Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([N:35]([CH3:34])[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CNCc1ccccc1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N(C)Cc4ccccc4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methylbenzylamine. ES-MS m/e (%): 490 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][CH:14]([N:17]([CH2:25][CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1.I.CS[C:30]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[NH:31]>C(O)C>[CH2:25]([N:17]([CH:14]1[CH2:13][CH2:12][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:30]([C:32]4[S:33][CH:34]=[CH:35][CH:36]=4)=[NH:31])[CH:3]=3)[NH:7][CH:6]=2)[CH2:16][CH2:15]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH3:26]
Reactant: CSC(=N)c1cccs1
Reactant: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(N)cc23)CC1
Agent: I
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 24 h
Yield: 76.6 %

Procedure:
A solution of compound 119 (0.4 g, 1.119 mmol) in dry ethanol (20 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.63 g, 2.239 mmol) at room temperature and stirred for 24 h. The solvent was evaporated, diluted with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2×25 mL). The CH2Cl2 layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and crude material was purified by column chromatography on silica gel (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 120 (0.4 g, 60%) as a yellow solid in 2:3 ratio of cis-trans diastereomers. 1H NMR (DMSO-d6) δ 0.98-1.08 (m, 3H), 1.38-1.56 (m, 11H), 1.68-1.85 (m, 4H), 2.05-2.18 (m, 2H), 3.02-3.17 (m, 3H), 3.70-3.76 (m, 1H), 6.31 (brs, 2H), 6.62-6.67 (m, 1H), 6.96-7.01 (m, 1H), 7.09-7.11 (m, 1H), 7.22-7.30 (m, 2H), 7.60 (d, 1H, J=5.1 Hz), 7.70-7.72 (m, 1H), 10.59, 10.62 (2s, 1H); ESI-MS m/z (%): 467 (MH+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([OH:14])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C)C.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([O:14][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)Cl
Reactant: CNC(=O)N(O)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CCOC(=O)ON(C(=O)NC)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-hydroxy-3-methylurea (15 grams; 0.06 mol) is isopropyl alcohol (50 ml), and pyridine (7 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer. Ethyl chloroformate (7 ml; 0.09 mol) was then slowly added, with stirring, at a temperature of 10° to 15°C. After the addition was completed stirring was continued for an additional period of about one-half hour resulting in the formation of a precipitate. After this time, the reaction mixture was poured onto ice and the precipitate recovered by filtration. The precipitate was recrystallized from a benzene-hexane mixture to yield 1-(3,4-dichlorophenyl)-1-ethoxycarbonyloxy-3-methylurea having a melting point of 97°-98°C and having the following elemental analysis as calculated for C11H12Cl2N2O4 :
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Al+3].[Li+].[Cl-].[Cl-].[Cl-].[NH2:11][C:12]1[S:13][C:14]2[CH2:20][CH:19]([C:21]([N:23]3[CH2:28][CH:27]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=O)[CH2:18][CH2:17][C:15]=2[N:16]=1>C(OCC)C.O1CCCC1>[C:29]1([C:26]2[CH2:27][CH2:28][N:23]([CH2:21][CH:19]3[CH2:18][CH2:17][C:15]4[N:16]=[C:12]([NH2:11])[S:13][C:14]=4[CH2:20]3)[CH2:24][CH:25]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Nc1nc2c(s1)CC(C(=O)N1CC=C(c3ccccc3)CC1)CC2
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1nc2c(s1)CC(CN1CC=C(c3ccccc3)CC1)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
