Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.S(Cl)(Cl)=O.[CH3:15]O>>[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:15])=[O:9])[N:4]=[CH:3]1
Reactant: CO
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1c[nH]cn1
Temperature: 25 °C

Procedure:
1H-Imidazol-4-ylacetic acid hydrochloride (20.0 g) was suspended in methanol (200 mL). To this suspension, thionyl chloride (8.87 mL) was added at room temperature, and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. To this reaction solution, a saturated aqueous solution of sodium bicarbonate was added, and the solvent was distilled off under reduced pressure. To the obtained residue, tetrahydrofuran and anhydrous magnesium sulfate were added, and insoluble matter was filtered off. The solvent in the filtrate was distilled off under reduced pressure to obtain the title compound (14.3 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][CH:18]=[O:19])[C:15](=[O:20])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[C:21]1([C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N+]=[N-])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.CCOCC>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][CH:18]=[O:19])[C:15](=[O:20])[N:10]2[C:11]=1[C:12]([O:14][CH:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Yield: 40 %

Procedure:
A solution of (6R,7R)-3-acetoxymethyl-7-formamidoceph-3-em-4-carboxylic acid (6.20g, 20mmole) in dry tetrahydrofuran (150ml) was stirred with a solution of diphenyldiazomethane (20mmole; prepared in ether solution, then evaporated) in dry tetrahydrofuran (20ml) at +20 to +25° for 16 hrs. The solvent was evaporated and the solution of the residue in methylene chloride (150ml) was washed successively with 2N-hydrochloric acid 3%-aqueous sodium bicarbonate solution. The solution was dried and [leaving a foam which was chromatographed on kieselgel G (250g) in benzeneethyl acetate (9:1, then 1:1). The appropriate fractions were combined, evaporated, and triturated with ethyl acetate to give the title compound as a crystalline solid (3.789g, 8.1mmole, 40%), m.p. 158.6 to 160.4(cap.); [α]D +32.8; λmax 261 nm (ε7,750); νmax 3410 (NH), 1788 (azetidin-2-one), 1732 OCOCH3), 1705 (CO2R) and 1698 and 1502 cm -1 (CONH); τ 1.80 (1H,d,J9Hz, NH), 2.70(10H,m, ]C6H5 ]CH), 3.03(1H,s, ]C6H5 ]2CH), 4.10 (1H,dd,J9 ; and 4.5Hz, C7 -H), 4.90 and 5.23 (2H, ABq, J14Hz, CH2OCOCH3 ), 5.04 (1H, d, J5Hz, C6 -H), 6.38 and 6.72 (2H, ABq, J18Hz, C2 -H2), 8.00 (3H,s, OCOCH3). (Found: C, 62.1; H,4.8; N,5.8; S,6.9. C24H22N2O6S(466.5) requires C, 61.8; H,4.8; N,6.0; S,6.9%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:11]=[C:12]([CH2:15][O:16][CH3:17])[S:13][CH:14]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31](=[O:36])N(OC)C)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]([C:14]2[S:13][C:12]([CH2:15][O:16][CH3:17])=[CH:11][C:10]=2[Br:9])=[O:36])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: COCc1cc(Br)cs1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCc1cc(Br)c(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Add lithium diisopropyl amide (13.20 mL, 26.37 mmol, 1.05 equivalents) to a stirred, cold (−78° C.) solution of 4-bromo-2-methoxymethyl-thiophene (5.20 g, 25.11 mmol, 1.00 equivalents) in tetrahydrofuran (dry, 24.30 mL). Stir at −78° C. for 1 hour and add a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (6.84 g, 25.11 mmol, 1.00 equivalents) in tetrahydrofuran (dry, 16.40 mL), dropwise. Stir the resulting solution at −78° C. for 3 hours. Quench the reaction mixture with saturated sodium chloride (aqueous, 50 mL). Allow the resulting mixture to warm to room temperature and extract with a mixture of ethyl acetate: diethyl ether (1:1, 3×35 mL). Combine the extracts, dry over magnesium sulfate, filter and evaporate. Purify the residue via flash column chromatography eluting with a mixture of n-heptane:ethyl acetate (4:1) to yield the desired product as a yellow oil (9.47 g). LC/MS (ESI), m/e 362 (M-56) and 418 (MH+), retention time 2.08 minutes. Condition II.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([C:16]([F:19])([F:18])[F:17])[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[N:9]1.N1C=CC=CC=1.[NH2:33][C:34]1[CH:35]=[CH:36][C:37]([Cl:43])=[C:38]([C:40](=[O:42])[CH3:41])[CH:39]=1.Cl>CN(C=O)C.ClCCl.C1COCC1>[C:40]([C:38]1[CH:39]=[C:34]([NH:33][C:13]([C:12]2[N:8]([CH3:7])[N:9]=[C:10]([C:20]([F:26])([F:25])[C:21]([F:24])([F:22])[F:23])[C:11]=2[C:16]([F:18])([F:17])[F:19])=[O:15])[CH:35]=[CH:36][C:37]=1[Cl:43])(=[O:42])[CH3:41]
Reactant: CC(=O)c1cc(N)ccc1Cl
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Temperature: 40 °C
Reaction time: 9 h
Yield: 79.8 %

