Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:17][C:18]1[C:19]([OH:31])=[C:20]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH:21]=[CH:22][C:23]=1[OH:24]>ClCCCl.ClCCl>[Cl:1][C:2]1[C:3]([C:8]([OH:7])=[O:9])=[C:4]([C:5]([C:22]2[CH:21]=[C:20]([CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:19]([OH:31])=[C:18]([Cl:17])[C:23]=2[OH:24])=[O:6])[CH:10]=[CH:11][CH:12]=1
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Reactant: COC(=O)CCc1ccc(O)c(Cl)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)CCc1cc(C(=O)c2cccc(Cl)c2C(=O)O)c(O)c(Cl)c1O
Yield: 48.5 %

Procedure:
To a solution of 3-chlorophthalic anhydride (3.7 g, 20 mmol) ((J. Org. Chem., 1987, 52, 129-134) in 60 mL of anhydrous 1,2-dichloroethane was added 6.6 g (50 mmol) of AlCl3 followed by 4.6 g (20 mmol) of methyl 3-(3-chloro-2,4-dihydroxyphenyl)propanoate (WO 03/023357). The reaction was heated at reflux for 30 min, cooled and concentrated. The resultant gelatinous material was partitioned between cold 2 N HCl (100 mL) and ethyl acetate (100 mL). The organic layer was washed with 1 N HCl, brine, dried over Na2SO4 and concentrated to afford an oily material (mixture of 6- and 2-chloroisomers). The oil was dissolved in dichloromethane (˜40 mL) and briefly sonicated (ultrasound bath) to initiate crystallization. The mixture was cooled (ice/water bath) and allowed to crystallize for 30 min (extended crystallization time will result in co-crystallization of undesired 2-chloro isomer). The crystals were collected by filtration washed with cold dichloromethane. Drying under vacuum afforded 4.01 g of desired 6-chloro isomer (32). 1H NMR (DMSO-d6) δ 12.47 (br s, 1H), 10.78 (br s, 1H), 8.06 (d, J=7.7 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.71 (t, J=7.9 Hz, 1H), 6.76 (s, 1H), 3.46 (s, 3H), 2.27 (m, 2H), 2.41 (t, J=6.6 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH3:18])[C:8]([CH3:17])=[C:9]([CH2:11][CH2:12][C:13]([O:15]C)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CO>[CH2:20]([NH:38][C:13](=[O:15])[CH2:12][CH2:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]([OH:19])=[C:7]([CH3:18])[C:8]=1[CH3:17])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCc1cc(C(C)(C)C)c(O)c(C)c1C
Reaction time: 4 h

Procedure:
A mixture consisting of 10.6 grams of methyl 3-(5-tert.-butyl-2,3-dimethyl-4-hydroxyphenyl)propionate and 11.9 grams of n-octadecylamine were heated together for 1 hour at 160° to 165° and then at 175° to 180° for 4 hours, the methanol of reaction being removed continuously by distillation. Crystallization from methanol yielded white crystals melting at 85° to 87° (Compound 35).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[C:6]([Cl:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][CH:28]([NH2:30])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:11][C:6]1[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=[C:2]([NH:30][CH:28]2[CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:29]2)[C:7]=1[CH2:8][CH2:9][OH:10]
Reactant: C[C@H]1COCCN1c1nc(Cl)c(CCO)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H]1COCCN1c1nc(Cl)c(CCO)c(NC2CN(C(=O)OC(C)(C)C)C2)n1
Temperature: 75 °C
Yield: 86.2 %

