Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:28](OC)=[O:29])([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:10]=2[CH:9]=1.O>O1CCCC1>[Cl:7][C:8]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH2:28][OH:29])([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:10]=2[CH:9]=1
Reactant: COC(=O)C1(CCN(C)C)c2ccccc2N(C)c2ccc(Cl)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCC1(CO)c2ccccc2N(C)c2ccc(Cl)cc21
Yield: 89.1 %

Procedure:
14 cc of tetrahydrofuran were cooled to 0°C and 0.9 gm of lithium aluminum hydride and then a solution of 1.4 gm of 2-chloro-9-methoxycarbonyl-9-(β-dimethylaminoethyl)-10-methyl-acridane in 14 cc of tetrahydrofuran were added thereto while maintaining the temperature below +10°C. The reaction mixture was then heated at reflux for 21/2 hours and cooled to 0°, +5°C and 10 cc of tetrahydrofuran containing 20% water and then 50 cc of water were added thereto. The reaction mixture was extracted with methylene chloride and filtered. The organic phases were washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness to obtain 1.15 gm of 2-chloro-9-hydroxymethyl-9-(β-dimethylaminoethyl)-10-methyl-acridane which was used as is for the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([OH:26])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:21]2[C:12](=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]2[CH:22]=[CH:23][CH:24]=[C:25]([O:26][C:35](=[O:37])[CH3:36])[C:17]2=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CC(=O)Cl
Reactant: CN(C)CCNC(=O)c1cccc2nc3ccc4c(O)cccc4c3nc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc2c1ccc1nc3cccc(C(=O)NCCN(C)C)c3nc12

Procedure:
A mixture of 4-hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide: hydrobromide salt (45 mg), triethylamine (71 μL) and acetyl chloride (20 μL) in dichloromethane (1.4 mL) was stirred at room temperature for 2 hours. All volatiles were removed in vacuo and the residue was purified using column chromatography (10% methanol in dichloromethane) to yield the title compound as a yellow solid (27 mg).
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[C:14]([CH2:17]OS(C)(=O)=O)=[CH:13][C:12]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=2)=[N:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([N:10]1[C:15](=[O:16])[C:14]([CH2:17][N:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)=[CH:13][C:12]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=2)=[N:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Product: Cc1cc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Yield: 80.1 %

Procedure:
Following the procedure of Example 1(10), 2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 80.1%).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[CH3:2].S(=O)(=O)(O)O.[CH3:20]O>>[CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH3:20])=[O:6])[CH3:2]
Reactant: CCc1c(C(=O)O)ccc(OC)c1C
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCc1c(C(=O)OC)ccc(OC)c1C

Procedure:
5.0 g of 2-ethyl-4-methoxy-3-methylbenzoic acid are refluxed with 0.5 ml of conc. sulfuric acid and 50 ml of methanol in a round-bottomed flask for 2 days. The solvent is distilled off, 100 ml of water are added to the residue, and the precipitated solid is filtered off with suction and dried, giving 5.2 g of methyl 2-ethyl-4-methoxy-3-methylbenzoate (quant); MS-FAB (M+H+)=209.1; Rf (polar method): 2.46 min.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:7]=[C:8]([CH2:13]O)[CH:9]=[CH:10][C:11]=1[CH3:12]>>[Cl:3][CH2:13][C:8]1[CH:9]=[CH:10][C:11]([CH3:12])=[C:6]([F:5])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CO)cc1F
Product: Cc1ccc(CCl)cc1F
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.892 g, 7.5 mmol) was added to a solution of the product of STEP 1 (1.0 g, 6.4 mmol) dropwise at 0° C. After 30 min, the reaction was quenched with crushed ice carefully, and diluted with H2O. The product was extracted with ether. The organic layer washed with saturated NaHCO3, brine and dried with Na0.2SO4. Ether was evaporated and the residue was purified by chromatography (on silica gel, ethyl acetate/hexane=1/9) to give a clear liquid in 10.5 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl-].[Mg+2].[Cl-].[C:15](Cl)(=[O:17])[CH3:16].Cl>ClCCl.N1C=CC=CC=1>[C:2]([CH:3]([C:15](=[O:17])[CH3:16])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])(=[O:1])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)C(C(C)=O)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
34.2 ml (0.21 mol) of tert-butyl 3-oxobutanoate were dissolved in 300 ml of dichloromethane, and 20 g (0.21 mol, 1.0 eq.) of anhydrous magnesium chloride were added. At 0° C., 33.9 ml (0.42 mol, 2.0 eq.) of dry pyridine were added to the suspension, which was stirred vigorously. After 15 minutes, 14.3 ml (0.21 mol, 1.0 eq.) of acetyl chloride were added dropwise, and the mixture was stirred at RT for 1 hour. At 0° C., excess pyridine was neutralized with dilute hydrochloric acid (37 ml of conc. hydrochloric acid and 100 ml of water), and the organic phase was separated off. The aqueous phase was extracted with MTBE (3×100 ml), and the combined organic phases were washed with saturated NaCl solution and dried over MgSO4. Removal of the solvent gave 41.2 g (0.206 mol, 98%) of tert-butyl 2-acetyl-3-oxobutanoate in the form of a pale yellow oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1.O>C1COCC1.C(OCC)(=O)C>[F:30][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[CH:14][C:10]=2[CH:11]=1
Reactant: c1cc2cc(C3OCCO3)ccc2o1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc2cc(C3OCCO3)ccc2o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 138.6 %

