Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-]=[N+]=[N-].[Na+].[N:13](CC)(CC)[CH2:14]C.Cl.Cl>O.CN1CCCC1=O>[C:14]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:1]=[O:8])#[N:13]
Reactant: CCN(CC)CC
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A compound having the above formula was prepared in the following manner. A solution of m-cyanobenzaldehyde was prepared by dissolving 2.0 gms. (15.2 mmoles) of the benzaldehyde along with 2.98 gms. (45.8 mmoles) of NaN3 and 2.9 gms. (21.1 mmoles) of Et3N.HCl, all of which were dissolved in 50 ml. of 1-methyl-2-pyrrolidinone. The reaction mixture was refluxed under argon. After 1 hour and 45 minutes the reaction mixture was cooled to room temperature and poured into 200 ml. of water and acidified with 10% hydrochloric acid. The reaction mixture was extracted with successive ethyl acetate washes. The ethyl acetate extracts were combined and washed with brine and dried over magnesium sulfate. The ethyl acetate extract was chromatographed through silica gel, yielding 0.3 gms. of the product having the above formula as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][C:6]=2[CH:7]=1.[CH3:18][O:19][C:20](=[O:32])[C@H:21]([N:29]=[C:30]=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1>[CH3:18][O:19][C:20](=[O:32])[C@H:21]([NH:29][C:30]([O:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][C:6]=2[CH:7]=1)=[O:31])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCc1cc2cc(-c3ccccc3)ccc2o1
Reactant: COC(=O)[C@@H](Cc1ccccc1)N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 50 °C
Yield: 63.7 %

Procedure:
A mixture of 2-hydroxmethyl-5-phenyl-benzofuran 17 (1.20 g, 5.85 mmole), (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5 (1.2 g, 5.9 mmole), triethylamine (1.7 ml), and THF (30 ml) was heated to 50° C. under a nitrogen atmosphere for 6 hrs. The solvent was removed under reduced pressure and the residue was purified by chromatography giving about 1.6 g of (R)-2-(phenyl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid methyl ester 18, mp. 85-86° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)=[O:21])[N:13]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:41])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:42]([O:46][C:47](=[O:55])[C:48](N1C=CN=C1)=[O:49])([CH3:45])([CH3:44])[CH3:43]>ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)=[O:21])[N:13]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH:41][C:48](=[O:49])[C:47]([O:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:55])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(=O)n1ccnc1
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CNC(=O)C(=O)c2c[nH]c3ccccc23)cc1
Solvent: ClCCl
Product: COc1ccc(CN2Cc3sc(NC(=O)C(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c3CC2CNC(=O)C(=O)c2c[nH]c3ccccc23)cc1
Reaction time: 24 h
Yield: 57.5 %

Procedure:
To a solution of 2-amino-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (143 mg, 0.25 mmol) in dichloromethane (5 ml) was added imidazol-1-yl-oxo-acetic acid tert-butyl ester (144 mg, 0.75 mmol) and the flask was purged with nitrogen. After 24 hours an additional portion of imidazol-1-yl-oxo-acetic acid tert-butyl ester (169 mg, 0.86 mmol) was added and the reaction mixture allowed stirred for an additional 24 hours. The mixture was then concentrated in vacuo. The residue was purified by flash chromatography using a mixture of ethyl acetate/hexanes (2:5) as eluent, which afforded 101 mg (58%) of 2-(tert-butyoxyoxalyl-amino)-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a oil.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=S)[NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:3].N.OO>CO>[CH3:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:11][C:12]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[N:1][C:2]2=[O:3]
Reactant: Cc1ccc(C(=O)NC(=S)Nc2ccc(C)cc2C(N)=O)cc1
Agent: N
Agent: OO
Solvent: CO
Product: Cc1ccc(C(=O)Nc2nc(=O)c3cc(C)ccc3[nH]2)cc1
Reaction time: 48 h
Yield: 10.7 %

Procedure:
To a stirred mixture of 5.2 g of the above benzamide, 100 ml of methanolic ammonia and 100 ml of methanol was added dropwise, in increments, 20 ml of 30% hydrogen peroxide. After stirring 48 hours, the solid was collected, partially dissolved in 400 ml of hot acetonitrile and filtered. The filtrate was chilled, giving 0.5 g of the desired product as white crystals, mp 242°-244° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([NH:23][NH2:24])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(OCc2ccc(OC)cc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(COc2ccc(C(=O)NN)cc2)cc1

