Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].Cl[C:12]([S:14]Cl)=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:12](=[O:13])[S:14][N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1cccc(Cl)c1
Product: O=c1oc(-c2cccc(Cl)c2)ns1
Reaction time: 1.5 h

Procedure:
m-Chlorobenzamide (75 g. 0.48 mol) and chlorocarbonylsulfenyl chloride (79 g, 0.6 mol, 25% excess) were reacted as described in Example 2 for 1.5 hours. Volatile components were removed under reduced pressure. The dark brown oil was taken up in hot cyclohexane, and the mixture was filtered. Cooling resulted in separation of a dark orange solid. The solid, recrystallized twice from hot ethyl acetate, gave 64.21 g (0.316 mol, 65.8%) of off-white slid, m.p. 83°-84.5°.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=2)[O:5][CH2:4]1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=1[C:19](Cl)=[O:20]>N1C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[C:18]([CH:22]=1)[C:19]([NH:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[CH:9][CH:10]=2)[O:5][CH2:4]1)=[O:20]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: COc1ccc2c(c1)OCC(N)C2
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)OCC(NC(=O)c1cc(Cl)ccc1OC)C2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
15.1 g (70 mmol) of 3-amino-7-methoxychroman hydrochloride (Eur. J. Med. Chem. 11 (1976), 251-256) were dissolved in 80 ml of pyridine, and 14.8 g of 2-methoxy-5-chlorobenzoyl chloride were added at 0° C. The mixture was stirred at room temperature for 1.5 hours and at 60° C. for 1 hour. The cooled reaction mixture was partitioned between water and methylene chloride. The aqueous phase was extracted three times with methylene chloride. The combined organic phases were washed with 2N hydrochloric acid, water and bicarbonate solution. After drying and evaporation of the organic phase, the residue was dissolved in a little toluene and the product was precipitated with excess diethyl ether. 3-(5-chloro-2-methoxybenzamido)-7-methoxychroman of melting point 92°-93° C. was obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:16][CH2:17][CH:18]2[O:23][CH2:22][C:21](=O)[N:20]([CH3:25])[CH2:19]2)[CH:9]=[CH:8]1>O1CCCC1>[CH2:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:16][CH2:17][CH:18]2[O:23][CH2:22][CH2:21][N:20]([CH3:25])[CH2:19]2)[CH:9]=[CH:8]1
Reactant: CN1CC(COc2cccc3c2CC=C3)OCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCOC(COc2cccc3c2CC=C3)C1
Yield: 38 %

Procedure:
In 200 ml. of anhydrous tetrahydrofuran was suspended 1.4 g. of lithium aluminum hydride and after adding thereto slowly a solution prepared by dissolving 5.8 g. of 2-(7-indenyloxymethyl)-4-methylmorpholin-5-one in 30 ml. of tetrahydrofuran, the mixture was treated in a similar manner as in Example 1 to provide 2.1 g. (yield 38%) of oily 2-(7-indenyloxymethyl)-4-methylmorpholine.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:10][C:11]1[CH:45]=[CH:44][C:14]([C:15]([NH:17][C:18]2[C:19]3[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[S:30][C:20]=3[N:21](C(OC(C)(C)C)=O)[N:22]=2)=[O:16])=[CH:13][CH:12]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:1][N:2]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]2[C:19]3[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:34])[S:30][C:20]=3[NH:21][N:22]=2)=[O:16])=[CH:44][CH:45]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C(=O)Nc2n[nH]c3sc(C(=O)NN(C)c4ccccc4)cc23)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 360 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide and 121 μL (1.11 mmol) of N-methylaniline are successively added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 15 days, and then poured onto ice. It is then extracted twice with a 50/50 mixture of ethyl acetate and heptane. The organic extracts are combined, washed with saturated brine, dried over magnesium sulfate and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 4 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography on a cartridge of 15 g of silica gel (0.015-0.040 mm), eluting with pure dichloromethane and then with a dichloromethane/methanol/28% aqueous ammonia mixture (12/3/0.5 by volume) at a flow rate of 10 mL/min. The fractions containing the expected product are combined and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (conditions B). 11 mg of 4-[(methylphenylamino)methyl]-N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]benzamide are thus obtained in the form of a beige-colored powder melting at 242° C. LC-MS-DAD-ELSD: 511(+)=(M+H)(+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[CH3:13]S(O)(=O)=O>CO>[CH3:13][O:11][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: CS(=O)(=O)O
Reactant: O=C(O)c1n[nH]c2ccccc12
Solvent: CO
Product: COC(=O)c1n[nH]c2ccccc12
Yield: 60 %

