Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH:6]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20](=[O:32])[CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[CH2:28][CH2:27][CH2:26][NH:25][C:24]=4[N:23]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9])C.[OH-].[Na+]>C1COCC1.O>[N:23]1[C:24]2[NH:25][CH2:26][CH2:27][CH2:28][C:29]=2[CH:30]=[CH:31][C:22]=1[CH2:21][C:20]([NH:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:33])=[O:3])[CH:11]=[CH:12]2)=[O:32]
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(NC(=O)Cc3ccc4c(n3)NCCC4)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(CC(=O)O)n1ccc2cc(NC(=O)Cc3ccc4c(n3)NCCC4)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 75.3 %

Procedure:
To a solution of 3-[5-(2-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-acetylamino)-indol-1-yl]-hexanoic acid ethyl ester (50 mg, 0.12 mmol) in THF (1.0 mL) was added a solution of NaOH (18 mg, 0.45 mmol) in H2O (0.15 mL), and stirred at ambient temperature for 14 h. Solvents were evaporated. To the resulting residue was added 1N HCl until the solution reached a pH of 5. The mixture was extracted with EtOAc/DCM (9:1) several times until the aqueous layer was free from product by TLC. The extracts were combined, dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with MeOH/DCM (2.5, 5, and 7.5%) to afford the title compound (38 mg, 81% yield) as a pale brown solid. 1H NMR (CDCl3) δ 7.79 (d, 1H, J=1.9 Hz), 7.57 (d, 1H, J=7.3 Hz), 7.45 (d, 1H, J=8.9 Hz,), 7.34 (d, 1H, J=3.2 Hz), 7.23 (dd, 1H, J=2.0, 8.8 Hz), 6.69 (d, 1H, J=7.3 Hz), 6.46 (d, 1H, J=3.2 Hz), 3.83 (s, 0.9 H), 3.81 (s, 0.5H), 3.49 (t, 2H, J=5.6 Hz), 2.89 (d, 2H, J=7.2 Hz), 2.83 (t, 2H, J=6.1 Hz), 2.67–1.86 (m, 4H), 1.19–0.99 (m, 2H), 0.86 (t, 3H, J=7.3 Hz). Mass spectrum (LCMS, ESI) calculated for C24H29N4O3 421.2 (M+H); found 421.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]2[C@H:16]([NH2:17])[CH2:15][CH:14]=[CH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:18]1([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:26](Cl)=[O:27])[CH2:20][CH2:19]1>ClCCl>[CH:18]1([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:26]([NH:17][C@H:16]2[C@@H:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:12][CH:13]=[CH:14][CH2:15]2)=[O:27])[CH2:19][CH2:20]1
Reactant: COc1ccc([C@H]2CC=CC[C@H]2N)cc1OC
Reactant: O=C(Cl)c1ccc(OCC2CC2)c(OCC2CC2)c1
Solvent: ClCCl
Product: COc1ccc([C@H]2CC=CC[C@H]2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Yield: 93.5 %

Procedure:
20 g of (±)-cis-6-(3,4-dimethoxyphenyl)-cyclohex-3-enylamine (compound G1) are dissolved in 125 ml of dichloromethane and treated with a solution of 24.1 g of 3,4-bis-cyclopropylmethoxybenzoyl chloride in 125 ml of dichloromethane at room temperature. After 1 h the reaction mixture is extracted with 2 N hydrochloric acid and water, the organic phase is dried using sodium sulfate and concentrated. 38.3 g of the title compound of m.p. 152-153.5° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH:18]1([C:23](O)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)C1CCCC1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)C4CCCC4)cc3c2C1
Yield: 57.6 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 11.6 mg (0.101 mMol) cyclopentanecarboxylic acid, 7.5 mg (53%) of the title compound were recovered as a light beige solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[CH:10]2.[C:17](=O)(O)[O-:18].[Na+]>CN(C=O)C>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[CH:17]=[O:18]
Reactant: O=C([O-])O
Reactant: Cn1ccc2cc(Cl)ccc21
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1cc(C=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
While stirring DMF (70 ml) at 0° C., phosphoryl chloride (4.97 ml, 53.3 mmol) was added dropwise in portions. After completion of the dropwise addition, the reaction mixture was stirred further for 10 minutes at the same temperature. A solution of 5-chloro-1-methylindole (5.89 g, 35.6 mmol) in DMF (10 ml) was added. The resulting mixture was stirred for cyclohexanecarboxylic time at 60° C. for 6 hours. The reaction mixture was cooled to room temperature, and added to a saturated aqueous solution of sodium bicarbonate in portions, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent under reduced pressure. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate eluate fractions, 5-chloro-1-methylindole-3-carbaldehyde (5.51 g, 80%) was obtained as a colorless solid.
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5]Cl.[I-].[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][N:30]1[CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)[CH2:32][CH2:31]1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(=O)CCCN3CCN(c4cccc(Cl)c4)CC3)ccc2N1
Reaction time: 2 h

