Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C1COCC1.[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=1)=[O:9]>CO>[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][C:11]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=1)=[O:9]
Reactant: COC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=Cc1ccc(C(F)(F)F)cc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (3.9 mL, 11.8 mmol) was added to a THF (10 mL) and MeOH (5 mL) solution of methyl 2′-formyl-5′-(trifluoromethyl)-[1,1′-biphenyl]-4-carboxylate (1.2 g, 3.9 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off, dried in vacuo, and purified via HPLC to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Br:10]Br>C(O)(=O)C>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][C:4]=1[CH:5]=[O:6]
Reactant: BrBr
Reactant: O=Cc1cccc(O)c1
Solvent: CC(=O)O
Product: O=Cc1cc(O)ccc1Br
Temperature: 15 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
3-hydroxybenzaldehyde (10 g, 81.9 mmol) was dissolved in glacial acetic acid (50 mL) and cooled at 15° C. To the stirred solution, bromine (15.7 g, 98.2 mmol) was added dropwise while keeping the temperature below 22° C. After overnight stirring at room temperature, the volatiles were removed under vacuum without heating; the residue was co-evaporated three times with hexane (15 mL) and taken up in warm chloroform. Upon cooling, 9.05 g of 2-bromo-5-hydroxybenzaldehyde 3 were obtained as a white solid in two crops. Yield 55%. 1H NMR (300 MHz, CD3COCD3) δ ppm: 10.24 (s, 1H), 9.05 (s, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.34 (d, J=3.1 Hz, 1H), 7.10 (dd, J1=8.7 Hz, J2=3.1 Hz, 1H); 13C NMR (75 MHz, CD3COCD3) δ ppm: 192.8, 159.3, 136.7, 136.2, 125.1, 117.3, 117.2; HRMS (EI) m/z: calcd for C7H5BrO2: 199.9472. found: 199.9463; mp: 132-134° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:27][CH2:26][N:25]([C:28]([NH:30][OH:31])=[NH:29])[CH2:24][CH2:23]3)[O:19][C:16]2=[CH:17][N:18]=1.[C:32](Cl)(=O)[CH2:33][CH2:34][CH3:35]>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:23][CH2:24][N:25]([C:28]4[N:29]=[C:32]([CH2:33][CH2:34][CH3:35])[O:31][N:30]=4)[CH2:26][CH2:27]3)[O:19][C:16]2=[CH:17][N:18]=1
Reactant: CCCC(=O)Cl
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)c(F)c1
Product: CCCc1nc(N2CCC(C3Cc4cc(-c5ccc(CS(C)(=O)=O)cc5F)ncc4O3)CC2)no1

Procedure:
The title compound is prepared from 4-[5-(2-fluoro-4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-N-hydroxy-piperidine-1-carboxamidine and butyryl chloride following a procedure analogous to that described in Example 8. LC (method 6): tR=1.58 min; Mass spectrum (ESI+): m/z=501 [M+H]+.
Reaction SMILES: O1CCCC1.[CH3:6][O:7][C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20])=[O:9].Cl>CO>[OH:15][CH2:14][C:13]1[CH:17]=[CH:18][C:10]([C:8]([O:7][CH3:6])=[O:9])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(CO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
Tetrahydrofuran solution of 1.0M borane-tetrahydrofuran complex was added dropwise to tetrahydrofuran solution (45 mL) of 2.25 g of 4-methoxycarbonyl-3-nitrobenzoic acid and stirred at room temperature for 48 hours. Methylalcohol (2 ml) and 1N hydrochloric acid (10 ml) were added thereto and concentrated. After ethyl acetate and water were added, liquid separation was conducted. The organic layer was washed with saturated sodium hydrogen carbonate and dried over sodium sulfate. After removing the solvent, the obtained crude material was purified with silica gel column chromatography to obtain 1.33 g of methyl 4-hydroxymethyl-2-nitrobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2.O1CCCC1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1)[C:6]([CH:21]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]([N:37]([CH3:45])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5]2
Reactant: CCCCCCC(Nc1ccc(C(=O)N(C)CCC(=O)OCC)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCC(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a mixture of ethyl 3-[({4-[(1-{5-chloro-1-[3-(trifluoromethyl)phenyl]-1H-indol-2-yl}heptyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (254 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (223 mg, 92%) as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)[C:43]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:44])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: c1cc(CNc2ccc(OCCN3CCCC3)cc2)cc(OC2CCCCO2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCCCC1)N(Cc1cccc(OC2CCCCO2)c1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[3-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (119 mg, 0.3 mmol) and triethylamine (0.125 mL, 0.90 mmol) in methylene chloride was added to a vial charged with cyclohexanecarbonyl chloride (88 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium bicarbonate was added until the solution was basic and the layers were separated. The aqueous layer was washed with methylene chloride. The organic layers were combined and evaporated under a stream of nitrogen to give the title compound of Step A.
