Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[S:3]([N:13]1[C:17]2=[N:18][CH:19]=[C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:21]=[C:16]2[CH:15]=[CH:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].Br[CH2:31][C:32]([C@@H:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][CH2:43][CH:44]2[C:56]3[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=3[C:50]3[C:45]2=[CH:46][CH:47]=[CH:48][CH:49]=3)=[O:41])[CH2:35]1)=[O:33]>CN(C=O)C>[CH:46]1[C:45]2[CH:44]([CH2:43][O:42][C:40]([N:36]3[CH2:37][CH2:38][CH2:39][C@@H:34]([C:32](=[O:33])[CH2:31][N:22]([C:23]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:29])[C:20]4[N:21]=[C:16]5[CH:15]=[CH:14][N:13]([S:3]([C:6]6[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=6)(=[O:5])=[O:4])[C:17]5=[N:18][CH:19]=4)[CH2:35]3)=[O:41])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:50]=2[CH:49]=[CH:48][CH:47]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NC(=O)OC(C)(C)C)cnc32)cc1
Reactant: O=C(CBr)[C@@H]1CCCN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)[C@@H]4CCCN(C(=O)OCC5c6ccccc6-c6ccccc65)C4)C(=O)OC(C)(C)C)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
NaH (60% dispersion in mineral oil, 0.041 g, 1.0 mmol) was added to anhydrous DMF (5 mL). The suspension was cooled to about 0° C. and a solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.40 g, 1.0 mmol) in anhydrous DMF (5 mL) was added drop-wise. The reaction mixture was allowed to warm to ambient temperature and (R)-(9H-fluoren-9-yl)methyl 3-(2-bromoacetyl)piperidine-1-carboxylate (0.441 g, 1.03 mmol, Preparation #LL.1) was added. The reaction mixture was stirred for about 30 min before it was partitioned between EtOAc (30 mL) and brine (2×100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (12 g column) eluting with a gradient of 10-50% EtOAc in heptane to give (R)-(9H-fluoren-9-yl)methyl-3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)piperidine-1-carboxylate as a clear oil (0.21 g, 26%): LC/MS (Table 2, Method a) Rt=3.16 min; MS m/z: 736 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:7]=O)([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCC1.Cl>C(O)C>[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:10]([CH:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1OCCN1CCOCC1
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: Cl
Solvent: C1CCNC1
Solvent: CCO
Product: CC(C)c1cc(C=C2C(=O)Nc3ccc(Br)cc32)cc(C(C)C)c1OCCN1CCOCC1
Reaction time: 12 h
Yield: 12.4 %

Procedure:
A mixture of 3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzaldehyde (0.4 g), 5-bromo-2-oxindole (0.27 g) and pyrrolidine (0.5 ml) in ethanol (2 ml) was held in a sealed tube at 100° C. for 12 hours. The mixture was then added to 1N hydrochloric acid (100 ml) and the solids removed by filtration and washed with more water (50 ml). The solids were then dissolved in ethyl acetate (200 ml), the solution washed with 1N hydrochloric acid (75 ml) and brine (75 ml), dried with magnesium sulfate and concentrated. The crude solid was chromatographed (silica, 4:4:1 dichloromethane:hexanes:methanol) to give 80 mg (13%) of 5-bromo-3-[3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-1,3-dihydroindol-2-one as a reddish-brown solid.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:13]([C:11]1[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[C:2]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(C)(C)c1cc(Br)cc2c1OCC2(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-c2ccco2)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A mixture of 5-bromo-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan (1.13 g, 4.0 mmol), 2-(tributylstannyl)furan (1.71 g, 4.8 mmol), tetrakis(triphenylphosphine)palladium (0.46 g, 0.4 mmol), and 20 mL of toluene is heated under argon at reflux of 30 min. The reaction mixture is cooled to room temperature, concentrated in vacuo, diluted with ether, washed with 10% aqueous ammonium hydroxide solution and with brine, dried over anhydrous magnesium sulfate, and concentrated to give a dark oil. Purification by flash column chromatography on silica gel (1% ethyl acetate-hexane) yields about 0.47 g (43%) of the title compound as a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[N:10]=[CH:9]N(C(OC(C)(C)C)=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:19][N:20]([CH:22]([C:28](OCC)=O)[C:23](OCC)=O)[CH3:21]>C1COCC1.CCOCC>[CH3:19][N:20]([CH3:21])[CH:22]1[CH2:28][C:7]2[C:11]3=[C:3]([CH:2]=[CH:9][N:10]3[CH2:23]1)[CH:4]=[CH:5][CH:6]=2
Reactant: CCOC(=O)C(C(=O)OCC)N(C)C
Reactant: CC(C)(C)OC(=O)n1cnc2c(CBr)cccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)C1Cc2cccc3ccn(c23)C1

