Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.N1C=C[CH:23]=[CH:22][CH:21]=1.C(OCC)(OCC)(OCC)CC>C1(C)C=CC=CC=1.ClC(Cl)C>[CH2:22]([C:23]1[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:21]
Reactant: Nc1cnc2ccccc2c1NCCOCCO
Reactant: c1ccncc1
Agent: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1nc2cnc3ccccc3c2n1CCOCCO
Temperature: 25 °C
Yield: 904.4 %

Procedure:
A mixture of 2-{2-[(3-aminoquinolin4-yl)amino]ethoxy}ethanol (43.0 g, 155 mmol) and pyridine hydrochloride (1.79 g, 15.5 mmol) in toluene (200 mL) and dichloroethane (100 mL) was heated at reflux until a solution formed. The solution was allowed to cool to room temperature, then was cooled to 0° C. Triethyl orthopropionate (30.1 g, 171 minol) was added and the mixture was heated at reflux for 3 hours. The solution was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was diluted with chloroform and 4 M NaOH was added to adjust the pH to 9. The mixture was filtered and the isolated solid dissolved when it was washed with water and chloroform. The filtrate was transferred to a separatory fimnel and washed twice with brine. The combined aqueous layers were back-extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to provide 40.0 g of 2-[2-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethanol as a tan solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+]([O-])=O)[CH:5]=1)([O-:3])=[O:2].[CH3:13][O-:14].[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([O:14][CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cccc([N+](=O)[O-])c1

Procedure:
m-Nitroanisole was prepared by reacting m-dinitrobenzene with sodium methoxide at 25° C. for 16 hours in hexamethylphosphotriamide solvent (N. Kornblum et al., J. Org. Chem., 41, 1560 (1976)).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH:15]C(=O)C)[NH:13][CH:14]=2)=[CH:6][CH:5]=1>O.CO.S(=O)(=O)(O)O>[F:19][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[NH:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1nc(-c2ccc(OC(F)F)cc2)c[nH]1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: Nc1nc(-c2ccc(OC(F)F)cc2)c[nH]1
Yield: 98.7 %

Procedure:
N-[4-(4-Difluoromethoxy-phenyl)-1H-imidazol-2-yl]-acetamide (1.2 g, 4.5 mmol, 1.0 eq) was dissolved in water (30 mL) and methanol (30 mL), and 30 drops of sulfuric acid were added. The reaction was refluxed for 2 days, then the mixture was dried; the residue was diluted with water, the pH adjusted to 8 with NaOH 2N, the product was extracted with DCM and concentrated under reduced pressure to give 1.0 g of the title compound (yield: 99%)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12](=[O:15])([O-])[O-].[Na+].[Na+].[CH2:18]1[CH2:22]O[CH2:20][CH2:19]1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:5][N:4]1[C@H:3]2[C@@:18]([CH3:22])([C:18]3[CH:22]=[CH:8][C:7]([C:2]4[CH:3]=[N:4][C:5]5[C:10]([CH:11]=4)=[CH:9][CH:8]=[CH:7][CH:6]=5)=[CH:6][C:19]=3[CH2:20][CH2:2]2)[CH2:19][CH2:20][C:12]1=[O:15]
Reactant: O=C([O-])[O-]
Reactant: Brc1cnc2ccccc2c1
Reactant: C1CCOC1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cnc5ccccc5c4)cc3CC[C@@H]12
Yield: 56 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3-bromoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. An additional 23 mg of the palladium reagent was added, and the mixture was heated an additional 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 130 mg (56%) of the title compound as an amorphous solid. mp: 180°-185°. FDMS: m/e=356. α[D]589 =+80.22 (c=0.37,chloroform).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2].[CH2:12]=[CH:13][CH:14]=[CH2:15]>C1(C)C=CC=CC=1>[C:1]([O:4][C@@H:5]1[CH2:15][CH:14]=[CH:13][CH2:12][C@H:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C=COC(C)=O
Reactant: C=CC=C
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CC=CC[C@H]1OC(C)=O
Temperature: 170 °C

