Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C([N-]C(C)C)(C)C.[Li+].[CH3:18][O:19][C:20](=[O:36])[C:21]1[CH:26]=[C:25]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])[C:24]([F:33])=[C:23]([F:34])[C:22]=1F>O1CCCC1>[CH3:18][O:19][C:20](=[O:36])[C:21]1[CH:26]=[C:25]([S:27](=[O:32])(=[O:31])[N:28]([CH3:30])[CH3:29])[C:24]([F:33])=[C:23]([F:34])[C:22]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[Cl:1]
Reactant: Nc1ccc(I)cc1Cl
Reactant: COC(=O)c1cc(S(=O)(=O)N(C)C)c(F)c(F)c1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(=O)(=O)N(C)C)c(F)c(F)c1Nc1ccc(I)cc1Cl
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
To a stirring cold (−78° C.) solution comprised of 2-chloro-4-iodoaniline (0.143 g, 5.64×10−4 mol) in anhydrous tetrahydrofuran (5 ml) under a nitrogen atmosphere was added a commercially available lithium diisopropylamide solution (Aldrich, 2.0 M in tetrahydrofuran/heptane/ethylbenzene, 0.300 ml, 6.0×10−4 mol). After stirring for 5 minutes, a solution comprised of 5-dimethylsulfamoyl-2,3,4-trifluoro-benzoic acid methyl ester (0.15 g, 5.0×10−4 mol) in tetrahydrofuran (10 ml) was added via syringe. The cold bath was removed and the reaction mixture was stirred for 2 hours. The reaction mixture was then partitioned between diethyl ether (125 ml) and saturated aqueous sodium bicarbonate (125 ml). The aqueous bicarbonate phase was extracted with an additional portion (125 ml) of diethyl ether. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was crystallized from heptane-ethyl acetate to afford 0.060 g of an off-white powder; 23% yield; mp 154-156° C.; 1H-NMR (400 MHz; CDCl3) δ9.74 (s, 1H), 8.30 (d, 1H, J=7.1 Hz), 7.72 (s, 1H), 7.49 (d, 1H, J=8.3 Hz), 6.73-6.69 (m, 1H), 3.92 (s, 3H), 2.84 (s, 3H), 2.83 (s, 3H); 19F-NMR (376 MHz; CDCl3) δ−123.90 (d), −139.55 (d).
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:22][CH2:23][CH2:24][O:25][CH3:26]>CC#N>[Br-:22].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:23][CH2:24][O:25][CH3:26])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Reactant: COCCBr
Solvent: CC#N
Product: COCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)C2
Product: [Br-]
Yield: 24.1 %

Procedure:
Following the general procedure outlined in Example 1, 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (30.8 mg, 0.110 mmol) and 1-bromo-2-(methyloxy)ethane (0.03 mL, 0.3 mmol) in 2 CH3CN/3 CHCl3 (2.5 nm) were reacted to give the desired product (11.1 mg, 24%). EI-MS m/z 338 (M+) Rt (1.64 min).
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[C:17]4[C:20]5[C:25]([C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=6[C:16]4=[CH:15][C:14]=3[C:13]3[CH:12]=[C:11](B4OC(C)(C)C(C)(C)O4)[CH:10]=[CH:9][C:8]2=3)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[N+:48]([O-:50])=[O:49].C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N+:48]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[C:11]1[CH:10]=[CH:9][C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:19]3[CH:18]=[C:17]4[C:20]5[C:25]([C:26]6[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=6[C:16]4=[CH:15][C:14]=3[C:13]=2[CH:12]=1)=[CH:24][CH:23]=[CH:22][CH:21]=5)([O-:50])=[O:49]
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: CC1(C)OB(c2ccc3c(c2)c2cc4c5ccccc5c5ccccc5c4cc2n3-c2ccccc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1-c1ccc2c(c1)c1cc3c4ccccc4c4ccccc4c3cc1n2-c1ccccc1
Temperature: 90 °C
Yield: 68.6 %

Procedure:
A mixture of 11.5 g (22.1 mmol) of 10-phenyl-13-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)-10H-phenanthro[9,10-b]carbazole, 5.4 g (26.5 mmol) of 1-bromo-2-nitrobenzene, 0.44 g (0.4 mmol) of tetrakis(triphenylphosphine)palladium, 30 ml of 2M Na2CO3, 40 ml of EtOH and 80 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. overnight. After finishing the reaction, the mixture was allowed to cool to room temperature. The solution was extracted with 250 ml of ethyl acetate and 500 ml of water. The organic layer was dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (Hx-EA) to give product 7.8 g (69%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[C:5]([Br:24])=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.N1C=CC=CC=1.