Procedure:
This compound was prepared by following the procedure of Example 18, but substituting methyl 7-(bromomethyl)-1H-indole-1-carboxylate for t-butyl 4-(bromomethyl) -1 H-benzimidazole-1-carboxylate and diethyl (dimethylamino)malonate for diethyl (dipropylamino) malonate. The bulk of the product was converted to the maleate salt, mp 114°-115° C. from THF/ether.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.[CH2:25]([NH:27][CH2:28][CH:29]1[CH2:31][CH2:30]1)[CH3:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]([CH2:28][CH:29]4[CH2:31][CH2:30]4)[CH2:25][CH3:26])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: Fc1ccc2c(c1)C(c1ccccc1F)=NCc1nnc(CCl)n1-2
Reactant: CCNCC1CC1
Product: CCN(Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1F)=NC2)CC1CC1

Procedure:
In the manner given in Preparation 29, 8-fluoro-1-(chloromethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with ethyl(cyclopropylmethyl)amine to give 8-fluoro-1-[[(cyclopropylmethyl)ethylamino]methyl]-6-(o-fluorophenyl)-4-H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 36 9-(Trifluoromethyl)-1-[[(cyclopropylmethyl)methylamino]methyl]-6-phenyl-4-H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: Br.C[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1.[OH-].[Na+].C(O)(=O)C>C(OCC)(=O)C>[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: COc1ccc2c(c1)C(=O)N(Cc1cccnc1)CC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1c2cc(O)ccc2CCN1Cc1cccnc1
Yield: 46.7 %

Procedure:
To 84 ml of 47% aqueous hydrogen bromide was added 11.3 g of 3,4-dihydro-7-methoxy-2-(3-pyridylmethyl)-1 (2H)-isoquinolinone, and the mixture was refluxed under heating for 4.5 hours. After ice cooling, the mixture was neutralized with aqueous sodium hydroxide, made weakly acidic with acetic acid and shaken with ethyl acetate. The organic layer was washed with water and saturated brine in order, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 5.00 g of the titled compound.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[Cl:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=1[Cl:28])([CH3:18])([CH3:17])[CH3:16]
Reactant: Nc1ccccc1Cl
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(CNc1ccccc1Cl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
4.07 g of sodium triacetoxyborohydride (19.3 mmol) was added to a solution of 3.00 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (16.0 mmol), 2.04 g of 2-chloroaniline (16.0 mmol) and 0.92 ml of acetic acid (16.0 mmol) in methylene chloride (160 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 3.49 g of the title compound (yield: 73%).
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]1>>[O:28]1[CH2:33][CH2:32][CH:31]([CH2:34][C:35]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH:6]=[CH:5][S:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:36])[CH2:30][CH2:29]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Reactant: O=C(O)CC1CCOCC1
Agent: Cl
Product: O=C(CC1CCOCC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 4 starting from trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (150 mg, 0.33 mmol) and tetrahydropyran-4-yl-acetic acid (50 mg, 0.35 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). Off-white crystals (108 mg, 69%), MS (ISP) m/z=471.2 [(M+H)+].
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[CH:16][C:15]=1[C:27]([F:30])([F:29])[F:28].Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([NH2:13])=[C:15]([C:27]([F:28])([F:29])[F:30])[CH:16]=2)=[N:22]1)=[O:12])[CH3:9]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2ccc(N)c(C(F)(F)F)c2)n[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ccc(N)c(C(F)(F)F)c2)cc1C
Reaction time: 6 h
Yield: 48.2 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) and ethyl isocyanate (0.09 g, 1.3 mmol) were added to a solution of 3-(4-amino-3-trifluoromethylphenyloxy)-5-methylpyrazole (0.30 g, 1.2 mmol) in ethyl acetate (5 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 6 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellowish solid of N-ethyl-3-(4-amino-3-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.19 g, yield: 50.5%). mp: 102-104° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (t, J=7.3 Hz, 3H), 2.56 (d, J=0.8 Hz, 3H), 3.37 (dq, J=5.9 and 7.3 Hz, 2H), 4.11 (br s, 2H), 5.61 (q, J=0.8 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 6.93 (br s, 1H), 7.14 (dd, J=2.7 and 8.8 Hz, 1H), 7.27 (d, J=2.7 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=O)=[N:23][CH:24]=4)[CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[C:5]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:4]=1.CN.F[P-](F)(F)(F)(F)F.[N:44]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:48]2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[NH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][N:15]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([NH:44][CH3:48])=[O:27])=[N:23][CH:24]=4)[CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[C:5]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[N:4]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(C(=O)O)nc3)CC4)nc(N)n2)CC1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-{7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic acid HCl salt (16.4 mg, 0.0296 mmol), methylamine (0.018 ml, 0.036 mmol) (2.0 M solution in THF), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (14.4 mg, 0.0326 mmol) and 4-methylmorpholine (16.3 uL, 0.148 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at r.t. overnight. The mixture was purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=459.4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][S:9]Cl)=[CH:4][CH:3]=1.[CH3:11][NH:12][C:13]([F:15])=[O:14]>>[CH3:11][N:12]([S:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:13]([F:15])=[O:14]
Reactant: CNC(=O)F
Reactant: Cc1ccc(SSCl)cc1
Product: Cc1ccc(SSN(C)C(=O)F)cc1