Procedure:
A solution of 2-{4,6-dichloro-2-[(3S)-3-methylmorpholin-4-yl]pyrimidin-5-yl}ethanol (as prepared in Preparation 2)(0.652 g, 2.23 mmol) and 3-amino-azetidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.9 mmol) in DMSO (10.0 mL) was treated with DIPEA (0.7 mL, 4 mmol) and heated at 75° C. for 5 days in a sealed tube. The mixture was poured into a flask containing water and the resulting solids were collected by filtration and rinsed with water. The solids were taken up in DCM, dried over MgSO4 and filtered. The filtrate was purified directly by silica gel chromatography using a gradient of 25-100% EtOAc/heptane as eluent to give 0.823 g (86%) of the title compound as a crisp foam. 1H NMR (400 MHz, DMSO-d6) δ 7.30 (d, J=5.6 Hz, 1 H), 4.71 (t, J=5.2 Hz, 1 H), 4.62-4.53 (m, 1 H), 4.47-4.40 (m, 1 H), 4.13-4.04 (m, 3 H), 3.89-3.78 (m, 3 H), 3.66 (d, J=11.4 Hz, 1 H), 3.55-3.44 (m, 3 H), 3.36 (dt, J=11.7, 2.9 Hz, 1 H), 3.04 (dt, J=12.9, 3.7 Hz, 1 H), 2.69 (t, J=6.9 Hz, 2 H), 1.39 (s, 9 H), 1.14 (d, J=6.7 Hz, 3 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH2:25].Cl>CC(O)CCC.C(O)(C)C>[F:22][C:23]1[CH:29]=[C:28]([CH3:30])[C:27]([OH:31])=[CH:26][C:24]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COCCOCCOc1cc2nncc(Cl)c2cc1OC
Agent: Cl
Solvent: CCCC(C)O
Solvent: CC(C)O
Product: COCCOCCOc1cc2nncc(Nc3cc(O)c(C)cc3F)c2cc1OC

Procedure:
A solution of 4-chloro-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]cinnoline (130 mg, 0.41 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (70 mg, 0.5 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (3 ml) containing 5M hydrogen chloride in isopropanol (2drops) was heated at reflux for 45 minutes. After cooling the solid was filtered off, washed with isopropanol followed by ether to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]cinnoline as an hydrochloride salt (159 mg, 88%).
Reaction SMILES: Cl.[NH:2]=[C:3]([CH2:8][CH2:9]C)C(OC)=O.[C:11](O)(=O)[C:12](O)=O.[NH2:17][CH:18]([C:24]#[N:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])(=O)C.[Na+]>C(O)C>[NH2:25][C:24]1[N:2]=[C:3]([CH2:8][CH2:9][CH2:11][CH3:12])[NH:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(N)C#N
Reactant: O=C(O)C(=O)O
Reactant: CCCC(=N)C(=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(N)c(C(=O)OCC)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
A mixture of methyl iminovalerate hydrochloride (4.8 g), ethyl 2-amino-2-cyanoacetate oxalate (4.0 g), anhydrous sodium acetate (9.1 g) and absolute ethanol (75 mL) was stirred at room temperature for 18 hours. Solids were removed by filtration and the filtrate was evaporated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated NaCl, dried over MgSO4, and evaporated. Flash chromatography on silica gel, eluting with a gradient of dichloromethane-ethyl acetate (75:25) to ethyl acetate gives the title compound (2.7 g) as a pale yellow solid, mp 103°-106° C. MS (DEI) 211 (m).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH2:15])=[O:14].C(OP(C#N)(=O)OCC)C.[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH2:50][C@@H:51]([CH:67]([CH3:69])[CH3:68])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([O:61][CH2:62][CH2:63][CH2:64][O:65][CH3:66])[CH:54]=1)[C@@H:35]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[CH2:36][C@@H:37]([CH3:41])[C:38](O)=[O:39])=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[C:13]([CH2:12][CH2:11][CH2:10][NH:9][C:38](=[O:39])[C@H:37]([CH3:41])[CH2:36][C@H:35]([O:42][Si:43]([C:46]([CH3:47])([CH3:49])[CH3:48])([CH3:45])[CH3:44])[C@@H:34]([NH:33][C:31]([O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:32])[CH2:50][C@@H:51]([CH:67]([CH3:68])[CH3:69])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([O:61][CH2:62][CH2:63][CH2:64][O:65][CH3:66])[CH:54]=1)(=[O:14])[NH2:15]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](C)C(=O)O)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Reactant: NCCCC(N)=O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H](C[C@@H](C)C(=O)NCCCC(N)=O)O[Si](C)(C)C(C)(C)C)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
67 μl of triethylamine, 34 mg of 4-aminobutyric acid amide hydrochloride and 38 μl of cyanophosphonic acid diethyl ester are added in succession to 128 mg of 5(S)-tert-butoxycarbonylamino-4(S)-tert-butyldimethylsilyloxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxy-propyloxy)-phenyl]-octanoic acid in 8 ml of dimethylformamide at 0° C. The reaction mixture is stirred for a further 18 hours at room temperature. The reaction mixture is concentrated by evaporation and 20 ml of 10% citric acid solution and ice are added to the residue. The mixture is extracted repeatedly with ethyl acetate and the organic phases are then washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. After concentration by evaporation, the residue is purified by means of FC (70 g of silica gel, dichloromethane/methanol=9:1). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.38.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(O)[CH2:43][CH2:42]C[CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:43][CH2:42]2)=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCCCCC1
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1NC(=O)OC1CCCCCC1
Yield: 62.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cycloheptanol (54 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (89 mg, yield 61%).
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[NH:17][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:15][CH2:14]1)C>O.C1COCC1.CO>[C:18]1([C:16]2[NH:17][N:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:24])=[O:5])[CH2:14][N:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CCCCCCN1CN=C(c2ccccc2)N1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCCCCN1CN=C(c2ccccc2)N1
Yield: 99.9 %

