+](=O)[O-])c1

Procedure:
(4-Methyl-2-nitrophenyl)methanol D139 (1.028 g, 6.15 mmol), pyridinium dichromate (3.47 g, 9.22 mmol)+molecular sieves (7 g, 6.15 mmol) in dry dichloromethane (DCM) (14 mL) was stirred under argon at R.T. overnight. The reaction mixture was filtered by silica/kieselguhr (1:1) and extracted with water and DCM. Organic layers were combined and evaporated to give a pale yellow solid which was used without further purification (0.665 g, 65.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][NH:13][CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=1.C(N(CC)CC)C.[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:14][N:13]([C:30]([N:29]([CH3:33])[CH3:28])=[O:31])[CH2:12][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=1
Reactant: CN(C)C(=O)Cl
Reactant: Fc1ccc(F)c(C2=CC(c3ccccc3)CNC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC(c2ccccc2)C1

Procedure:
5-(2,5-difluorophenyl)-3-phenyl-1,2,3,6-tetrahydropyridine (1-7, 1.0 mg, 4 μmol) was dissolved in anhydrous CH2Cl2 (1.0 mL) and treated with excess triethylamine (10 μL) and dimethylcarbamoyl chloride (1.1 mg, 12 μmol). Upon completion the reaction was directly subjected to flash column chromatography (SiO2, 0-80% EtOAc-hexanes gradient) to yield 5-(2,5-difluorophenyl)-N,N-dimethyl-3-phenyl-3,6-dihydropyridine-1(2H)-carboxamide (1-8). MS 343.4 found 343.4 (M+H+) required.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15]OS(C)(=O)=O)=[O:11])[CH2:5][CH2:4]1)[CH3:2].Cl.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.Cl.ClC1C=C(N2CCNCC2)C=CC=1>>[CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C@@H:12]2[CH2:14][C@H:13]2[CH2:15][N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:11])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2COS(C)(=O)=O)CC1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: Clc1cccc(N2CCNCC2)c1
Product: CC[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3ccc(Cl)cc3)CC2)CC1

Procedure:
Follow the procedure of Example 11e, and substitute methane sulfonic acid 2-(trans-4-ethyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester, Example 13d for 2-(trans-4-methyl-cyclohexylcarbamoyl)-trans-cyclopropylmethyl ester and 4-(4-chlorophenyl)-piperazine hydrochloride for 1-(3-chloro-phenyl)-piperazine hydrochloride therein, to obtain the title compound LC/MS, m/z=404 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:37]1[CH:38]=[CH:39][C:40](=[O:43])[NH:41][N:42]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[CH:38]=[CH:39][C:40](=[O:43])[NH:41][N:42]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: O=c1ccc(Cl)n[nH]1
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]n2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-chloropyridazin-3(2H)-one following a procedures analogous to that described in Example 1 Step 3. LC-MS Method 2 tR=1.231, m/z=490; 1H NMR (CD3OD) 1.33 (m, 1H), 1.56 (d, 3H), 1.61 (m, 1H), 1.98 (m, 2H), 2.21 (m, 1H), 2.31 (m, 1H), 2.43 (m, 2H), 3.13 (m, 1H), 3.48 (m, 2H), 5.53 (m, 1H), 6.69 (d, 1H), 7.07-7.13 (m, 4H), 7.32 (m, 2H), 7.63 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[S:3]([CH2:6][C:7](O)=[O:8])(=[O:5])=[O:4].ON1C(=O)CCC1=O.[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[S:34][C:33]([CH3:35])=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12>>[F:1][C:2]([F:11])([F:10])[S:3]([CH2:6][C:7]([NH:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[S:34][C:33]([CH3:35])=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12)=[O:8])(=[O:5])=[O:4]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: O=C(O)CS(=O)(=O)C(F)(F)F
Agent: O=C1CCC(=O)N1O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(=O)(=O)C(F)(F)F)[C@H]3SC2)s1

