Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:11][CH2:12][C:13](Cl)=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C.C1COCC1>[CH2:4]([O:11][CH2:12][C:13]([NH:2][NH2:3])=[O:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NN
Reactant: O=C(Cl)COCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: NNC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of hydrazine hydrate (10 ml) in ethanol (100 ml) at 0° C. was added a solution of (benzyloxy)acetyl chloride (6.4 ml) in THF (40 ml) by syringe pump over 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The ethanol was removed under reduced pressure and the remaining aqueous mixture extracted with dichloromethane (3×100 ml). The combined organic extracts were washed with aqueous K2CO3 (100 ml) then brine (100 ml) and dried (MgSO4). Concentration under reduced pressure gave 2-(benzyloxy)acetohydrazide as a colourless oil that crystallized on standing (5.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][CH2:23][CH2:24][OH:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:15]([NH:22][CH2:23][CH2:24][OH:25])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)O)c3)nc12
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncnc2ccc(-c3cc(F)cc(C(=O)NCCO)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 3 (100 mg, 0.35 mmol) was reacted with 2-aminoethanol (CAS 141-43-5) (43 mg, 0.7 mmol), HATU (276 mg, 0.7 mmol) and DIPEA (0.30 mL, 1.8 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-5-fluoro-N-(2-hydroxyethyl)benzamide 7. LC/MS (ESI+): m/z 328 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[CH:12][C:13]#[N:14])=[CH:4][CH:3]=1.N.[H][H].[ClH:18]>[Ni].C(OCC)C>[ClH:18].[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1
Reactant: N#CC=C1CCCc2ccc(F)cc21
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CCOCC
Product: NCCC1CCCc2ccc(F)cc21
Temperature: 60 °C
Reaction time: 5 h

Procedure:
0.011 mol of the compound obtained in Step F is dissolved in 100 ml of 95° alcohol and introduced into a 400 ml autoclave; 0.5 g of Raney nickel is then added. The solution is saturated with ammonia gas, and hydrogen is introduced until a pressure of 50 bars is obtained. The reaction mixture is stirred for 5 hours at 60° C. and is then cooled, filtered and evaporated under reduced pressure. The oil obtained is dissolved in anhydrous ethyl ether and a solution of ethyl ether saturated with gaseous hydrogen chloride is added dropwise. The precipitate formed is filtered off under suction and recrystallised.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([F:14])([F:13])[C:4]([F:12])([F:11])[C:5]([F:10])([F:9])[CH2:6][CH2:7]I.[P:17](OCC)([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][P:17]([CH2:7][CH2:6][C:5]([F:10])([F:9])[C:4]([F:12])([F:11])[C:3]([F:14])([F:13])[C:2]([F:16])([F:15])[F:1])(=[O:18])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CCOP(=O)(OCC)OCC
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI
Product: CCOP(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Temperature: 160 °C
Yield: 90 %