Procedure:
Ethyl 3-acetoxyacrylate (1, 11.0 g, 69.6 mmol) and butadiene (30.0 ml, 0.8 mol) were dissolved in toluene (distilled from calcium hydride, 25 ml); the mixture was placed in a 500 ml autoclave at -78° C. The autoclave was sealed, and then heated for 15 hours at 170° C. The autoclave was cooled and opened, the contents centrifuged, and the gummy residue extracted with toluene (3×100 ml). The toluene was removed under vacuum, and the mixture of cis and trans 1-acetoxy-2-carboethoxycyclohex-4-ene (3 and 2) was isolated by distillation (101° C. at 2 torr).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CCCCCCCBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCOc1ccc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5-bromosalicylaldehyde (5.00 g) and potassium carbonate (10.3 g) in N,N-dimethylformamide (50 ml) was added heptyl bromide (4.10 ml), and the mixture was stirred at room temperature for 1.5 hr, and further at 50° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (7.61 g) as a yellow oil.
Reaction SMILES: [CH2:1]([C:4]#[N:5])[C:2]#[N:3].[C:6](OCC)(OCC)([O:9][CH2:10][CH3:11])[CH2:7][CH3:8]>C(O)C>[CH2:10]([O:9][C:6](=[C:1]([C:4]#[N:5])[C:2]#[N:3])[CH2:7][CH3:8])[CH3:11]
Reactant: N#CCC#N
Reactant: CCOC(CC)(OCC)OCC
Solvent: CCO
Product: CCOC(CC)=C(C#N)C#N

Procedure:
33.03 g (0.5 mol) of malonodinitrile and 88.13 g (99.02 ml, 0.5 mol) of triethyl orthopropionate are heated at 100° C. for two hours, and the ethanol which is formed during this is distilled off overhead. The reaction mixture is left to cool and added to ca. 500 ml of water. The aqueous phase is extracted with ethyl acetate, then the organic phase is dried with sodium sulfate and, after filtering off the drying agent, is concentrated by evaporation. The resulting 72 g (purity ca. 90%) of (1-ethoxy-propylidene)malononitrile are used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH2:12][C:11]1[C:6]2([CH2:18][C:19]#[N:20])[CH2:7][CH2:8][C:9](=[O:17])[CH:10]=1.C1C=CC=CC=1.[CH2:27](O)[CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH2:27]1[CH2:28][O:29][C:9]2([CH2:8][CH2:7][C:6]3([CH2:18][C:19]#[N:20])[C:11](=[CH:12][CH2:13][C:14]4[C:5]3=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=4)[CH2:10]2)[O:17]1
Reactant: COc1ccc2c(c1)C1(CC#N)CCC(=O)C=C1CC2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2c(c1)C1(CC#N)CCC3(CC1=CC2)OCCO3

Procedure:
A mixture of the crude enone III, benzene (2.5 l), ethylene glycol (150 ml) and p-toluenesulphonic acid (4.0 g) was refluxed with water separation (Dean-Stark trap) for 17 hrs. cooled and evaporatd at reduced pressure to approximately 500 ml. Dichloromethane (2.5 l) was added; the mixture worked up, the organic solution was evaporated to approximately 700 ml and diluted with ether (1.5l). The ketal IV was obtained in two crops as colorless needles (249 g, 80%); m.p. 174°-175° C.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14](Br)[CH:13]3[CH2:19][CH:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([Cu])#[N:30]>CN(C=O)C.O.C(Cl)Cl.[Cu]I>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][C:14]([C:29]#[N:30])=[C:13]3[CH2:19][CH:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH2:21][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: CCCN(CCC)C1CC2CN(C(=O)c3ccccc3)C3=C2C(C1)C(Br)C=C3
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCCN(CCC)C1Cc2c(C#N)ccc3c2C(C1)CN3C(=O)c1ccccc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 82.6 %

Procedure:
To a solution of (±)-1-benzoyl-6-bromo-4-(di-n-propylamino)hexahydrobenz[cd]indole (5.5 g, 12.5 mmol) in DMF (100 mL) under a N2 atmosphere was added 3.4 g (37.5 mmol) of CuCN and 7.1 g (37.5 mmol) of CuI. The reaction mixture was then stirred at 140° C. for 6 hr. The reaction mixture was poured onto ice, diluted with water, CH2Cl2 added and stirred for 30 minutes. The mixture was filtered through a Celite pad and the filtrate was extracted twice with CH2Cl2. The organic solution was washed twice with saturated NaCl solution. The CH2Cl2 solution was dried over MgSO4 and then evaporated to provide 4 g of a solid. Chromatography of this crude product over silica gel with 1:19 MeOH/CH2Cl2 as eluent gave 3 g (62%) of product. mp=122°-124° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(=O)C(C)(C)C)[N:6]=[C:5]2[CH3:17].O=[C:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](OC(C)(C)C)=O)[CH2:20]1.C(=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:25]([N:21]1[CH2:20][CH2:19][CH2:24][CH:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[CH3:17])[CH2:22]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1nn(C(=O)C(C)(C)C)c2ccc(N)cc12
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Product: Cc1n[nH]c2ccc(NC3CCCN(Cc4ccccc4)C3)cc12

