Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C@H:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][OH:25]>>[OH:25][CH2:24][C@H:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N[C@@H](CO)c3ccccc3)cc2c1=O
Yield: 75 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (R)-2-amino-2-phenyl-ethanol according to the GPA affording 31.2 mg (75%) of a red powder. Rt=4.11 min.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[Na].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]2[C:24]3[CH:53]=[CH:52][N:51](S(C4C=CC(C)=CC=4)(=O)=O)[C:25]=3[N:26]=[C:27]([NH:29][C:30]3[CH:38]=[C:37]4[C:33]([CH2:34][CH2:35][N:36]4S(C4C=CC(C)=CC=4)(=O)=O)=[CH:32][C:31]=3[O:49][CH3:50])[N:28]=2)[C:14]=1[C:15]([NH2:17])=[O:16].O>C1COCC1>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]2[N:28]=[C:27]([NH:29][C:30]3[CH:38]=[C:37]4[C:33]([CH2:34][CH2:35][NH:36]4)=[CH:32][C:31]=3[O:49][CH3:50])[NH:26][C:25]3=[N:51][CH:52]=[CH:53][C:24]=23)[C:14]=1[C:15]([NH2:17])=[O:16]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(S(=O)(=O)c1ccc(C)cc1)CC2
Agent: [Na]
Solvent: c1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)NCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.8 %

Procedure:
To a degassed solution of naphthalene (14 g, 109 mmol) in THF (300 mL) were added sodium cubes (2.6 g, 108 mmol). The cubes were crushed, and then stirred for 4 h. A total of 60 mL of the resulting deep green solution was added dropwise to a −78° C. solution of 2-fluoro-6-({2-({5-(methyloxy)-1-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-indol-6-yl}amino)-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (3.7 g, 4.99 mmol) in THF (100 mL). Water (5 mL) was then added, the resulting mixture was allowed to warm to rt, and filtered. The filtrate was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to obtain 2-fluoro-6-[(2-{[5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide as a yellow solid (710 mg, 33%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.88 (t, J=8.33 Hz, 2H), 3.39 (t, J=8.15 Hz, 2H), 3.76 (s, 3H), 5.07 (br s, 1H), 6.24 (s, 1H), 6.83 (s, 1H), 6.89-7.02 (m, 2H), 7.40 (s, 1H), 7.50 (q, J=7.69 Hz, 1H), 7.64 (s, 1H), 8.03 (s, 1H), 8.10 (s, 1H), 8.47 (d, J=8.42 Hz, 1H), 10.46 (s, 1H), 11.39 (s, 1H); ESIMS (M+H)+=434.17.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][CH2:16][CH2:17]Br)[CH:11]=2)[CH:6]=1.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C(O)C>[CH2:19]([N:21]([CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][CH2:16][CH2:17][N:21]([CH2:22][CH3:23])[CH2:19][CH3:20])[CH:11]=2)[CH:6]=1)[CH3:20]
Reactant: CCNCC
Reactant: BrCCCc1ccc2cc(CCCBr)ccc2c1
Solvent: CCO
Product: CCN(CC)CCCc1ccc2cc(CCCN(CC)CC)ccc2c1

Procedure:
To a solution of 132 mg of 2,6-bis(3-bromopropyl)naphthalene in 1 ml of absolute ethanol was added dropwise 368 μl of diethylamine at a room temperature with stirring, and the mixture was refluxed for 2.5 hours and then cooled. The reaction mixture was evaporated under a reduced pressure, and after adding 20 ml of water, extracted with 50 ml of benzene. The extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, filtered, and evaporated under a reduced pressure to obtain 78 mg of the title compound as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=3)[N:10]([N:19]=O)[CH2:9]2)=[CH:4][CH:3]=1.[Cl-].[NH4+].O.[CH3:24][C:25]([CH3:27])=O>[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=3)[N:10]([N:19]=[C:25]([CH3:27])[CH3:24])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Cc1ccc2c(c1)CC(c1ccc(F)cc1)CN2N=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: CC(C)=NN1CC(c2ccc(F)cc2)Cc2cc(C)ccc21