Procedure:
5.0 Grams of 6-(1-oxo-4-chlorobutyl)-3,4-dihydrocarbostyril and 7.5 g of sodium iodide were dispersed in 120 ml of anhydrous dimethylformamide and the mixture was stirred at 50°-60° C. for 2 hours. To this reaction mixture were added 10 g of 4-(3-chlorophenyl)piperazine and 5 ml of triethylamine and was stirred at 50°-60° C. for 6 hours, then stirred at a room temperature for 24 hours. The reaction mixture was concentrated under a reduced pressure to obtain a residue. To the residue thus obtained was added 80 ml of 5%-sodium hydrogencarbonate solution and the organic layer was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was crystallized with ether to obtain crude crystals and the crude crystals were recrystallized from ethanol to obtain 6.5 g of 6-{1-oxo-4-[4-(3-chlorophenyl)-1-piperazinyl]butyl}-3,4-dihydrocarbostyril in colorless needle-like crystals.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:12][B-:13]([F:16])([F:15])[F:14].[CH3:17][O+](C)C>C(Cl)Cl>[F:12][B-:13]([F:16])([F:15])[F:14].[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N+:3]=1[CH3:17]
Reactant: Brc1nccc2ccccc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[n+]1ccc2ccccc2c1Br

Procedure:
The starting material was prepared by reaction of 1-bromoisoquinoline with trimethyloxonium tetrafluoroborate in CH2Cl2 to give 1-bromo-2-methylisoquinolinium tetrafluoroborate, m.p. 162°.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5].[CH3:27][Mg]I.Cl>C1COCC1.CCOCC>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([N:9]2[CH:10]=[C:6]([C:4](=[O:5])[CH3:27])[N:7]=[C:8]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:16][CH:15]=1
Reactant: CON(C)C(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: C[Mg]I
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Yield: 97 %

Procedure:
A solution of 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid methoxy-methyl-amide I-7e (1.64 g, 3.99 mmol) in THF (16 ml) was cooled to 0° C., and methylmagnesium iodide (4.4 ml of a 3.0 M solution in Et2O, 9.9 mmol) was added dropwise via syringe. The resultant solution was stirred at 0° C. for 1 h, and then the reaction mixture was poured into cold 1N HCl (100 ml). The mixture was extracted with ethyl acetate (2 85-ml portions), and the combined extracts were washed with saturated aqueous sodium chloride (100 ml). The organics were dried over anhydrous magnesium sulfate and were concentrated to afford 1-[1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazol-4-yl]-ethanone I-7f (1.41 g, 97%) that was used in the next reaction without any further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C1(C=CC(O)=CC=1)O>CC(O)C>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:10][CH2:9][C:7]2[CH:6]=[CH:5][C:4]([N+:11]([O-:13])=[O:12])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: C=Cc1ccc([N+](=O)[O-])c(OC)c1
Agent: Oc1ccc(O)cc1
Solvent: CC(C)O
Product: COc1cc(CCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 69.4 %