Procedure:
Prepared by the procedure of Example II by reacting 4-methylphenylthiosulfenyl chloride with methylcarbamoyl fluoride. b.p. 92°-100° C/0.25 Torr ND22.5 1.5735.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Cl.[Cl:6][C:7]1[C:8]([F:27])=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([OH:26])=[C:21]([CH:24]=[O:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:6][C:7]1[C:8]([F:27])=[C:9]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:4][CH2:3][O:2][CH3:1])=[C:21]([CH:24]=[O:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COCCCl
Reactant: O=Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Temperature: 90 °C

Procedure:
2-Chloroethyl methyl ether (0.967 g, 6.2 mmol) was added to a stirred suspension of 4-[(3-chloro-2-fluorophenyl)amino]-7-hydroxyquinazoline-6-carbaldehyde (1.0 g, 3.1 mmol) and K2CO3 (1.30 g, 9.45 mmol) in dimethyl formamide (10 ml) at room temperature. The resulting suspension was heated at 90° C. for 8 hours, cooled to room temperature, concentrated and purified by preparative LCMS (standard basic system) to give 4-[(3-chloro-2-fluorophenyl)amino]-7-(2-methoxyethoxy)quinazoline-6-carbaldehyde as a pale yellow solid, (0.150 g, 15%); Mass Spectrum: (M+H)+ 376.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of methyl 4-{[(5-chloro-1,3-thiazol-2-yl)amino]sulfonyl}benzoate (Preparation 3, 3.2 g, 9.6 mmol, 1 eq) in dioxane (20 ml) was added a 2M solution of lithium hydroxide (20 ml) and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with water, washed with ethyl acetate and then acidified with concentrated HCl. The resulting precipitate was collected by filtration to yield the title compound as a light brown solid (3.0 g, 9.0 mmol, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH3:29][NH:30][CH2:31][CH3:32]>>[CH2:31]([N:30]([CH3:29])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:32]
Reactant: CCNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(N3CCCCC3)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C20H23ClN6O2, 414.9
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][CH2:16][C:17]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27][C:21]=4[CH:20]=3)=[O:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.I[CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:30])[CH2:15][CH2:16][C:17]([C:19]3[CH:29]=[CH:28][C:22]4[CH2:23][CH2:24][N:25]([CH2:32][CH3:33])[CH2:26][CH2:27][C:21]=4[CH:20]=3)=[O:18])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=C(CCC(=O)N1CCC(c2ccc(Cl)cc2)CC1)c1ccc2c(c1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN1CCc2ccc(C(=O)CCC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2CC1
Yield: 47.4 %

Procedure:
A solution of 4-[4-(4-chlorophenyl)-1-piperidinyl]-4-oxo-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-butanone (200 mg, 0.47 mmol) obtained in Example 15, iodoethane (0.0376 ml, 0.47 mmol) and potassium carbonate (138 mg, 1.0 mmol) in acetonitrile (5 ml) was stirred at room temperature for 12 hours, then poured into water and extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the residues were purified by alumina silica gel column chromatography (developing solvent; ethyl acetate), whereby 101 mg of the title compound was obtained as colorless powder.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].S(Cl)([Cl:15])=O>>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([Cl:15])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Reactant: O=S(Cl)Cl
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Yield: 98 %

