Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([O:15]CC)=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1.Br>O.CC(O)=O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnc2cc(O)ccc2c1
Reaction time: 2 h

Procedure:
According to Scheme A, ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (VIII) is obtained in four steps from commercially available synthetically accessible m-anisidine (II). m-Anisidine is combined with diethyl ethoxymethylenemalonate at temperatures ranging from 100° C. to about 125° C., preferably 125° C. for a period of 1 to 5 h, preferably about 3 h to provide diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate. Ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (III) is obtained by heating Dowtherm™ at a temperature of 257° C. and diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate for a period of 15 minutes to 2 h. Compound (IV) ethyl 7-methoxyquinoline-3-carboxylate is commercially available or synthetically accessible from ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (III) in two steps. Chlorination of compound (III) under conditions known to one skilled in the art, for example, but not limited to, oxalyl chloride, thionyl chloride, or phosphorus oxychloride, with or without a catalytic amount of DMF, in the presence or absence of a solvent such as DCM or CHCl3, at temperatures ranging from 50° C. to about 70° C., for a period ranging from 2 to 4 h, preferably 2.5 h, provides ethyl 4-chloro-7-methoxyquinoline-3-carboxylate. Subsequent reduction of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate, employing Pd/C under hydrogenation conditions, in a solvent such as MeOH or EtOH, in the presence or absence of an acid such as acetic or formic acid, provides ethyl 7-methoxyquinoline-3-carboxylate (IV). Commercially available or synthetically accessible ethyl 7-methoxyquinoline-3-carboxylate (IV) is reacted under demethylation conditions, for example, HBr in H2O or HOAc, at temperatures ranging from 80° C. to about 110° C., preferably 105° C. for a period of 0.5 h to 24 h, preferably about 2 h, to provide 7-hydroxyquinoline-3-carboxylic acid. Ethyl 7-hydroxyquinoline-3-carboxylate (V), where R3 is H, is obtained by esterification of 7-hydroxyquinoline-3-carboxylic acid, employing methods known to one skilled in the art, for example, but not limited to, reaction of 7-hydroxyquinoline-3-carboxylic acid with an acid such as H2SO4, and the like, in a solvent such as EtOH, at temperatures ranging from 60° C. to about 80° C., preferably 75° C. for a period of about 12 to 24 h, preferably 20 h.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([NH:17][CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:16])[CH3:15]>>[CH3:26][CH:24]([N:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:18][N:17]([CH:14]([CH3:16])[CH3:15])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: CC(C)NCCN(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)N(CCN(C(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(C)C

Procedure:
Following the procedure of Example 1, p-nitrobenzenesulfonyl chloride was reacted with N,N',N'-triisopropyl ethylene diamine to obtain the free base as a yellow solid, m.r. 98°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:17][Si:18](Br)([CH3:20])[CH3:19]>C1C=CC=CC=1>[CH3:17][Si:18]([CH3:20])([CH3:19])[NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9]
Reactant: C[Si](C)(C)Br
Reactant: Nc1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C[Si](C)(C)Nc1c(Cl)cccc1Cl
Yield: 75.1 %