Procedure:
Oxalyl chloride (0.65 ml, 0.95 g, 7.5 mmol, 1.5 eq.) followed by DMF (3 drops) were added to 1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (1.56 g, 5.00 mmol) in dichloromethane (20 ml), and the mixture was heated to 40° C. After 9 h at 40° C., the mixture was concentrated under reduced pressure, THF (20 ml) and pyridine (0.8 ml, 0.8 g, 2.0 eq.) were added, followed by 1-(5-amino-2-chlorophenyl)ethanone (0.85 g, 5.00 mmol, 1.0 eq.) in THF (5 ml). The mixture was left at room temperature for 2 d. HCl N aq. solution) was added, the mixture was extracted with ethyl acetate and the extract was washed with HCl (1N aq. solution), NaOH ON aq. solution) and sat. aq. sodium chloride solution. The extract was dried over MgSO4 and, after concentration under reduced pressure, the product was purified by column chromatography on silica gel (hexane/ethyl acetate) to give N-(3-acetyl-4-chlorophenyl)-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (1.85 g, 80%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)=[CH:30][CH:29]=2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)cc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using 5-(methylsulfonyl)-1H-indole (intermediate-21) and tert-butyl-4-(4-bromophenoxy)piperidine-1-carboxylate (intermediate-77) (0.130 g, 24%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](=O)[CH2:22][C:23](=O)[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]=2[CH3:30])=[CH:4][CH:3]=1.O.[NH2:32][NH2:33].C1COCC1>CCO>[C:24]([C:23]1[NH:33][N:32]=[C:21]([C:10]2[C:9]([CH3:30])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=2)[CH:22]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1c(C(=O)CC(=O)C(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(-c2cc(C(C)(C)C)[nH]n2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 90 °C
Yield: 63.4 %

Procedure:
To a suspension of 1-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-4,4-dimethylpentane-1,3-dione (555 mg, 1.20 mmol) (B) in EtOH (5.5 mL) was added hydrazine monohydrate (0.12 g, 2.4 mmol). The reaction mixture was refluxed at 90° C. for 6 hours. After cooled down to room temperature, the resulting suspension was dissolved by addition of THF (15 mL) and further purified by prep HPLC to provide 350 mg (0.761 mmol, 63%) of the title compound.
Reaction SMILES: CN([Sn:4]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH3:8])C.[CH3:17][S:18]([CH3:20])=[O:19].CNC>>[CH3:17][S:18]([CH2:20][Sn:4]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH3:8])=[O:19]
Reactant: CS(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)N(C)C
Agent: CNC
Product: CCCC[Sn](CCCC)(CCCC)CS(C)=O
Reaction time: 8 h