Procedure:
To 5-ethenyl-2-nitrophenyl methyl ether (0.55 g, 3.1 mmol) in 10 mL of iPrOH was added, 1-methylpiperazine (0.614 g, 6.13 mmol), and catalytic hydroquinone (0.033 g, 0.31 mmol). The mixture was heated to 90° C. for 18 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step C (0.6 g, 2.15 mmol, 70%). 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (d, J=8.24 Hz, 1H), 6.93 (s, 1H), 6.84 (dd, J=8.33, 1.19 Hz, 1H), 3.93 (s, 3H), 2.79-2.89 (m, 2H), 2.40-2.69 (m, 10H), 2.29 (s, 3H).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][C@H:9]([C:35]([O:37][CH3:38])=[O:36])[CH2:10][O:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]([NH:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)=[O:26])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)C=CC=CC=1.[ClH:51]>O1CCOCC1>[ClH:51].[N:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][NH:27][C:25]([NH:24][C:20]1[CH:19]=[C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C@@H:9]([C:35]([O:37][CH3:38])=[O:36])[NH2:8])[CH:13]=2)[CH:23]=[CH:22][CH:21]=1)=[O:26]
Reactant: COC(=O)[C@H](COc1cccc(-c2cccc(NC(=O)NCc3ccccn3)c2)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)COc1cccc(-c2cccc(NC(=O)NCc3ccccn3)c2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
The compound of Example 9 (1369,8 mg, 2.07 mmol, 1 equiv) was dissolved in dioxane (4 mL) and treated with a 1M solution of hydrochloric acid in dioxane (4.5 mL, 4.5 mmol, 2.2 equiv) at room temperature. The reaction mixture was stirred for 3.5 h at ambient temperature. The solvents were removed under reduced pressure and the crude product was titurated with diethylether. The white precipitate was filtered off and dried in vacuuo. Yield 615.4 mg, 65.2% of a white solid. 1H NMR (DMSO, 200 MHz) δ 9.69 (s, 1H-NH); 8.95 (s, 2H); 8.79 (d, 1H); 8.52-8.38 (m, 1H); 7.99-7.72 (m, 3H); 7.55-7.32 (m, 4H); 7.25-7.17 (m, 3H); 7.02 (d, 1H); 4.82-4.59 (m, 2H); 4.51-4.40 (m, 1H); 3.80 (s, 3H), 2.55 (s, 2H). MS (ESI) 443 (M+Na), 421 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH:10]([CH2:20]/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)C>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][CH:11]([CH3:19])[CH:10]([CH2:20]/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=Nc2ccccc2N(Cc2ccccc2)C(=O)C1C/C=C/c1ccccc1
Solvent: CCOCC
Product: CC1Nc2ccccc2N(Cc2ccccc2)C(=O)C1C/C=C/c1ccccc1
Yield: 77 %

Procedure:
Using 1-benzyl-4-methyl-3((E)-3-phenyl-2-propen-1-yl)-1,3-dihydro-1,5-benzodiazepin-2(2H)-one, the titled compound was synthesized by substantially the same procedure as in Working Example 24 in a yield of 77%, m.p. 119°-120° C. (diethyl ether).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[N:22](COCC[Si](C)(C)C)[C:21]4[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=4[N:19]=3)=[CH:13][CH:12]=2)[C:3]1=[O:35].[ClH:37]>CCO>[ClH:37].[ClH:37].[NH:19]1[C:20]2[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=2[N:22]=[C:18]1[O:17][C:14]1[CH:15]=[CH:16][C:11]([N:4]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:10]3[C:2]([CH3:1])([CH3:36])[C:3]2=[O:35])=[CH:12][CH:13]=1
Reactant: CC1(C)C(=O)N(c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Agent: Cl
Solvent: CCO
Product: CC1(C)C(=O)N(c2ccc(Oc3nc4ccccc4[nH]3)cc2)c2ncccc21
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A mixture of 3,3-dimethyl-1-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (258 mg) and 2N HCl in EtOH (5 mL) in EtOH (5 mL) was stirred at 60° C. for 10 h. After cooling to room temperature, the solvent was removed. The residue was recrystallized from EtOH-AcOEt to give 1-[4-(1H-benzimidazol-2-yloxy)phenyl]-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one dihydrochloride (152 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][CH3:24])=[C:6]([C:8]2[NH:9][C:10](=[O:21])[C:11]3[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=3[N:13]=2)[CH:7]=1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35])[CH2:27][CH2:26]1>>[CH2:23]([O:22][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:34]([CH2:33][CH2:32][CH2:31][N:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)(=[O:36])=[O:35])=[CH:7][C:6]=1[C:8]1[NH:9][C:10](=[O:21])[C:11]2[N:16]([CH3:17])[N:15]=[C:14]([CH2:18][CH2:19][CH3:20])[C:12]=2[N:13]=1)[CH3:24]
Reactant: O=S(=O)(Cl)CCCN1CCOCC1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(N)ccc3OCC)nc12
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(NS(=O)(=O)CCCN4CCOCC4)ccc3OCC)nc12