Procedure:
Using the procedure in Example 1 trifluoromethylsulfonylacetic acid is esterified with N-hydroxysuccinimide and then is reacted with 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid using the procedure of Example 3 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:27]1[N:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30]>C1COCC1>[Cl:36][C:34]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[O:9])=[CH:6][CH:7]=2)[N:35]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a suspension of (4-aminophenyl)(morpholino)methanone (9.02 g, 43.8 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (66.7 mL, 66.7 mmol, 1M solution in THF) dropwise over 15 min. at −78° C. under nitrogen. The reaction mixture was stirred for one hour at −78° C. To the resulting brown solution was added a solution of 2,6-dichloronicotinic acid (4 g, 20.83 mmol) in THF (12 ml) dropwise at −78° C. The reaction mixture was removed from the dry ice bath and stirred overnight at rt. The resulting dark solids were washed with a small amount of THF to remove (4-aminophenyl)(morpholino)methanone on the surface, followed by the addition of water and 18 ml of 6N HCl (pH of 2). The solids were filtered and the resulting pink filter cake was washed with water (˜1 i) until the filter cake was white powder and the filtrate was colorless. The filter cake was transferred to a flask with MeOH and CH2Cl2, and dried on a rotary evaporator with MeOH to give 6.60 g of 6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinic acid as a white solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=S.[CH2:13]([N:15]([CH2:28][CH3:29])[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)[CH3:14].CN(C)[CH:32]=[O:33]>>[CH2:13]([N:15]([CH2:28][CH3:29])[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:32]=[O:33])=[CH:21][CH:20]=1)[CH3:14]
Reactant: CN(C)C=O
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Agent: S=C(n1ccnc1)n1ccnc1
Product: CCN(CC)CCOc1ccc(N=C=O)cc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Thiocarbonyldiimidazole (4.56 g, 25.6 mmol) (Aldrich) was dissolved in N,N-dimethylformamide (25 mL) and the solution cooled to −15° C. A solution diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine (5 g, 25.7 mmol) (from Step B above) in N,N-dimethylformamide (75 mL) was added dropwise and the mixture was then stirred at room temperature for 1 hour. The solution was cooled to 0° C. and poured into ice/water (1000 mL), stirred 30 minutes, and the precipitate was filtered off, washed with water and dried under high vacuum to give 4.95 g, (83%) diethyl-[2-(4-isocyanato-phenoxy)-ethyl]-amine. Mass spectrum (ES) MH+=251.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[C:13]1([CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[C:15]=1[OH:16])[OH:14].P(Cl)(Cl)(Cl)=O.[Cl-].[Ca+2].[Cl-]>[Cl-].[Zn+2].[Cl-].O>[OH:14][C:13]1[C:15]([OH:16])=[C:17]([OH:18])[CH:19]=[CH:20][C:21]=1[C:1]([C:2]1[CH:3]=[C:4]([OH:5])[C:6]([OH:7])=[C:8]([OH:9])[CH:10]=1)=[O:12]
Reactant: Oc1cccc(O)c1O
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=C(c1cc(O)c(O)c(O)c1)c1ccc(O)c(O)c1O

Procedure:
A reaction of the Fries type was used: ##STR4## 32 g of Gallic acid, 32 g of pyrogallol, 55 g of anhydrous zinc chloride and 100 cm3 of phosphorus oxychloride were mixed in a balloon flask equipped with a condenser and an ampoule of calcium chloride, and were heated to 80° C for 2 hours. After cooling the reaction mixture, a mixture of water and ice was added, whereupon the reaction product precipitated. The reaction product was washed once with water, treated with a solution of sodium bicarbonate, then washed again with water, and finally recrystallised from aqueous solution. Yield: 15 g of crystalline 2,3,3',4,4',5'-hexahydroxybenzophenone having a melting point of 270° C.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][N:24]2[C:33](=[O:34])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][C:25]2=[O:35])[C:10](=[O:36])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.Cl[C:38]([O:40][CH2:41][CH3:42])=[O:39]>N1C=CC=CC=1>[CH2:41]([O:40][C:38](=[O:39])[N:15]([CH2:14][CH2:13][CH2:12][N:11]1[C:10](=[O:36])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1])[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][CH2:23][N:24]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][C:25]1=[O:35])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:42]
Reactant: CCOC(=O)Cl
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCNCCCCNCCCn1c(=O)[nH]c2ccccc2c1=O
Solvent: c1ccncc1
Product: CCOC(=O)N(CCCCN(CCCn1c(=O)[nH]c2ccccc2c1=O)C(=O)OCC)CCCn1c(=O)[nH]c2ccccc2c1=O
Reaction time: 2 h

Procedure:
3-(3-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylamino}propyl)-1H-quinazoline-2,4-dione(2 g, 4.1 mmol) was dissolved in 40 mL pyridine and ethyl chloroformate (0.46 mL, 4.9 mmol) was added thereto. After 2 hours, pyridine was removed under reduced pressure and dichloromethane and water was added to the remaining residue. After each layer was separated, dichloromethane was removed and silica gel column-chromatography of the remaining residue was performed to give the title compound of yellow solid (0.61 g, 24%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH3:26])[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: CNC
Product: CN(C)c1cc(C(F)(F)F)cc2nc(NC(=O)c3cccnc3)nn12
Temperature: 120 °C
Yield: 40.8 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.14 mmol; 1.0 eq) and dimethylamine (43.0 μL; 0.73 mmol; 5.0 eq), heated at 120° C., to give the title compound as a white solid (20 mg, 39%). HPLC, Rt: 2.52 min. (purity 99.7%). LC/MS, M+(ESI): 350.8, M−(ESI): 348.9.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[C:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][CH:26]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:25][CH2:24]4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO>[CH2:29]([CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][C:20]#[C:19][C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[NH:10][CH:11]=[CH:12]3)[CH2:24][CH2:25]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(C#CCCN3CCC(Cc4ccccc4)CC3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C(#Cc1ccc2[nH]ccc2c1)CCN1CCC(Cc2ccccc2)CC1
Yield: 80.4 %