An ice-cold solution of aluminum chloride (0.80 g) in 20 ml of diethyl ether is added dropwise to a suspension of lithium aluminum chloride (0.65 g) in 30 ml of tetrahydrofuran and 30 ml of diethyl ether under nitrogen. The mixture is stirred at room temperature for 15 minutes and a solution of (±)-1-[(2-amino-4,5,6,7-tetrahydro-6-benzothiazolyl)-carbonyl]-1,2,3,6-tetrahydro-4-phenylpyridine (3.5 g) (Example 6a) in 50 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred at 40° C. for 30 minutes. After cooling in an ice bath, the reaction is quenched by careful addition of 4 ml of a 10% solution of hydrochloric acid, 4 ml of a 30% solution of sodium hydroxide and 4 ml of water. The salts that precipitate are filtered through Celite and the filtrate evaporated and purified by MPLC (silica; 5% methanol, 95% dichloromethane). The title compound is obtained as a beige solid; mp 187° -190° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([O:24]CC)=[O:23])[C:12]1=[CH:11]2)#[N:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]1[CH2:17][CH2:18][CH2:19][CH:20]([CH2:21][C:22]([OH:24])=[O:23])[C:12]1=[CH:11]2)#[N:2]
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(OC(C)C)c(C#N)c3)ccc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCCC2CC(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of ethyl 2-(2-(3-cyano-4-isopropoxybenzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (70 mg, 0.157 mmol) in dioxane (1 mL) was added 1 M LiOH aqueous solution (0.627 mL, 0.627 mmol). The reaction was stirred at room temperature for 8 h, diluted with water, and acidified to pH 4 with 0.5 M aqueous citric acid solution. The light pink solid was collected to give the title compound (63 mg). LCMS m/z=419.4 [M+H]+; 1H NMR (400 MHz, CDCl3) 1.40 (d, J=6.1 Hz, 6H), 1.55-1.65 (m, 1H), 1.98-2.12 (m, 1H), 2.15-2.25 (m, 2H), 2.65 (dd, J=16.1, 8.6 Hz, 1H), 3.01 (dd, J=−16.1, 5.3 Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.92 (m, 1H), 4.12-4.18 (m, 1H), 4.61-4.68 (m, 1H), 5.01 (s, 2H), 6.22 (s, 1H), 6.86 (dd, J=8.8, 2.4 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 7.58 (dd, J=8.7, 2.2 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([NH:15][C:16]1[CH:17]=[C:18]([CH:32]2[N:36]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=3)[CH:35]([C:47]3[CH:52]=[CH:51][C:50]([NH:53][C:54]([C@@H:56]4[CH2:60][CH2:59][CH2:58][N:57]4[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:55])=[CH:49][CH:48]=3)[CH2:34][CH2:33]2)[CH:19]=[CH:20][C:21]=1[NH:22]CC1C=CC(OC)=CC=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl.O>[NH2:22][C:21]1[CH:20]=[CH:19][C:18]([CH:32]2[N:36]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([CH3:45])([CH3:44])[CH3:46])=[CH:41][CH:42]=3)[CH:35]([C:47]3[CH:48]=[CH:49][C:50]([NH:53][C:54]([C@@H:56]4[CH2:60][CH2:59][CH2:58][N:57]4[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:55])=[CH:51][CH:52]=3)[CH2:34][CH2:33]2)=[CH:17][C:16]=1[NH:15][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:14]
Reactant: COc1ccc(CNc2ccc(C3CCC(c4ccc(NC(=O)[C@@H]5CCCN5C(=O)OC(C)(C)C)cc4)N3c3ccc(C(C)(C)C)cc3)cc2NC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc(C2CCC(c3ccc(N)c(NC(=O)[C@@H]4CCCN4C(=O)OC(C)(C)C)c3)N2c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.5 %

Procedure:
To a solution of the product from Example 179F (1.06 g, 1.16 mmol) in CH2Cl2 (40 mL) and H2O (2 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.316 g, 1.393 mmol) in several portions. The mixture was stirred at rt for 20 min and was washed with saturated. aq. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-25% EtOAc in hexane to give the title compound (0.53 g, 57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:10]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:9]([C:20]([O:22]C)=[O:21])[S:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[C:20]([C:9]1[S:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=2[C:10]=1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1sc2cccc(OC)c2c1CCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc2sc(C(=O)O)c(CCc3ccccc3)c12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a solution of 4-methoxy-2-methoxycarbonyl-3-(2-phenylethyl)benzo[b]thiophene (1.09 g) in tetrahydrofuran (6 mL)-methanol (21 mL) was added 1 mol/L aqueous sodium hydroxide solution (21 mL), and the mixture was heated for reflux for 3.5 hours. The reaction mixture was cooled to room temperature. To the mixture was added 2 mol/L hydrochloric acid (11 mL), and the precipitated crystals were collected by filtration. The crystals were dried under reduced pressure to give the title compound (1 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:26])[N:14]([C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.C1COCC1.[CH3:32][C:33]1[CH:37]=[CH:36][O:35][C:34]=1[C:38](Cl)=[O:39]>CCN(CC)CC>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:26])[N:14]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:38]([C:34]5[O:35][CH:36]=[CH:37][C:33]=5[CH3:32])=[O:39])=[CH:23][CH:24]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1ccn(-c2ccc(N)cc2)c(=O)c1N1CCc2nc(N)ncc2C1
Reactant: Cc1ccoc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1ccc(-n2ccc(C)c(N3CCc4nc(N)ncc4C3)c2=O)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-(4-aminophenyl)-4-methylpyridin-2(1H)-one (25 mg, 0.075 mmol) in2 mL of THF under N2(g) containing 3 mL of NEt3 was treated with 3-methylfuran-2-carbonyl chloride (13 mg, 0.090 mmol). The reaction mixture was heated to 40° C. and allowed to stir for 3 h. The reaction was cooled and then extracted with EtOAc (3×˜10 mL) and water (˜10 mL). The combined organic layers were then washed with ˜20 mL of NaHCO3 (aq). The organic layers were then dried over anhydrous Na2SO4, filtered and then concentrated in vacuo. The crude mixture was purified over silica (EtOAc/Hexanes gradient). Following concentration of the appropriate fractions the title compound was collected as a grey solid (25 mg, 76%). 1H NMR (DMSO) δ: 9.52 (s, 1H), 7.92 (s, 1H), 7.81 (d, J=5.6 Hz, 1H), 7.45-7.52 (m, 2H), 7.41 (d, J=6.7 Hz, 1H), 7.24-7.31 (m, 2H), 6.65 (d, J=5.6 Hz, 1H), 6.28 (s, 2H), 6.17 (d, J=7.0 Hz, 1H), 3.96 (br. S, H), 3.29 (s, 2H), 2.66(t, j=5.3 Hz, 2H), 2.35 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:10][CH:9]1C)=O)(C)(C)C.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[CH:10]12[CH2:14][CH:13]([NH:8][CH2:9]1)[CH2:12][N:11]2[CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:40][CH2:39][CH2:38][C:33]3[CH:34]=[C:35]([F:37])[CH:36]=[C:31]([F:30])[CH:32]=3)[N:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC(C)N1C(=O)OC(C)(C)C
Reactant: NCCc1cc(F)cc(F)c1
Product: Fc1cc(F)cc(CCNc2nccc(-c3cccc(CN4CC5CC4CN5)c3)n2)c1

Procedure:
Intermediate 142 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 422. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.78 (s, 1H) 8.38 (d, 2H) 8.00 (d, 1H) 7.77 (t, 1H) 7.68 (d, 1H) 7.00 (d, 2H) 6.75 (t, 1H) 4.84 (d, 1H) 4.65 (s, 2H) 4.60 (d, 1H) 4.24 (d, 1H) 4.10 (d, 1H) 3.89 (d, 1H) 3.68 (d, 1H) 3.63 (t, 2H) 3.07 (t, 2H) 2.86 (d, 1H) 2.37 (d, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li][CH2:23][CH2:24][CH2:25][CH3:26]>CCOCC.CCCCCCC>[CH2:23]([C:24]1[CH:23]=[C:2]([C:1]([CH:8]2[C:7]3[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)([CH3:4])[CH3:3])[CH2:26][CH:25]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: [Li]CCCC
Solvent: CCCCCCC
Solvent: CCOCC
Product: CCCCC1=CCC(C(C)(C)C2c3cc(C(C)(C)C)ccc3-c3ccc(C(C)(C)C)cc32)=C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 153.4 %

Procedure:
To 2,7-di-tert-butylfluorene (27.8 g, 100 mmol) dissolved in Et2O (200 mL) was added n-BuLi (11 mL of 10 M in hexanes, 110 mmol) at 0° C. The mixture was warmed to room temperature and stirred overnight. To the anion solution was added to 2-butyl-6,6-dimethylpentafulvene (F-2) (20 g, 123 mmol) at −78° C. in less than one minute. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and saturated NH4Cl aqueous solution. The mixture was extracted with Et2O. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum gave a viscous oil. The oil was dissolved in heptane and purified through silica gel column with 5-10% CH2Cl2 in heptane. A mixture of isomers for the desired product (33.8 g, 76.8% yield) was obtained as a viscous oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][CH3:15].[Cl:20][C:21]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([Cl:33])[C:22]=1[CH:23]=[O:24]>O1CCCC1>[Cl:20][C:21]1[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([Cl:33])[C:22]=1[CH:23]([OH:24])[CH:14]([CH3:15])[C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)CC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)C(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 3.8 ml of anhydrous diisopropylamine in 50 ml anhydrous tetrahydrofuran was added 14.7 ml of n-butyllithium (1.61 moles/liter in hexane) at 0° C., the mixture was stirred at 0° C. for 30 minutes, and 2.4 ml of ethyl propionate in 10 ml of anhydrous tetrahydrofuran was thereafter added to the mixture. The resulting mixture was stirred at -78° C. for 1 hour, and 5.0 g of 2,6-dichloro-4-trifluoromethylbenzaldehyde (7) in 10 ml of anhydrous tetrahydrofuran was thereafter added to the mixture, followed by stirring at -78° C. for 30 minutes and then at room temperature for 1 hour. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate, washing with brine, drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/6), affording 7.2 g of the desired product in the form of a yellow oil (yield 91.1%).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])=[O:9])[CH3:22]
Reactant: CCNCC
Reactant: Cc1occc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccoc1C
Temperature: 0 °C
Yield: 83.4 %

Procedure:
To a solution of 2-methyl-3-furoic acid (34.75 g, 0.3469 mol) in dry methylene chloride (200 ml) under an argon atmosphere, were added a catalytic amount of dimethylformamide followed by dropwise addition of oxalyl chloride (45.5 ml, 0.5216 mol). After the addition the reaction mixture was allowed to stir until the effervescence had subsided (4.0 hours). The excess oxalyl chloride/methylene chloride was evaporated and the residue was dissolved in methylene chloride (200 ml). The solution was cooled (ice/acetone) and diethylamine (75.0 ml, 0.725 mol) in methylene chloride (100 ml) was added dropwise. After the addition (1.0 hour) the reaction was poured into ice/water and the solution was acidified to a pH of 3.0. The mixture was extracted with diethyl ether (4×200 ml). The combined extracts were washed with saturated sodium carbonate solution (2×50 ml), water (4×50 ml), brine (2×25 ml), and dried (MgSO4). Solvent evaporation gave 59.75 g of crude product. The oil was distilled to give 52.45 g (83% yield) of product which crystallized upon standing (bp: 91° C./1.2 mmHg; mp 32°-34° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[CH:11][N:10]=[N:9]2)[N:3]=1.[NH2:13][C:14]1[S:15][C:16]([C:22]2[C:27]([F:28])=[CH:26][C:25]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:24][C:23]=2[F:33])=[CH:17][C:18]=1[C:19]([NH2:21])=[O:20]>>[F:33][C:23]1[CH:24]=[C:25]([C:29]([OH:32])([CH3:31])[CH3:30])[CH:26]=[C:27]([F:28])[C:22]=1[C:16]1[S:15][C:14]([NH:13][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]3[CH:12]=[CH:11][N:10]=[N:9]3)[N:3]=2)=[C:18]([C:19]([NH2:21])=[O:20])[CH:17]=1
Reactant: Clc1cccc(-n2ccnn2)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(-n4ccnn4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 2-chloro-6-(1H-1,2,3-triazol-1-yl)pyridine (72 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) according to the general procedure in Example 1.