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[Br:24][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([S:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:46])=[O:45])[CH2:15][CH2:16]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1ncc(Br)c(N2CCN(S(=O)(=O)c3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of tert-butyl 4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazine-1-carboxylate (250 mg, 0.62 mmol) in CH2Cl2 (2.5 mL) at 0° C. was treated with TFA (2.5 mL) and stirred at 0° C. for 1.5 h. After this time, the solvents were evaporated in vacuo and the excess TFA removed by azeotroping with toluene (3×10 mL). The residue was suspended in CHCl3 (3 mL) and pyridine (3 mL) and treated with benzenesulfonyl chloride (1.1 eq, 0.68 mmol, 0.09 mL), warmed to room temperature and stirred for 12 h. The solvents were removed in vacuo and the residue partition between water (5 mL) and EtOAc (5 mL). The aqueous layer was extracted with EtOAc (2×5 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. Column chromatography (hexane-EtOAc, 1:1) gave the product (107 mg, 39% for two steps) as a yellow solid; 1H-NMR (500 MHz, DMSO-d6) 3.09 (br s, 8H, 2× piperazine N(CH2)2), 7.08 (br s, 2H, NH2), 7.67-7.70 (m, 2H, phenyl H-3 & H-5), 7.74-7.78 (m, 3H, phenyl H-2, H-4 & H-6), 8.16 (s, 1H, pyridine H-6);
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C@H:20]2[CH2:28][N:27]3[C@@H:22]([CH2:23][O:24][CH2:25][CH2:26]3)[CH2:21]2)=[C:15]([N+:29]([O-])=O)[CH:14]=1.C(N(CC)CC)C.Cl[C:45](Cl)([O:47]C(=O)OC(Cl)(Cl)Cl)Cl>[Pt].O1CCCC1.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@H:20]3[CH2:28][N:27]4[C@@H:22]([CH2:23][O:24][CH2:25][CH2:26]4)[CH2:21]3)[C:45](=[O:47])[NH:29][C:15]=2[CH:14]=1
Reactant: O=[N+]([O-])c1cc(/C=C2\c3ccccc3COc3cc(F)ccc32)ccc1N[C@@H]1C[C@@H]2COCCN2C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Pt]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc(/C=C3\c4ccccc4COc4cc(F)ccc43)ccc2n1[C@@H]1C[C@@H]2COCCN2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
Hydrogenate a mixture of (E)-[4-(3-fluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-((7R,8aR)-hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-amine (52 g, 0.107 mol), triethylamine (33 mL, 0.237 mol) and 5% platinum on carbon (18 g) in tetrahydrofuran (450 mL) at room temperature at 50 psi for 2 h. Filter off the catalyst, rinse with tetrahydrofuran, and concentrate to obtain a brown foam. Dissolve the foam in anhydrous tetrahydrofuran (500 mL) and cool in an ice bath. Add triphosgene (31.5 g, 0.106 mol) in tetrahydrofuran (450 mL) dropwise over 30 min and stir at room temperature for 16 h. Concentrate the solution, dissolve in 5% methanol in dichloromethane and purify through a short silica gel plug. Concentrate to obtain a brown solid. Suspend the solid in saturated sodium bicarbonate (1.5 L) and stir on the rotary evaporator for one hour. Filter and dry in vacuo. Dissolve in warm 1:1 methanol/dichloromethane (approximately 6 L) and treat with poly (4-vinylpyridine) 2% cross-linked resin (170 g). Stir the slurry for 30 min and filter through diatomaceous earth. Concentrate the filtrate to approximately 1.5 L volume and collect the resulting solids by filtration. Dry at 80° C./20 mm Hg overnight to obtain the title compound as a white solid (38.1 g, 74%). [α]D20−20.5 (c=1.0 in DMSO). 1H NMR (400 MHz, DMSO-d6) δ 1.48 (m, 1H), 2.02 (m, 1H), 2.19 (m, 2H), 2.52 (m, 1H), 2.91 (d, 1H), 3.03 (d, 1H), 3.25 (t, 1H), 3.50 (t, 1H), 3.79 (d, 1H), 3.88 (d, 1H), 4.95 (m, 1H), 5.03 (broad s, 1H), 5.60 (broad s, 1H), 6.59 (m, 2H), 6.78 (m, 2H), 6.97 (s, 1H), 7.02 (d, 1H), 7.25 (t, 1H), 7.38 (t, 1H), 7.48-7.61 (m, 3H), 10.72 (s, 1H, NH). LC-MS m/z 484.0 [M+H]+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([F:28])=[C:21]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[CH:22]=1>C(O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([F:28])=[C:21]([CH:23]2[CH2:3][C:2](=[O:1])[CH2:26][C:25](=[O:27])[CH2:24]2)[CH:22]=1