Procedure:
The title compound was prepared by reaction of 1-(5-amino-3-methyl-1H-indazol-1-yl)-2,2-dimethylpropan-1-one with tert-butyl 3-oxopiperidine-1-carboxylate using the method of Example 3, deprotection using the method of Example 4, reaction with benzaldehyde following the method of Example 8, and final deprotection using the method of Example 9.
Reaction SMILES: Cl.[C:2]([N:5]([CH2:37][C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=1)[CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:8]2[CH:19]=[CH:20][C:21]([N:23]=C(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:22][C:7]1=2)(=[O:4])[CH3:3]>O1CCCC1.C(OCC)(=O)C>[C:2]([N:5]([CH2:37][C:38]1[CH:39]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:41]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:43]=1)[CH:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:8]2[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:7]1=2)(=[O:4])[CH3:3]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(N=C(c3ccccc3)c3ccccc3)cc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(N)cc21
Reaction time: 0.25 h
Yield: 75 %

Procedure:
Add 2 N hydrochloric acid (2 mL) to a solution of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-(benzhydrylideneamino)-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (example 6b) (0.920 g, 1.32 mmol) in tetrahydrofuran (10 mL) at room temperature and stir for 15 min. Dilute the mixture with ethyl acetate (20 mL) and wash with saturated sodium hydrogen carbonate solution and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (1:1), to provide the title compound as an off-white solid (0.526 g, 75%); APCI MS 531 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[N:5].BrCC1C=CC=C(C#N)C=1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2([C:28]3=[CH:29][C:30]4[O:34][CH2:33][O:32][C:31]=4[CH:35]=[C:27]3[O:26][CH2:25]2)[C:17]1=[O:36]>>[O:36]=[C:17]1[C:18]2([C:28]3=[CH:29][C:30]4[O:34][CH2:33][O:32][C:31]=4[CH:35]=[C:27]3[O:26][CH2:25]2)[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]1[CH2:2][CH2:3][C:4]#[N:5]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: N#CCCBr
Agent: N#Cc1cccc(CBr)c1
Product: N#CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in PREPARATION 7 and making non-critical variations using 3-bromopropionitrile to replace α-bromo-m-tolunitrile, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propanenitrile was obtained (86%) as a colorless solid: mp 200-202° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.32 (ddd, J=7.6, 7.4, 1.2 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.15 (d, J=6.7 Hz, 1H), 7.04 (ddd, J=7.4, 7.4, 1.0 Hz, 1H), 6.66 (s, 1H), 6.24 (s, 1H), 5.89 (d, J=2.2 Hz, 2H), 4.69 (ABq, J=9.3 Hz, 2H), 4.10-3.88 (m, 2H), 2.95 (t, J=6.5 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 177.1, 155.8, 148.8, 142.2, 141.9, 132.3, 129.3, 124.1, 123.7, 120.1, 119.1, 109.8 103.6, 101.9, 93.7, 80.3, 57.9, 35.9, 16.2; MS (ES+) m/z 335.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:26])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([O:20][CH3:21])[N:13]=1)[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]2=[O:25].Cl.Cl.[NH2:30][CH:31]1[CH2:34][NH:33][CH2:32]1.CN1CCCC1>C(#N)C>[NH2:30][CH:31]1[CH2:34][N:33]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:25])[C:8]([C:22]([OH:24])=[O:23])=[CH:9][N:10]3[C:12]3[C:17]([F:18])=[CH:16][C:15]([F:19])=[C:14]([O:20][CH3:21])[N:13]=3)=[CH:5][C:4]=2[F:26])[CH2:32]1
Reactant: COc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CC#N
Product: COc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Yield: 33.1 %

Procedure:
To 500 mg of acetonitrile were added 75 mg of 8-chloro-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 65 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was heated under reflux for 1 hour. The precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 28 mg of the title compound as a colorless powder. 5 Melting point: 171 to 175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30].CCN(CC)CC>C1COCC1>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: COc1cc(CC(=O)OCc2ccccc2)ccc1N
Reactant: O=C=Nc1ccccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(CC(=O)OCc2ccccc2)ccc1NC(=O)Nc1ccccc1F
Reaction time: 3 h
Yield: 100.9 %

