Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([S:14][CH3:15])[C:5]=1[CH2:16][S:17][CH2:18][CH3:19].C1(C(C)=O)CC1>CO.O1CCCC1>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:14][CH3:15])[C:5]=1[CH2:16][S:17][CH2:18][CH3:19]
Reactant: CCSCc1c(Cl)ccc(C(=O)OC)c1SC
Agent: CC(=O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCSCc1c(Cl)ccc(C(=O)O)c1SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Methanol (2 drops) was added to a mixture of sodium hydride (0.9 g) and tetrahydrofuran heated under reflux conditions. A mixture of methyl 4-chloro-3-ethylsulphenylmethyl-2-methylsulphenylbenzoate (4.0 g) and methyl cyclopropyl ketone (2.5 g) in tetrahydrofuran (36 ml) was added during 0.5 hours whilst maintaining at reflux. The mixture was stirred overnight at ambient temperature, and then quenched with methanol. Ether and water were added and the aqueous layer acidified (dilute hydrochloric acid), extracted (ether) and the ethereal solution extracted (sodium carbonate solution). This basic extract was re-acidified (hydrochloric acid), extracted (ether) and evaporated to give 4-chloro-3-ethylsulphenylmethyl-2-methylsulphenylbenzoic acid (3.0 g), NMR (CDCl3) 1.35 (t,3H), 2.5 (s,3H), 2.7 (q,2H), 4.3 (s,2H), 7.5 (d,1H), 7.8 (d,1H).
Reaction SMILES: Br[CH2:2][C:3]1([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:5]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=2[Cl:13])[O:4]1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C[O-].[Na+]>CN(C)C=O>[N:21]1([CH2:2][C:3]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:5]([C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=3[Cl:13])[O:4]2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(C2(CBr)OC2c2ccc(Cl)cc2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(C2(Cn3ccnc3)OC2c2ccc(Cl)cc2Cl)cc1
Reaction time: 8 h
Yield: 47.6 %

Procedure:
A solution of 10 g of 2-bromomethyl-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-oxirane (isomer A) in 50 mL of N,N-dimethylformamide was added dropwise, at 100° C., to a melt which comprised 15.6 g of imidazole with 1.37 g of sodium methylate and from which the liberated methanol had been distilled off beforehand. After 8 hours, the reaction solution was poured onto water and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated down under reduced pressure, and the residue was chromatographed over a silica gel column using methylene chloride/methanol (100:2). The purified fractions were evaporated down, and the residue was crystallized from diisopropyl ether. 4.6 g (47.5%) of 2-(1H-imidazol-1-yl-methyl)-2-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-oxirane (isomer A) of melting point 102°-103° C. were obtained (compound 1).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[N:27]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][C:31]=3[CH3:36])[N:28]=[CH:29][C:22]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C@@H:4]([O:3][C:21]2[C:22]3[CH:29]=[N:28][N:27]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][C:31]=4[CH3:36])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:15][O:16][CH:17]([CH3:19])[CH3:18])=[N:9][CH:10]=1
Reactant: Cc1cnccc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1ccc(NC(=O)[C@@H](O)COC(C)C)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ccncc2C)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
60% Sodium hydride in mineral oil (48.8 mg, 1.22 mmol) was added in one portion to (S)-2-hydroxy-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (Intermediate C7) (194 mg, 0.81 mmol) in anhydrous THF (5 mL) cooled to 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes and then 4-chloro-1-(3-methylpyridin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate M1) (200 mg, 0.81 mmol) as suspension in dry THF (4 mL) added dropwise over 1 minute. The mixture was stirred at 0° C. for 15 mins, allowed to warm slowly to ambient temperature and stirred for 2 hours. 1M Citric acid (2 mL) was added and the mixture extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography with ethyl acetate to give the product (300 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 1.17 (3H, d), 1.19 (3H, d), 2.29 (3H, s), 2.34 (3H, s), 3.69-3.76 (1H, m), 4.09 (2H, d), 6.01 (1H, t), 7.51 (1H, d), 7.53 (1H, dd), 8.09-8.10 (1H, m), 8.13 (1H, d), 8.43 (1H, s), 8.60 (1H, s), 8.62 (1H, dd), 8.67 (1H, s), 8.68 (1H, s); m/z (ESI+) (M+H)+=448; HPLC tR=1.78 min.
Reaction SMILES: [SH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.C([N:14](CC)CC)C.NOS(O)(=O)=O>ClCCl.O>[CH3:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([S:1][NH2:14])=[N:3][CH:4]=1
Reactant: Cc1cnc(S)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Agent: NOS(=O)(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1cnc(SN)c([N+](=O)[O-])c1