Procedure:
Add a solution of potassium hydroxide (1.8 g, 32 mmol) in water (70 mL) to a solution of 7-(5-phenyl-4H-[1,3,4]triazol-3-yl)heptanoic acid ethyl ester (4.9 g, 16 mmol) in THF (50 mL) and methanol (50 mL) at room temperature under nitrogen and heat the mixture at reflux for 3 hours. Remove the solvent under reduced pressure, dilute the residue with water (200 mL) and wash with ethyl acetate (200 mL). Adjust the pH of the aqueous layer to 3 with concentrated HCl and extract with ethyl acetate (3×200 mL). Wash the combined organic extracts with brine (200 mL), dry over sodium sulfate and remove the solvent under reduced pressure to afford 7-(5-phenyl-4H-[1,3,4]triazol-3-yl)heptanoic acid (4.4 g, 99%). APCI mass spectrum m/z 273 [C15H19N3O2]−.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12]1([NH:18][NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)(=O)C>[CH3:10][C:9]1[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:19]=1.[CH3:10][C:9]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:19]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(-c2ccccc2)n1
Product: CCOC(=O)c1cc(C)nn1-c1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2 ml ethyl 2,4-dioxovalerate and 1.2 g phenyl hydrazine were dissolved in 20 ml acetic acid, followed by stirring at 100° C. for 2 hours. After evaporating acetic acid, ethyl acetate was added to the residue. The mixture was washed with aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to silica gel column chromatography, to give 0.37 g of ethyl 3-methyl-1-phenyl-1H-5-pyrazolecarboxylate with hexane:ethyl acetate (14:1) and 0.46 g of ethyl 5-methyl-1-phenyl-1H-3-pyrazolecarboxylate with hexane:ethyl acetate (9:1).
Reaction SMILES: C([O:8][C:9]1[CH:39]=[CH:38][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:37])[C:21]([CH2:34][CH2:35][CH3:36])([CH2:31][CH2:32][CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][C:25]([F:30])=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.C(OC1C=CC2NC(C3C(=O)C(CCC)(CCC)C4C(C=3O)=CC=CC=4)=NS(=O)(=O)C=2C=1)C1C=CC=CC=1>>[F:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[C:21]([CH2:34][CH2:35][CH3:36])([CH2:31][CH2:32][CH3:33])[C:20](=[O:37])[C:19]([C:14]1[NH:13][C:12]3[CH:38]=[CH:39][C:9]([OH:8])=[CH:10][C:11]=3[S:16](=[O:17])(=[O:18])[N:15]=1)=[C:28]2[OH:29]
Reactant: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2cc(F)ccc21
Agent: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3cc(O)ccc3N2)=C(O)c2cc(F)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 2G, substituting the compound of Example 15A for the compound of Example 2F. 1H NMR (300 MHz, DMSO-d6): δ 0.57 (m, 2 H) 0.68 (m, 6 H) 0.89 (m, 2 H) 2.01 (dd, J=12.13, 8.82 Hz, 2H) 2.17 (m, 2 H) 7.18 (m, 2 H) 7.62 (m, 2 H) 7.83 (m, 2 H) 10.41 (s, 1 H) 13.46 (s, 1 H).
Reaction SMILES: Cl[C:2]1(Cl)[C:8](=[O:9])[CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[N+](=[CH2:20])=[N-].CO.CCOCC>C(O)(=O)C>[CH2:10]([CH:6]1[CH2:5][CH2:4][CH:3]2[CH:7]1[CH2:20][C:8](=[O:9])[CH2:2]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=[N+]=[N-]
Reactant: CCCCCCCC1CCC2C1C(=O)C2(Cl)Cl
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCCC1CCC2CC(=O)CC12
Temperature: 70 °C