Reaction SMILES: [OH:1][C:2]1[C:3]([I:15])=[C:4]([C:7]([N+:12]([O-:14])=[O:13])=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].Br[CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:17]([O:1][C:2]1[C:3]([I:15])=[C:4]([C:7]([N+:12]([O-:14])=[O:13])=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6])[CH3:18]
Reactant: COc1cc([N+](=O)[O-])c(C#N)c(I)c1O
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(OC)cc([N+](=O)[O-])c(C#N)c1I
Temperature: 60 °C
Yield: 38.9 %

Procedure:
To a solution of the product of step (a) (6.95 g, 21.7 mmol) and bromoethane (1.78 ml, 23.8 mmol) in DMF (70 ml) was added potassium carbonate (4.49 g, 32.5 mmol) and the reaction was heated to 60° C. for 18 h. After cooling, the reaction mixture was partitioned between 2N aqueous HCl and EtOAc, the organic layer was separated, washed with H2O, dried over MgSO4 and evaporated. The crude product was purified on silica gel, eluting with CH2Cl2/MeOH (97/3, v/v) to afford the subtitle compound as a colourless solid (2.94 g, 39%). Rf 0.68 (CH2Cl2/MeOH 95/5, v/v). MS m/z 366 (MNH4+).
Reaction SMILES: [OH:1][CH2:2][C:3](=O)[CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].N1C=CC=CC=1.Cl.[CH3:22][O:23][NH2:24]>CO>[CH3:22][O:23][N:24]=[C:3]([CH2:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13])[CH2:2][OH:1]
Reactant: O=C(CO)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(CO)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 24 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a stirred solution of 1-hydroxy-3-(2,4,6-trichloro-phenyl)-propan-2-one (30 g; 118 mmol) in methanol (240 ml) was added pyridine (15 ml; 189 mmol) followed by a portionwise addition of methoxyamine hydrochloride (15 g; 178 mmol). The reaction mixture was stirred at 24° C. for 18 h under nitrogen. Methanol was removed under reduced pressure, the residue poured in water (300 ml) and 1N hydrochloric acid was added (100 ml). The solution was extracted with dichloromethane (3×150 ml). Combined organic layers were washed with water (300 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford 33 g (99% of theory) of 1-hydroxy-3-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime (isomers E/Z 1:1) as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][C:35]1[C:36]([CH:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][CH3:52])[CH2:46][CH2:45]2)=[CH:37][C:38]([O:42][CH3:43])=[C:39]([CH:41]=1)[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[C:35]([CH3:34])[C:36]([CH:44]4[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][CH3:52])[CH2:46][CH2:45]4)=[CH:37][C:38]=3[O:42][CH3:43])[N:7]=2)[CH:18]=1
Reactant: CCCN1CCC(c2cc(OC)c(N)cc2C)CC1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCCN1CCC(c2cc(OC)c(Nc3nccc(-c4c(-c5cccc(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)cc2C)CC1
Temperature: 120 °C
Yield: 57.9 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 5-methyl-2-(methyloxy)-4-(1-propyl-4-piperidinyl)aniline (Example 157, step D) (51 mg, 0.19 mmol), and p-toluenesulfonic acid (99 mg, 0.52 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (76 mg, 0.110 mmol, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 9.41 (d, J=6.41 Hz, 1H), 8.47 (s, 1H), 8.32 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.04 (d, J=7.87 Hz, 1H), 7.80 (d, J=7.87 Hz, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.59 (t, J=7.78 Hz, 1H), 7.52 (s, 1H), 7.44-7.49 (m, 1H), 7.35-7.42 (m, 1H), 7.19 (t, J=8.15 Hz, 2H), 6.99 (t, J=6.68 Hz, 1H), 6.90 (s, 1H), 6.50 (d, J=5.31 Hz, 1H), 3.80 (s, 3H), 2.89-2.99 (m, 2H), 2.58-2.66 (m, 1H), 2.20-2.27 (m, 2H), 2.17 (s, 3H), 1.90-2.01 (m, 2H), 1.62-1.73 (m, 4H), 1.39-1.49 (m, 2H), 0.85 (t, J=7.33 Hz, 3H). MS (ESI): 688 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][CH2:3]1.C(O)C.[BH4-].[Na+]>O>[OH:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([NH:12][C:13](=[O:15])[CH3:14])[CH2:4][CH2:3]1