Temperature: 15 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-6-methyl-1-nitroso-1,2,3,4-tetrahydroquinoline (0.28 g, 0.00103 mol) in acetone (15 mL) was added saturated ammonium chloride solution (0.6 mL), and water (0.6 mL) at RT. The resulting brown colored reaction mixture was cooled to 15° C. Zinc dust (0.269 g, 0.00414 mol) was added portionwise at the same temperature, and after the addition, the reaction mixture was stirred for 1 h at RT. The reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to obtain product as a brown colored oil (0.27 g, 92.7% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:27]=[C:26]3[C:18]([N:19]4[C:24](=[CH:25]3)[C:23](=[O:28])[NH:22][CH2:21][CH2:20]4)=[N:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:27]=[C:26]3[C:18]([N:19]4[C:24](=[CH:25]3)[C:23](=[O:28])[NH:22][CH2:21][CH2:20]4)=[N:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cnc3c(c2)cc2n3CCNC2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCn2c1cc1cc(OC3CCNCC3)cnc12
Yield: 41.8 %

Procedure:
The solution of 0.45 g (1.17 mmol) 4-(1-oxo-1,2,3,4-tetrahydro-2,4a,5-triaza-fluoren-7-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in 10 mL dichloromethane was cooled to 0° C., 5 mL (7.4 g, 65.3 mmol) trifluoroacetic acid were added and the cooling bath was removed. After 1 h the volatile components were removed at a rotary evaporator, the residue was dissolved in dichloromethane and was washed with 1M aqueous sodium hydroxide solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 140 mg (42%) of the desired product as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1.C(N(CC)CC)C.[S:25](Cl)([CH3:28])(=[O:27])=[O:26]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1)[S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CNc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(c1ccc([N+](=O)[O-])c(N2CCCCC2)c1)S(C)(=O)=O
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of N-methyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine (128 mg, 0.54 mmol, as prepared in the previous step) and triethylamine (301 μL, 2.16 mmol) in 4 mL of CH2Cl2 was added mesyl chloride (125 μL, 1.62 mmol) via microsyringe and the reaction was allowed to stir overnight. At this time it was diluted with CHCl3 (50 mL), washed with satd aq NaHCO3 (2×50 mL), and dried (Na2SO4). Concentration of the solvent in vacuo and purification of the crude material using preparative TLC (4% MeOH—CHCl3) afforded 154 mg (91%) of the title compound as an oil. Mass spectrum (ESI, m/z): Calcd. for C13H19N3O4S, 314.1 (M+H), found 314.1.
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:16][CH:15]([NH:31][C:32]([N:34]3[CH:38]=[CH:37]N=C3)=[O:33])[C:14]1=[O:39])=[O:11])[CH2:2]2.N[C:41]1[CH:42]=[C:43]([CH:46]=CC=1)[CH2:44][OH:45].C(OCC)(=O)C.O>CN(C)C=O>[CH:5]12[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:10]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:16][CH:15]([NH:31][C:32]([NH:34][C:38]3[CH:37]=[CH:41][CH:42]=[C:43]([CH2:44][OH:45])[CH:46]=3)=[O:33])[C:14]1=[O:39])=[O:11])[CH2:4]2
Reactant: O=C(CN1C(=O)C(NC(=O)n2ccnc2)N=C(c2ccccc2F)c2ccccc21)N1CC2CCC(CC2)C1
Reactant: Nc1cccc(CO)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc(CO)c1)NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of [(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-3-(imidazol-1-yl)carbonylamino-5-(2-fluoro-phenyl)-1H-1,4-benzodiazepin-2-one (500 mg) and 3-aminobenzyl alcohol (128 mg) in dimethylformamide (5.0 ml) was stirred at 100° C. for 5 hours. Ethyl acetate and water were added to the reaction mixture at room temperature, and organic layer was separated, washed with water and brine, dried over magnesium sulfate, and isolated by column chlomatography on silica gel to afford N-[(3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'- (3-hydroxymethylphenyl)urea.