Procedure:
The title compound was prepared from 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and 3-morpholinopropylsulphonyl chloride, following the procedure of Example 41, and was obtained as brown crystals (14%), m.p. 157°-159° C. Found: C,55.42; H,6.53; N,16.01. C24H34N6O5S requires C,55.58; H,6.61; N,16.21%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH2:14][S:15][CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29].N1C=CC=CC=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]#[C:17][CH2:16][S:15][CH2:14][C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][S:37]([CH3:36])(=[O:39])=[O:38])(=[O:39])=[O:38]
Reactant: Oc1ccccc1CCCCC#CCSCC#CCCCCc1ccccc1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccccc1CCCCC#CCSCC#CCCCCc1ccccc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
To a solution of 82 (0.2 g, 0.9 mmol) in 2 mL of anhydrous CH2Cl2 at 0° C. was added anhydrous pyridine (71 mg, 0.9 mmol) and methylsulfonyl chloride (0.1 g, 0.9 mmol) under argon (FIG. 2N). The solution was stirred at room temperature for 6 h. The reaction was carefully quenched with water and extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with water, dried (MgSO4), and concentrated in vacuo. Chromatography on silica gel (EtOAc:hexanes, 5:95) gave the desired methylsulfonyloxy derivative 124 as a colorless oil (0.22 g, 84%). 1H NMR (CDCl3) δ7.51-7.53 (dd, 1 H, J=7.6 Hz and 2.6 Hz, ArH), 7.40-7.42 (dd, 1 H, J=7.9 Hz and 2.8 Hz, ArH), 7.26-7.30 (m, 2 H, ArH), 3.66 (t, 2 H, J=1.3 Hz CH2), 3.24 (s, 3 H, CH3), 2.11-2.13 (m, 2 H, CH2), 1.26-1.41 (m, 4 H, CH2), 0.84-0.87 (t, 3 H, J=7.1 Hz, CH3); 13C NMR (CDCl3) δ147.63, 130.77, 129.18, 127.82, 127.59, 123.20, 84.74, 74.54, 38.50, 30.52, 21.97, 21.77, 18.37, 13.53.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10])[NH2:5].[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]=[C:12]=[O:13])[CH:6]=[C:7]([Cl:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1c(Cl)cc(N)cc1Br
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(N=C=O)cc1Br
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of 3-bromo-5-chloro-4-methoxyaniline (13.0 g) in toluene (100 ml) was dropwise added to a toluene solution containing 20 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-bromo-5-chloro-4-methoxyphenyl isocyanate (14.4 g). The thus obtained crude substance was added to an isopropanol solution (50 ml) containing triethylamine (1 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of benzene and tetrahydrofuran as the eluent to give isopropyl N-(3-bromo-5-chloro-4-methoxyphenyl)carbamate (Compound No. 33) (16.4 g) in a yield of 92% (calculated from the starting 3-bromo-5-chloro-4-methoxyaniline). M.P., 112°-113.5° C.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.S1C2C(=[N:16]C=CC=2)C=C1CN>>[N:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:2][NH2:16]
Reactant: NCc1cc2ncccc2s1
Reactant: BrCc1nc2cccnc2s1
Product: NCc1nc2cccnc2s1

Procedure:
Intermediate S was prepared from 2-(bromomethyl)thiazolo[5,4-b]pyridine (S-4) following similar procedured for synthesizing intermediate C from C-5, as described above. MS (m/z): 166 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][C:12]3[N:11]=[C:10]([CH3:15])[NH:9][C:8](=[O:16])[C:7]=3[C:6]=2[CH:17]=1.BrN1C(=O)CCC1=O.N1C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[N:11]=[C:10]([CH3:15])[NH:9][C:8](=[O:16])[C:7]=3[C:6]=2[CH:17]=1
Reactant: Cc1nc2c(c(=O)[nH]1)-c1cc(Br)ccc1CC2
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1nc2ccc3ccc(Br)cc3c2c(=O)[nH]1