Procedure:
5-[1,3]Dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in THF (2 mL) and the solution was cooled down to −78° C. Butyl lithium (180 uL, 1.1 eq.) was added dropwise. This mixture was stirred 30 min at 25° C. Then the reaction mixture was cooled down to −78° C. and N-fluorodibenzenesulfonamide (91 mg, 1.1 eq.), dissolved in 1 mL THF, was added dropwise to the reaction mixture. The mixture was stirred overnight between −78° C. and room temperature. Water and ethyl acetate were added to the mixture and the aqueous layer was extracted 3 times. Combined organic phases was dried over MgSO4, filtrated and evaporated, to give the 2-Fluoro-5-[1,3]dioxolan-2-yl-benzofuran (75 mg) mixed with side products. However it was sufficiently pure to be used for the next step.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=O.CCCCCC>O1CCCC1>[F:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:36][C:35]1[CH:34]=[C:33]([F:32])[CH:40]=[CH:39][CH:38]=1
Reactant: FCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: FCCCC=Cc1cccc(F)c1
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a mixture of 4-fluorobutyltriphenylphosphonium bromide 273 g (660 mmol) and tetrahydrofuran (abbreviated THF hereinafter) 1000 ml, potasium-tert-butoxide 88 g (684 mmol) was added under ice cooling and stirred for one hour. Then, under ice cooling, a solution of 3-fluorobenzaldehyde 74 g (596 mmol) in THF 200 ml was added dropwise, and the mixture was stirred for one hour at room temperature. The reaction mixture was poured into hexane 1000 ml, and the crystals deposited were filtered off. The filtrate was concentrated, and distilled (93° C./6 mmHg) to obtain 3-(5-fluoro-1-pentenyl)fluorobenzene 86 g. (Yield:79.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.O=S(Cl)Cl.C(N(CC)CC)C.C[Si]([CH:30]=[N+:31]=[N-:32])(C)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCCCCC.O1CCCC1.CN(C=O)C>[N+:31](=[CH:30][C:6]([C:5]1[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:8])=[N-:32]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc(C(=O)C=[N+]=[N-])ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.3 %