Procedure:
A stirred mixture of indazole-3-carboxylic acid (5.00 g, 0.0309 mole), methanesulfonic acid (1 ml), and methanol (100 ml) was heated at reflux temperature for 5 hours and then concentrated to a volume of 30 ml and treated with excess saturated aqueous sodium bicarbonate solution. Water was added to give a volume of 200 ml and the suspended solid was collected by filtration. The wet solid was dissolved in methylene chloride (200 ml), and the solution separated from a small amount of water and some insoluble material. The methylene chloride solution was dried (magnesium sulfate) and concentrated to yield 3.25 g (60%) of indazole-3-carboxylic acid methyl ester.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=1[CH3:32]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[C:24]([CH3:32])[CH:25]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)O)cc1C
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: COc1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1C

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-methoxy-3-methylbenzoic acid. MS (m/e): 420.8 (MH−, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:5][CH:4]=1.[BH4-].[Na+].[NH4+].[Cl-].C[OH:18]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([OH:18])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CCCC2
Reactant: CO
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc2c(c1)CC(O)CC2
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
A solution of 7-methoxy-3,4-dihydro-1H-naphthalene (5.00 g, 28.4 mmol) in MeOH (5 mL) is added to a suspension of NaBH4 (2.8 g, 74 mmol) in MeOH (40 mL) at −20° C. The mixture is stirred at −20° C. for 10 min. Solid NH4Cl is added, and the mixture is concentrated to remove most of the MeOH. The residue is partitioned between EtOAc and, sequentially, aq. NH4Cl and brine. The organic layer is dried over MgSO4 and concentrated to afford 7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ol as a red solid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([NH:20][NH:21]C(OC(C)(C)C)=O)=[O:19])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1>C(OCC)(=O)C.CO>[ClH:1].[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([NH:20][NH2:21])=[O:19])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: COc1cc(/C=C/C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (3 mL) was added to a solution of tert-butyl N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazinecarboxylate (668 mg) in ethyl acetate (5 mL) and methanol (1 mL), and the reaction solution was stirred at room temperature for two hours. The solid precipitated in the reaction solution was collected by filtration and washed with diethyl ether to obtain 658 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:19][C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: NCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3c(Cl)cccc3Cl)c2O1)OCc1ccccc1
Yield: 93.7 %

Procedure:
Treatment of (±)-1-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.290 g, 0.877 mmol) with diisopropylethylamine (0.170 g, 1.315 mmol) followed by benzyl chloroformate (0.165 g, 0.965 mmol) generally according to the procedure described for Intermediate 12 provided 0.352 g (94%) of (±)-benzyl {[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. mp 198-200° C.; Anal. calcd. for C23H19Cl2NO3: C, 64.5; H, 4.47; N, 3.27. Found: C, 64.2; H, 4.43; N, 3.21. Chiral HPLC separation of (±)-benzyl {[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]carbamate (Chiralcel AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt=5.174 min, Chiralcel AD, ethanol:hexane 1:1); Fraction 2 (Rt=6.229 min, Chiralcel AD, ethanol:hexane 1:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH:27]1([O:35][CH2:36][CH2:37]O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:37][CH2:36][O:35][CH:27]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:7][CH:6]=1
Reactant: OCCOC1CCCCCCC1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOC2CCCCCCC2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.27 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.303 g), stirred for 15 minutes and treated with the tosylate prepared from 2-(cyclooctyloxy)ethanol (2.18 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane-ethyl acetate; 80:20:2) to provide 1.0 g of pure 4-[[2-(cyclooctyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][C:31]([C:33]1[CH:34]=[C:35]([C@H:39]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[C@@H:40]([OH:44])[C:41](O)=[O:42])[CH:36]=[CH:37][CH:38]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:26]([O:30][C:31]([C:33]1[CH:34]=[C:35]([C@H:39]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[C@@H:40]([OH:44])[C:41]([N:16]2[CH2:17][CH2:18][CH2:19][C@H:15]2[C:14]([NH:13][CH2:12][C:11]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=2[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:42])[CH:36]=[CH:37][CH:38]=1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)c1cccc([C@H](c2ccccn2)[C@@H](O)C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H](O)[C@H](c1cccc(C(=O)OC(C)(C)C)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (0.026 g, 0.07 mmol), (2R,3R)-3-[3-(tert-butoxycarbonyl)phenyl]-2-hydroxy-3-pyridin-2-ylpropanoic acid from step 6 (20 mg, 0.058 mmol), and HOBT hydrate (12 mg, 0.087 mmol) in DMF (1 mL) was added EDC (0.017 g, 0.087 mmol). Diisopropylethylamine (0.0122 mL, 0.07 mmol) was added and the mixture was stirred at ambient temperature for 3 days, at which time HPLC analysis indicated complete consumption of the proline starting material. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and 10% aqueous Na2CO3 (20 mL). The EtOAc layer was separated, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Waters PrepPak using 10% to 100% CH3CN:H2O with 0.1% TFA as eluant over 60 min. The product-containing fractions were combined and the acetonitrile was removed under reduced pressure. The remaining aqueous solution was basicified with saturated aqueous NaHCO3, extracted with 4×20 mL CH2Cl2, dried over Na2SO4 and filtered. The filtrate solvent was removed under reduced pressure to give 1-((2R,3R)-3-(3-tert-butyloxycarbonylphenyl)-3-(2-pyridyl)-2-hydroxypropanoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide an oil (0.018 g, 45%). HPLC RT=2.54 min, method B; LC-MS M+H=693, 695.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][NH:27][CH2:28][CH3:29])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4].[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>>[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:17]([CH2:26][N:27]([C:34]([CH:31]3[CH2:33][CH2:32]3)=[O:35])[CH2:28][CH3:29])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]=1)[CH3:4]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1nc2ccccc2cc1-c1cc(CC(=O)OCC)ccc1OC
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 5, using the following starting materials: [3-(2-ethylaminomethyl-quinolin-3-yl)-4-methoxy-phenyl]-acetic acid ethyl ester, dihydrochloride and cyclopropanecarbonyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[Cl:9].[Cu][C:11]#[N:12].C(OCC)(=O)C>CN(C)C=O>[Cl:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[C:11]#[N:12]
Reactant: N#C[Cu]
Reactant: Cc1ccc(Br)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)c(Cl)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 93.8 %