Procedure:
Dimethylamino tributyltin (33.4 g.; 0.1 moles) and dimethylsulfoxide (100 g.; 1.28 moles) were stirred in a 250 ml reaction flask, under a positive pressure argon atmosphere, for 4.5 hours at 80° C. During the reaction, liberated dimethylamine gas exited from the reaction flask through an open port with the moving argon gas. The reaction stood overnight at ambient temperature. Excess dimethylsulfoxide was distilled at 75° C at 15 mm Hg. The reaction product was distilled through a semi-micro distillation apparatus at 138° C at 0.1 mm Hg. Yield of 25 g (68%) was identified as (methylsulfinylmethyl) tributyltin by 'H NMR and infrared spectra.
Reaction SMILES: Br[CH2:2]C(C1C=CC(OC)=C(OC)C=1)=O.ClC1C=NNC=1C(OC)=O.[Cl:25][C:26]1[CH:27]=[N:28][N:29]([CH2:35][C:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=2)=[O:37])[C:30]=1[C:31]([O:33][CH3:34])=[O:32]>>[Cl:25][C:26]1[CH:27]=[N:28][N:29]([CH2:35][C:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[C:40]([O:46][CH3:47])[CH:39]=2)=[O:37])[C:30]=1[C:31]([O:33][CH2:34][CH3:2])=[O:32]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: COC(=O)c1c(Cl)cnn1CC(=O)c1ccc(OC)c(OC)c1
Agent: COC(=O)c1[nH]ncc1Cl
Product: CCOC(=O)c1c(Cl)cnn1CC(=O)c1ccc(OC)c(OC)c1

Procedure:
Following the procedure of Example 5.01, beginning with 2-bromo-1-(3,4-dimethoxyphenyl)ethanone (1.20 g, 4.63 mmol) and methyl 4-chloro-1H-pyrazole-5-carboxylate (855 mg, 5.33 mmol), methyl 4-chloro-1-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-1H-pyrazole-5-carboxylate 5.21 was synthesized.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH:42]1([N:47]2[CH2:52][CH2:51][CH:50]([NH2:53])[CH2:49][CH2:48]2)[CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:53][CH:50]5[CH2:51][CH2:52][N:47]([CH:42]6[CH2:46][CH2:45][CH2:44][CH2:43]6)[CH2:48][CH2:49]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCN(C2CCCC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C3CCCC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a mixture of 0.050 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.08 mL (0.44 mmole) of ethyldiisopropyl amine and 0.021 g (0.12 mmole) of 1-cyclopentyl-piperidin-4-ylamine in 1.5 mL of dimethylformamide was added 0.053 g (0.12 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-85:15) gave 0.029 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-cyclopentyl-piperidin-4-yl)-3-methoxy-benzamide (I-63).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH:7]=[CH:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[OH:18])=[O:4]>CO>[OH:4][CH2:3][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH:7]=[CH:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[OH:18]
Reactant: COc1ccc(O)c(CC=Cc2ccccc2C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(O)c(CC=Cc2ccccc2CO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (35 mg) was added in one portion to a solution of 2-(o-formylcinnamyl)-4-methoxyphenol (240 mg; 0.89 mM) in 5 ml of methanol. The reaction was stirred at room temperature for 2 hours and then the solvent was removed in vacuo. The residue was taken up in 2N aqueous hydrochloric acid and extracted with ether. The ethereal phase was washed with water, dried over magnesium sulfate, stripped of solvent, and filtered through 11/2" of silica gel in a 30 ml fritted funnel with 100 ml of 50% ethyl acetate/hexane providing 240 mg (99%) of pure 2-(o-hydroxymethylcinnamyl)-4-methoxyphenol.
Reaction SMILES: N.[Na].[C:3](#[N:5])[CH3:4].[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10]>O1CCCC1.C(OCC)C>[NH2:10][C:9]([C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[Cl:6])=[CH:4][C:3]#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: CC#N
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CC=C(N)c1ccccc1Cl