Procedure:
A solution of 12 g of 2-mercapto-5-methyl-3- nitropyridine and 28.6 g of triethylamine in 180 cm3 of dichloromethane is treated dropwise with 12 g of hydroxylamine-O-sulfonic acid dissolved in the minimum amount of water. At the end of the reaction, the solvent is removed under partial vacuum and the residue is taken up in 20 cm3 of water. The precipitate obtained is collected on a filter, washed with water and dried. It is recrystallized from a dichloromethane/petroleum jelly mixture.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:14]#[N:15])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1.Cl>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:14]#[N:15])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[CH3:2]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C(C#N)=Cc1ccc(Br)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)C(c1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 85 °C
Yield: 90.7 %

Procedure:
A solution of 3-(4-bromo-phenyl)-2-cyano-acrylic acid ethyl ester (1.5 g, 5.36 mmol) in dry toluene (12 ml) was added dropwise to 4-chlorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran, 6.96 ml, 6.96 mmol) at 0° C. The reaction mixture was heated to 85° C. for 3 hours, poured onto ice, acidified with 1N HCl and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated, the crude product was purified over flash silica chromatography eluting with petroleum ether to ethyl acetate/petroleum ether (5:95) to afford the desired product (1.91 g, 91% yield). LC/MS: (PS-A2) Rt 3.78 [M+H]− 391.93.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[F:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: C1CSCCN1
Solvent: c1ccncc1
Product: CC1COc2c(N3CCSCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 22.9 %

Procedure:
A mixture of 0.18 g (0.6 mmol) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, 0.3 ml (3.0 mmol) of thiomorpholine and 20 ml of pyridine was heated under reflux for 21 hours. The solution was evaporated to dryness, the residue was triturated with hot methanol, and filtered to give 0.05 g of the title compound, mp>300°.
Reaction SMILES: [CH:1]1([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[C:10]([CH3:16])([CH3:15])[C:9]2=[O:17])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]1(O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[CH:1]1([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]([CH3:15])([CH3:16])[C:9]2=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Oc1ccccc1
Reactant: CC1(C)C(=O)N(C2CCCCCC2)CC1CO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)N(C2CCCCCC2)CC1COc1ccccc1
Temperature: 80 °C