Procedure:
A 250 mL round bottomed flask was charged with ethyl 4-(4-methoxybenzyloxy)benzoate (11.45 g, 60.18 mmol) and ethanol (110 mL). Hydrazine monohydrate was then added and the mixture was placed under reflux for 48 h. The reaction mixture was concentrated to dryness and chloroform (150 mL) was added. The mixture was decanted and the insoluble white residue was washed once more with chloroform to remove traces of starting material. The white solid (5.3 g, 32%) was dried in vacuo and 1H NMR analysis was consistent with the title compound. 1H NMR (DMSO d6, 400 MHz) δ 9.6 (br s, 1H), 7.77 (d, J=9 Hz, 2H), 7.36 (d, J=9 Hz, 2H), 7.03 (d, J=9 Hz, 1H), 6.94 (d, J=9 Hz, 1H), 5.05 (s, 2H), 3.74.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.N1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:22](=[O:23])[O:21][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(-c2ccncc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccncc2)cc1)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of 4-(4-pyridinyl)aniline (50 mg) in dichloromethane (1.50 mL) and pyridine (356.4 μL) was added dropwise benzyloxycarbonyl chloride (75.5 μL) at ambient temperature and the mixture was stirred at the same temperature for 1 hour. The resulting mixture was concentrated in vacuo and water (10 mL) was added to the residue. The aqueous solution was extracted with ethyl acetate (15 mL) and the organic layer was washed successively with saturated sodium bicarbonate aqueous solution and brine, then dried and concentrated. The residual solid was triturated with diisopropylether (2.0 mL) to give benzyl [4-(4-pyridinyl)phenyl]carbamate (70.3 mg) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7](O[C:10](=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].C([O-])(=O)C.C(N)=[NH2+:19]>CC(O)C>[Br:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:10][NH:19][C:7]2=[O:8]
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: NC=[NH2+]
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=c1[nH]cnc2ccc(Br)cc12
Temperature: 25 °C

Procedure:
A solution of 5-bromoisatoic anhydride (5.0 g, 21 mmol) and formamidinium acetate (2.2 g, 21 mmol) in 60 mL of i-PrOH was heated at reflux for 10 hours. The reaction mixture was cooled to rt and the white solid was collected by filtration. The white solid was washed with small amount of i-PrOH and dried in air to give desired product 6-bromoquinazolin-4(3H)-one. MS (ESI, pos. ion) m/z: 224.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C@H:26]([OH:28])[CH3:27])[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].N1C=CN=C1.[CH3:34][C:35]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])[CH3:36]>CN(C=O)C>[Si:38]([O:28][C@H:26]([CH3:27])[C@@H:11]([NH:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=1)[C:12]([NH:14][NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)=[O:13])([C:35]([CH3:37])([CH3:36])[CH3:34])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 98.3 %

Procedure:
To a pre-cooled (0° C.) solution of N′-((2R,3R)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoyl)-4-cyanobenzohydrazide (1.65 g, 4.15 mmol) in DMF (100 mL) was added imidazole (2.26 g, 33.4 mmol) then TBSCl (2.50 g, 16.60 mmol). The reaction was warmed slowly to room temperature, stirred for 19 h, cooled to 0° C. and quenched with H2O (300 mL). The solution was extracted with EtOAc (250 mL). The organic extract was washed with H2O (2×100 mL) and 5% aq. citric acid (3×80 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (10-30% EtOAc in hexanes) to provide the title compound as a colourless amorphous solid (2.09 g, 98%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.06 (dm, J=8.6 Hz, 2H), 7.92 (dm, J=8.6 Hz, 2H), 7.53 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.91 (dd, J=2.4, 8.8 Hz, 1H), 6.26 (d, J=7.6 Hz, 1H), 4.42 (pentet, J=5.5 Hz, 1H), 4.31 (dd, J=5.5, 7.8 Hz, 1H), 1.35 (d, J=6.3 Hz, 3H), 0.87 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[N:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCNc1c(N)cnc2cccnc12
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 3-[(3-nitro[1,5]naphthyridin-4-yl)amino]propylcarbamate (20.0 g, 57.6 mmol), 5% platinum on carbon, and ethyl acetate was hydrogenated on a Parr apparatus for 2 hours at 30 psi (2.1×105 Pa). The mixture was filtered through CELITE filter agent, which was rinsed afterwards with ethyl acetate (150 mL). The filtrate was concentrated to afford tert-butyl 3-[(3-amino[1,5]naphthyridin-4-yl)amino]propylcarbamate as a yellow foam, all of which was used in the next step.
Reaction SMILES: C[O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:27][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:14]3)[NH:12][C:11](=[O:28])[C:10]=2[CH:29]=1.[OH-].[Na+]>O.O1CCOCC1>[C:21]1([CH2:20][CH2:19][N:15]2[CH2:16][CH2:17][CH2:18][C:13]3([NH:12][C:11](=[O:28])[C:10]4[CH:29]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:30])=[O:2])[CH:7]=[CH:8][C:9]=4[O:27]3)[CH2:14]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(CCc3ccccc3)C1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(CCc3ccccc3)C1)O2