Procedure:
Neat 1,1,1,2,2,3,3,4,4-nonafluoro-6-iodohexane (10 mmol) was added to 50 mmol of triethyl phosphate. The reaction mixture was heated at 160° C. overnight to produce diethyl(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phosphonate, which was isolated by fractional distillation (90-95% yield). Neat trimethylsilyl bromide (21 mmol) was added slowly to a solution of diethyl(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phosphonate (7 mmol) in dry CH2Cl2 (25 mL) at 0° C. The reaction mixture was stirred overnight at room temperature, after which time water (30 mmol) was added to the reaction mixture. Volatiles were removed in vacuo leaving (3,3,4,4,5,5,6,6,6-nonafluorohexyl)phosphonic acid as a white crystal (>95% yield). The procedure for producing the phosphonic acid salt was similar as described for Intermediate 1.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C=O)C.[CH2:30]1[O:41][C:40]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=2[O:31]1>O>[CH2:30]1[O:41][C:40]2[CH:39]=[CH:38][C:34]([C:35]([N:4]3[CH2:5][CH2:6][N:1]([C:7]4[CH:8]=[C:9]5[C:14](=[CH:15][CH:16]=4)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]5)[CH2:2][CH2:3]3)=[O:36])=[CH:33][C:32]=2[O:31]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CCc2cc(N3CCN(C(=O)c4ccc5c(c4)OCO5)CC3)ccc2N1
Temperature: 25 °C
Yield: 37.5 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 2.34 ml of triethylamine were added to 40 ml of DMF. The mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 2.7 g of 3,4-methylenedioxybenzoyl chloride. After completion of addition, the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol to give 1.6 g of 6-[4-(3,4-methylenedioxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 191°-192.5° C., colorless needles.
Reaction SMILES: O[C@@H:2]1[C@@H:19](N2CCNCC2)[CH2:18][C@@:17]2([CH3:26])[CH:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:27])[CH2:3]1.C1(C(N2CCC[C@H]2C(O)=O)=O)C2C(=CC=CC=2)C=CC=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:13][C@:12]12[CH2:14][CH2:15][C@H:16]3[C@@H:7]([CH2:6][CH2:5][CH:4]4[C@:17]3([CH3:26])[CH2:18][CH2:19][CH2:2][CH2:3]4)[C@@H:8]1[CH2:9][CH2:10][C:11]2=[O:27]
Reactant: C[C@]12C[C@H](N3CCNCC3)[C@@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)[C@@H]1CCCN1C(=O)c1cccc2ccccc12
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@]12CCCCC1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 8 h
Yield: 143 %

Procedure:
To a solution of compound 23 (150 mg, 0.40 mmol) in anhydrous DMF (7 mL) at room temperature under an atmosphere of argon were added carboxylic acid 20 (119 mg, 0.44 mmol), PyBOP (229 mg, 0.44 mmol), HOBt (60 mg, 0.44 mmol), and DIPEA (220 μL, 1.26 mmol). The solution was subsequently stirred overnight at room temperature. The resulting solution was then poured into water and extracted with EtOAc (2×30 mL), washed with brine, dried with MgSO4 and evaporated to dryness. Purification by flash chromatography (Hexanes/Acetone: 1:1) yielded 157 mg (63%) of compound 24. 1H NMR (CDCl3) δ: 0.89 (s, 18-CH3 and 19-CH3), 0.70-2.50 (residual CH and CH2), 3.45-3.90 (broad, NCH2 of proline and 2×CH2NCO), 3.95 (m, 3β-CH), 5.09 (broad, NCHCO of proline), 7.55 (m, 2×CH of naphthalene), 7.61 (m, CH of naphthalene), 7.87 (m, 3×CH of naphthalene), 8.06 (s, CH of naphthalene).
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:8][C:7]1[C:2]([N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:13]3[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=3)[CH2:22][CH2:21]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncccc1Br
Reactant: Fc1ccc(NC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(NC2CCN(c3ncccc3Br)CC2)cc1
Yield: 57.1 %

Procedure:
2-Chloro-3-bromopyridine (0.25 g, 1.3 mmol), D2 (0.25 g, 1.3 mmol) and potassium carbonate (0.23 g, 2.9 mmol) in DMF (5 ml) were heated at 120° C. for 16 h. The mixture was concentrated and the residue partitioned between EtOAc and water (50 ml each). The aqueous was re-extracted with EtOAc (50 ml) and the combined organics washed with water, dried (Na2SO4) and concentrated. Purification by column chromatography on silica (0-50% diethyl ether\40-60 pet. ether gradient) gave the title compound as a yellow solid (0.26 g). δH (CDCl3) 1.64 (2H, m), 2.17 (2H, d), 2.98 (2H, m), 3.43 (2H, m), 3.74 (2H, m), 6.58 (2H, m), 6.77 (1H, m), 6.89 (2H, m), 7.78 (1H, d), 8.22 (1H, dd). MS (ES): MH+ 351.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.[C:17]([NH:24][C@@H:25]([C:29](O)=[O:30])[CH:26]([CH3:28])[CH3:27])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(Cl)CCl>C(Cl)Cl>[C:17]([NH:24][C@@H:25]([C:29]([N:1]1[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6]1)=[O:30])[CH:26]([CH3:27])[CH3:28])([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18]
Reactant: C1=CNCCC1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC=CCC1
Temperature: 25 °C

