Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)=[O:3].[CH:11]([NH2:13])=[O:12]>CN(C)C1C=CN=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN1CCCC1=O>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: NC=O
Reactant: CC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(C(N)=O)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
0.122 g of bis(triphenylphosphine)-palladium(II) chloride, 3.439 g of 4-bromoacetophenone, 3.12 g of formamide, 2.37 g of 4-dimethylamino-pyridine and 20 ml of 1-methyl-2-pyrrolidinone are placed in a 200 ml glass autoclave. The autoclave is closed, flushed with nitrogen three times and then 5 bars carbon monoxide are applied. The reaction mixture is heated to 120° C. and stirred for 18 hours. It is then cooled, and the solution is diluted with ethyl acetate and water, and extracted. The aqueous phase is extracted by shaking 3 times with ethyl acetate, and afterwards the organic phases are collected, dried over magnesium sulphate and concentrated. The oil obtained is chromatographed over silica gel. The yield of title compound is 35% (part of the product remains in the water phase).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)[CH2:26][CH2:27]1)#[N:2]
Reactant: c1ccc(OCCN2CCNCC2)nc1
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2ccccn2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-[2-(2-pyridyloxy)ethyl)piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: P(=O)(O)(O)O.O.[Cl:7][C:8]1[C:17]([CH:18]=[CH:19][O:20]C)=[C:16]([Cl:22])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>O1CCOCC1>[Cl:7][C:8]1[C:17]([CH2:18][CH:19]=[O:20])=[C:16]([Cl:22])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC=Cc1c(Cl)ccc(C(=O)OC)c1Cl
Agent: O=P(O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cl)c(CC=O)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.7 %

Procedure:
6 ml of 85% strength phosphoric acid and 6 ml of H2O were added dropwise to 2.6 g (10 mmol) of methyl 2,4-dichloro-3-(2-methoxyethen-1-yl)benzoate in 80 ml of dioxane. The mixture was heated under reflux for 12 hours and then stirred at room temperature for 12 hours. The solvent was removed and the residue was taken up in ethyl acetate, washed with 10% strength sodium bicarbonate solution, dried and concentrated. The residue was chromatographed over silica gel (eluent: cyclohexane:ethyl acetate=9:1). 1.4 g (57% of theory) of methyl 2,4-dichloro-3-(2-oxoeth-1-yl)benzoate were obtained.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=1)[C:30](O)=[O:31]>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=1)[C:30]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:31]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: COc1ccc(Cl)cc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(C)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-Chloro-2-methoxy-benzoic acid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14].[Cl:15]N1C(=O)CCC1=O>C(#N)C>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([Cl:15])[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH2:14]
Reactant: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Nc1c(OCCCl)cc(Cl)cc1[N+](=O)[O-]
Yield: 95.3 %

Procedure:
A solution of 2-(2-chloro-ethoxy)-6-nitro-phenylamine (30.0 g, 0.14 mol), N-chlorosuccinimide and acetonitrile (1.3 L) was refluxed for 4 hours. The mixture was concentrated under vacuum and the residue was diluted with ethyl acetate (500 ml). The organic layer was washed with water (2×250 ml) and brine (250 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was removed under vacuum to give an orange solid residue. Crystallization from ethyl acetate-hexanes gave 33.5 g (95.3%) of product as an orange solid: mp 109-110° C.; MS (EI) 250/252/254 m/e (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]=[C:4]([NH:12][CH:13]2[CH2:15][CH2:14]2)[N:3]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>O1CCOCC1>[CH:16]1([NH:19][C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH2:11][CH2:10]3)[N:5]=[C:4]([NH:12][CH:13]3[CH2:15][CH2:14]3)[N:3]=2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: Clc1nc(NC2CC2)nc(NC2CC2)n1
Solvent: C1COCCO1
Product: C1CC1Nc1nc(NC2CC2)nc(NC2CC2)n1
Temperature: 140 °C