Procedure:
A mixture of 1-benzenesulfonyl-5-[4-(4-benzyl-piperidin-1-yl)-but-1-ynyl]-1H-indole (1.49 g, 3.1 mmol) is stirred in EtOH (200 mL) and 50% NaOH (1 mL) at room temperature for 3 days. Most of the EtOH is evaporated and the residue diluted with water (200 mL). The precipitate is filtered off and washed copiously with water. The precipitate is recrystallized from hot EtOH to give the title compound as an off-white solid (854 mg): mp 165-166° C.
Reaction SMILES: Br.C(O)(=O)C.C(O[C:11]([N:13]([C:15]1[CH:39]=[CH:38][C:18]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30][C:28]3=[O:29])[CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1)C)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:11][NH:13][C:15]1[CH:16]=[CH:17][C:18]([C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30][C:28]3=[O:29])[CH2:25][CH2:26]2)=[O:20])=[CH:38][CH:39]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CNc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture (5 ml) of hydrobromic acid and acetic acid (35% solution) is added to 1-{1-[4-(N-t-butoxycarbonyl-N-methylamino)benzoyl]-4-piperidinyl}-3,4-dihyrocarbostyril (1.8 g) and the mixture is stirred at room temperature overnight. The reaction mixture is poured into water and the pH value thereof is adjusted to pH 12-14 by adding potassium carbonate. The mixture is extracted with chloroform, dried with sodium carbonate and then purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=1:1). The resultant is recrystallized from n-hexane/ethanol to give 1-{1-[4-(N-methylamino)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.2 g), as white powder, m.p. 184°-186° C.
Reaction SMILES: COC1C=CC(C[N:10]2[C:16]3[N:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:22])[C:12]3[CH:23]=[CH:24][CH:25]=[N:26][C:11]2=3)=CC=1>FC(F)(F)C(O)=O>[CH3:22][N:13]1[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=2[NH:10][C:11]2[N:26]=[CH:25][CH:24]=[CH:23][C:12]1=2
Reactant: COc1ccc(CN2c3ncccc3C(=O)N(C)c3cccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)c2cccnc2Nc2ncccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
50 ml of trifluoroacetic acid was added to 10.3 g (0.030 mol) of 5,11-dihydro-11-[(4-methoxyphenyl)methyl]-5-methyl-6H-dipyrido [3,2-b:2',3'-e][1,4]-diazepin-6-one, and the mixture was stirred for one hour at room temperature. The acid was removed in vacuo and the residue was stirred for one hour with 0.5% ammonia. The solid was filtered and dried to give 6.70 g (98% of theory) of pure 5,11-dihydro-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one, m.p. 230°-232° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1C(=O)N(C)CCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:42][O:43][C:44]1[C:51]([O:52][CH3:53])=[C:50]([O:54][CH3:55])[CH:49]=[CH:48][C:45]=1[CH2:46]I.C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C.O>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:46][C:45]2[CH:48]=[CH:49][C:50]([O:54][CH3:55])=[C:51]([O:52][CH3:53])[C:44]=2[O:43][CH3:42])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(CI)c(OC)c1OC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCC(=O)O
Solvent: O
Product: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)c(OC)c1OC
Reaction time: 0.25 h

Procedure:
A solution of 1.368 g (4.48 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [Example 2b)] in 5 ml of abs. THF and 0.91 ml (1.67 equivalents) of DMPU is cooled down to -75° C., under argon, and treated dropwise, at an internal temperature of below -70° C. and over the period of approximately 20 min, with 8.78 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF (Aldrich). After a further 15 min, a solution of 1.38 g (1 equivalent) of 2,3,4-trimethoxybenzyl iodide in 2.5 ml of abs. THF is added dropwise to this mixture, within the period of approximately 15 min, and the mixture is allowed to react at -75° C. for a further 2.25 h. For the working-up, the reaction mixture is treated with 1.67 ml of propionic acid and 1.67 ml of water, and the temperature is allowed to rise to 0° C. The mixture is poured onto 20 ml of (cold) 10% citric acid, and approximately 50 ml of (cold) ethyl acetate is added to this mixture. After stirring for a further 5 min, the phases are separated. The organic phase is washed, in succession, with saline, sat. sodium bicarbonate solution and saline once again. The combined aqueous phases are reextracted twice with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated. The residue which remains after removing the solvent is chromatographed on silica gel (hexane:ethyl acetate, 3:1), and the title compound thereby obtained. HPLC tRet =16.49 min (gradient II). FAB-MS (M+H)+ =486 and M+ =485. IR(KBr)=inter alia, 3312, 1759, 1686, 1603, 1537, 1165 and 1104 cm-1. 1H-NMR(CD3OD)=inter alia, 7.30-7.10 (m, 5H); 6.84 and 6.66 (each d, each 1H); 3.85, 3.82 and 3.87 (each s, each 3H); 1.30 (s, 9H).