Procedure:
To a stirred solution of benzyl 4-amino-3-methoxyphenylacetate (1.36 g, 5 mmol) in THF (20 mL) was added 2-fluorophenyl isocyanate (561 ul, 5 mmol) and a catalytic amount of Et3N. The resulting mixture was stirred for 3 hr. The mixture was quenched by the addition of H2O (10 mL) and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with CHCl3 as eluent to give 2.06 g (q.y.) benzyl 4-[N′-(2-fluorophenyl)ureido]-3-methoxyphenylacetate as a green oil. 1H-NMR (CDCl)3 δ3.63 (2H, s), 3.82 (3H, s), 5.14 (2H, s), 6.79-7.37 (12H, m), 8.01 (1H, d, J=7.8 Hz), 8.09-8.14 (1H, m).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N+:8]([O-])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[OH:12][C:13]1[C:14]([N+]([O-])=O)=NC=CC=1.[O:22]([CH3:24])[Na].BrBr>CO>[O:12]=[C:13]1[CH2:14][O:11][C:5]2[CH:4]=[CH:3][C:2]([CH:24]=[O:22])=[N:7][C:6]=2[NH:8]1
Reactant: O=[N+]([O-])c1ncccc1O
Reactant: CO[Na]
Reactant: O=[N+]([O-])c1nc(Br)ccc1O
Agent: BrBr
Solvent: CO
Product: O=Cc1ccc2c(n1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Bromo-2-nitro-pyridin-3-ol. To a solution of 3-hydroxy-2-nitropyridine (20 g, 140 mmol) in CH3OH (400 mL) was added a solution of 25% NaOCH3 in CH3OH (33.0 mL, 153 mmol). After stirring at RT for 30 min, the reaction mixture was cooled to 0° C. and Br2 (7.2 mL, 140 mmol) added slowly. The mixture was stirred for 30 min, and then was quenched with glacial acetic acid (2.5 mL). The solvent was removed under reduced pressure. A portion of the crude material was purified on SiO2 (50% EtOAc/hexanes) to provide the title compound as a white solid. MS (ESI): exact mass calculated for C5H3BrN2O3, 217.93; m/z not found. 1H NMR (400 MHz, CDCl3): 10.24 (s, 1H), 7.74 (d, J=8.6, 1H), 7.54 (d, J=8.6, 1H).
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH2:8]([SH:10])[CH3:9].[NH2:11][C:12]1[N:20]=[C:19](Cl)[N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[Cl-].[Na+].O>[NH2:11][C:12]1[N:20]=[C:19]([S:10][CH2:8][CH3:9])[N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCS
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 110 °C
Yield: 80.9 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added ethanethiol (2 ml, 27 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred under heating at 110° C. for 3.5 hours. Brine was added thereto and the mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate, filtered and the solvent in the filtrate was evaporated. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (90 mg, yield 82%).
Reaction SMILES: [I:1]I.P([O:9][CH3:10])(OC)(OC)=O.[CH3:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>O>[I:1][C:13]1[CH:14]=[C:15]([CH3:16])[C:10]([OH:9])=[CH:11][CH:12]=1
Reactant: COP(=O)(OC)OC
Reactant: CCCCCC
Reactant: II
Solvent: O
Product: Cc1cc(I)ccc1O
Reaction time: 12 h