Procedure:
A mixture of 20 g of 2-chloro-4,6-bis-cyclopropylamino-s-triazine, 10.1 g of cyclopropylamine and 80 ml of dioxan is heated at 140° C. in an autoclave for 22 hours. The reaction mixture is concentrated in vacuo to half its volume and 300 ml of water are added. The mixture is extracted with ethyl acetate, the product phase is dried over sodium sulfate and the solvents are removed in vacuo. The residue is recrystallised from dioxan/petroleum ether; melting point 75°-77° C.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][N:15]=[C:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][CH2:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].[Cl:33]CCl.Cl>C(O)C>[ClH:33].[CH:27]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:16](=[N:15][O:14][CH2:13][CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:17]=2[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCON=C2c3ccccc3CCc3ccccc32)C1
Reactant: ClCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCON=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The above ester (1.0 g, 3.0 mmol) was dissolved in ethanol (25 ml) and a 4 N sodium hydroxide solution (3.4 ml) was added. The mixture was stirred vigorously at room temperature for 22 h. The solvent was evaporated in vacuo to give an oily residue. Dichloromethane (75 ml) was added and the mixture was cooled on an ice-bath. A concentrated hydrochloric acid solution (1.6 ml) was added. The mixture was stirred vigorously for a few minutes and the phases were separated. The organic phase was dried over sodium sulphate and the solvent was evaporated in vacuo. The residue was re-evaporated three times with dichloromethane and once with acetone to give 0.95 g of the title compound as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:18][CH2:19][C:20]1[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=1[CH2:26][CH2:27][CH3:28]>>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:18][CH2:19][C:20]2[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=2[CH2:26][CH2:27][CH3:28])=[O:17])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: Cc1nn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 3 (step c) from 6-bromo-3-methyl-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (0.24 g, 0.808 mmol) and 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (0.219 g, 1.010 mmol). The title compound was collected as a white solid (0.35 g, 92%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.33 Hz, 3H) 1.41 (d, J=6.57 Hz, 6H) 1.49-1.60 (m, 2H) 2.12 (s, 3H) 2.39 (s, 3H) 2.53 (s, 1H) 4.33 (d, J=5.05 Hz, 2H) 4.88-5.00 (m, 1H) 5.89 (s, 1H) 7.12 (d, J=1.52 Hz, 1H) 8.02 (d, J=1.77 Hz, 1H) 8.48 (t, J=4.93 Hz, 1H) 11.50 (s, 1H); LCMS (ES+): 459.1 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][CH2:17][CH2:18]Br>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:18][CH2:17][O:16][CH3:15])[CH:7]=1
Reactant: COCCBr
Reactant: Oc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cncc(Br)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-5-hydroxypyridine (Aldrich, Buchs, Switzerland, 611 mg, 3.51 mmol), potassium carbonate (971 mg, 7.02 mmol) and 2-bromoethyl methyl ether (537 mg, 3.86 mmol) in 30 ml DMF was stirred for 14 h at rt and for 2 h at 80° C. The reaction mixture was quenched with water and extracted with EtOAc (2×). The organic layers were washed with brine (3×), dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (dichloromethane/MeOH 0% to 3%) to give the title compound as an oil. (HPLC: tR 2.38 min (Method A); M+H=232, 234 MS-ES).
Reaction SMILES: [C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH2:18][CH2:19][CH3:20])(=[O:4])[CH2:2][CH3:3].[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>>[Cl:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[C:5]([C:1](=[O:4])[CH2:2][CH3:3])=[C:6]1[CH2:18][CH2:19][CH3:20]
Reactant: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)CC
Reactant: Clc1ccccc1CBr
Product: CCCc1c(C(=O)CC)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Yield: 115.2 %