Procedure:
A solution of 60 ml of benzene, 5.0 g (30.9 mmole) of 2,6-dichloroaniline, 10.6 ml (76.0 mmole) of triethylamine, and 8.08 ml (61.1 mmole) of trimethylsilyl bromide was heated at reflux for 54 hours, cooled, filtered, and the solvent was removed from the filtrate in vacuo. The residue was evacuated at 1 mm to remove any excess trimethylsilyl bromide. The residual mixture was filtered into a round-bottomed flask and distilled using a short Vigreaux column to provide 5.43 g (23.2 mmole, 75.0 percent yield) of the N-trimethylsilyl-2,6-dichloroaniline as a 97 percent pure amber oil, bp 74° C.-75° C. at 0.4 mm.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[C:7]2=[O:13].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:64]=[CH:63][C:62]([CH2:65][C:66](O)=[O:67])=[CH:61][CH:60]=1>>[Cl:12][C:11]1[C:2]([NH:1][C:66](=[O:67])[CH2:65][C:62]2[CH:61]=[CH:60][C:59]([C:58]([F:69])([F:57])[F:70])=[CH:64][CH:63]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:13])[N:6]([C@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:5]=[CH:4]2
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: C[C@H](C(N)=O)n1ccc2c(N)c(Cl)ccc2c1=O
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: C[C@H](C(N)=O)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)cc3)c(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propanamide (50 mg, 0.0002 mol), N,N-dimethylformamide (1 mL, 0.01 mol), N,N-diisopropylethylamine (60 μL, 0.0004 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.0004 mol) and 2-(4-(trifluoromethyl)phenyl)acetic acid (46 mg, 0.00022 mol) and the reaction stirred at room temperature overnight. The reaction was only 60% complete. Stirring for an additional 6 hours did not improve the reaction. The solvent was removed and the residue purified by preparative HPLC (reverse phase) to obtain the product as an off white solid. MS m/z=452.2 (M+H). 1H NMR (400 MHz; DMF) δ 10.41 (s, 1H), 8.34 (d, J=8.71 Hz, 1H), 7.93 (d, J=8.22 Hz, 1H), 7.84 (d, J=10.96 Hz, 1H), 7.80 (t, J=9.13 Hz, 1H), 7.68 (d, J=8.53 Hz, 1H), 7.44 (bs, 1H), 6.62 (d, J=7.89 Hz, 1H), 5.67-5.61 (q, J=7.24 Hz, 1H), 4.09 (s, 2H), 1.72 (d, J=7.50 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=O)[CH2:4][C:5]1([CH3:17])[CH2:9][C:8]2[C:10]([CH3:16])=[CH:11][C:12]([CH3:15])=[C:13]([CH3:14])[C:7]=2[O:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:17][C:5]1([CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])[CH2:9][C:8]2[C:10]([CH3:16])=[CH:11][C:12]([CH3:15])=[C:13]([CH3:14])[C:7]=2[O:6]1
Reactant: Cc1cc(C)c2c(c1C)OC(C)(CC(=O)N(C)C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(c1C)OC(C)(CCN(C)C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
N,N-dimethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl acetamide (3.1 g, 11.9 mmol) was dissolved in tetrahydrofuran (50 ml) and lithium aluminum hydride (0.45 g) was added slowly under cooling. The reaction mixture was stirred for 30 minutes at room temperature and then poured into ice-cold water. The product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (chloroform-methanol, 95:5) to obtain the desired compound (2.2 g, yield: 81.6%) as oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=1)[CH2:31][N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[C:13]([C:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)=[O:12])=[CH:14]1
Reactant: ClCc1cccc(Cl)c1
Reactant: O=C(c1ccc2c(c1)OCCO2)c1c[nH]c2ccccc2c1=O
Product: O=C(c1ccc2c(c1)OCCO2)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Yield: 24.4 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 3-(2,3-Dihydro-benzo[1,4]dioxine-6-carbonyl)-1H-quinolin-4-one 70 mg (0.228 mmol) and 71.1 mg (0.296 mmol) 1-Chloro-3-chloromethyl-benzene, to give 24 mg of desired compound. LCMS (M+H)+: 432.
Reaction SMILES: [CH:1]1([CH2:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCC.[CH:14](OCC)=[O:15]>O1CCCC1>[CH:1]1([CH:6]([C:7]#[N:8])[CH:14]=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC1CCCC1
Reactant: CCOC=O
Solvent: C1CCOC1
Solvent: CCCCC
Product: N#CC(C=O)C1CCCC1
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-cyclopentylacetonitrile (0.50 g, 4.59 mmol) in tetrahydrofuran (10 mL) was cooled to −60° C. then treated with 1.7 M tert-buytllithium in pentane (3.25 mL, 5.50 mmol) while maintaining the reaction temperature at less than −55° C. The solution was stirred for 10 minutes then ethyl formate (0.41 g, 5.50 mmol) was added dropwise. The mixture was warmed to ambient temperature and stirred an additional 16 hours. The mixture was concentrated under reduced pressure and the resulting residue applied to a silica gel column and eluted with dichloromethane/ethyl acetate (95:5). The fractions containing material with an Rf of 0.1–0.3 [TLC, dichloromethane/ethyl acetate (95:5), potassium permanganate stain) were combined and concentrated to give an oil which was used without further purification: 1H NMR (Chloroform-d, 400 MHz) δ 9.57 (s, 1H), 3.54 (d, 1H), 2.45 (m, 1H), 1.4–1.9 (m, 8H).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]3[O:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([OH:17])[CH2:16][NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C(c2ccccc2)N2CCN(CC3CO3)CC2)cc1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(CNc1ccccc1)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 49.8 %