Procedure:
The procedure followed is the same as that described in Example 29 substituting the starting material from Example 34, 6,6-dichloro-2-(hept-1-yl)bicyclo[3.2.0]heptan-7-one {7,7-dichloro-4-heptylbicyclo[3.2.0]heptan-6-one} and isomers (14.2 g, 0.051 moles), an etheral diazomethane solution (175 ml), methanol (5 ml), and acetic acid (15 ml). After the acetic acid is added the solvent is removed under vacuum leaving a clear yellow oil. The crude product is then dissolved in acetic acid (100 ml) and stirred while zine powder (29 g) is slowly added. The reaction is heated in a 70° C. water bath for 1 hour, after which time ether (500 ml) is added and the solution filtered. The filtrate is washed with brine (100 ml) and then with a solution of saturated bicarbonate. The ether layer is separated and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (4.3 g, 0.015 moles).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15]2)[C:7]1=[O:21].[H-].[Na+].Br[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:31](=[O:32])[O:30]1.Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:18](=[O:19])[NH:17][C:16](=[O:20])[N:15]2[CH:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31](=[O:32])[O:30]2)[C:7]1=[O:21]
Reactant: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Reactant: O=C1OC(Br)c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OC(N2C(=O)NC(=O)C23C(=O)N(Cc2ccc(Cl)c(Cl)c2)c2ccccc23)c2ccccc21
Reaction time: 0.5 h
Yield: 16.4 %

Procedure:
1'-(3,4-Dichlorobenzyl)-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (1.8 g.) was stirred in anhydrous N,N-dimethylformamide (50 ml.) under an atmosphere of nitrogen at 25° C. Sodium hydride (0.25 g; 50% w/v oil dispersion) was added, and the mixture stirred for 30 minutes. 3-Bromophthalide (1.15 g.) was then added. The mixture was stirred for 16 hours and then poured into water (150 ml.). The mixture was acidified (concentrated hydrochloric acid) and then extracted with ethyl acetate (150 ml.). The extract was washed with water (2×150 ml.), brine (150 ml.) and then dried (MgSO4). The dry solution was evaporated onto silica gel (10 g., Merck type 7734) which was then added to the top of a column of silica gel (150 g., Merck type 7734) made up in toluene. The column was eluted with an increasing concentration of ethyl acetate in toluene up to 25% v/v. The fractions containing the major product [Relative flow value: 0.5 on Merck SiO2TLC plates No. 5715; eluant: EtOAc/toluene, 1:1 v/v] were collected and evaporated to give an oil which crystallised on treatment with ethyl acetate/petrol 60-80 to give 1'-(3,4-dichlorobenzyl)-3-phthalidyl-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (0.4 g.), m.p. 154°-158° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[S:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.CN(C=O)C.[CH2:23]([O:25]/[CH:26]=[CH:27]/B1OC(C)(C)C(C)(C)O1)[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH:12]1([C:10]2[S:9][C:4]3[N:5]=[C:6]([CH3:8])[N:7]=[C:2](/[CH:24]=[CH:23]/[O:25][CH2:26][CH3:27])[C:3]=3[CH:11]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCO/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nc(Cl)c2cc(C3CCCCC3)sc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCO/C=C/c1nc(C)nc2sc(C3CCCCC3)cc12
Temperature: 85 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a mixture of 4-chloro-6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine (1.0 g) and DMF (40 mL) were added (E)-1-ethoxyethene-2-boronic acid pinacol ester (900 mg) and K3PO4 (4.3 g), and Pd(PPh3)4 (500 mg) was added thereto under an argon atmosphere, followed by heating and stirring at 85° C. for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, then concentrated under reduced pressure, and purified by silica gel column (hexane/EtOAc) to obtain 6-cyclohexyl-4-[(E)-2-ethoxyvinyl]-2-methylthieno[2,3-d]pyrimidine (885 mg).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[B:17](OC)([O:20]C)[O:18]C.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:9][C:7]1[CH:6]=[CH:5][C:4]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:3]([B:17]([OH:20])[OH:18])[CH:8]=1
Reactant: COB(OC)OC
Reactant: Fc1ccc(OC2CCCCO2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1cc(F)ccc1OC1CCCCO1
Temperature: 25 °C