Procedure:
25.0 g 4-bromo-3-chlorotoluene and 21.8 g copper (I) cyanide were dissolved in 200 ml dimethylformamide and stirred at 150° C. for three hours. The cooled reaction mixture was diluted by addition of 300 ml ethyl acetate and washed three times with portions of 150 ml saturated NH4Cl solution. The precipitates were filtered off and the filtrate dried over MgSO4 and then reduced in vacuo to obtain 17.3 g 2-Chloro-4-methyl-benzonitrile. This material was used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[CH:23]=2)=[CH:4][CH:3]=1.I[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[N:12][N:11]3[C:23]=2[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)cn3n2)CC1
Reactant: Ic1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccncc4)n3n2)CC1
Temperature: 135 °C
Yield: 44.5 %

Procedure:
A mixture of 0.90 g (2.89 mmol) of 2-(4-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine (Synthesis, 2001, 4, 595-600), 0.71 g (3.5 mmol) of 4-iodopyridine, 0.032 g (0.14 mmol) of palladium acetate and 0.48 g (3.5 mmol) of potassium carbonate in 18 mL of dimethylformamide is heated at 135° C. for 18 hours. After cooling, the reaction medium is poured into water and the product is extracted with ethyl acetate. The organic phase is washed with water and dried over sodium sulfate, and the solvent is evaporated off under reduced pressure. The residue is purified on a column of silica gel, eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5) to give 0.5 g of crystals after recrystallization from acetonitrile, filtering off and drying under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:19][C:20]([CH2:22][NH2:23])=[O:21])[CH:8]=2)[N:3]=1.Cl[CH2:25][CH2:26][CH2:27][C:28]([NH2:30])=[O:29]>>[NH2:1][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:25][CH2:26][CH2:27][C:28]([NH2:30])=[O:29])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:19][C:20]([CH2:22][NH2:23])=[O:21])[CH:8]=2)[N:3]=1
Reactant: NC(=O)CCCCl
Reactant: NCC(=O)Nc1ccc2nc(N)nc(-c3ccccc3O)c2c1
Product: NCC(=O)Nc1ccc2nc(N)nc(-c3ccccc3OCCCC(N)=O)c2c1

Procedure:
Analogous reaction of 2-amino-6-aminomethylcarbonylamino-4-(2-hydroxyphenyl)quinazoline with 4-chlorobutyramide gives the compound 2-amino-6-aminomethylcarbonylamino-4-[2-(3-aminocarbonylpropoxy)phenyl]quinazoline (“A61”).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:13])([CH3:12])[C:4](=[O:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[Cl:1][CH2:2][C:3]([CH3:13])([CH3:12])[C:4](=[O:11])[C:5]([N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1
Reactant: CC(C)(CCl)C(=O)Cn1cncn1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: O
Product: CC(C)(CCl)C(=O)C(=Cc1ccc(Cl)cc1)n1cncn1
Yield: 94.4 %