Reactant: CC(=O)C=Cc1cc(Cl)ccc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: O=C1CC(=O)CC(c2cc(Cl)ccc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (7.4 g) was added at room temperature diethyl malonate (3.6 g), and then added little by little 4-(5-chloro-2-fluorophenyl)-3-buten-2-one (4.3 g). The mixture was stirred at room temperature for 30 minutes and then for 2 hours while heating, and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (17 ml), and the mixture was refluxed for 1 hour and cooled. To the mixture was added 2.5M sulfuric acid (17 ml) for 10 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered and washed with water and isopropylether to give 5-(5-chloro-2-fluorophenyl)cyclohexane-1,3-dione (4.1 g) as pale yellow crystals.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].[F:23][C:24]([F:36])([F:35])[C:25]1[CH:34]=[CH:33][C:28]([C:29](=O)[CH2:30]Br)=[CH:27][CH:26]=1>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:30]=[C:29]([C:28]3[CH:33]=[CH:34][C:25]([C:24]([F:23])([F:35])[F:36])=[CH:26][CH:27]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Product: O=C(O)c1cc(-c2nc(-c3ccc(C(F)(F)F)cc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 40 %

Procedure:
2′-Nitro-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (120 mg, 40%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 4-(trifluoromethyl)phenacyl bromide (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.16 (s, 1H), 8.59 (s, 1H), 8.51 (s, 1H), 8.27-8.31 (m, 3H), 8.15 (d, J=8.1 Hz, 1H), 7.77-7.87 (m, 3H), 7.66 (t, J=8.0 Hz, 1H), 7.42-7.49 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH:14]=[CH:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cnc(-c2ccc(F)cc2)nc1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cnc(-c2ccc(F)cc2)nc1

Procedure:
945 mg (4.67 mmol) of 2-(4-fluoro-phenyl)-pyrimidine-5-carbaldehyde, 1544 mg (14.84 mmol) of malonic acid and 4197 mg (49.29 mmol) of piperidine in 50 ml of pyridine were stirred at 125° C. for 17 h. After concentration, water and hydrochloric acid were added, and the solid product was filtered off with suction and dried. Yield: 1.01 g.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[C:6]([CH3:12])=[N:5]1)[CH3:3].[CH3:13][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:3][CH:2]([N:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:13])=[O:10])[C:6]([CH3:12])=[N:5]1)[CH3:1]
Reactant: Cc1nn(C(C)C)cc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1cn(C(C)C)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 1-(1-methylethyl)-3-methyl-1H-pyrazole-4-carboxylic acid (2.00 g, 11.9 mmol) in benzene (15.9 mL) and methanol (7.93 mL) at room temperature was added 2M trimethylsilyldiazomethane (23.8 mL). The resulting solution was stirred at room temperature for 3 hours. Solvent was removed at reduced pressure on a rotary evaporator to yield the title compound (2.17 g, 111.89 mmol, 100% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][N:38]=2)[CH2:33][CH2:32]1>>[CH3:14][C:6]1[C:5]2[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=3[CH2:25][CH2:26][CH3:27])=[O:16])=[CH:3][C:2]([C:40]3[CH:39]=[N:38][C:37]([N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)=[CH:42][CH:41]=3)=[CH:10][C:9]=2[N:8]([CH:11]([CH3:13])[CH3:12])[N:7]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C)CC3)nc2)cc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 67 from 6-bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.10 g, 0.218 mmol) and 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (0.086 g, 0.283 mmol). The title compound was collected as a white solid (0.105 g, 84%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.33 Hz, 3H), 1.45 (d, J=6.57 Hz, 6H), 1.50-1.63 (m, 2H), 2.12 (s, 3H), 2.22 (s, 3H), 2.38-2.45 (m, 7H), 2.52-2.59 (m, 2H), 3.51-3.60 (m, 4H), 4.37 (d, J=5.05 Hz, 2H), 4.96-5.10 (m, 1H), 5.90 (s, 1H), 6.94 (d, J=8.84 Hz, 1H), 7.32 (d, J=1.26 Hz, 1H), 7.89 (d, J=1.26 Hz, 1H), 7.98 (dd, J=8.84, 2.53 Hz, 1H), 8.40 (t, J=5.05 Hz, 1H), 8.56 (d, J=2.27 Hz, 1H), 11.50 (s, 1H); LCMS (ES+) m/z: 556.1.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.CN1C(=O)N(C)CCC1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][CH:21]=1.CI>C1COCC1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:2])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][CH:21]=1