Procedure:
A mixture of 9-Bromo-5,6-dihydro-3-methylbenzo[f]quinazolin-1(2H)-one (1.0 g, 3.4 mmoles), N-bromosuccinimide (0.63 g, 3.5 mmoles) and pyridine (0.3 ml, 3.7 mmoles) in dry benzene (350 ml) was reacted in the same manner as for the corresponding 3-pivalamide (Example 2). After cooling, benzene and excess pyridine were removed under reduced pressure. The residue was triturated with methanol:water (1:1) and filtered to leave a crude product which was recrystallized from methanol to give 9-bromo-3-methylbenzo[f]quinazolin-1(2H)-one as an off-white solid. (0.47 g, 37%) 1H NMR(DMSO-d61 200MHz) δ: 2.57(s, 3H, CH3); 7.73(d, J=9.0 Hz, 1H, Ar); 7.86(dd, J=8.6, 2.0 Hz, 1H, Ar); 8.09(d, J=8.7 Hz, 1H, Ar); 8.41(d, J=8.8 Hz, 1H, Ar); 9.92(d, J=2.0 Hz, 1H, Ar).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C:7]=1[CH2:8][CH2:9][CH3:10].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:11]1([C:5]2[O:6][C:7]([CH2:8][CH2:9][CH3:10])=[C:3]([CH2:2][O:17][C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)[N:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCc1oc(-c2ccccc2)nc1CCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A mixture of 4-chloromethyl-2-phenyl-5-propyloxazole (2.26 g), 4-hydroxybenzaldehyde (1.33 g), anhydrous potassium carbonate (1.76 g) and N,N-dimethylformamide (50 mL) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water, and the precipitated solid was collected by filtration and dried with air to give crystals (2.75 g, 89%) of 4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzaldehyde. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 76-77° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:17](OC(OCC)OCC)C>>[CH3:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[N:1]=[CH:17][N:6]([C:7]1[NH:11][N:10]=[N:9][N:8]=1)[C:4]2=[O:5]
Reactant: Cc1ccc(N)c(C(=O)Nc2nnn[nH]2)c1
Reactant: CCOC(OCC)OCC
Product: Cc1ccc2ncn(-c3nnn[nH]3)c(=O)c2c1

Procedure:
2-Amino-5-methyl-N-(1H-tetrazol-5-yl)benzamide in an excess of triethoxymethane was refluxed for 60 hours to give 6-methyl-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 285°-286° C. after recrystallization from a mixture of dimethylsulfoxide and water.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]=[O:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
2-(4-Benzyloxy-phenyl)-ethanol (0.64 g, 2.80 mmol) obtained in Step B was dissolved in DCM (10 mL), and Dess-Martin periodinane (2.38 g, 5.60 mmol) was added thereto. The reactant was stirred at room temperature for 2 hours, diluted with DCM, and washed with Na2S2O3.5H2O aqueous solution. The remained organic solution was dried with MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (0.50 g, 79%).
Reaction SMILES: [N:1]1([C:5]2([C:15]#N)[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:17][C:18]1[CH:19]=C([Mg]Br)[CH:21]=[CH:22][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[F:17][C:18]1[CH:19]=[C:15]([C:5]2([N:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: N#CC1(N2CCC2)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1cccc(C2(N3CCC3)CCC3(CC2)OCCO3)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 8-azetidin-1-yl-1,4-dioxaspiro[4,5]decane-8-carbonitrile (13.9 g, 62.53 mmol) in anhydrous tetrahydrofuran (70 ml) was added dropwise under argon and with ice cooling to a 1M solution of 3-fluorophenyl magnesium bromide in tetrahydrofuran (250 ml, 250 mmol) and then the mixture was stirred for 24 h at room temperature. Then saturated ammonium chloride solution (150 ml) was added with ice cooling and the mixture was stirred vigorously for 20 min. The phases were then separated and the aqueous phase was extracted with diethyl ether (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated to small volume under vacuum. The crude product was obtained in this way in a yield of 18 g (99%) as a yellow oil.