Procedure:
Step A To a solution of 3-methoxy-4-nitrobenzoic acid (Alfa) (10 g, 51 mmol) in toluene (75 mL) was added SOCl2 (11.5 g, 97 mmol), and a catalytic amount of DMF. The mixture was heated at refluxing for 3 h, then cooled to room temperature. The mixture was concentrated. The residue was dissolved into tetrahydrofuran (125 mL) and triethylamine (8.4 g, 83 mmol), and the temperature of the mixture was lowered to 0° C. A hexane solution (Alfa, 2 M) of (trimethylsilyl)diazomethane (41 mL, 83 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The mixture was poured into an aqueous saturated NaHCO3 solution, extracted with ethyl acetate three times. The combined organic extract was washed with brine, dried over MgSO4, and concentrated to give crude 2-diazo-1-(3-methoxy-4-nitro-phenyl)-ethanone as a brown oil (Yield 5 g, 45%).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]1[C:23]2[C:18](=[C:19]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])[CH:20]=[CH:21][C:22]=2[OH:24])[CH2:17][CH2:16][C:15]1=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.S([O-])(O)(=O)=O.[K+]>O.CS(C)=O>[CH2:7]([N:14]1[C:23]2[C:18](=[C:19]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])[CH:20]=[CH:21][C:22]=2[O:24][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:17][CH2:16][C:15]1=[O:33])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1NC(=O)C(Cc2ccc(O)c3c2CCC(=O)N3Cc2ccccc2)S1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NC(=O)C(Cc2ccc(OCc3ccccc3)c3c2CCC(=O)N3Cc2ccccc2)S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
55.5 mg of potassium tert-butoxide was added to a DMSO solution (1 ml) of 90 mg of 5-(1-benzyl-8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione, followed by stirring at room temperature for 1 hour. 30 μl of benzyl bromide was added thereto, followed by stirring at room temperature for 1 hour. Water was added to the reaction liquid, potassium hydrogensulfate was added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by preparative silica gel thin layer chromatography (dichloromethane:methanol=20:1), giving 84.5 mg (76% yield) of 5-(1-benzyl-8-benzyloxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione as a colorless amorphous solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:18]2[CH:19]=[C:20]([NH:24][S:25]([C:28]3[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[CH:4][N:3]=1.[NH2:36][CH:37]1[CH2:42][CH2:41][CH:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:39][CH2:38]1>C(O)CCC>[F:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[S:25]([NH:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:9]2[N:10]=[C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:36][C@H:37]3[CH2:42][CH2:41][C@H:40]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:39][CH2:38]3)[N:7]=2)[CH:19]=1)(=[O:27])=[O:26]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Solvent: CCCCO
Product: CS(=O)(=O)N[C@H]1CC[C@H](Nc2nccc(-c3sc(N4CCCC4)nc3-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3)n2)CC1
Temperature: 60 °C

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-pyrrolidinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide was dissolved in n-butanol and N-(4-aminocyclohexyl)methanesulfonamide (27.0 mg, 0.140 mmol) was added at rt followed by TEA (52.2 μl, 0.375 mmol). The reaction was heated to 60° C. for 12 h. Purified via Gilson Acidic HPLC (10 to 90% gradient, Acetonitrile/H2O+TFA; C18 column). Desired fractions were combined and washed with NaHCO3, dried over MgSO4 and solvent removed to give the title compound as a yellow solid (0.010 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73 (d, J=5.1 Hz, 1H), 7.38-7.55 (m, 1H), 7.11-7.31 (m, 2H), 6.93-7.10 (m, 3H), 6.72-6.88 (m, 1H), 6.42-6.48 (m, 1H), 6.28-6.35 (m, 1H), 5.79-5.88 (m, 1H), 3.52-3.63 (m, 1H), 3.29-3.45 (m, 6H), 3.05-3.16 (m, 1H), 2.91 (s, 3H), 1.77-2.02 (m, 6H), 1.19-1.42 (m, 4H). MS (ESI): 690 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]2[N:8]=[C:9]([N:11]3[CH2:21][CH2:20][CH:14]([C:15]([O:17]CC)=[O:16])[CH2:13][CH2:12]3)[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl>C(O)C>[N+:1]([C:4]1[CH:23]=[CH:22][C:7]2[N:8]=[C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:15]([OH:17])=[O:16])[CH2:20][CH2:21]3)[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1CCN(c2nc3ccc([N+](=O)[O-])cc3s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCN(c2nc3ccc([N+](=O)[O-])cc3s2)CC1
Yield: 98.8 %