Reactant: CC(=O)NC1CCC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N[C@@H]1CC[C@@H](O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 19.2 g. of N-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)acetamide and 275 ml. of absolute ethanol is stirred under a nitrogen atmosphere and 3.58 g. sodium borohydride added. The reaction mixture is stirred at room temperature for 16 hours, then 200 ml. of water is added and the stirring continued for 4 hours. Next, the reaction mixture is evaporated to dryness in vacuo and the residue treated with 250 ml. of water. The mixture is cooled in an ice bath and acidified with concentrated hydrochloric acid. The precipitated yellow solid is collected and dried; weight 6 g., m.p. 120°-127° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:34][C:33](=[O:35])[NH:32][N:31]=2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[NH:31][N:32]=[C:33]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:34]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Product: COc1ccc(-c2cc(Oc3ncnc4cc(OCCCS(C)(=O)=O)c(OC)cc34)n[nH]2)cc1
Yield: 0.1 %

Procedure:
Using a procedure analogous to that described in Example 34, 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (150 mg, 0.45 mol) was reacted with 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (105 mg, 0.54 mol), (prepared as described for the starting material in Example 10), to give 4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (220 mg, 91%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)[CH:3]=1.B(Br)(Br)Br.Cl.O>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: COc1ccc(Cc2cc(Br)sc2Cl)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Cc2cc(Br)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of thiophene 3 (5.44 g, 17.1 mmol) in CH2Cl2 (50 mL) was added boron tribromide (20 mL, 1M in CH2Cl2) at 0° C. The mixture was warmed up to room temperature slowly and stirred at room temperature for 3 hours. To the mixture was added aq. 1N HCl solution (35 mL) dropwise at 0° C. and H2O was added to the mixture. The mixture was extracted with EtOAc (50 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 4 was dried under high vacuum and used without further purification. (5.1 g, 99%)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.CCCCCC.[CH3:17][C:18]([CH3:28])([CH3:27])/[CH:19]=[N:20]/[S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22]>C1COCC1>[CH3:17][C:18]([CH3:28])([CH3:27])[CH:19]([NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)/C=N/S(=O)C(C)(C)C
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(NS(=O)C(C)(C)C)c1nccs1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a solution of thiazole (247 mg, 206 μl, 2.91 mmol) in 10 mL dry THF under argon at −73° C. was slowly added a 1.6M solution of BuLi in hexane (1.82 ml, 2.91 mmol). The resulting reaction mixture was stirred at −75° C. for 30 min and a solution of (E)-N-(2,2-dimethylpropylidene)-2-methylpropane-2-sulfinamide (Example 306a) (500 mg, 2.64 mmol) in 5 mL dry THF was added. The reaction mixture was stirred at −75° C. for 30 min, then cooling bath was removed and reaction stirred at r.t for 1 h. The reaction was quenched by the addition of few drops of water, the reaction mixture poured into ethyl acetate, and the solution was then extracted with aqueous NaHCO3 1M. The organic phase was collected, dried over Na2SO4 and evaporated down to dryness to give the title compound (666 mg, 92%) as crude dark orange oil. The crude was used without any further purification, MS (EI): m/e=275.2 [M+H]+.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[C:30]([O:32][CH3:33])=[O:31])(=O)=O.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[C:30]([O:32][CH3:33])=[O:31])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
Diphenylphosphine (0.72 mL, 4.14 mmol, 1 eq) was added to a stirred solution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (1.384 g, 4.14 mmol, 1 eq), triethylamine (0.64 mL, 4.59 mmol, 1.1 eq) and palladium acetate (0.005 g, 0.02 mmol, 0.005 eq) in degassed DMF (10 mL) instantly giving a red coloration. The solution was heated at reflux under nitrogen for 17 hours. The blood-red solution was allowed to cool and an aliquot taken for NMR analysis.