Procedure:
A solution of (±)-(E)-3-{1′-(2-phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester (300 mg, 0.73 mmol) in water (2.5 ml) and dioxane (5 ml) was treated with 1 M NaOH (0.96 ml) as described in Example 30, Step A to give (±)-(E)-3-{1′-(2-phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid as a white said [LC-MS: (ES+) MH+: 393]. The acrylic acid was suspended in DCM (5 ml), treated with TEA (0.15 ml, 1.1 mmol) and then with EDC (208 mg, 1.09 mmol), HOBt (147 mg, 1.09 mmol) and NH2OTHP (102 mg, 0.871 mmol) following the procedure described in Example 30, Step B, giving (±)-(E)-3-{1-(2-phenyl-ethyl)-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (165 mg) as a light yellow solid.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[C:10]([CH3:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13].[CH3:19]O>C1C=CC=CC=1>[Br:8][C:9]1[C:10]([CH3:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([O:14][CH3:19])=[O:13]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Product: COC(=O)c1cccc(Br)c1C

Procedure:
Trimethylsilyldiazomethane solution (2M in Hexane) (60.5 mL, 121 mmol) was added dropwise to a stirred solution of 3-bromo-2-methylbenzoic acid (26 g, 121 mmol) in benzene containing 20% of methanol (total: 300 mL) at rt until solution retained a yellow color. The mixture was concentrated to remove the organic solvent. The remaining oil was poured over a silica gel plug in a 60-mL filter frit funnel and eluting with 500 mL of hexane containing 10% ethyl acetate. The filtrate was then concentrated to dryness to afford the title compound as a bright yellow oil.
Reaction SMILES: [C:1]([C:4]1[N:13]=[C:12]2[C:7]([C:8]([C:14]3[CH:15]=[CH:16][C:17]([F:28])=[C:18]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:19]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:29][Mg]Br.[NH4+].[Cl-]>C1COCC1>[F:28][C:17]1[CH:16]=[CH:15][C:14]([C:8]2[C:7]3[C:12](=[N:13][C:4]([C:1]([OH:3])([CH3:29])[CH3:2])=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)=[CH:19][C:18]=1[C:20]1[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)c1ccc2c(-c3ccc(F)c(-c4ccccc4C#N)c3)ccnc2n1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(-c3ccc(F)c(-c4ccccc4C#N)c3)ccnc2n1
Temperature: -78 °C
Reaction time: 1.42 h
Yield: 69.1 %

Procedure:
To a stirred solution of 5′-[7-acetyl-[1,8]naphthyridin-4-yl]-2′-fluorobiphenyl-2-carbonitrile (from Example 58) (28.6 mg, 0.0778 mmol) in anhydrous THF (2 mL), cooled under nitrogen to −78° C., was added dropwise methylmagnesium bromide (3.0 M solution in Et2O, 26.0 μL, 0.078 mmol). The mixture was stirred at −78° C. for a total of 85 min, adding more methylmagnesium bromide (3.0 M solution in Et2O, 26.0 μL, 0.078 mmol) after 45 min and 70 min. Saturated aqueous NH4Cl (2 mL) was then added and the mixture was allowed to warm to room temperature. The mixture was partitioned between ethyl acetate (15 mL) and water (10 mL). The aqueous layer was extracted further with ethyl acetate (15 mL), and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 3% MeOH/CH2Cl2, to afford 20.6 mg (69%) of the title compound as a white solid. δH (360 MHz, CDCl3) 1.67 (6H, s), 5.32 (1H, s), 7.44 (1H, t, J 9.1), 7.51 (1H, d, J 4.6), 7.54 (1H, td, J 7.7, 1.1), 7.58-7.65 (4H, m), 7.71 (1H, td, J 7.7, 1.1), 7.84 (1H, dd, J 7.7, 1.1), 8.51 (1H, d, J 8.8), 9.15 (1H, d, J 4.2). m/z (ES+) 384 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11].[OH-].[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([NH:13][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CC(C)N
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)Nc1cc(Cl)nc(N)n1

Procedure:
600 g of 2-amino-4,6-dichloro-pyrimidine (3.66 mols) are added to 3000 cc of alcohol, 395 g of isopropylamine (8.05 mols) are added, and the mixture is slowly heated to 80° during the course of 2 hours while stirring. After the material is dissolved, the solution is heated under reflux for 3 hours. The alcohol is then distilled off and the residue dissolved in dilute sulphuric acid. The solution must give a clearly acid reaction. The solution is shaken out several times with chloroform. A layer of 3000 cc of chloroform is subsequently placed under the aqueous solution and the solution is made alkaline with a caustic soda solution (pH 11), whereby the temperature should not exceed 35°. After shaking out the chloroform phase is separated and the aqueous phase is again shaken out with chloroform. The combined chloroform solution is dried with Glauber's salt after washing with water and the chloroform is evaporated. After standing for a short time, the oily residue crystallizes. The product may be recrystallized as described in Example 1 for purposes of purification.
Reaction SMILES: [Cl:1][C@@H:2]([CH3:16])[CH2:3][C@H:4]([CH3:15])[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2O)=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:11][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][C:6]([O:5][C@@H:4]([CH3:15])[CH2:3][C@@H:2]([Cl:1])[CH3:16])=[CH:7][CH:8]=3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(C(=O)O)cc1
Reactant: CCCCOc1ccc(-c2ccccc2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCOc1ccc(-c2ccc(OC(=O)c3ccc(O[C@@H](C)C[C@H](C)Cl)cc3)cc2)cc1
Yield: 49.5 %