Reaction SMILES: C(Cl)(Cl)Cl.[CH:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][C:18](=[O:20])[C:17]([C:21](=O)[CH2:22][CH3:23])=[C:16]([OH:25])[CH2:15]2)=[CH:10][CH:9]=1)=[O:6].[CH2:26]([O:28][NH2:29])[CH3:27]>C(O)C>[CH2:26]([O:28][N:29]=[C:21]([C:17]1[C:18](=[O:20])[CH2:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][CH:5]=[O:6])=[CH:9][CH:10]=2)[CH2:15][C:16]=1[OH:25])[CH2:22][CH3:23])[CH3:27]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NC=O)cc2)CC1=O
Reactant: CCON
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCON=C(CC)C1=C(O)CC(c2ccc(NC=O)cc2)CC1=O
Reaction time: 3 h
Yield: 66.9 %

Procedure:
Into 25 ml of chloroform was dissolved 1.3 g of 5-(4-formamidophenyl)-3-hydroxy-2-propionyl-2-cyclohexen-1-one and to the solution was added 1.0 g of ethoxyamine and 5 ml og ethanol. The mixture was kept for 3 hours in a water bath having 40° C. and the reacting solution was washed with a dilute hydrochoric acid solution and water. The solution was extracted with 15 ml of aqueous solution containing 5% of sodium hydroxide and to the alkaline solution was added a dilute hydrochloric acid solution and the crystal sedimented was extracted with chloroform. The solution was washed with water and to the solution was added anhydrous magnesium sulfate and a small amount of active carbon. And then, the mixture was agitated and filtered and the filtrate solution was concentrated. Ethyl ether was added in the residue and the crystal sedimented was collected with a filtering step and 1.0 g of desired compound was obtained. It was in the form of colorless crystals having a melting point of 111°-113.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([OH:15])=O)[CH2:8][CH2:7][CH2:6]2.[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[CH:20]=[N:19]1)[CH3:17]>>[CH2:16]([N:18]1[CH:22]=[C:21]([CH2:23][N:24]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:30]=2)[C:13]([CH:9]2[C:10]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:15])[CH:20]=[N:19]1)[CH3:17]
Reactant: COc1ccc2c(c1)CCCC2C(=O)O
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCCc3cc(OC)ccc32)c2ccc(C(C)C)cc2)cn1
Yield: 69.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using 6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.31 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.45 g) was obtained. melting point: 111-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]([C:27]([O:29][CH3:30])=[O:28])[C:15]2[NH:16][C:17]3[CH:18]=[C:19]([CH:25]=[O:26])[CH:20]=[CH:21][C:22]=3[C:23]=2[N:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:27]([O:29][CH3:30])=[O:28])[C:15]3[NH:16][C:17]4[CH:18]=[C:19]([CH:25]=[O:26])[CH:20]=[CH:21][C:22]=4[C:23]=3[N:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(C=O)ccc12
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: COC(=O)c1cc(-c2cccc(Cl)c2)nc2c1[nH]c1cc(C=O)ccc12
Temperature: 70 °C
Yield: 61.1 %

Procedure:
A mixture of 3-chlorophenylboronic acid (73.8 mg, 0.472 mmol), methyl 2-bromo-7-formyl-5H-pyrido[3,2-b]indole-4-carboxylate (131 mg, 0.393 mmol), powdered potassium phosphate tribasic (200 mg, 0.944 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (32.3 mg, 0.079 mmol), and Pd(OAc)2 (8.8 mg, 0.039 mmol) in a microwave vial was flushed with nitrogen. THF (2 mL) was added, the vial was capped and the reaction was heated in a 70° C. oil bath for 24 hr. The reaction was partitioned between EtOAc (10 mL) and water (10 mL). The precipitate was collected by filtration, washed with EtOAc and water and air dried to leave methyl 2-(3-chlorophenyl)-7-formyl-5H-pyrido[3,2-b]indole-4-carboxylate (88 mg, 0.24 mmol, 61% yield) as a yellow solid. MS (ESI) m/z 364.99 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.04 (1H, br. s.), 10.18 (1H, s), 8.47 (1H, d, J=8.06 Hz), 8.41 (1H, s), 8.28 (1H, s), 8.25 (1H, s), 8.17 (1 H, d, J=7.55 Hz), 7.83 (1H, d, J=8.06 Hz), 7.56 (1H, t, J=7.81 Hz), 7.47-7.53 (1H, m), 4.07 