Procedure:
106 g of the ethyl N-(6-nitrobenzothiazol-2-yl)isonipecotate obtained in the Preparation Example 10 was dissolved in 300 ml of ethanol. 150 ml of 5M sodium hydroxide aqueous solution was added to the solution and the mixture was heated for 3 h. The reaction mixture was poured into dilute hydrochloric acid and precipitates thus formed were recovered by filtration, washed with water and then with ether, and dried to give 96 g of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[C:7]#N.[H-].C([Al+]CC(C)C)C(C)C.[O:21]1CCCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:10])=[C:6]([CH:9]=1)[CH:7]=[O:21]
Reactant: C1CCOC1
Reactant: N#Cc1cc(Br)ccc1I
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: O=Cc1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-bromo-2-iodobenzonitrile (7.49 g, 24.2 mmol) in tetrahydrofuran (40 mL) at −78° C. was added diisobutylaluminum hydride (1.0M in hexanes; 24.2 mL, 24.2 mmol) over 5 minutes, and the reaction was allowed to warm to room temperature and monitored by analytical TLC. After stirring overnight at room temperature, starting material was still present, so the mixture was cooled to 0° C. and additional diisobutylaluminum hydride (1.0M in hexanes; 10.0 mL, 10.0 mmol) was added. After stirring for 2 hours at room temperature, no starting material was seen by analytical TLC, so the mixture was carefully quenched with freshly saturated aqueous sodium sulfate and diluted with ethyl acetate. The mixture was stirred vigorously for 1 hour and then filtered through Celite. The filtrate was concentrated, and the resulting oil solidified on standing. The solid was stirred vigorously in dichloromethane and 1N aqueous hydrochloric acid, and the aqueous layer was separated and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:10].[Cu][C:12]#[N:13].[OH-].[NH4+]>CN(C=O)C>[NH2:6][C:5]1[CH:7]=[C:8]([F:9])[C:2]([C:12]#[N:13])=[C:3]([Cl:10])[CH:4]=1
Reactant: Nc1cc(F)c(Br)c(Cl)c1
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cc(N)cc1Cl
Temperature: 190 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
A mixture of 4-bromo-3-chloro-5-fluoroaniline (2.08 g, 9.27 mmol) and copper(I)cyanide (0.83 g, 9.27 mmol) in DMF (15 ml) was heated in microwave reactor at 190° C. for 1 h. Reaction mixture was poured into 12% ammonium hydroxide (200 ml) and stirred for 30 min. Thus formed precipitate was filtered, washed with water and dried in vacuum to obtain 1.21 g (77%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 6.44 (dd, 1H), 6.60 (m, 1H), 6.86 (bs, 2H).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]2[C:10](=[N:11][CH:12]=1)[N:9]=[CH:8][N:7]=[CH:6]2.[Br:13]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(N(C)C)=O>[Br:13][CH2:2][C:3]1[N:4]=[C:5]2[C:10](=[N:11][CH:12]=1)[N:9]=[CH:8][N:7]=[CH:6]2
Reactant: BrBr
Reactant: OCc1cnc2ncncc2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: BrCc1cnc2ncncc2n1

Procedure:
Condensation of 2,4,5,6-tetraaminopyrimidine with dihydroxyacetone gave 6-hydroxymethylpteridine 1. Compound 1 was treated with bromine and triphenyl phosphine in dimethylacetamide to give the corresponding 6-bromomethylpteridine which was coupled in situ with 4-aminobenzoic acid to afford pteroylbenzoic acid 2. Purity of the crude product was about 85% as analyzed by HPLC. Due to the low solubility of this compound in most solvents, purification by recrystallization proved to be impractical. The corresponding sodium salt, however, was soluble in hot water and crystallized upon cooling. Although compound 2 decomposes in hot aqueous hydroxide, treatment of the crude product with dilute sodium bicarbonate gave the sodium salt without observable decomposition. Recrystallization of the salt from dilute aqueous bicarbonate raised product purity to 93% or above. The purified salt was then converted back to acid 2 by treatment with aqueous acetic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=3[F:22])=[CH:12][C:4]=2[O:3]1.[CH:24]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[K+]>ClCCCl>[CH:24]1([CH2:27][CH2:28][NH:29][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][C:11]3[CH:10]=[CH:9][C:5]4[C:6](=[O:8])[O:7][C:2]([CH3:1])([CH3:23])[O:3][C:4]=4[CH:12]=3)=[C:15]([F:22])[CH:16]=2)[CH2:26][CH2:25]1
Reactant: CC1(C)OC(=O)c2ccc(Oc3ccc(C=O)cc3F)cc2O1
Reactant: NCCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [K+]
Agent: [Na+]
Solvent: ClCCCl
Product: CC1(C)OC(=O)c2ccc(Oc3ccc(CNCCC4CC4)cc3F)cc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(2,2-Dimethyl-4-oxo-4H-benzo[1,3]dioxin-7-yloxy)-3-fluoro-benzaldehyde (I-1b-1: 24.8 g) and 2-cyclopropyl-ethylamine (6.2 g) were combined in 1,2-dichloroethane (1.0 L). After stirring at ambient temperature for 1 hour, sodium triacetoxyborohydride (83 g) was added to the solution. After stirring overnight, the reaction mixture was treated with an aqueous 2 N potassium hydroxide solution, the organic phase was separated, dried over magnesium sulfate, filtered, and evaporated to provide the title compound (I-1c-2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7](Cl)(=[O:9])[CH3:8].CN(C=O)C.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:25]=[CH:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:19][CH:18]=1>COC(C)(C)C>[C:7]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]([O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:25]=[CH:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:19][CH:18]=1)(=[O:9])[CH3:8]
Reactant: Oc1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(=O)Oc1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1