Procedure:
A 150 ml. portion of ammonia is condensed in a reaction flask and a small piece of sodium is added. The blue color is discharged by the addition of ferric chloride and 3.22 g. of sodium are added. After the color is discharged, 5.75 ml. of acetonitrile in 10 ml. of diethyl ether are added. The reaction is cooled in a dry ice-acetone bath and 13.3 g. of 2-chlorobenzonitrile in 25 ml. of tetrahydrofuran are added dropwise. The ammonia is allowed to evaporate, the solvent is blown off with nitrogen and water is added. The mixture is extracted with methylene chloride. The organic extracts are dried over sodium sulfate and filtered through Magnesol®. The filtrate is evaporated with the addition of hexanes giving β-amino-2-chlorocinnamonitrile as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][CH:15]=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]CCCCC.C([Li])CCC.CI.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH3:17])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCC
Reactant: CC(C)(C)OC(=O)N1CCc2sccc2C1
Agent: [Li]CCCC
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-t-Butoxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (330 mg, 1.4 mmol) was dissolved in anhydrous tetrahydrofuran (18 ml), n-butyl lithium hexane solution (3.0 mmol) was added dropwise to the solution which was cooled in an ice bath, and then the mixture was stirred for 1 hour. This was further mixed with methyl iodide (430 mg, 3.0 mmol), and the stirring was continued while increasing the reaction temperature to room temperature spending 2 hours. The reaction solution was mixed with water and the reaction product was extracted therefrom with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate, and then the solvent was removed by evaporation under a reduced pressure and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 110 mg (0.42 mmol, 31% in yield) of the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[OH-].[Na+].[C:14](Cl)(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC=CC=1>CC(C)=O.O>[C:14]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Oc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: c1ccccc1
Solvent: O
Product: O=C(C=Cc1ccccc1)Oc1ccc2ccccc2c1
Reaction time: 0.12 h
Yield: 80.5 %

Procedure:
In 70 ml of acetone was dissolved 6.4 g of 2-naphthol. A 25% queous sodium hydroxide solution was added to the solution. A solution of 8.1 g of cinnamoyl chloride in 10 ml of acetone was dropwise added to the mixture over 4 minutes while stirring. After the stirring was continued for 7 minutes, benzene and water were added to the system to effect liquid separation. After the organic phase was washed with an aqueous hydrogen sodium carbonate solution, the system was dried over anhydrous potassium carbonate and the solvent was distilled off. The residue was treated with n-hexane and benzene to give crystals of the product. The product was recrystallized from a solvent mixture of n-hexane and benzene to give 9.8 g of the product.
Reaction SMILES: C(OC(=O)[CH2:5][C:6]([CH:8]=[CH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)=O)C.[CH2:21]([O:23][C:24](=[O:33])[CH:25]=[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[NH2:27])[CH3:22]>C(O)C>[CH2:21]([O:23][C:24]([C:25]1[CH:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH:8]([C:24]([O:23][CH2:21][CH3:22])=[O:33])[C:6]([CH3:5])=[N:27][C:26]=1[N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:33])[CH3:22]
Reactant: CCOC(=O)C=C(N)N1CCCC1
Reactant: CCOC(=O)CC(=O)C=Cc1cccc2ccccc12
Solvent: CCO
Product: CCOC(=O)C1=C(N2CCCC2)N=C(C)C(C(=O)OCC)C1c1cccc2ccccc12
Yield: 52 %

Procedure:
Boiling a solution of 13.4 g of naphth-1-ylmethylideneacetoacetic acid ethyl ester and 9.2 g of 3-pyrrolidino-3-aminoacrylic acid ethyl ester in 100 ml of ethanol for 2 hours yields 2-pyrrolidino-6-methyl-4-naphth-1-yl-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 121° C. (ethanol).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=1[OH:25]>C(O)(C)C>[ClH:2].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:20][C:19]=1[OH:25]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(Cl)c(O)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(Cl)c(O)c3)c2cc1OC
Yield: 85.8 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (500 mg, 1.916 mmol), (prepared as described for the starting material in Example 2), and 4-chloro-3-hydroxyaniline (300 mg, 2.09 mmol), (as described in UK patent 1427658), in isopropanol (10 ml) was heated at reflux for 2 hours. The mixture was allowed to cool, the solid product collected by filtration, washed with isopropanol and dried to give 4-(4-chloro-3-hydroxyanilino)-6,7-dimethoxyquinazoline hydrochloride (605 mg, 86%). m.p. >250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.BrC1C=CC(OC)=CC=1.[Mg].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=O)[CH2:28][CH2:27][CH2:26]2>O1CCCC1.C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[C:29]([C:30]1[CH:31]=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)=[CH:28][CH2:27][CH2:26]2
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: COc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2=CCCc3cc(OC)ccc32)cc1