Procedure:
A solution of Example 3A (50 mg, 0.2 mmoles), phenol (23.5 mg, 0.25 mmoles), and triphenyl phosphine (85.8 mg, 0.33 mmoles) was stirred in anhydrous Toluene (1.25 mL). To the reaction, di-tert-butyl azodicarboxylate (76.9 mg, 0.33 mmoles) was added and heated to 80° C. for one hour. The reaction mixture was partitioned between toluene and water. The organic phase was separated and solvent evaporated in vacuo. The crude reaction mixture was purified by preparative reverse phase HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 um particle size) using a gradient of 20% to 100% acetonitrile:water (0.1% trifluoroacetic acid) over eighteen minutes at a flow rate of 40 mL/minute to provide the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.27-7.32 (m, 2H), 6.95-6.99 (m, 1H), 6.88-6.91 (m, 2H), 4.06-4.19 (m, 1H), 4.07 (dd, J=9.15, 5.65 Hz, 1H), 3.92 (t, J=8.77 Hz, 1H), 3.51 (dd, J=9.92, 7.63 Hz, 1H), 3.13 (dd, J=9.76, 7.78 Hz, 1H), 2.45 (qd, J=7.86, 5.72 Hz, 1H), 1.43-1.82 (m, 12H), 1.25 (s, 3H), 1.05 (s, 3H). MS (APCI+) m/z 316.2 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:23]([NH:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])=[O:16])[CH3:14])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][C:39]([NH:41][C@H:42]([C:48](OC2C=CC([N+]([O-])=O)=CC=2)=[O:49])[CH2:43][CH2:44][C:45]([NH2:47])=[O:46])=[O:40])=[CH:33][CH:32]=1>CN(C)C=O.CCOCC>[NH:41]([C:39]([O:38][CH2:37][C:34]1[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1)=[O:40])[C@H:42]([C:48]([NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:15]([NH:17][C@H:18]([C:23]([NH:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:24])[C@H:19]([CH2:21][CH3:22])[CH3:20])=[O:16])[CH3:14])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:6])([CH3:8])[CH3:7])=[O:49])[CH2:43][CH2:44][C:45](=[O:46])[NH2:47]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C)C(=O)NCC(=O)OC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C)C(=O)NCC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.6 g of the H-Thr(tBu)-Ala-Ile-Gly-OMe described under 28) in 30 ml of dimethylformamide, are mixed with 3.5 g of Z-Gln-ONP and stirred at room temperature until the mixture becomes solid. After allowing to stand overnight the mixture is diluted with ether and the precipitate is filtered off and washed with ether until free of nitrophenol. The protected pentapeptide shows Rf = 0.14 in the system chloroform-methanol (95:5) in a thin layer chromatogram on silica gel. Melting point: > 250° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])([CH3:4])([CH3:3])[CH3:2].C(O[CH:17](N(C)C)[N:18]([CH3:20])[CH3:19])(C)(C)C>>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8]/[C:7](=[CH:17]\[N:18]([CH3:20])[CH3:19])/[C:6]1=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)C1CCCCC1=O
Product: CN(C)/C=C1\CCCC(C(C)(C)C)C1=O

Procedure:
2-tert-Butylcyclohexanone (93 mg, 0.60 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (105 mg) as a yellow oil which was used directly in the next step. MS ISP (m/e): 210.2 (100) [(M+H)+].
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[C:8]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)=[N:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:33]1[C:38]([I:39])=[CH:37][N:36]=[CH:35][N:34]=1>CS(C)=O.O>[I:39][C:38]1[C:33]([O:31][C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[N:15][N:16]=3)=[CH:30][CH:29]=2)=[N:34][CH:35]=[N:36][CH:37]=1
Reactant: Clc1ncncc1I
Reactant: Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Ic1cncnc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a brown mixture of cesium carbonate (2.79 g, 8.58 mmol) and 4-(4-phenylphthalazin-1-ylamino)phenol hydrochloride (1.00 g, 2.86 mmol) in 10 mL DMSO was added 4-chloro-5-iodopyrimidine (0.687 g, 2.86 mmol). The reaction was allowed to stir at RT for 1 h. The reaction was heated to and maintained at 70° C. overnight. The reaction was cooled and diluted with water. The solid was filtered and dried in vacuo to give N-(4-(5-iodopyrimidin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine as a gray solid. MS m/z=518 [M+H]+. Calc'd for C24H16IN5O: 517.3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[CH3:2].[CH:11](OCC)(OCC)[O:12][CH2:13][CH3:14].C(OC(=O)C)(=O)C>>[CH2:1]([O:3][C:4](=[O:10])[C:5]([S:6]([CH3:9])(=[O:8])=[O:7])=[CH:11][O:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CS(C)(=O)=O
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)S(C)(=O)=O
Temperature: 135 °C

Procedure:
A mixture of methanesulfonyl-acetic acid ethyl ester (example 61b) (90 g, 0.547 mol), triethyl orthoformate (242.9 g, 0.641 mol), and acetic anhydride (227 mL) was heated at 130-140° C. for three hours. After cooling the reaction to room temperature, solvent was removed under reduced pressure to give 3-ethoxy-2-methanesulfonyl-acrylic acid ethyl ester (purity 50%). The crude compound was used in the following reaction without further purification. LC-MS m/e 223 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:15]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N+:4]([O-:15])[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)cnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(F)c[n+]([O-])c1C
Reaction time: 16 h