Procedure:
0-Cresol, 0.023 ml, iodine, 3 g, and 25 ml of trimethyl phosphate were held at 87° C under nitrogen for 12 hours with stirring. The iodine color having disappeared, 2.9 g more of iodine (total iodine 0.023 mol) was added and held 12 hours again. The iodine was gone but a brown color had developed. The mixture was poured into water and extracted with hexane. Three layers formed: the hexane layer containing the product, a dark viscous oil at interface of hexane, and water (which was a phosphate ester of product) the aqueous layer. The hexane layer was separated, dried and evaporated. The residue, 5 g, contained about 60% of the desired product (GLC, RT=108 sec. on 6 ft. SE 30 column at 150° and 40 ml of He/min. flow) and 40% trimethyl phosphate (40%, RT=60 sec.). There were indications of less than 1% 6-iodo-2 -cresol (RT=112 sec.) and about 1% 4,6-diiodo-2-cresol (RT=180 sec.). This crude mixture was warmed on a steam-bath with 8% aqueous sodium hydroxide, cooled, acidified, and the solid obtained filtered and washed. The same treatment was given to the heavy oil insoluble in hexane. The crude weight of 4-iodo-2-cresol obtained in this way were 3.5 g, 65% and 0.35 g, 6%, respectively. Recrystallization of first fraction gave shiny, beige-colored needles, mp 66.5°-68° (colorless melt), 1.55 g, 29% reported (C. M. Suter, R. D. Shultz, J. Org. Chem., 16, 1117 (1951)) mp 64°-65°. The second crop from the filtrate combined and recrystallized with the 0.35 g fraction gave 1.1 g, 20%, of darker beige needles, mp 65°-67° (amber melt).
Reaction SMILES: [SH2:1].[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1.C(N(CC)CC)C>N1C=CC=CC=1>[NH2:2][C:3]1[C:8]([C:9](=[S:1])[NH2:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1
Reactant: CSc1ncc(C#N)c(N)n1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CSc1ncc(C(N)=S)c(N)n1
Reaction time: 1.75 h

Procedure:
Hydrogen sulfide is passed through a suspension of 4-amino-2-methylthio-5-pyrimidinecarbonitrile (16.621 g., 0.100 mole) in a mixture of pyridine (150 ml.) and triethylamine (14.0 ml., 0.100 mole) for 2 hours. The nitrile dissolves in the course of the reaction. After ca. 1.75 hours a solid begins to separate. The mixture is poured into water (500 ml.), and the yellow solid collected by filtration washed with water, dried at 100° C., house vac. The yield of product melting at 230° C. dec. (uncorr.) is 18.93 (94.5%). This material is recrystallized from dimethylformamide-water (Darco G-60) to give yellow rods melting at 229° C. dec. (uncorr.) in a yield of 15.685 g. (78.3%).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:11][CH:12]=1)=O.[C:27]([NH2:35])(=[NH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C>[C:28]1([C:27]2[N:35]=[C:5]([C:7]3[CH:8]=[C:9]([P:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:3][N:34]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CN(C)C=CC(=O)c1cccc(P(c2ccccc2)c2ccccc2)c1
Reactant: N=C(N)c1ccccc1
Solvent: CCO
Product: c1ccc(-c2nccc(-c3cccc(P(c4ccccc4)c4ccccc4)c3)n2)cc1
Yield: 79 %

Procedure:
10 mmol of 4 are dissolved in 100 ml of ethanol and mixed with 10 mmol of benzamidine. The mixture is refluxed for 90 min, subsequently the solvent is removed. Recrystallization from acetic acid ethyl ester gives a colorless solid. Yield: 79%. ESI MS, m/z (%): 417.4674 (100) [M+H]+. 31P{1H} NMR (101.2 MHz, 25° C., DMSO-d6): δ −7.37.
Reaction SMILES: [OH:1][C:2]1[C:7]2[NH:8][C:9](=O)[C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:11]=3[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:22][OH:23]>C1COCC1>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:15]=[CH:16][C:10]2[CH2:9][NH:8][C:7]3=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=[C:6]3[NH:12][C:11]=2[N:13]=1.[F:20][C:17]([F:18])([F:19])[C:14]1[CH:15]=[CH:16][C:10]2[CH2:9][NH:8][C:7]3[CH:2]=[CH:3][CH:4]=[C:22]([OH:23])[C:6]=3[NH:12][C:11]=2[N:13]=1
Reactant: O=C1Nc2c(O)cccc2Nc2nc(C(F)(F)F)ccc21
Reactant: CO
Solvent: C1CCOC1
Product: Oc1cccc2c1NCc1ccc(C(F)(F)F)nc1N2
Product: Oc1cccc2c1Nc1nc(C(F)(F)F)ccc1CN2
Temperature: 40 °C

Procedure:
To 7-hydroxy-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one (113 g, 0.38 mol) in THF (1.7 L) at 0° C. was added BH3 (1 M/THF, 1.5 L, 1.5 mol). After gas evolution subsided, the reaction was heated at 40° C. for 1 h. The reaction mixture was cooled to 0° C. and poured slowly into methanol. The resulting solution was partially concentrated, diluted with ethyl acetate, washed with 1 N HCl, saturated NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The residue was slurried in heptane, and the solid was collected by filtration to give the title compound as a 1:1 mixture with 2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-10-ol.