Procedure:
A solution of 4-methoxyphenyl magnesium bromide, freshly prepared in the normal manner in tetrahydrofuran (200 mL) from 4-bromoanisole (101 g) and magnesium metal (14.5 g), was added over 45 minutes with stirring to a chilled (0° C.) solution of 6-methoxytetralone (85 g) in dry tetrahydrofuran (500 mL). After the addition was completed, the reaction was stirred at room temperature for 2 hours and the excess reagent was destroyed by the careful addition of water (50 mL). Most of the solvent was removed in vacuo and the concentrate was partitioned between ethyl acetate and 1N sodium hydroxide. After the resultant solids were filtered off, the layers were separated and the organic layer was washed with brine, then was dried (MgSO4) and evaporated to give 123 g of crude carbinol as an oil. A solution of the above carbinol (100 g) in toluene (800 mL) containing p-toluenesulfonic acid (1 g) was refluxed for 3 hours in a flask equipped with a Dean-Stark trap. The cooled solution was washed with 10% sodium bicarbonate solution and with brine, then was dried (MgSO4) and evaporated. The residual material was passed though a short column of silica gel (250 g) made up in dichloromethane-hexane (1:3) and the product was eluted with dichloromethane-hexane (1:1). Evaporation of the appropriate fractions and crystallization of the residue from toluene-hexane (2x) gave 37.1 g of 3,4-dihydro-6-methoxy-1-(4-methoxyphenyl)naphthalene, mp 100.5°-102° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH2:31][CH3:32])[N:23]=[CH:22][N:21]=2)=[CH:13][CH:12]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[CH3:33][S:34]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]2[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH2:31][CH3:32])[N:23]=[CH:22][N:21]=2)=[CH:13][CH:12]=1)(=[O:36])=[O:35]
Reactant: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCOS(C)(=O)=O)cc1
Yield: 97.7 %

Procedure:
Triethylamine (0.88 g, 8.70 mmol) was added to a solution of ethyl 4-(2(4-(2-hydroxyethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (1.50 g, 4.37 mmol) in methylene chloride (40 ml). The mixture was stirred under ice-cooling, and methanesulfonyl chloride (0.60 g, 5.24 mmol) was added dropwise to the mixture. The resulting mixture was stirred under ice-cooling for 10 minutes after the addition. Then, water (40 ml) was added to the reaction mixture. The mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=1/1) to give the desired ethyl 4-(2-(4-(2-methylsulfonyloxyethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (1.80 g, 98%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH:12]([F:14])[F:13].CC(C)([O-])C.[K+].[C:21]([N:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C1COCC1>[F:13][CH:12]([F:14])[O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:34][CH:31]1[CH2:30][CH2:29][N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:33][CH2:32]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(OC(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2OC(F)F)CC1
Yield: 28 %

Procedure:
Using similar procedure detailed below for Compound 133, but using 1-chloro-2-(difluoromethoxy)-4-nitrobenzene (prepared according to US patent application no. 2010/090875) (1.12 g, 5.0 mmol), potassium tert-butoxide (1.18 g, 10.0 mmol) and N-Boc-4-hydroxypiperidine (2.0 g, 10.0 mmol) in THF (30 mL) was stirred for a weekend at room temperature to give the product (406 mg, 28% yield) after workup and purification by column chromatography on silica gel using EtOAc/heptane (1:9 to 1:1) as eluent. The product was about 70% purity by LC/MS and 1H NMR.