Procedure:
0.21 g of (S, S)-4-(3'-chloro-1'-methylbutoxy)benzoic acid, 0.21 g of 4-n-butoxyphenyl phenol, 0.19 g of dicyclohexylcarbodiimide, 0.03 g of 4-pyrrolidinopyridene and 6 ml of methylene chloride were stirred together at room temperature for five hours. The dicyclohexyl urea thus precipitated was filtered and the filtrate was desolvated. The crude product thus obtained was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (9:1) as a developing solvent to thereby give 0.2 g of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>C1COCC1.CCCCCC>[CH2:11]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: c1ccsc1
Reactant: CCCCCCBr
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCc1cccs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a cooled (−70° C.) mixture of thiophene (17.6 g, 0.21 mol) in anhydrous THF (100 mL) was added dropwise a solution of n-BuLi (137.5 ml, 1.6 M, 0.22 mol) in hexane. After stirring for 1 hour at 0° C., the mixture was cooled to −40° C. followed by addition of 1-hexylbromide (0.22 mol). The mixture was slowly heated to r.t. Water (250 mL) was added and the mixture was extracted with diethylether (3×150 mL). The combined organic fractions were dried over MgSO4 and concentrated in vacuo. The product was purified by means of vacuum distillation. This product was prepared according to the general procedure and obtained as a colourless oil (26.5 g, 75%).
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH2:8][CH2:7]2.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[C:18](I)[CH:17]=1)([OH:15])=[O:14]>[Cu]>[C:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[C:18]([S:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[CH2:9][CH2:8][CH2:7]3)[CH:17]=1)([OH:15])=[O:14]
Reactant: Sc1ccc2c(c1)CCC2
Reactant: O=C(O)Cc1ccc(C(=O)O)cc1I
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(C(=O)O)cc1Sc1ccc2c(c1)CCC2
Temperature: 0 °C

Procedure:
To 50% aqueous potassium hydroxide solution (500 g) under argon was added 5-mercaptoindan (30.0 g, 0.2 mole) and copper powder (16.3 g). Then 4-carboxy-2-iodophenylacetic acid (38.25 g, 0.125 mole) was added with mechanical stirring and the reaction mixture was stirred under reflux (oil-bath 140°-145° C.) for 3 hours. The mixture was diluted with ice-water (800 ml), filtered, and the filtrate was treated with charcoal and refiltered. Acidification of the alkaline solution precipitated a solid which was collected, washed well with water and drained thoroughly on the filter. The solid was stirred with hexane (200 ml) to remove mercaptoindane and was refiltered to yield 33.55 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
A stirred solution of 10.0 grams (0.037 mole) of 2,6-dichloro-4-phenylmethoxyphenol (known compound) and 4.7 grams (0.041 mole) of 1-bromo-4-chlorobutane in 225 mL of DMF was cooled in an ice bath, and 7.7 grams (0.060 mole) of potassium carbonate was added. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. The reaction mixture was then poured into 1000 mL of an aqueous solution saturated with sodium chloride. The mixture was extracted with four 150 mL portions of diethyl ether, and the combined extracts were washed with 50 mL of water. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:3 methylene chloride:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 10.7 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[CH3:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:21]=2[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][C:24]([O:27][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]5[CH2:16][CH2:15]5)=[O:13])[N:10]=4)[N:7]=3)=[CH:23][C:21]=2[N:22]=1
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2s1
Yield: 69.7 %

Procedure:
Using N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (355 mg, 1.08 mmol), 2-methyl-1,3-benzothiazole-5-ol (286 mg, 1.73 mmol), potassium carbonate (448 mg, 3.24 mmol) and N,N-dimethylformamide (4.0 mL) as starting materials and in the same manner as in Example 95, the title compound (275 mg, 70%) was obtained as a pale-yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]([S:32]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[CH3:21])[CH2:18][CH2:19]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NC)CC1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(Cl)cc2)CC1

Procedure:
from trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-methylcyclohexylamine and 4-chlorobenzenesulphonic acid chloride. Melting point: 105°-106° C.