Procedure:
201.5 g (1 mole) of 1-chloro-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butan-3-one, 140.5 g (1 mole) of 4-chlorobenzaldehyde, 9,9 ml of piperidine and 30 g of glacial acetic acid in 300 ml of toluene were heated under reflux for 8 hours, the water of reaction formed being removed azeotropically. The reaction mixture was then washed with water and with dilute sodium bicarbonate solution, dried over sodium sulphate and evaporated in vacuo. 305.9 (94.4% of theory) of crude 1-chloro-5-(4-chlorophenyl)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-4-penten-3-one of boiling point 165° C./0.1 mm Hg were obtained as the E/Z-isomer mixture. The E-isomer could be isolated as crystals by stirring the product with isopropanol or ethanol. The E-isomer had a melting point of 112° C.
Reaction SMILES: [O:1]=[C:2]([CH2:13][CH3:14])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH2:12])=O)[CH2:6][CH2:5]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:12][CH2:10][CH:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH:2]([OH:1])[CH2:13][CH3:14])[CH2:9][CH2:8]1
Reactant: CCC(=O)CN1CCC(C(N)=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)CN1CCC(CN)CC1
Temperature: 25 °C
Yield: 109.1 %

Procedure:
To a stirred mixture of 1-(2-oxobutyl)piperidine-4-carboxamide (Example 13, Step 1, 1.60 g, 8.07 mmol) in tetrahydrofuran (200 mL) was added portionwise lithium aluminum hydride (920 mg, 24.21 mmol) at room temperature. The resulting mixture was refluxed for 5 h and cooled to room temperature. The mixture was treated with water (1.8 mL), 2N aqueous sodium hydroxide (3.6 mL) and water (1.8 mL). The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to afford 1.64 g (97%) of the title compound as colorless oil.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([CH3:17])[CH2:12][CH2:13][O:14]2)[CH2:9]1)C1C=CC=CC=1.[ClH:18]>CO.[Pd]>[ClH:18].[ClH:18].[CH3:17][N:11]1[CH:10]2[CH:15]([CH2:16][NH:8][CH2:9]2)[O:14][CH2:13][CH2:12]1
Reactant: CN1CCOC2CN(Cc3ccccc3)CC21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1CCOC2CNCC21

Procedure:
A solution of 9.4 g (40 mmol) of 8-benzyl-5-methyl-2-oxa-5,8-diazabicyclo[4.3.0]nonane in 150 ml of methanol and 7.4 ml of concentrated hydrochloric acid is hydrogenated on 3 g of palladium-on-active charcoal (10% of Pd) at 80° C. under 100 bar. The catalyst is filtered off with suction and the filtrate is concentrated. The residue is triturated with butanol/acetone 1:1 and the crystals are filtered off with suction and dried over P4O10 in a desiccator. The product is very hygroscopic.
Reaction SMILES: [C:1]([CH:4]([CH3:29])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[CH:10]=[C:9]2[CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1[O:27][CH3:28])(O)=[O:2].Cl.CN(C)CCCN=C=NCC.[CH2:42]([NH2:47])[CH2:43][CH2:44][CH2:45][CH3:46]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:28][O:27][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:17]=1[CH2:16][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][CH:4]([C:1](=[O:2])[NH:47][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH3:29])[CH:7]=2)[N:11]([CH3:15])[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(CC(C)C(=O)O)cc23)c(OC)c1
Reactant: CCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCNC(=O)C(C)Cc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
A mixture of methyl 4-[5-(2-carboxypropyl)-1-methylindol-3-ylmethyl]-3-methoxybenzoate (0.7 g), 4-dimethylaminopyridine (0.249 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.391 g) and pentylamine (0.154 g) was dissolved in methylene chloride (15 ml), and stirred for 18 hr, under an atmosphere of nitrogen. Methylene chloride (50 ml) was added, the solution was washed with 1M hydrochloric acid and brine, and dried (MgSO4). The solvent was evaporated and the residual oil purified by flash chromatography, eluting with 40:50:5 hexane:methylene chloride:ethyl acetate, to give a foam which was crystallized from a mixture of methylene chloride and hexane to give methyl 3-methoxy-4-[1-methyl-5-[2-(pentylcarbamoyl)propyl]indol-3-ylmethyl]benzoate (0.66 g, 80%) as white crystals; mp 128°-130°; partial NMR (250 MHz, DMSO-d6): 0.78(t, J=7 Hz, 3H, CH2CH3), 0.95(d, J=6.4 Hz, 3H, CHCH3), 1.05-1.25[m, 6H, (CH2)3 ], 2.5(m, 2H), 2.9(m, 3H), 3.68(s, 3H), 3.83(s, 3H), 3.92(s, 3H), 3.99(s, 2H, ArCH2Ar'), 7.61(br t, 1H, NHCO).