Procedure:
1.245 g of tetrahydropyridine in 50 ml of CH2Cl2 are treated with 1.5 mmol per mmol of tetrahydropyridine of HOBT, 2.17 g of N-BOC-(R)-valin and 1.5 mmol per mmol of tetrahydropyridine of EDC and the mixture obtained is stirred at RT. From the mixture obtained solvent is evaporated, the evaporation residue obtained is mixed with EE and the mixture obtained is extracted with 0.1N HCl and saturated aqueous NaHCO3 solution. The organic phase obtained is dried and solvent is evaporated. N—(N-BOC-(R)-valyl-1,2,5,6-tetrahydropyridine is obtained.
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[N:18]1([S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])(=[O:4])=[O:3])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: C[C@@H](CS(=O)(=O)N1CCCCC1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 1 g benzyl 3-chlorosulfonyl-2(R)-methylpropionate from Example 3 in 25 mL CH2Cl2. The solution was cooled to 0° C. and 4 mL of piperdine was slowly added. The reaction was stirred 1 hour then concentrated in vacuo. The residue was partioned between ethyl acetate and water. The organic phase was washedwith brine, dried, and concentrated in vacuo to give 1 g of benzyl 3-(1-piperidinyl)sulfonyl-2(R)-methylpropionate suitable for use without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1N

Procedure:
Prepared from (2-nitro-4-thiophen-3-yl-phenyl)-carbamic acid tert.-butyl ester (Example B2) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a white solid (278 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1)[CH3:13].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>CN(C)C=O>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[NH:11][C:22](=[O:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:12][CH3:13])=[CH:16][CH:17]=1
Reactant: CCOc1ccc(CC(=O)O)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CN(C)C=O
Product: CCOc1ccc(CC(=O)Nc2cc([N+](=O)[O-])ccc2N)cc1
Temperature: 100 °C
Yield: 63.6 %

Procedure:
4-Nitro-benzene-1,2-diamine 40 (1.00 g, 6.53 mmol) was dissolved in anhydrous dimethylformamide (20 mL) in a small, argon purged flask fitted with an condenser and magnetic stirbar. (4-Ethoxy-phenyl)-acetic acid 5 (1.53 g, 8.49 mmol) followed by 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.099 g, 8.49 mmol) are added quickly as solids and resulting solution heated in an oil bath at 100° C. for 17 hours. After cooling to room temperature the solution was diluted with ice cold H2O (25 mL) resulting in the formation of a yellow precipitate that was collected on a sintered glass funnel and washed with H2O. The solid was slurried in boiling ethanol, filtered and dried to yield solid 41 N-(2-Amino-5-nitro-phenyl)-2-(4-ethoxy-phenyl)-acetamide Yield: 1.31 grams (67.5%). 1H NMR (DMSO) δ: 1.31 (t, 3H, J=6.9), 3.61 (s, 2H), 4.00 (q, 2H, J=6.9), 6.50 (br s, 2H, exchange w. D2O), 6.75 (d, 1H, J=9.0), 6.87 (d, 2H, J=8.4), 7.25 (d, 2H, J=8.7), 7.84 (dd, 1H, J=9.0, 2.7), 8.20 (d, 1H, J=2.7), 9.37 (br s, 1H, exchange w. D2O); MS (APCI+): 316 (MH+, 10%), 298 (MH+-H2O, 100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:11]([S:26][CH3:27])[CH:10]=1.Cl.[OH-]>CCOCC.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:11]([S:26][CH3:27])[CH:10]=1
Reactant: COc1ccc(CC(=O)c2ccc(OC)cc2SC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(CC(O)c2ccc(OC)cc2SC)cc1
Temperature: 0 °C