Procedure:
48.6 g (2.00 mol) of magnesium and 510 g (1.85 mol) of 2-bromo-4-fluoro-1-(tetrahydropyran-2-yloxy)benzene in 1250 ml of THF were used to prepare a Grignard reagent. This Grignard reagent was slowly added dropwise at −78° C. to a mixture of 241.6 ml (2.00 mol) of trimethyl borate in 500 ml of THF. On completion of addition, the reaction mixture was allowed to warm to room temperature and was hydrolyzed by addition of 100 ml of saturated potassium carbonate solution and 1000 ml of water. The organic phase was washed with saturated sodium chloride, solution. (1×500 ml) and subsequently concentrated to dryness. The yield was 428.2 g (1.78 mol), and the product was obtained as a waxy solid which contained varying proportions of boronic anhydride and borinic acids and was used in the following stage without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([N:10]=[N+]=[N-])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([C:30]2[S:31][CH:32]=[CH:33][N:34]=2)=[CH:26][C:23]=1[CH:24]=O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:24][C:23]2[CH:26]=[C:27]([C:30]3[S:31][CH:32]=[CH:33][N:34]=3)[CH:28]=[CH:29][C:22]=2[O:21][CH3:20])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4]
Reactant: COC(=O)C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1
Reactant: COc1ccc(-c2nccs2)cc1C=O
Product: COC(=O)C1CCC(NCc2cc(-c3nccs3)ccc2OC)C1c1ccc(F)cc1

Procedure:
The title compound was prepared by employing the method described in Example 91, Step D with (1RS,2RS,3RS)-2-(4-fluorophenyl)-3-azidocyclopentanecarboxylic acid methyl ester (from Example 89, Step A) and the known 2-methoxy-5-(thiazol-2-yl)benzaldehyde (P. J. Ward, et al., J. Med. Chem. 1995, 38, 4985-92).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)=[CH:10]3)[C:6]=2[CH:21]=1.[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([SH:32])[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([N:26]1[CH2:31][CH2:30][CH:29]([S:32][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=5)[N:8]=[C:7]4[C:6]=3[CH:21]=2)[CH2:28][CH2:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Brc1ccc2c(c1)-c1nc(-c3ccccn3)cn1CCO2
Reactant: CC(C)(C)N1CCC(S)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Temperature: 140 °C

Procedure:
A mixture of 9-bromo-2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 3 (200 mg, 0.58 mmol), 1-tert-butylpiperidine-4-thiol (202 mg, 1.69 mmol), Pd2(dba)3 (160 mg, 10 mol %), XantPhos (68 mg, 20 mol %) and DIPEA (410 μL, 2.34 mmol) in dioxane (5 mL) was purged with argon and heated at 140° C. for 1 h using microwave irradiation. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM then C18, gradient 2-25% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording 154 as a white solid (36 mg, 15%). LCMS: RT 2.40 min [M+H]+ 435.1. 1H NMR (CDC3, 400 MHz): δ 8.15-8.14 (1H, m), 7.76 (1H, td, J=8.52, 2.20 Hz), 7.67 (1H, s), 7.33 (1H, dd, J=8.45, 3.89 Hz), 7.15-7.15 (1H, m), 6.96 (1H, d, J=8.43 Hz), 4.46-4.45 (4H, m), 3.03-2.98 (4H, m), 2.20 (2H, t, J=11.00 Hz), 2.06-1.94 (3H, m), 1.66-1.62 (2H, m), 1.06 (9H, s)