Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si](C(C)(C)C)(C)C)=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.Cl[C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1>C1COCC1>[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=[C:28]1[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: Clc1nc2ccccc2o1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Oc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-t-butyldimethylsilyloxybenzene (8.3 g; 29 mmol) in THF (60 ml) at -78° C. is added a solution of butyllithium in hexane (14 ml; 35 mmol) over 10 minutes. This is allowed to stir 1 hour and 2-chlorobenzoxazole (4 ml; 35 mmol) is added dropwise over 5 minutes. After stirring 15 minutes, the reaction is allowed to warm to 0° C. and is quenched with MeOH. This is then poured into 1N HCl and after stirring 1 hour is extracted with ethyl acetate. The organic extracts are dried (MgSO4) and then concentrated to yield 4-(benzoxazol-2-yl)phenol which is used directly in Step C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=[O:8].[CH3:10][Si](C=[N+]=[N-])(C)C>CO.O1CCOCC1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cn1cccc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cccn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 1-methyl-2-pyrrolecarboxylic acid (1.03 g, 8.22 mmol) in MeOH (5 mL) and dioxane (5 mL) at room temperature, trimethylsilyldiazomethane (2M in ether, 5.0 mL, 10.0 mmol) was added. After being stirred at room temperature for 1 h, the mixture was concentrated in vacuo to give methyl 1-methyl-2-pyrrolecarboxylate as a volatile oil (1.14 g).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[CH:26]1([CH2:29]O)[CH2:28][CH2:27]1>>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([O:14][CH2:29][CH:26]2[CH2:28][CH2:27]2)=[O:13])=[CH:6][CH:5]=1
Reactant: OCC1CC1
Reactant: Nc1ccc(CC(C(=O)O)c2cn(C3CCCCC3)cn2)cn1
Agent: Cl
Product: Nc1ccc(CC(C(=O)OCC2CC2)c2cn(C3CCCCC3)cn2)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1 ml of an HCl-saturated ether solution was added to a solution of 50.0 mg (0.16 mmol) of the compound from example 1i in 2 ml of cyclopropylcarbinol and stirred at room temperature for 12 h. The solution was then concentrated to dryness, and the resulting residue was dried under high vacuum. Purification by chromatography on silica gel with CH2Cl2/methanol as mobile phase afforded 29 mg of the title compound in the form of an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[N-:11]=[C:12]=[S:13].[K+].[Na+].[I-]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:11]=[C:12]=[S:13]
Reactant: [N-]=C=S
Reactant: Fc1c(Cl)cccc1CBr
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1c(Cl)cccc1CN=C=S

Procedure:
One molar equivalent of 3-chloro-2-fluoro-benzyl bromide (commercially available from e.g., Lancaster Synthesis, Ltd.) is permitted to react with 2 molar equivalents of potassium isothiocyanate in dimethylformamide (DMF) containing 0.5 molar equivalent of NaI at 90° C. for 5 hours with stirring to yield 3-chloro-2-fluorobenzyl isothiocyanate. The reaction mixture is permitted to cool to room temperature, and the solution is diluted with H2O and extracted with ether. The ether phase containing the product is removed and the reaction mixture extracted twice more with fresh ether. The ether phases are combined and the product is concentrated in a Speed Vac® vacuum centrifuge (using house vacuum) set in a water bath at about 45° C. When the ether has evaporated, the unpurified 3-chloro-2-fluorobenzyl isothiocyanate is a viscous liquid.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][CH2:7][O:8][CH2:9][C:4]=2[C:3]([C:10]([OH:12])=O)=[N:2]1.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:3]3[C:4]4[CH2:9][O:8][CH2:7][CH2:6][C:5]=4[O:1][N:2]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1noc2c1COCC2
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1noc2c1COCC2
Yield: 13.26 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 6,7-dihydro-4H-pyrano[3,4-d]isoxazole-3-carboxylic acid (0.174 g, 1.026 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.22 g, 0.789 mmol). The product was purified by LC/MS-trigger. Yield 13.26%. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 2.93 (t, 2H), 3.91 (t, 2H), 4.27 (dd, 1H), 4.42 (dd, 1H), 4.50-4.60 (m, 1H), 4.89 (d, 2H), 6.63 (d, 1H), 7.37 (d, 1H), 7.50 (d, 1H), 7.59 (dd, 1H), 7.76-7.77 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH:8]([C:10]2[C:11]3[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31][C:12]=3[N:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)[N:15]=2)[CH3:9])[N:3]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH:8]([C:10]2[C:11]3[CH2:34][NH:33][CH2:32][CH2:31][C:12]=3[N:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)[N:15]=2)[CH3:9])[N:3]=1
Reactant: COc1cc(Nc2nc3c(c(C(C)n4nc(C)cc4C)n2)CN(C(=O)OC(C)(C)C)CC3)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Nc2nc3c(c(C(C)n4nc(C)cc4C)n2)CNCC3)ccc1-n1cnc(C)c1
Yield: 76.8 %