Procedure:
Potassium carbonate (0.075 g) and acetyl chloride (0.035 ml) were added to DMF (3 ml) solution of phenyl N-(4-hydroxyphenyl)-3-(phenoxy)acrylimidate (0.15 g) at room temperature and stirred for two hours at the same temperature and for three hours at 50° C. t-Butyl methyl ether (80 ml) was added to the reaction solution, and it was successively washed with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain phenyl N-(4-acetoxyphenyl)-3-(phenoxy)acrylimidate (0.11 g) as colorless oil.
Reaction SMILES: [CH2:1]([C:3]([OH:18])([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(C(C)=O)C(C)C>[Cl:17][C:13]1[CH:12]=[C:11]([C:3]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:8][CH:9]=2)([OH:18])[CH2:1][CH3:2])[CH:16]=[CH:15][CH:14]=1
Reactant: ClCCCN1CCCCC1
Reactant: CCC(O)(c1ccc(O)cc1)c1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCC(O)(c1ccc(OCCCN2CCCCC2)cc1)c1cccc(Cl)c1

Procedure:
7.9 g. of α-ethyl-α-(3-chlorphenyl)-4-hydroxybenzyl alcohol, 14 g. of anhydrous potassium carbonate and 6.6 g. of N-(3-chloropropyl)-piperidine hydrochloride in 80 ml. of methyl isobutyl ketone are boiled under moderate reflux for three hours. The solvent is distilled off under reduced pressure, to the residue water is added and it is extracted with benzene. The benzene phase is washed with an aqueous potassium hydroxide solution and subsequently with water, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo. Crystallization of the residue from n-hexane yields 8.6 g. of the title compound, melting at 80° to 81° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][N:9]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CC(=O)NCCCl
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(CCNC(C)=O)CC2
Yield: 14.8 %

Procedure:
Into a 1-neck round-bottom flask was added 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.5 g, 2.20 mmol), N-(2-chloro-ethyl)-acetamide (0.45 mL, 4.41 mmol), potassium iodide (92 mg, 0.55 mmol), and potassium carbonate (900 mg, 7 mmol), in N-methylpyrrolidinone (5 mL), and the reaction was heated at 90 overnight. The reaction mixture was next partitioned between water and ethyl acetate, and the layers separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic extracts were washed with water, dried (MgSO4), filtered, and concentrated, and the product was isolated by flash chromatography on SiO2 (MeOH/dichloromethane 0-20%) to give N-[2-(7-Methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethyl]-acetamide (100 mg, 15%). 1H-NMR (CDCl3) δ 7.67 (s, 1H), 6.84 (s, 1H), 6.11 (br s, 1H), 3.94 (s, 3H), 3.38 (m, 2H), 2.95 (m, 2H), 2.89 (m, 2H), 2.66 (m, 6H), 2.01 (s, 3H); LC/MS (ESI+): 308.02 (M+H).