Procedure:
3.08 g (0.01 mol) of 1-(diphenylmethyl)-4-(2,3-epoxypropyl)piperazine and 0.93 g (0.01 mol) of aniline were refluxed with heating together with 200 ml of DMF for 21 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 4 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography by using solvent mixtures of ethyl acetate--methanol and methylene chloride--methanol respectively to obtain 2 g of the subject compound as yellow crystals.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[N:25]2[N:26]=[C:27](Cl)[CH:28]=[CH:29][C:24]2=[N:23][N:22]=1>>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:27]2[CH:28]=[CH:29][C:24]3[N:25]([C:21]([Cl:20])=[N:22][N:23]=3)[N:26]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2nnc(Cl)n2n1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Product: Clc1nnc2ccc(N3CCN(C(c4ccccc4)c4ccccc4)CC3)nn12

Procedure:
A mixture of 1-benzhydrylpiperazine and 3,6-dichloro-1,2,4-triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 2 to give 6-(4-benzhydrylpiperazin-1-yl)-3-chloro-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-])=O)[C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C.CO.[Ni]>[CH3:1][N:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25])[C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C(=O)CCCCCCC(=O)c1ccccc1)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C(=O)CCCCCCC(=O)c1ccccc1)c1ccccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a solution of amide 87 (420 mg, 1.14 mmol) in a mixture of ethyl acetate and methanol (5 mL, 9:1) was added catalytic amount of a suspension of Raney Nickel. The mixture was stirred at room temperature under hydrogen pressure for 2 hours and then without pressure for 10 hours. The reaction mixture was filtered through a short pad of Celite and the solvents were removed in vacuo. Purification by flash silica gel chromatography (2% methanol in dichloromethane) afforded the corresponding amide 88 (180 mg, 47% yield). 1H NMR (300 MHz, CDCl3): δ 7.96-7.90 (m, 2H), 7.58-7.41 (2 m, 4H), 7.17-7.10 (m, 1H), 6.98 (dd, J=1.5, 7.5 Hz, 1H), 6.80-672 (m, 2H), 3.18 (s, 3H), 2.91 (t, J=7.2 Hz, 2H), 2.15-1.95 (m, 2H), 1.73-1.51 (m, 4H), 1.35-1.20 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:31])[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH2:14][C@H:13]([NH:22][C:23]([O:25]C(C)(C)C)=O)[C:12]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9](=[O:31])[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([C:33]([O:35][CH3:36])=[O:34])[CH2:14][C@H:13]([NH:22][C:23](=[O:25])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N1C[C@H](NC(=O)c2ccccc2)C(=O)N(CC(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 201.3 %