Reactant: COc1ccc(CCC(=O)OC(C)(C)C)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(CC(C)C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
An oven dried flask was charged with THF (40 mL) under nitrogen and cooled to −78° C. and 2M LDA in THF (7.62 mL, 15.23 mmol) was added dropwise followed by DMPU (8 mL, 6.09 mmol). Tert-butyl 3-(4-methoxyphenyl)propanoate (1.44 g, 6.09 mmol) was added by cannula in THF (4×5 mL), and the reaction was stirred at −78° C. for 1 hr. Methyl iodide (1.143 mL, 18.28 mmol) was added dropwise, and the reaction was stirred 30 minutes at −78° C. and then warmed to room temperature for 1 hr. The reaction was then quenched with water (40 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with 1N HCl (2×30 mL) and brine (2×30 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 60% ethyl acetate/hexanes) afforded of tert-butyl 3-(4-methoxyphenyl)-2-methylpropanoate. 1H NMR (CDCl3, 500 MHz) δ 7.09 (d, J=8.5 Hz, 2H), 6.81 (d, J=8.5 Hz, 2H), 3.78 (s, 3H), 2.89 (multiplet, 1H), 2.57 (multiplet, 2H), 1.38 (s, 9H), 1.10 (d, J=6.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1C=C(C=CC=1)C(OO)=O.CS[C:14]1[N:15]=[CH:16][C:17]2[S:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:18]=2[N:19]=1.[S:33]([O-:37])([O-])(=[O:35])=S.[Na+].[Na+]>ClCCl>[CH3:2][S:33]([C:14]1[N:15]=[CH:16][C:17]2[S:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:18]=2[N:19]=1)(=[O:37])=[O:35]
Reactant: COC(=O)c1sc2cnc(SC)nc2c1-c1ccccc1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1sc2cnc(S(C)(=O)=O)nc2c1-c1ccccc1
Reaction time: 2.5 h

Procedure:
2.3 g of 3-chloroperoxybenzoic acid (75%) are added slowly, in fractions, to a solution of 1.6 g of methyl 2-(methylsulfanyl)-7-phenylthieno[3,2-d]pyrimidine-6-carboxylate (example 4) in 25 ml of dichloromethane, cooled in an ice bath. The mixture is stirred for 2.5 h while cold, and then left at ambient temperature overnight. The mixture is then diluted with 80 ml of dichloromethane and treated with 60 ml of saturated sodium thiosulfate solution. After stirring and settling out, the aqueous phase is extracted with 60 ml of dichloromethane. The organic phases are washed with 60 ml of a saturated sodium bicarbonate solution, and then with 60 ml of a saturated sodium chloride solution. The organic phases are dried over magnesium sulfate, filtered, and then concentrated under vacuum so as to obtain the crude product, which is purified on 200 g of silica, elution being carried out with dichloromethane, so as to obtain 1.4 g of methyl 2-(methylsulfonyl)-7-phenylthieno[3,2-d]pyrimidine-6-carboxylate in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](Cl)(=[O:12])=[O:11])=[O:4].Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:12])(=[O:11])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][C:25](=[O:28])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1)=[O:4]
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Agent: Cl
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 2-(methoxycarbonyl)thiophene-3-sulphonyl chloride and 1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.37 (t, J=6.0 Hz, 4 H), 3.50 (t, J=6.0 Hz, 4 H), 3.89 (s, 3 H), 6.90 (d, J=9.1 Hz, 2 H), 6.96 (d, J=9.1 Hz, 2 H), 7.33 (d, J=6.9 Hz, 1 H), 7.90 (d, J=6.9 Hz, 1 H), 9.50 (s, 1 H); MS (ES) m/z: 395.0 (MH+); HRMS Calcd. for C17H19N2O5S2(MH+): 395.0736. Found: 395.0721.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][C:10](O)=[O:11])=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:1][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1