Procedure:
A solution of tert-butyl 4-(1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (397 mg, 0.71 mmol) and TFA (0.547 mL, 7.10 mmol) in DCM was stirred for one hour at 40° C. The reaction mixture was cooled and sat aqu NaHCO3 was added until the mixture was neutralized. The organic phase was separated and the water phase was washed repeatedly with DCM yielding 4-(1-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (250 mg, 77%)
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH2:17])=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([OH:25])=O.Cl.C[N:28](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.CO>[NH2:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:5]3[CH:4]=[C:3]([NH:28][C:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[O:25])[CH:2]=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]=12
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cccs1
Reactant: Nc1ccc(-n2ncc3c(N)ncnc32)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2-c1cccc(NC(=O)c2cccs2)c1
Reaction time: 0.17 h
Yield: 12.5 %

Procedure:
Title compound 11A, 1-(4-amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (39 mg, 1.1 eq, 0.17 mmol) was added to a solution 2-thiophenecarboxylic acid (20 mg, 1.0 eq, 0.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27 mg, 1.1 eq, 0.17 mmol), 1-hydroxybenzotriazole (21 mg, 1.0 eq, 0.16 mmol) in DMF (1 ml) which had been stirred for 10 minutes under an inert atmosphere. The reaction was stirred at room temperature for 17 hours, after which methanol (1 ml) was added, and the solvents were removed in vacuo. The residue was then triturated with methanol and the resultant solid was isolated by filtration to yield the title compound as a pale yellow solid (7.3 mg, 0.02 mmol, 13%). LCMS: [M+H]+=337, Rt=1.58 min, 100% purity.
Reaction SMILES: Cl[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2([CH3:29])[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([CH3:28])=[CH:22][C:23]=3[CH3:27])[O:18]2)=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[NH2:30][C:31](N)=[S:32].S1(CCCC1)(=O)=[O:35].Cl>COCCO>[CH3:29][C:17]1([CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][CH:2]3[S:32][C:31](=[O:35])[NH:30][C:3]3=[O:4])=[CH:14][CH:13]=2)[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([CH3:28])=[CH:22][C:23]=2[CH3:27])[O:18]1
Reactant: NC(N)=S
Reactant: O=S1(=O)CCCC1
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)cc(C)cc3O2)cc1
Agent: Cl
Solvent: COCCO
Product: Cc1cc(C)c2c(c1)OC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)CC2