Procedure:
A mixture of 3-fluoro-5,6-dimethyl-pyridine (0.230 g, 1.84 mmol) (Ife, R. J. Eur. Pat. Appl. (1987), EP 246774), 3-chloroperoxybenzoic acid (77%, 1.24 g, 5.5 mmol) in CH2Cl2 (25 mL) was stirred for 16 h. The solution was concentrated, and the residue was purified by flash chromatography on a silica gel column (8:1 EtOAc/MeOH), affording 3-fluoro-5,6-dimethyl-pyridine-1-oxide as a white solid (0.225 g 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1ccc(N)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.2 %

Procedure:
1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (5.15 g, 26 mmol, 1.05 eq) was dissolved in dichloromethane (30 mL). A solution of p-methoxyaniline (3.07 g, 25 mmol, 1 eq) in dichloromethane (20 mL) was added dropwise and the mixture was stirred at room temperature for 20 hours. The mixture was filtered and washed with dichloromethane (5 mL×2). The solid was dissolved in ethyl acetate (50 mL), and the resulted solution was washed with diluted hydrochloric acid (1 N, 10 mL) and saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 1-(4-chloro-3-trifluoromethylphenyl)-3-(4-methoxyphenyl)urea A6 (4.5 g, yield 52%) as a white solid.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.C(N(CC)CC)C.[Cl:14][C:15]1[N:20]=[C:19]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:18]=[C:17]2[N:36]([CH2:42][C:43]3[C:48]([CH3:49])=[C:47]([O:50][CH3:51])[C:46]([CH3:52])=[CH:45][N:44]=3)[N:37]=[C:38]([CH2:39][CH:40]=[O:41])[C:16]=12>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[N:18]=[C:17]2[N:36]([CH2:42][C:43]3[C:48]([CH3:49])=[C:47]([O:50][CH3:51])[C:46]([CH3:52])=[CH:45][N:44]=3)[N:37]=[C:38]([CH2:39][CH:40]([C:5]#[N:6])[OH:41])[C:16]=12
Reactant: C[Si](C)(C)C#N
Reactant: COc1c(C)cnc(Cn2nc(CC=O)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(Cn2nc(CC(O)C#N)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reaction time: 16 h
Yield: 94 %

Procedure:
Trimethylsilyl cyanide (0.219 mL) and triethylamine (0.198 mL) were added to a mixture composed of the above di-tert-butyl {4-chloro-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-3-(2-oxoethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate (796 mg) and dichloromethane (10 mL) under cooling in an ice bath. Then, the ice bath was removed and the mixture was stirred for 16 hours. Chloroform (80 mL) and a 0.5 N hydrochloric acid solution (100 mL) were added to the reaction mixture, followed by separation. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (20 mL). A 1 N hydrochloric acid solution (10 mL) was added and the mixture was stirred at room temperature for 30 minutes. A saturated sodium bicarbonate solution (80 mL) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the solvent was evaporated to obtain a crude product of the title compound (788 mg, 94%). The resulting compound was directly used for the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[Cl:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[N:18][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:16]2[CH:17]=[N:18][CH:19]=[C:14]([Cl:13])[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: Oc1cncc(Cl)c1
Reactant: COC(=O)c1cc(Cl)ccc1F
Product: O=C(O)c1cc(Cl)ccc1Oc1cncc(Cl)c1