Procedure:
Methyl 1-(2-chlorobenzyl)-3-propionyl-2-propylindole-6-carboxylate (436 mg) was prepared from methyl 3-propionyl-2-propylindole-6-carboxylate (260 mg) and 2-chlorobenzyl bromide (215 mg) in a similar manner to that of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[N:14]1([C:8]([C:7]2[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=2)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N2CCOCC2)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
To a solution of 3-(methoxycarbonyl)benzoic acid (200 mg, 1.11 mmol) in DCM (10 mL) were added morpholine (200 mg, 2.30 mmol) and TEA (300 mg, 2.96 mmol) and the resulting solution was stirred for 10 min at 20° C. To the mixture was added HATU (500 mg, 1.31 mmol) and the reaction mixture was stirred at 20° C. for 1 h. The mixture was concentrated and the residue was purified via column chromatography to obtain the title product (250 mg, Yield 90.5%). LCMS (m/z): 250.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)([CH2:12][CH2:13][O:14][Si](C(C)(C)C)(C)C)[C:8]1=[O:37].[F-].[NH4+]>>[CH3:44][O:43][C:39]1[CH:38]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:40]=1[O:41][CH3:42])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)([CH2:12][CH2:13][OH:14])[C:8]1=[O:37]
Reactant: COc1cc(CN2CCC(CCO[Si](C)(C)C(C)(C)C)(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2=O)cc(OC)c1OC
Agent: [F-]
Agent: [NH4+]
Product: COc1cc(CN2CCC(CCO)(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 23.2 using 1-(3,4,5-trimethoxybenzyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine (0.20 g, 0.31 mmol) and ammonium fluoride (0.07 g, 1.93 mmol) to give the title compound: Rf=0.45 (silica gel, ethyl acetate).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40]2[C:49]3[C:44](=[CH:45][C:46]([CH3:50])=[CH:47][CH:48]=3)[N:43]=[C:42]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=3[OH:57])[N:41]=2)[CH2:36][CH2:35]1.C(N(CC)CC)C>CN(C=O)C>[OH:57][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=1[C:42]1[N:41]=[C:40]([N:37]2[CH2:36][CH2:35][CH:34]([NH:33][C:6]([C@H:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:8])[CH2:39][CH2:38]2)[C:49]2[C:44](=[CH:45][C:46]([CH3:50])=[CH:47][CH:48]=2)[N:43]=1
Reactant: Cc1ccc2c(N3CCC(N)CC3)nc(-c3ccccc3O)nc2c1
Reactant: O=C(O)[C@H]1CCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCC(NC(=O)[C@H]4CCCO4)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
(R)-Tetrahydrofuran-2-carboxylic acid (193 mg, 1.66 mmol) was dissolved in DMF (6 mL), followed by the addition of HATU (696 mg, 1.83 mmol). The mixture was then stirred for 15 min at room temperature under an N2 atmosphere. The 2-[4-(4-Amino-piperidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol (556 mg, 1.66 mmol) was dissolved in DMF (8 mL) and added to the mixture, followed by triethylamine (336 mg, 0.463 mL, 3.32 mmol). After 30 min, theDMF was removed in vacuo and the crude product partitioned between water and ethyl acetate. The aqueous layer was separated, washed with ethyl acetate, and the combined organic layers dried over MgSO4, filtered, and concentrated to give crude product as an orange oil. Purification via silica gel chromatography (20% ethyl acetate/80% 1:1 CH2Cl2:hexane) gave pure (R)-Tetrahydro-furan-2-carboxylic acid {1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-amide (303 mg, 42%). 1H NMR (400 MHz, DMSO-d6) δ 8.44 (dd, J=8.2, 1.5 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.67 (s, 1H), 7.40-7.36 (m, 2H), 6.97-6.93 (m, 2H), 4.48-4.45 (m, 2H), 4.20 (dd, J=8.2, 5.3 Hz, 1H), 4.06-3.96 (m, 1H), 3.88 (dd, J=14.3, 6.6 Hz, 1H), 3.74 (dd, J=14.5, 6.7 Hz, 1H), 3.43-3.32 (m, 2H), 2.51 (s, 3H), 2.16-2.07 (m, 1H),
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH:4]([C:7]1[CH:23]=[CH:22][C:10]([C:11]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](O)=[O:16])=O)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[N:3]=[C:11]([C:10]2[CH:9]=[CH:8][C:7]([CH:4]([CH3:5])[CH3:6])=[CH:23][CH:22]=2)[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]1=[O:16]
Reactant: CNN
Reactant: CC(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1ccc(-c2nn(C)c(=O)c3ccccc23)cc1
Yield: 67 %