Procedure:
Following a procedure similar to that described in Example 1, but using 1.52 g of ethyl 2-chloro-3-[4-(2,5,7-trimethylchroman-2-ylmethoxy)phenyl]propionate (prepared as described in Preparation 27), 0.83 g of thiourea, 5 ml of sulfolane, 15 ml of ethylene glycol monomethyl ether and 4 ml of 3N aqueous hydrochloric acid, 1.18 g of the title compound were obtained as a pale yellow powder, softening at 85°-108° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]#[N:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:22]=1)[C:17](Cl)=[O:18].O>C(#N)C>[C:11]([CH2:10][NH:9][C:17](=[O:18])[C:16]1[CH:20]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:22]=[C:14]([Cl:13])[CH:15]=1)#[N:12]
Reactant: N#CCN
Reactant: CCCCOc1cc(C(=O)Cl)cc(Cl)n1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCOc1cc(C(=O)NCC#N)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
3.3 g (0.033 mol) of triethylamine was added to a solution of 1.9 g (0.02 mol) of aminoacetonitrile hydrochloride in 30 ml of acetonitrile. The mixture was stirred at room temperature for 30 min. 2.5 g (0.01 mol) of 2-chloro-6-n-butoxyisonicotinoyl chloride was added dropwise thereto under cooling at 5° to 10° C. The mixture was stirred at room temperature for 1 h, poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous common salt solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the crude product was purified according to silica gel column chromatography to obtain 1.9 g (yield: 70.9%) of white crystals having a melting point of 72° to 73° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5](Cl)=[O:6])[CH3:3].[C:8]([O:12][C:13](=[O:27])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1)([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.O>C(Cl)Cl>[C:8]([O:12][C:13](=[O:27])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:5](=[O:6])[CH2:4][N:2]([CH3:3])[CH3:1])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: CN(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN(C)CC(=O)N1CCC(c2ccc(NC(=O)OC(C)(C)C)cc2)CC1
Reaction time: 6 h

Procedure:
Dimethylamino-acetyl chloride (0.14 g, 0.86 mmol) and (4-piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol) were combined in CH2Cl2 (5 mL) and triethylamine (0.21 g, 2.2 mmol) was added. After 6 h, water (5 mL) was added. The reaction mixture was extracted with CH2Cl2 (3×5 mL) and the combined organic extracts were dried (MgSO4) and concentrated. The compound was found to be unstable on silica and therefore carried on without further purification. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.04 (s, 1H), 7.52 (d, 2H, J=8.5 Hz), 7.16 (d, 2H, J=8.5 Hz), 3.06 (s 2H), 2.76-2.82(m, 2H), 2.59-2.65 (m, 1H), 2.37 (s, 6H), 1.78-1.81 (m, 2H), 1.54-1.64 (m, 2H), 1.48 (s, 9H), 1.30 (br s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[OH:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:2]=2[O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH:25]=[CH:24]3)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COc1ccc(-c2cncc(C#N)c2Cl)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2cncc(C#N)c2Oc2ccc3[nH]ccc3c2)cc1OC
Temperature: 80 °C
Yield: 74 %

Procedure:
A mixture of 4-chloro-5-(3,4-dimethoxyphenyl)nicotinonitrile (120 mg, 0.44 mmol), 5-hydroxyindole (71 mg, 0.53 mmol) and K2CO3 (91 mg, 0.66 mmol) in CH3CN (4.0 mL) was heated at 80° C. for 4 h. After cooling to r.t., the reaction mixture was diluted with water (20 mL) and the precipitate was collected by filtration and washed with ether containing MeOH to give 121 mg (74%) of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-yloxy)nicotinonitrile 220 as a tan solid. MS: 372.2; melting range: 192-194° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17]([OH:19])=O)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(N(CC)CC)C.C([Cl:36])(=O)OCC.[NH2:37][CH2:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C1COCC1>[ClH:36].[ClH:36].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17]([NH:37][CH2:38][CH2:39][CH2:40][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:19])[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2cc(Oc3ccccc3C(=O)O)ccn2)n1
Reactant: NCCCN1CCOCC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Oc3ccccc3C(=O)NCCCN3CCOCC3)ccn2)n1
Product: Cl
Yield: 149.2 %