Procedure:
A vigorously-stirred, 0° C. solution of (3S)-2-oxo-3-(benzoylamino)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid benzyl ester (600b) (461 mg, 1.07 mmol) in THF (5 ml) and sat. aq. NaHCO3 (2.5 ml) was treated with a THF solution (0.35 ml) of methyl chloroformate (151 mg, 1.6 mmol) and the reaction was stirred for 45 min at RT. The reaction was poured onto CH2Cl2 and washed with H2O, dried over Na2SO4 and concentrated in vacuo. Chromatography (flash, SiO2, 0% to 10% MeOH/CH2Cl2) gave 525 mg of 602j as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[NH4+].[H][H]>CO.[Ni]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][NH2:15])=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: N#Cc1cncnc1-c1ccc(F)cc1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCc1cncnc1-c1ccc(F)cc1
Yield: 32 %

Procedure:
A mixture of 4-(4-fluorophenyl)pyrimidine-5-carbonitrile (1.0 equiv.) and Raney-nickel (20 mol %) in MeOH (0.1 M) was degassed under vacuum and followed by the addition of 30% ammonium hydroxide (10 equiv.). The resulting mixture was hydrogenated with hydrogen gas at room temperature overnight. The mixture was filtered through a pad of celite and the cake was rinsed with MeOH. The filtrate was concentrated and further dried to give a brown oil, which was purified by silica gel column chromatography (0-10% MeOH in DCM, 25 g column) to give the title compound (32% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ (ppm) 9.19 (s, 1H), 8.88 (s, 1H), 7.71-7.78 (m, 2H), 7.17-7.24 (m, 2H), 3.99 (s, 2H), 1.41 (br. s., 2H). MS (ESI) m/z 204.1 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[NH2:52][C:53]1[CH:54]=[C:55]2[N:61]=[C:60]([CH3:62])[N:59]([CH3:63])[C:56]2=[N:57][CH:58]=1>CN(C=O)C>[CH3:62][C:60]1[N:59]([CH3:63])[C:56]2=[N:57][CH:58]=[C:53]([NH:52][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:21])[CH:54]=[C:55]2[N:61]=1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Cc1nc2cc(N)cnc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc2n1C
Temperature: 20 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution, stirred at 20° C., of 0.25 g (0.87 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid prepared in step 1.1, 183 mg (0.96 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and 129 mg (0.96 mmol) of 1-hydroxybenzotriazole (HOBT) in 8 mL of DMF are added 130 microliters (0.96 mol) of triethylamine and then 224 mg (1.13 mmol) of 6-amino-2,3-dimethyl-3H-imidazo[4,5-b]pyridine hydrochloride (Ukrainskii Khimicheskii Zhurnal 1981, 47, 867). The reaction mixture is stirred for 8 hours at 20° C. and then concentrated under reduced pressure. The resulting product is taken up in 100 mL of water, and a precipitate is collected by filtration and is purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. The fractions containing the product are combined and evaporated to a quarter of their volume. 50 mL of n-heptane are added to the solution, and a solid is collected by filtration and dried under reduced pressure. 150 mg of the expected product are thus isolated.
Reaction SMILES: [CH2:1]([C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[CH2:12][C:11]2[CH:17]=[C:18]([C:21](OC(C)(C)C)=[O:22])[CH:19]=[CH:20][C:10]=2[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[CH2:38][NH:39][CH3:40].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[CH2:1]([C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[CH2:12][C:11]2[CH:17]=[C:18]([C:21]([N:39]([CH3:40])[CH2:38][C:30]3[N:29]([CH3:28])[C:37]4[C:32]([CH:31]=3)=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:22])[CH:19]=[CH:20][C:10]=2[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: CN1Cc2cc(C(=O)OC(C)(C)C)ccc2N[C@H](Cc2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccc2c(c1)CN(C)C(=O)[C@@H](Cc1ccccc1)N2
Yield: 99 %

Procedure:
According to the procedure of Example 8, except using tert-butyl (2R)-2-benzyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.75 g, 2.1 mmole), 1-methyl-2-(methylaminomethyl)indole (0.34 g, 2.1 mmole), Et3N (0.59 mL, 4.2 mmole), HOBt H2O (0.28 g, 2.1 mmole), and EDC.HCl (0.41 g, 2.1 mmole), the title compound (0.97 g, 100%) was prepared as an off-white solid following flash chromatography on silica gel (gradient: 80-90% EtOAc/hexanes): MS (ES) m/e 467.1 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2].CC(O)=[O:42]>>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33](=[O:42])[CH3:34])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 22 h