Procedure:
Methyl hydrazine (8.05 g, 0.175 mol) was added to a mixture of 2-(4-isopropylbenzoyl)benzoic acid (40.2 g, 0.15 mol) in toluene (350 mL) and the mixture was heated to reflux for 3 hours with the removal of water with a Dean Stark trap. The reaction mixture was hot filtered through celite, the filtrate was concentrated to 125 mL and the filtrate was diluted with hexane (100 mL) and cooled. A solid was collected by filtration to afford 27.97 g (67%) of 2-methyl-4-(4-isopropylphenyl)-1-(2H)-phthalazinone, m.p. 107°-107.5° C.
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3]/[CH:4]=[CH:5]/[C@H:6]([OH:8])[CH3:7].[C:15]([O-])(=[O:19])[CH2:16]CC.C(OC(=O)C)(=O)C.N1C=CC=CC=1>>[C:15]([O:8][C@@H:6](/[CH:5]=[CH:4]/[CH2:3][C@H:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH3:7])(=[O:19])[CH3:16]
Reactant: CC(C)=CCC[C@@H](C)C/C=C/[C@@H](C)O
Reactant: CCCC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@H](C)/C=C/C[C@H](C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 99 %

Procedure:
A flame-dried 100 mL, three-necked flask with magnetic stirring bar was charged under argon with 2.0 g (10.2 mmol) of (2R,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol [(2R,6R)/(2S,6R)=90:10 by GC diastereomer analysis of butyrate derivative]. Then, after cooling in an ice-bath, 1.5 g (1.4 mL, 15 mmol) of acetic anhydride, 1.58 g (1.6 mL, 20 mmol) of dry pyridine and 12.3 mg (0.1 mmol) of 4-N,N-dimethylaminopyridine were added, and the reaction was stirred for 75 minutes at ambient temperature. Work-up as described in Example 9 followed by Kugelrohr distillation at ca. 110°/0.25 mm afforded 2.35 g (99%) of (2R,3E,6R)-6,10-dimethyl-3,9-undecadien-2-ol acetate as colorless liquid; GC purity 90%; [α]D25 =+47.17° (5.3% in CHCl3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[I-].[Na+].Cl.[OH-:26].[Na+]>CS(C)=O.O>[CH3:16][C:15]1[C:3]2[C:2](=[O:26])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH3:12])[NH:5][C:4]=2[N:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:14]=1
Reactant: Cc1cccc2nc3c(c(C)nn3-c3ccccn3)c(Cl)c12
Reactant: [OH-]
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc2[nH]c3c(c(C)nn3-c3ccccn3)c(=O)c12
Temperature: 100 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of 4-chloro-3,5-dimethyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.65 g, 5.34 mmol), sodium iodide (0.96 g, 6.41 mmol) and conc. hydrochloric acid (1 mL) in dimethylsulfoxide (20 mL) was heated and stirred at 100° C. for 2 hours. The solution was cooled to room temperature, and the residue was poured into water. The mixture was made basic by the addition of a sodium hydroxide solution, and organic matter was extracted with 10% methanol/chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate:hexane=90:10) to give the title compound (1.13 g, 73% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC=C)=[CH:9][C:8]=1[O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26]>C1(C)C=CC=CC=1.[Zn]>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:17][C:8]1[CH:9]=[C:10]([OH:13])[C:11]([C:25](=[O:27])[CH3:26])=[CH:12][C:7]=1[O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH3:23]
Reactant: C=CCOc1ccc(OCC(=O)OCC)c(OCC(=O)OCC)c1
Reactant: CC(=O)Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1cc(O)c(C(C)=O)cc1OCC(=O)OCC