Procedure:
Using the method of Example 32, 2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid (0.1 g, 0.3055 mmol), triethylamine (0.2129 mL, 1.527 mmol), ethyl carbonochloridate (0.03213 mL, 0.3360 mmol), 4-(3-aminopropyl)morpholine (0.1339 mL, 0.9164 mmol) in THF (2 mL) were reacted to provide 2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)-N-(3-morpholinopropyl)benzamide dihydrochloride (0.132 g, 81.26% yield) as an off white solid. 1H NMR (DMSO) δ 8.44 (t, 1H), 8.18 (d, 1H), 7.68 (dd, 1H), 7.59 (dt, 1H), 7.40 (dt, 1H), 7.26 (d, 1H), 6.57 (s, 1H), 6.54 (d, 1H), 6.50 (dd, 1H), 3.89 (m, 2H), 3.29 (m, 2H), 3.20 (quart; 2H), 2.96 (m, 4H), 2.49 (m, 2H, under DMSO) 2.22 (d, 3H), 1.77 (m, 2H); Mass spectrum (esi) m/z=454(100) (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].CN(C)[CH:40]=[O:41]>>[CH2:19]([O:20][C:40](=[O:41])[C:2]([O:32][C:30]1[CH:29]=[CH:28][C:19]2[O:20][CH2:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:35])[C:9]([CH3:33])([CH3:34])[CH2:10]3)[C:18]=2[CH:31]=1)([CH3:7])[CH3:3])[CH3:18]
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a cooled (0° C.) solution of 5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (250 mg, 0.51 mmol) in dimethylformamide (7 mL) was added sodium hydride (60% dispersion in oil, 31 mg, 0.76 mmol). The resulting mixture was stirred at 0° C. for 10 min. Ethyl 2-bromo-2-methyl propionate (149 mg, 0.76 mmol) was added. Stirring at 0° C. was continued 10 min before the mixture was warmed to rt and stirred 4 h. The reaction was then partitioned between ethyl acetate and water; the aqueous phase was back-extracted with additional ethyl acetate. The combined organic phases were washed thrice with water, brine and dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride—95:5 methylene chloride:methanol gradient) to afford the titled compound (233 mg, 76%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[Cl:9].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:46][OH:47].CN(C)[CH:50]=[O:51]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[C:46]([O:51][CH3:50])=[O:47]
Reactant: CN(C)C=O
Reactant: Cc1ccc(Br)c(Cl)c1
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)cc1Cl
Temperature: 80 °C
Yield: 28 %

Procedure:
To 4-bromo-3-chlorotoluene (4.97 g, 24.2 mmol) in dimethylformamide (25 mL) is added palladium acetate (0.54 g, 2.42 mmol), 1,3-bis(diphenylphosphino)propane (0.998 g, 2.42 mmol), triethylamine (12.5 mL) and methanol (12.5 mL). The reaction vessel is evacuated and purged three times with carbon monoxide gas. A balloon filled with carbon monoxide gas is used to maintain the carbon monoxide atmosphere. The reaction mixture is heated at 80° C. for 8 hr. The mixture is washed with water and extracted with hexanes (2×50 mL). The combined organic layers are dried over sodium sulfate, filtered, concentrated, and chromatographed with 0-3% ethyl acetate in hexanes. 1.24 g (28%) of methyl 2-chloro-4-methylbenzoate is isolated as a colorless oil.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=1N)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]>CN(C)C=O.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:24]=[CH:25][C:26]([F:30])=[C:27]([F:29])[CH:28]=1)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc2c(Oc3cc(F)c(F)cc3N)cccc2[nH]1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc2c(Oc3ccc(F)c(F)c3)cccc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl nitrite (0.575 ml, 4.85 mmol) is dissolved in 5 ml of dimethylformamide and heated to 65° C. A solution of 151 (1.6 g, 4.85 mmol) in 5 ml of dimethylformamide is added dropwise and the mixture is stirred of additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (1.78 g of a brown oil) is further purified by flash-chromatography (hexane/ethyl acetate 9:1).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:33])[CH2:23][NH:24][C:25]([CH2:27][C@H:28]4[CH2:30][C:29]4([CH3:32])[CH3:31])=[O:26])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)C.[H][H].[C].[Pd]>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:33])[CH2:23][NH:24][C:25]([CH2:27][C@H:28]4[CH2:30][C:29]4([CH3:31])[CH3:32])=[O:26])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CC1(C)C[C@@H]1CC(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)C[C@@H]1CC(=O)NCC(=O)N1CCC(=C2c3ccccc3CCc3ccccc32)CC1