Procedure:
In a flask were placed 400 g (1.913 moles) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid and sufficient thionyl chloride to create a slurry. The remainder of the thionyl chloride (total used was 412.6 g (5.74 moles)) was added dropwise with stirring under a nitrogen blanket, and the reaction mixture was stirred at room temperature overnight. The crude product was distilled at 66°-67° C. at 66.7 Pa (0.5 mm of Hg) to produce 426.4 g of 98% (cis)-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:18])=[N:13][N:14]([CH3:17])[C:15]=1[OH:16])=[O:10].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[N:22][C:21]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+]>>[Cl:19][C:20]1[CH:25]=[C:24]([O:16][C:15]2[N:14]([CH3:17])[N:13]=[C:12]([CH3:18])[C:11]=2[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[O:10])[N:23]=[N:22][C:21]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34]
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Reactant: Cc1ccccc1Oc1nnc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccccc1Oc1nnc(Oc2c(C(=O)c3ccc(Cl)cc3Cl)c(C)nn2C)cc1Cl
Temperature: 130 °C
Reaction time: 14 h
Yield: 80.6 %

Procedure:
109 mg (0.382 mmol) of (2,4-dichlorophenyl)(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)methanone, 1.62 g (6.35 mmol) of 4,6-dichloro-3-(2-methylphenoxy)pyridazine obtained in Example 1 (2) and 107 mg (0.775 mmol) of potassium carbonate were mixed, and the mixture was stirred at 130° C. for 14 hours. The reaction mixture was cooled up to room temperature, and purified by silica gel column chromatography (hexane:ethyl acetate, gradient) to obtain 155 mg (0.308 mmol, Yield: 80.6%) of (5-{[5-chloro-6-(2-methylphenoxy)-3-pyridazinyl]oxy}-1,3-dimethyl-1H-pyrazol-4-yl)(2,4-dichlorophenyl)methanone.
Reaction SMILES: [NH:1]([C:21]([O:23]CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH2:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[OH:5].[CH3:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[NH2:39][CH2:38][C:21]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH2:20])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[CH2:3][C:4](=[O:6])[OH:5])=[O:23].[CH3:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O

Procedure:
The title compound was synthesized by solid-phase methodology on a ACT90 automated peptide synthesizer (Advanced ChemTec, Louisville, Ky.) using tritylchloride-polystyrene(1%)divinylbenzene (TCP; loading: 0.96 mmol/g; PepChem, Tubingen) and Fmoc-Asp-Phe-NH2 (NovaBiochem, Laufelfingen) as starting materials. The Fmoc-protected dipeptide amide (320.4 mg; 0.72 mmol) was dissolved in 4 ml dichloromethane. After 1 eq N-methyl-morpholin (NM1) was added the solution was given to 444 mg (0.48 mmol) dry TCP resin. After 5 min an additional volume of 130 ul NNM was added yielding a total amount of 1.80 mmol NMM in solution. The mixture was shaken for further 60 min. Then the residual tritylchloride groups were capped by the addition of 0.5 ml methanol. After further 20 min the resin was filtered off and washed with dichloromethane, DMF and methanol. The resin was dried under reduced pressure. Loading of the resin was determined to be 0.057 mmol/g. The Fmoc group was removed by treatment with piperidine/dimethylformamide (1:1 v/v) for 2×10 min. Afterwards Fmoc-Gly-OH was coupled within 30 min in 30-fold excess in a double coupling procedure using 1 eq TBTU and 1 eq NMM as activing agents. After removal of the Fmoc group by the same procedure as described above Boc-Ada(Boc2)-OH was coupled manually in DMF within 17 h by using a 2.5-fold excess of the protected amino acid and equimolar amounts of TBTU and NMM for activation. Cleavage from the resin and deprotection of the peptide was performed according to example 8f). Instead of heptane trifluoroethanol (2 ml) was used to dissolve the deprotected peptide. From this solution the crude peptide was precipitated by the addition of 16 ml diethylether. After centrifugation the supernatant was discarded and the precipitate lyophilized from tert.-butanol/water (1:1 v/v). Ada-Gly-Asp-Phe-NH2.HCl (28 mg) was obtained as white lyophilisate.