Procedure:
The compound of example 65c (38 g; 112.5 mmol) was heated with acetyl chloride (9.74 ml; 137 mmol) and activated Zn (7.46 g) in toluene (250 ml) for 5 h (Synth. Commun, 1998, 28, 2203). to obtain the title compound which was processed as is routinely done and purified using flash chromatography (silica gel, 3% CH3CN in chloroform). Yield, 30 g (78.3%); MS (CI): 409 (M++29), 381(M+); analysis: C16H20O8 requires C, 56.47; H, 5.92; found: C, 56.05; H, 5.59%.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][CH3:10])[CH:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][CH3:10])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1cc(O)ncn1
Product: COCc1cc(Cl)ncn1

Procedure:
50 g of 6-hydroxy-4-methoxymethylpyrimidine were heated in 375 ml of phosphorus oxychloride until a clear solution had been produced. The excess phosphorus oxychloride was removed by distillation in vacuo, and the residue was poured into ice-water. Extraction with dichloromethane and drying over sodium sulfate were followed by concentration of the solution in vacuo. 58 g of 6-chloro-4-methoxymethylpyrimidine were obtained as an oil which was used without further purification in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:5][C:3]=1[NH2:4].[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[N:30]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:4][C:3]2[CH:5]=[C:6]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][N:11]=3)[CH:7]=[CH:8][C:2]=2[Cl:1])=[O:35])[N:30]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1cc2ncnc(Oc3ccc(Cl)c(N)c3)c2cc1OC
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Product: COc1cc2ncnc(Oc3ccc(Cl)c(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c3)c2cc1OC
Yield: 46.7 %

Procedure:
The title compound was prepared from 2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)aniline (100 mg, 0.3 mmol) and phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (140 mg, 0.4 mmol) using the procedure in Example 115C to give 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(2-chloro-5-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (80 mg, 0.14 mmol, 46%). 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.82 (s, 1H), 8.56 (s, 1H), 8.12 (d, 1H), 7.57-7.54 (m, 2H), 7.40-7.33 (m, 5H), 7.03 (dd, 1H), 6.34 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 2.37 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 587 (M+H)+.
Reaction SMILES: O1CCCCC1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=O.[C:19]([C:21]1[CH:35]=[CH:34][C:24]([CH2:25][NH:26][C:27](=[O:33])[C@@H:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)=[CH:23][CH:22]=1)#[N:20].ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:27](=[O:33])[C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:15](=[O:17])[C@@H:14]([CH2:13][C:8]2[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=2)[OH:18])=[CH:34][CH:35]=1)#[N:20]
Reactant: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2)cc1
Reactant: O=C(O)[C@H](O)Cc1ccccc1C1CCCCO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(CNC(=O)[C@@H]2CCCN2C(=O)[C@H](O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.5 g (20.4 mmol) of o-tetrahydropyranyl-3-phenyl-D-lactic acid (WO 93/18060) were dissolved in 30 ml of DMF and, successively, 5.4 g (20.4 mmol), N-(p-cyanobenzyl)prolin-amide, 3.3 g (20.4 nmol) of N-hydroxybenzotriazole, 3.0 g DIPEA and 4.33 g (20.6 mmol) of dicyclohexylcarbodiimide were added. The mixture was left to stir at room temperature for 48 h. The precipitated urea was filtered off with suction and then the solvent was substantially removed under reduced pressure, and the residue was mixed with 50 ml of water and extracted with ethyl acetate. After washing with water, NaHCO3 solution and drying over Na2SO4, the ethyl acetate was distilled off, the remaining oily residue was dissolved in methanol, and the pH was. adjusted to 2 with p-toluenesulfonic acid. This solution was left to stand at room temperature for 6 h. The methanol was then distilled off, and the residue was taken up in ethyl acetate and washed with water, 5% strength citric acid and NaBCO3 solutions. The residue obtained after drying over Na2SO4 and removal of the solvent by distillation was purified by column chromatography (eluent: methylene chloride/acetone/methanol, 45/5/2). 2.5 g of white crystals were obtained, and these melted at 108° C.-110° C. after crystallization from an ether/hexane mixture.