Procedure:
To a stirred solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-ethylbenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (intermediate AX) (10 g, 10.83 mmol) (prepared by methods analogous to those described in US20040138439) in AcOH (130 mL) at 120° C. was added K2CrO7 (6.3 g, 21.42 mmol) in one position. The mixture was stirred for 22 h at the same temperature. Volatiles were removed under reduced pressure, AcOEt was added, and the solids were removed by filtration. The organic layer was washed with a saturated solution of NaHCO3 and brine prior to drying over Na2SO4. Concentration of the organic solution and purification of the resulting residue by silical gel column (PE:EA=3:1) provided intermediate AY (2.3 g).
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH3:21][O:1][CH:2]1[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]
Reactant: CI
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1C(N2CCCC2=O)c2sccc2OC1(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 71.3 %

Procedure:
5,6-Dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (1.1 g, 4.11 mmol) was added to a mixture of sodium hydride (60% in mineral oil, 0.172 g, 4.32 mmol) in N,N-dimethylformamide (20 ml) at 0° C. and stirred for 1.5 h. Methyl iodide (0.28 ml, 4.52 mmol) was added to the resultant mixture and the mixture stirred at rt for 1 h. The mixture was poured into ice water (100 ml) and extracted with dichloromethane. The dichloromethane solution was washed with water (5×) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from dichloromethane and hexanes to give the product 0.825 g (71%) as a colorless solid; mp 117°-118° C.; IR(KBr): 2979, 1677, 1572 and 1420 cm-1 ; MS: m/z 282 (MH+); 1H NMR (CDCl3): δ1.27 (s, 3H), 1.48(s,3H), 2.05(m,2H), 2.50(m,2H), 3.33(m,2H), 3.41(d,J=8.8 Hz, 1H), 3.51(s,3H), 5.33(d,J=8.8 Hz, 1H), 6.55(d,J=5.4 Hz, 1H) and 7.09(d,J=5.4 Hz, 1H).
Reaction SMILES: O.Cl.[NH2:3][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[Na+].[C:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:17]=2[N:18]=1)#N.Cl>CO.O>[CH2:5]1[S:6]/[C:12](=[C:14]2/[N:18]=[C:17]3[C:16]([S:15]/2)=[CH:22][C:21](=[O:23])[CH:20]=[CH:19]3)/[NH:3][C@H:4]1[C:7]([OH:9])=[O:8]
Reactant: N[C@H](CS)C(=O)O
Reactant: N#Cc1nc2ccc(O)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1C=Cc2n/c(=C3\N[C@@H](C(=O)O)CS3)sc2=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
685 mg. (3.9 mMol) D-cysteine hydrochloride monohydrate are dissolved in 13 ml. water which has been previously gassed with nitrogen. A pH value of 8 is adjusted, under an atmosphere of nitrogen, with about 6 ml. of a 1N aqueous sodium hydroxide solution and then a solution of 528 mg. (3 mMol) 2-cyano-6-hydroxybenzothiazole in 22 ml. methanol (analytically pure) is added thereto under an atmosphere of nitrogen. The yellow solution is stirred under an atmosphere of nitrogen and with the exclusion of light for 1 hour at ambient temperature. Subsequently, the solution is acidified with 3 ml. of 2N hydrochloric acid and left to stand for about 3 hours at 4° C. The precipitated crystals are filtered off with suction under an atmosphere of nitrogen, washed with methanol and water (1:1 v/v) and dried in a desiccator with the exclusion of light. 0.75 g. D-Luciferin are obtained, which corresponds to a yield of 89.3% of theory. The compound melts at 187°-188° C., with decomposition, and is chromatographically identical with the product known from the literature but contains small amounts of impurities.