Procedure:
72.8 mg of palladium carbon (10% w/v) was added to 72.8 mg (0.171 mmol) of (1R)-N-{2-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethyl}-2,2-dimethylcyclopropanecarboxyamide in 10 ml of ethanol, and they were stirred at 4.0 MPa in hydrogen gas atmosphere overnight. After the filtration, the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[S:13]([OH:16])(=[O:15])=[O:14])([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:21]O>CN(C=O)C>[CH3:21][O:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[S:13]([OH:16])(=[O:15])=[O:14])=[O:3]
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of 190.0 g (0.77 mol) of 2-carboxy-5-nitrobenzenesulfonic acid, 10 ml of DMF and 250 ml (3.43 mol) of thionyl chloride is heated at boiling for 3 h. After separating off the insoluble constituents by filtration, the filtrate is concentrated. 200 ml (4.94 mol) of methanol are added to the residue which results. When addition is complete the reaction mixture is cooled to 0° C. The solid which precipitates is filtered off and dried. 70.9 g (35.3% of theory) of colorless, crystalline 2-methoxycarbonyl-5-nitrobenzenesulfonic acid (m.p.: 92°-94° C.) are thus obtained. By distilling off the volatile components from the mother liquor, a second fraction (62.5 g, 31.1% of theory) is obtained.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C(Cl)Cl.[C:10]1([C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][NH:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(N(CC)CC)C>[C:10]1([C@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][N:17]2[C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
Ethyl chloroformate (5.61 g) was slowly added to a mixture of methylene chloride (100 ml), (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (10 g) and triethylamine (5.32 g) at 5-15° C. over a period of 30 min. Thereafter, the reaction mass was warmed to 25-30° C. and stirred at 25-30° C. for 1 h. The reaction solution was sequentially washed with water (50 ml), 3% w/w hydrochloric acid (50 ml), water (50 ml) and 5% w/w aqueous sodium chloride (50 ml) at 25-30° C. The solvent was removed under reduced pressure at 30-40° C. to produce (1S)-ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate (13.0 g) as a pale yellow oil. Chromatographic Purity (By HPLC): 99.22%.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:11]2[CH:12]=[C:13]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]3=[O:28])[CH:14]=[CH:15][C:10]=2[S:9][N:8]=1.[Br:29]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:11]2[CH:12]=[C:13]([N:16]3[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]3=[O:28])[CH:14]=[CH:15][C:10]=2[S:9][N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccsc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(-c4sccc4CBr)c3c2)c1=O
Yield: 68.2 %

Procedure:
To a mixture of 3-[3-[3-(methyl)-2-thienyl]-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)uracil(0.420 g, 0.993 mmol) and carbon tetrachloride is added N-bromosuccinimide (0.200 g, 1.12 mmol) and benzoyl peroxide (10.0 mg). The resultant mixture is stirred overnight at reflux, cooled and filtered. The filtrate is concentrated in vacuo and the residue partitioned between water and methylene chloride. The organic layer is washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with methylene chloride-diethyl ether to afford a pale yellow oil, which is crystallized in diethyl ether to afford the title compound as a cream-colored solid (0.340 g, 68.1%, mp 169° C.(dec)) which is identified by NMR spectral analysis.