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35])=[CH:28][CH:27]=1>ClCCl.C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([S:34]([CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:35])=[O:36])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)CCc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice cold, stirred solution of 0.2 g of piperidin-4-ylmethyl-carbamic acid tert-butyl ester and 0.2 mL of N,N-diisopropylethylamine in 20 mL of dichloromethane was added 0.3 g of 2-(4-fluoro-phenyl)-ethanesulfonyl chloride. After stirring overnight the mixture was diluted with 50 mL of chloroform, washed with 50 mL of saturated sodium carbonate, dried over magnesium sulfate and concentrated to dryness under reduced pressure. Trituration with hexane gave a white solid:
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:25]=[CH:24][C:22](/[N:23]=[CH:1]/[C:3]2[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:5][CH:4]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1
Reactant: Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COc1ccc(/C=N/c2ccc(Cl)cc2)cc1

Procedure:
tert-Butyl (4-formylphenoxy)acetate (17.4 g, 73.4 mmol) was dissolved in dry toluene (120 mL) and 4-chloroaniline (9.37 g, 73.4 mmol) was added. The mixture was refluxed in a Dean-Stark apparatus for 20 hours, cooled and concentrated under reduced pressure. Hexane was added and a precipitate formed. This precipitate was filtered, washed twice with cold hexane and dried. This afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[NH:16]([C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17].C([O-])(O)=O.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C:18]3[N:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:17]=[C:10]([CH:11]([CH3:13])[CH3:12])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNc1ncccn1
Reactant: CC(C)C(=O)CC(=O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(-c2ccc(F)cc2)n(-c2ncccn2)n1
Temperature: 60 °C

Procedure:
To a solution of 1-(4-fluorophenyl)-4-methyl-1,3-pentanedione (preparation disclosed in Example 1, Step A) (155 g, 0.74 mol) in 1 l glacial acetic acid was added, under a N2 atmosphere at room temperature, 90 g (0.82 mol) of 2-hydrazinopyrimidine (prepared according to J. Chesterfield et al., J. Chem. Soc., 3478, 1955). This was heated to 60° C. for one hour, cooled to room temperature and poured into 4 l saturated NaHCO3 aqueous solution. The resulting mixture was extracted with EtOAc and the organic layer was separated and washed with water and brine. This solution was dried over MgSO4, filtered and concentrated in vacuo. The crude reaction mixture was flash chromatographed on a silica gel column, eluting with 10% EtOAc-toluene yielding 16.4 g of 2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]pyrimidine and 94 g of 5(3)-4-fluorophenyl)-3(5)-(1-methylethyl)-1H-pyrazole, mp 102°-103° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][S:13]([NH:16][CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].C[O-].[Na+]>CO>[CH3:1][C:2]1[C:3]2[NH:12][S:13](=[O:15])(=[O:14])[N:16]([CH:17]([CH3:19])[CH3:18])[C:5](=[O:6])[C:4]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1cccc(C)c1NS(=O)(=O)NC(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc2c1NS(=O)(=O)N(C(C)C)C2=O
Reaction time: 4 h

Procedure:
Methyl 3-methyl-2-((((1-methylethyl)amino)-sulfonyl)amino)benzoate (19.9 grams; 0.07 mole) and sodium methylate (7.5 grams; 0.14 mole) were mixed with 200 ml. of methanol and the resulting mixture heated at the reflux temperature thereof for a period of about 4 hours. The reaction mixture was then cooled and the methanol removed in vacuo. The resulting residue was dissolved in 200 ml. of water and the resulting solution extracted with 100 ml. of ether. The aqueous layer was then separated and acidified to a pH of about 2.0 with concentrated hydrochloric acid. The resulting precipitate formed upon acidification was recovered by filtration, dried and recrystallized from cyclohexane. As a result of these operations, the desired 8-methyl-3-(1-methylethyl)-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide compound was obtained as a crystalline solid having a melting point of 126.5°-127.5° C. and having carbon, hydrogen and nitrogen contents of 51.70, 5.63 and 11.15 percent, respectively, as compared with the theoretical contents of 51.93, 5.51 and 11.02 percent, respectively, calculated for the named structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[C:10]=1[N+:28]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[C:10]=1[NH2:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)c([N+](=O)[O-])c4CC[C@H]3[C@@H]1CCC2=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)c(N)c4CC[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a suspension of 3-benzyloxy4-nitroestra-1,3,5(10)-trien-17-one (84, 3.24 g, 8.0 mmol) in acetone (400 mL) were added 0.5 N aqueous NaOH (100 mL, 50 mmol) and sodium hydrosulfite (85%, 10 g) at 80° C.; the mixture was then stirred for 1 h. After the reaction mixture was cooled to room temperature, H2O (300 mL) was added; Acetone was then removed at reduced pressure, and the mixture allowed to stand for 3 h at 0° C. The precipitate was collected by filtration and washed with H2O to afford 2.29 g of 85 (76% yield) mp: 219-221° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH2:9]([C:13]1[O:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:10][C:11]#[CH:12]>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[C:11][CH2:10][CH2:9][C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[N:3][CH:4]=1
Reactant: C#CCCc1nc2ccccc2o1
Reactant: Fc1ccc(Br)nc1
Product: Fc1ccc(C#CCCc2nc3ccccc3o2)nc1
Yield: 4912.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-5-fluoropyridine (200 mg, 1.14 mol) and 2-(but-3-ynyl)benzo[d]oxazole (195 mg, 1.14 mmol, Example 8(A)). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM/MeOH 100:0 to 94:6, DCM/MeOH/NH4OH 94:5:1 to 90:8:2) to yield 15 mg (56 mmol, 5%) of 2-(4-(5-fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a white solid.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:9][C:8]([O:12][CH3:13])([O:10][CH3:11])[CH2:7]1)=[O:5].[CH2:15]([Mg]Br)[CH2:16][CH:17]=[CH2:18]>C1COCC1>[CH3:13][O:12][C:8]1([O:10][CH3:11])[CH2:7][CH:6]([C:4](=[O:5])[CH2:18][CH2:17][CH:16]=[CH2:15])[CH2:9]1
Reactant: C=CCC[Mg]Br
Reactant: CON(C)C(=O)C1CC(OC)(OC)C1
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CC(OC)(OC)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
N,3,3-trimethoxy-N-methylcyclobutanecarboxamide (12.19 g, 60.0 mmol) was dissolved in THF (130 mL), cooled to 0° C. and treated with 3-butenylmagnesium bromide (168 mL, 0.5 M/THF, 84 mmol). After stirring for 1.5 h at room temperature, the reaction was re-cooled to 0° C. and quenched with 1 N citric acid (30 mL), diluted with ethyl acetate, washed successively with water, saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5-40% ethyl acetate in heptane to afford the desired product 10.98 g (92%). Rf 0.77 (50% ethyl acetate in heptane). 1H NMR (CDCl3, 300 MHz) δ 5.87-5.72 (m, 1H), 5.06-4.95 (m, 2H), 3.17 (s, 3H), 3.13 (s, 3H), 3.06-2.88 (m, 1H), 2.54-2.48 (m, 2H), 2.38-2.28 (m, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]3[CH2:13][C:14]4C([C:11]3=[C:10](C=O)[C:9]=2[N:22]=1)=CC=C[CH:15]=4.CN(C)C=[O:26]>>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]3[C:11]([O:26][CH2:15][CH2:14][CH2:13]3)=[CH:10][C:9]=2[N:22]=1
Reactant: COc1ccc2c(n1)c(C=O)c1n2Cc2ccccc2-1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(cc3n2CCCO3)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under an inert atmosphere, 160 mg (4 mmol) of sodium hydride (60% in oil) are added slowly at 0° C., to a solution of 380 mg (1.34 mmol) of the compound obtained in Step E in 10 ml of N,N-dimethylformamide. The reaction mixture is stirred at 0° C., for 30 minutes before being hydrolysed with ice and then extracted with ethyl acetate. The organic phase is washed several times with water, dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:ethyl acetate/petroleum ether, 95:5) to yield the title compound in the form of a brown solid.