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=1)=O.[C:10]([CH:12]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:11]>C(Cl)(Cl)Cl>[CH3:9][S:8][C:5]1[S:4][C:3]([CH:1]=[CH:12][C:10]#[N:11])=[CH:7][CH:6]=1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CSc1ccc(C=O)s1
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C=CC#N)s1
Yield: 79.2 %

Procedure:
A solution of 2-formyl-5-methylthiothiphene (9.11 g., 58 mmole) and cyanomethylenetriphenylphosphorane (19.1 g., 64 mmole) in chloroform (200 ml.) was stirred at room temperature for 1 hr., and was then heated under reflux for 10 mins. to complete the reaction. The solvent was removed, and the residue was triturated with dry ether (50 ml.). Colourless crystals of triphenylphosphine oxide (m.p. 156°-157°), were filtered off, and were washed with ether (10 ml.). The combined filtrates were evaporated, and the dark red oily residue was distilled under reduced pressure to give 3-(5-methylthiothien-2-yl)-acrylonitrile (8.33 g., 80%) as a pale-yellow oil, b.p. 124°-135°/0.7 mm., λmax. 350, 241 nm, (ε 3440, 1460) [Found (on a redistilled sample): C, 52.9; H, 3.8; N, 7.4; S, 35.7. C8H7NS2 (181.3) requires C, 53.0; H, 3.9; N, 7.7; S, 35.4%].
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]([CH2:27]O)[N:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH:17]=1.C(N(CC)CC)C.CS([Cl:40])(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:40][CH2:27][C:15]1[N:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH:17]=[C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[N:14]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CO)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of [4-(5-methyl-3-phenyl-isoxazol-4-yl)-1-(4-nitro-phenyl)-1H-imidazol-2-yl]-methanol (50 mg, 0.13 mmol) in DCM (5 mL) at 0° C. was added triethylamine (92.6 μL, 0.66 mmol) and methanesulfonyl chloride (30.97 μL, 0.40 mmol) and the resulting mixture allowed to warm up to room temperature over 3 h and then stirred for a subsequent 2 h. The mixture was then poured onto a saturated solution of sodium hydrogen carbonate and extracted with DCM. The combined organic layers were then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (37 mg, 70%) which was obtained as a yellow foam. MS: m/e=395.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([NH:14][CH3:15])=[O:13])[CH:6]=O.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)([O-:18])=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][N:28]2[CH2:29][CH2:30][N:25]([C:22]3[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=3)[CH2:26][CH2:27]2)[CH:8]=[CH:9][C:10]=1[O:11][C:12]([NH:14][CH3:15])=[O:13]
Reactant: CNC(=O)Oc1ccc(C=O)cc1OC
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CNC(=O)Oc1ccc(CN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1OC
Temperature: 0 °C
Yield: 85.9 %

Procedure:
To a solution of 3-methoxy-4-(methylaminocarbonyloxy)benzaldehyde (1.01 g) in 1,2-dichloroethane (19.0 ml) was added 1-(4-nitrophenyl)piperazine (1.0 g), and sodium triacetoxyborohydride (1.54 g), with stirring. The reaction mixture was stirred for 3 hrs at ambient temperature, poured into ice/saturated sodium carbonate solution (100 ml) and extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was flash chromatographed (silica gel), eluting with dichloromethane, followed by 1% methanol:dichloromethane. The appropriate fractions were collected and concentrated to give 1.66 g (86%) of product. Recrystallization from ethyl acetate gave the analytical sample, mp 155-157° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH:32]=O)[N:23]=1>>[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH2:32][N:18]2[CH2:19][C@@H:20]([CH3:21])[C@H:16]([C:12]3[NH:13][C:14](=[O:15])[C:9]4[CH:8]=[N:7][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:10]=4[N:11]=3)[CH2:17]2)[N:23]=1
Reactant: O=Cc1cc2ccccc2nn1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1
Product: C[C@@H]1CN(Cc2cc3ccccc3nn2)C[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-cyclopentyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and cinnoline-3-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.49 (d, J=8.7 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.83-7.81 (m, 1H), 7.79-7.71 (m, 1H), 5.16-5.09 (m, 1H), 4.47-4.44 (m, 1H), 4.35-4.32 (m, 1H), 3.49-3.45 (m, 2H), 3.10-3.07 (m, 1H), 2.87-2.71 (m, 2H), 2.49-2.48 (m, 1H), 2.23 (m, 1H), 2.11-1.87 (m, 5H), 1.73-1.63 (m, 2H), 1.22 (d, J=7.1 Hz, 3H). MS: (M+H m/z=430.1).