Reactant: O=C(O)CCOc1ccc(CO)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCOc1ccc(CO)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-hydroxymethylphenoxy)propionic acid (4.00 g, 20.40 mmol) in THF (20 mL) is added a solution of LiAlH4 (10 mL, 1 M in THF). The mixture becomes warm and is diluted with THF (20 mL) before it is refluxed. After 1 and 2 h two further portions of LiAlH4 (2×10 mL, 1 M in THF) are added. The mixture is refluxed overnight, cooled to rt and carefully quenched by the addition of water (1.2 g), 15% aq. NaOH (1.2 g) and water (3.2 g). The white precipitate is filtered off, and the filtrate is evaporated and dried to give 3-(4-hydroxymethyl-phenoxy)-propan-1-ol. 1H NMR (D6-DMSO): δ 7.21-7.15 (m, 2H), 6.86-6.81 (m, 2H), 5.00 (t, J=5.9 Hz, 1H),4.51 (t, J=5.3 Hz, 1H), 4.39 (d, J=5.3 Hz, 2H), 3.99 (t, J=6.4 Hz, 2H), 3.57-3.50 (m, 2H), 1.83 (p, J 0 6.4 Hz, 2H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[NH:23][C:24]([CH3:26])=[N:25][C:15]=3[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:29]I.O>CN(C)C=O.C(Cl)(Cl)Cl>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]3[N:23]=[C:24]([CH3:26])[N:25]([CH3:29])[C:15]=3[CH2:14][CH2:13]2)=[O:11])=[CH:27][CH:28]=1)([O-:5])=[O:4]
Reactant: Cc1nc2c([nH]1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(n1C)CCN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a stream of argon, 144 mg of 60% sodium hydride was suspended in a small volume of N,N-dimethylformamide to which, with cooling on an ice bath, was then added dropwise a solution prepared by dissolving 500 mg of 6-(4-nitrobenzoyl)-2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine in 20 ml of N,N-dimethylformamide. After 1 hour of stirring at room temperature, the reaction solution was mixed with 0.11 ml of methyl iodide and stirred for 24 hours at room temperature. The reaction solution was mixed with water and chloroform, and the resulting organic layer was separated, washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. After removing the solvent by distillation under a reduced pressure, the thus obtained residue was subjected to silica gel column chromatography to obtain 351 mg of 6-(4-nitrobenzoyl)-2,3-dimethyl-3,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine from the chloroform-methyl alcohol (30:1) eluate.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[CH:7]1([C:10](OC)=[O:11])[CH2:9][CH2:8]1.C[O-].[Na+]>CS(C)=O>[CH:7]1([C:10](=[O:11])[CH2:1][C:2]([CH:4]2[CH2:6][CH2:5]2)=[O:3])[CH2:9][CH2:8]1
Reactant: COC(=O)C1CC1
Reactant: CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(CC(=O)C1CC1)C1CC1
Temperature: 52.5 °C

Procedure:
Cyclopropyl methyl ketone (2.5 mL; 25 mmol) was dissolved in DMSO (12.5 mL) and methyl cyclopropanecarboxylate (5.0 mL; 50 mmol; 2 equiv) was added. The reaction mixture was cooled in ice-water and sodium methoxide (2.70 g; 50 mmol; 2 equiv) was added. The reaction mixture was stirred for 5 min in the ice-water bath, the bath was removed, and the mixture was heated to 50-55° C. for 8 h. The reaction mixture was diluted with toluene (12.5 mL), cooled in ice-water, and 6 N HCl (9 mL) was added dropwise such that the temperature remained below 25 ° C. The layers were separated and the aqueous solution was extracted with additional toluene (10 mL). The combined organic solution was washed with aqueous sodium bicarbonate (10 mL), dried with sodium sulfate and concentrated to afford 3.50 g (92%) yield of 1,3-dicyclopropyl-1,3-propanedione.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)[C:12](Cl)=[O:13]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:8]=[C:12]=[O:13])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1ccc(F)cc1
Temperature: 50 °C
Yield: 100.9 %

Procedure:
To a solution of 4-fluorobenzamide (1 g, 7.2 mmol) in DCM (25 mL) was added slowly oxalylchloride (0.76 mL, 8.62 mmol). The mixture was heated to 50° C. for ˜18 hr. The mixture was allowed to cool to room temperature and concentrated in vacuo to afford crude 4-fluorobenzoyl isocyanate (1.2 g). The crude material was used in the next step without further purification.