Procedure:
0.3 g (7.9 mmol) lithium aluminium hydride is placed in 50.0 ml absolute ether and cooled in the ice bath to 0°-5° C. 1-(4-methoxy-2-methylthiophenyl)-2-(4-methoxyphenyl)ethanon (71) (6.9 mml) is dissolved in absolute ether and slowly added dropwise to the lithium aluminium hydride suspension. Following that it is heated for one hour to boiling point. After cooling, it is hydrolysed carefully with water, and acidified with dilute hydrochloric acid, until all the alumuinium hydroxide has gone into solution. It is extracted three times with ether, washed twice with water, dried over MgSO4, filtered and condensed in a water jet vacuum. The product is purified by column chromatography with silica gel 60 (eluction medium dichloromethane/ether (19:1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:5]=[CH:4][CH:3]=1.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([O:8][C:9]2[CH:28]=[CH:27][CH:26]=[C:11]([CH:12]=[C:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=2)[N:7]=1
Reactant: Cc1cccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cccc(Oc2cccc(C=C3CCNCC3)c2)n1

Procedure:
tert-Butyl 4-(3-(6-methylpyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (4.3 g, 11 mmol) from Step 4 was dissolved in CH2Cl2 (50 mL) and treated with HCl in dioxane (20 mL, 4.0 M, 80 mmol). After 16 h the reaction was concentrated in vacuo to provide the title compound as a white solid (4.0 g).
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[O:10]=[C:11]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[O:14][C:13]2[CH:21]=[CH:22][C:23]([C:25]([CH:27](C(OCC)=O)C(OCC)=O)=[O:26])=[CH:24][C:12]1=2>O>[C:25]([C:23]1[CH:22]=[CH:21][C:13]2[O:14][C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:20]3[C:11](=[O:10])[C:12]=2[CH:24]=1)(=[O:26])[CH3:27]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc2oc3ncccc3c(=O)c2c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccc2oc3ncccc3c(=O)c2c1

Procedure:
A mixture of 7.5 ml of glacial acetic acid, 0.9 ml of concentrated sulfuric acid, 4.5 ml of water and 4.6 g of diethyl 2-(5-oxo-5H-[1]benzopyrano[2,3-b]pyridin-7-yl-carbonyl)malonate is stirred under reflux for 2 hours. The reaction mixture is poured into 50 ml of cool water. The crystalline precipitate is filtered off, and suspended in water. The suspension is alkalified with 10% sodium hydroxide under ice cooling, and extracted with chloroform. The extract is washed thoroughly with water, dried, and concentrated. The residue is recrystallized from toluene to give 7 -acetyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at 194°-195°C.
Reaction SMILES: [C@H:1](Br)([C:7]([OH:9])=[O:8])[C@H:2](Br)[C:3]([OH:5])=[O:4].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>>[CH2:11]([NH:18][CH:2]([CH:1]([NH:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)[C@@H](Br)[C@@H](Br)C(=O)O
Reactant: NCc1ccccc1
Agent: Cl
Product: O=C(O)C(NCc1ccccc1)C(NCc1ccccc1)C(=O)O
Temperature: 50 °C

Procedure:
To a mechanically stirred solution of meso-2,3-dibromosuccinic acid (27.6 g, 0.100 mol) in alcohol (200 ml) was slowly added benzylamine (85 g, 0.80 mol) at ambient temperature. After complete addition the mixture was refluxed overnight. A heavy precipitate of salts appeared. The mixture was cooled to 50° C. and concentrated hydrochloric acid was added until pH was 4-5. The precipitate was filtered off, washed several times with water and alcohol and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29].[I-].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CC(C)OC(=O)CBr
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido[3,2,1-jk]carbazole-4-one (3 g) obtained in Example 59 was suspended in dimethyl sulfoxide (120 ml), and potassium carbonate (2.6 g) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and i-propyl bromoacetate (1.4 ml) and potassium iodide (1 grain) were added in succession to the mixture. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (500 ml), and the crystals precipitated were recovered by filtration. The crude crystals were purified by silica gel flash column chromatography (eluent: methylene chloride containing 1% methanol) to obtain the title compound (2.0 g, 51%).
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=2[O:2]1.Cl.[CH2:16]([O:23][C:24](=[O:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.C(OC(=O)[C@H](C)N)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(#N)C>[CH2:16]([O:23][C:24](=[O:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][C:13]2[O:14][CH2:1][O:2][C:3]=2[CH:4]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: C[C@H](N)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)C=Cc1ccc2c(c1)OCO2
Reaction time: 16 h
Yield: 74.9 %