Reaction SMILES: [CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][N:6]=1)[CH2:2][CH:3]=C.[O:14]1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O.C(OCC)(=O)C>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:5]([CH2:1][CH2:2][CH:3]=[O:14])=[N:6]1
Reactant: C=CCCc1noc2ccccc12
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=CCCc1noc2ccccc12
Reaction time: 1 h

Procedure:
Compound 26 (549 mg, 3.2 mmol), water (5 mL), 1,4-dioxane (15 mL) and osmium tetroxide (15 mg, 0.06 mmol) were stirred for 5 min. in a small flask. Sodium metaperiodate (1.56 g, 7.3 mmol) was added over 30 min. and the suspension was then stirred for 1 hour. Ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate and dichloromethane. The combined organic phases were dried over magnesium sulphate and evaporated to dryness to produce 784 mg of crude 27, which was used directly without further purification in the synthesis compound 28.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)=[O:7])[N:3]=[CH:2]1.[CH2:20]([Mg]Br)[CH:21]([CH3:23])[CH3:22]>C1COCC1>[NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)([OH:7])[CH2:20][CH:21]([CH3:23])[CH3:22])[N:3]=[CH:2]1
Reactant: CC(C)C[Mg]Br
Reactant: COc1ccc2cc(C(=O)c3c[nH]cn3)ccc2c1
Solvent: C1CCOC1
Product: COc1ccc2cc(C(O)(CC(C)C)c3c[nH]cn3)ccc2c1

Procedure:
In a similar manner to that described in Example 1-(iv), the reaction of (1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (0.60 g) with absolution of isobutylmagnesium bromide in THF (1.0 M, 2.4 ml) was carried out to give the titled compound (0.14 g) as a colorless solid.
Reaction SMILES: [C:1](=[O:11])([O:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[O:2][CH2:3]Cl.[I-:12].[Na+].O>C(#N)C>[C:1](=[O:11])([O:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[O:2][CH2:3][I:12]
Reactant: [I-]
Reactant: COCCCOC(=O)OCCl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COCCCOC(=O)OCI
Temperature: 55 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Chloromethyl [3-(methoxy)propyl] carbonate (3.7 g) was dissolved in acetonitrile (12 ml), and sodium iodide (12.0 g) was added. The mixture was stirred at 55° C. for 4 hours under an argon atmosphere. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with an aqueous 5% sodium thiosulfate solution (50 ml×2), water (50 ml) and a saturated sodium chloride aqueous solution (50 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain iodomethyl [3-(methoxy)propyl] carbonate (5.0 g) as a pale yellow liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:27]([CH3:28])=[C:26]([CH3:29])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>CO.O>[OH:20][N:19]=[C:1]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: NO
Reactant: CCOC(=O)COc1ccc(C(=O)CC)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)COc1ccc(C(CC)=NO)cc1
Yield: 76.7 %

Procedure:
To a solution of the product of step 1 (49 g, 0.2076 moles) in methanol (343 ml), hydroxylamine hydrochloride (28.6 g, 0.4152 moles) and a solution of sodium acetate (34 g, 0.4152 moles) in water (147 ml) were added and the reaction mixture was refluxed for 1 hour. The solvents were evaporated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure to yield 40 gm (76%) of product as solid.