Procedure:
The title compound was prepared according to the two steps procedure described in step 1 of Example 67 and step 2 of Example 99. Firstly, methyl 5-chloro-2-fluorobenzoate was reacted with 5-chloropyridin-3-ol. Next, the crude product was hydrolyzed to the corresponding carboxylic acid: 1H-NMR (DMSO-d6) δ 8.36 (1H, d, J=2.0 Hz), 8.25 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=2.6 Hz), 7.70 (1H, dd, J=8.8, 2.6 Hz), 7.50 (1H, dd, J=2.4, 2.0 Hz), 7.29 (1H, d, J=8.8 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:23](=[O:25])[CH3:24])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-(4-Nitrophenyl)piperazine (2.5 g, 12.1 mmol) was dissolved in dichloromethane (100 ml). Triethylamine (2.0 ml, 14.5 mmol) was added and the reaction was cooled to 0° C. Acetic anhydride (1.25 ml, 13.3 mmol) was added dropwise and the reaction was stirred at 0° C. for 1 h. Saturated sodium bicarbonate was added and the reaction was extracted (×3) with dichloromethane, dried (MgSO4), filtered and concentrated in vacuo to give 4-(4-nitrophenyl)-1-acetylpiperazine as a yellow solid (3.01 g,). GC/MS (EI, M+) m/z=249.
Reaction SMILES: CC1(C)[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]([O:18][CH2:19]C)=[O:17])[CH:5]=[CH:4][C:3]1=2.CC1(C)C2C(=CC=C(C#C)C=2)[S:26]CC1.COC(Cl)=O.C([Li])CCC>>[CH3:12][C:9]1([CH3:13])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([C:14]#[C:15][C:16]([O:18][CH3:19])=[O:17])[CH:7]=2)[S:26][CH2:11][CH2:10]1
Reactant: CCOC(=O)C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCS2
Agent: COC(=O)Cl
Agent: [Li]CCCC
Product: COC(=O)C#Cc1ccc2c(c1)C(C)(C)CCS2

Procedure:
Employing the same general procedure as used for the preparation of ethyl 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)propiolate (Compound A), but instead using 2.0 g (10 mmols) of (4,4-dimethyl-thiochroman-6-yl)ethyne, 2 g (21.3 mmols) of methylchloroformate and 11 mmols of n-butyl lithium the title compound was obtained as a yellow solid.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[Cl:26][C:27]1[CH:44]=[CH:43][C:30]([CH2:31][O:32][C:33]2[C:34]([O:41][CH3:42])=[CH:35][C:36]([CH:39]=[O:40])=[N:37][CH:38]=2)=[CH:29][CH:28]=1>O1CCCC1>[Cl:26][C:27]1[CH:44]=[CH:43][C:30]([CH2:31][O:32][C:33]2[C:34]([O:41][CH3:42])=[CH:35][C:36]([CH:39]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=3)[OH:40])=[N:37][CH:38]=2)=[CH:29][CH:28]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: COc1cc(C=O)ncc1OCc1ccc(Cl)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)ncc1OCc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
3-Iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (635, 180 mg, 0.450 mmol) was dissolved in tetrahydrofuran (2.5 mL) and the reaction was cooled to −20° C. under an atmosphere of nitrogen. Isopropylmagnesium chloride in tetrahydrofuran (2.00 M, 0.243 mL) was added. The reaction was stirred for 1 hour, during which the temperature rose to 0° C. The reaction was cooled to −20° C. and 5-(4-chloro-benzyloxy)-4-methoxy-pyridine-2-carbaldehyde (641, 80.0 mg, 0.288 mmol) in tetrahydrofuran (0.75 mL) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with methanol and adsorbed onto silica, then purified by silica gel chromatography, methanol: dichloromethane, to provide the desired product, (642, 94 mg, 59%). 1H-NMR was consistent with the desired compound. MS (ESI) [M+H+]+=552.4, 554.4, 555.4.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][CH:22]=2)[CH2:10][CH:11](C(OC)=O)[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Li+]>O.CS(C)=O>[C:1]1([C:7]2[CH:8]=[C:9]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(Cc1cccc(-c2ccccc2)c1)C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)CCc1cccc(-c2ccccc2)c1
Temperature: 165 °C
Yield: 80.7 %

Procedure:
A mixture of dimethyl (m-phenylbenzyl)malonate (1.00 g) and lithium chloride (0.285 g) in water (0.12 ml) and dimethylsulphoxide (8.5 ml) was heated at 165° C. for 3 hours then allowed to cool, poured into water and extracted with ether. The extracts were washed with water, dried, concentrated, and chromatographed using 10% ether in petrol as eluant to give methyl 3-(m-phenylphenyl)propanoate (0.65 g, 81%) as a colourless oil which solidified on standing, melting point 29°-30° C.