Procedure:
A solution of 192 mg (1.0 mmol) of 3,4-methylenedioxycinnamic acid, 121 mg (0.5 mmol) of proline benzyl ester hydrochloride and 108 mg (0.5 mmol) of alanine benzyl ester hydrochloride in 6 mL of acetonitrile was treated sequentially with 0.35 mL (2.0 mmol) of diisopropylethylamine and 443 mg (1.0 mmol) of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate. The mixture was stirred for 16 hrs then concentrated in vacuo. The residue was dissolved in 10 mL of dichloromethane and poured into 3 volumes of diethyl ether. The mixture was washed sequentially with water, 10% potassium bisulfate solution, water, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, using a stepwise gradient of 30%, 35%, 40%, and 45% ethyl acetate in hexane as eluant. Ester (9) (142 mg) was obtained as a colorless oil, Rf=0.4 (40% ethyl acetate/hexane); HPLC, Rt 12.26; 1H NMR (300 MHz) consistent with structure. Ester (10) (162 mg) was obtained as a colorless oil; TLC, Rf =0.22 (40% ethyl acetate/hexane); HPLC, Rt 11.84 min; 1H NMR (300 MHz) consistent with structure.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[K+]>CC(C)=O.O>[CH2:17]([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)cc1F
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A solution of 2-fluoro-4-hydroxy-benzonitrile (80 g, 0.58 mol), potassium carbonate (162 g, 1.17 mol) and benzyl bromide (76.4 mL, 0.64 mol) and potassium iodide (9.6 g, 0.058 mol) in acetone (600 mL) was stirred at RT and a significant exothermic reaction was observed. Stirring continued for 18 h without cooling. Reaction progress was monitored by TLC analysis. The reaction mixture was diluted with H2O (600 mL) and extracted with EtOAc (500 mL×2). The combined organic extracts were washed with saturated aqueous NaCl solution (500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resultant residue was triturated in cyclohexane (300 mL) and the crystalline solid was filtered off and washed to afford 4-Benzyloxy-2-fluoro-benzonitrile (118.2 g, 90%). 1H NMR (400 MHz, CDCl3): 7.51 (1 H, dd, J=8.70, 7.48 Hz), 7.40 (5 H, m), 6.86-6.76 (2 H, m), 5.11 (2 H, s).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[S:13])[CH3:12])=[CH:6][CH:5]=1.[OH-].[Na+].CCOC(C)=O>CCO.O>[CH3:12][C:11]1[S:13][C:8]2[CH:9]=[C:4]([O:3][C:2]([F:14])([F:1])[F:15])[CH:5]=[CH:6][C:7]=2[N:10]=1
Reactant: CC(=S)Nc1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 44.5 %

Procedure:
N-(4-(trifluoromethoxy)phenyl)ethanethioamide (38 g, 0.162 mol) was dissolved in EtOH (70 ml), water solution of NaOH (52.5 g, in 175 ml water) was added and the solution was diluted with 350 ml water. This solution was then added drop wise, within 30 min., into a solution of K2Fe(CN)6 (210 g) in 520 ml water at 85-95° C. The reaction mixture was then stirred at 85-95° C. for 1 hr and cooled. TLC (7:3-hexane:EtOAc) was performed. The product was extracted with DCM, the organic phase was dried over Na2SO4, filtered and evaporated and the residue was purified by flash column chromatography (5% EtOAc in hexane) to give 16.8 g (44.5%) of 2-methyl-6-(trifluoromethoxy)benzo[d]thiazole.