Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:6](=[O:7])[NH:5][NH:4][C:3]1=[O:8].[C:18]([O:24][CH3:25])(=[O:23])[CH:19]=[CH:20][CH:21]=[CH2:22].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>ClCCl>[CH3:1][C:2]1([CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:6](=[O:7])[N:5]2[CH2:22][CH:21]=[CH:20][CH:19]([C:18]([O:24][CH3:25])=[O:23])[N:4]2[C:3]1=[O:8]
Reactant: CC1(CCOC2CCCCO2)C(=O)NNC1=O
Reactant: C=CC=CC(=O)OC
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: ClCCl
Product: COC(=O)C1C=CCN2C(=O)C(C)(CCOC3CCCCO3)C(=O)N12
Temperature: 25 °C
Yield: 38.4 %

Procedure:
(B)(b) A mixture of 14.52 g (0.06 mol) of 4-methyl-4-[2-(tetrahydro-2-pyranyloxy)ethyl]pyrazolidine-3,5-dione and 6.72 g (0.066 mol) of methyl penta-2,4-dienoate in 150 ml of dry dichloromethane was stirred at room temperature under a stream of nitrogen. A solution of 26.64 g (0.06 mol) of lead tetraacetate in 100 ml of dry dichloromethane was added dropwise, the blue color being allowed to fade between additions. When the addition was complete and no blue color persisted, the resulting suspension was filtered. The filtrate was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated to give 8.12 g (38%) of methyl 2,3,5,8-tetrahydro-2-methyl-1,3-dioxo-2-[2-(tetrahydro-2-pyranyloxy)ethyl]-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate having a melting point of 126.5°-127.6° C. (from diethyl ether).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]#[N:11])[CH2:5][OH:6].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C(OC)(C)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]#[N:11])[CH:5]=[O:6]
Reactant: N#Cc1ccc(CO)cc1F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: N#Cc1ccc(C=O)cc1F

Procedure:
A solution of 22 g of 3-fluoro-4-cyanobenzyl alcohol in 50 ml of methylene chloride is added, with stirring, to 48 g of PCC in 150 ml of methylene chloride. After one hour 300 ml of methyl tert.-butyl ether are added to the reaction mixture and the latter is filtered, with the addition of Celite. Removing the solvent and recrystallising the residue from aqueous ethanol gives 3-fluoro-4-cyanobenzaldehyde, m.p. 83°-85°, IR (cm-1): 3089, 2880, 2239, 1699, 1571, 1499, 1486, 1428, 1392, 1299, 1251, 1140, 1111, 971, 900, 839, 753; 1H-NMR (200 MHz): (ppm): 7.7-8.0 (m, 3H, aromatic), 10.1 (s, 1H, CHO).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)#[N:2].[N-:19]=[N+:20]=[N-:21].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[C:12]1([C:9]2[C:8]3[CH:18]=[C:4]([CH2:3][C:1]4[NH:21][N:20]=[N:19][N:2]=4)[CH:5]=[CH:6][C:7]=3[O:11][CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1ccc2occ(-c3ccccc3)c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2coc3ccc(Cc4nnn[nH]4)cc23)cc1

Procedure:
A mixture of 4.6 g. (0.02 mole) of 5-cyanomethyl-3-phenylbenzofuran, 1.5 g. of sodium azide and 1.2 g. of ammonium chloride in 15 ml. of N,N-dimethylformamide is heated at 110° C. for 20 hours. The reaction mixture is poured into 200 ml. of water and stirred. The mixture is extracted with 50 ml. of chloroform. The extracts are washed with water, then dried over magnesium sulfate. Evaporation provides a residue which is recrystallized from ethyl acetate to provide 3-phenyl-5-(1H-tetrazol-5yl)methylbenzofuran.
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[C:31](=[O:32])[N:23]3[CH:24]([C:29]#[N:30])[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:33]=[N+:34]=[N-:35].[Na+].Cl.CN1CCCCC1>C(Cl)(Cl)Cl>[C:1]1([C:7]([NH:20][CH:21]2[C:31](=[O:32])[N:23]3[CH:24]([C:29]4[NH:35][N:34]=[N:33][N:30]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C#N
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN1CCCCC1
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1

Procedure:
A mixture of 6-triphenylmethylamino-2,2-dimethyl-3-cyanopenam (10 g. 0.0193 mole) sodium azide (7.41 g., 0.114 mole), N-methylpiperidine hydrochloride (3.39 g., 0.025 mole) and chloroform (100 ml.) is refluxed for four hours in a round-bottomed flask equipped with stirrer, condenser, and drying tube. The reaction mixture is then cooled and water (300 ml.) and chloroform (100 ml.) added. The mixture is thoroughly mixed, the chloroform layer separated and washed successively with 1N hydrochloric acid (100 ml.) and saturated brine (100 ml.). It is then filtered quickly through anhydrous sodium sulfate and concentrated under reduced pressure to about 75 ml. Hexane (20 ml.) is added to the concentrate to precipitate the product as white crystals. The crystals are recovered by filtration, washed with 20% hexane-methylene chloride (50 ml.) and dried in vacuo at room temperature. Yield = 2.7 g. (29.6%) m.p. 133°-136° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH:16][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2F)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(CNS(C)(=O)=O)c2ccccc2F)CC1
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
To a solution of 4-[2-Amino-1-(2fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (207) (0.71 g, 2.19 mmol) in THF (5 mL) at 0° C. was added diisopropylethylamine (0.42 mL, 2.42 mmol). The solution was allowed to stir for 10 min. Methansulfonyl chloride (0.17 mL, 2.19 mmol) was then added and the solution was allowed to stir at room temperature for 18 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with brine (50 mL) and H2O (50 mL). The organic phase was concentrated to dryness yielding 0.86 g (98%) product.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[CH:5]2[CH2:11][CH:12]=1.[S].BrBr>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: CC1=CCC2C(=O)OC(=O)C2C1
Agent: BrBr
Agent: [S]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(=O)OC2=O
Yield: 16 %

Procedure:
Various processes are known for preparing substituted phthalic anhydrides. In two such processes 4-methyl-1,2,3,6-tetrahydrophthalic anhydride is dehydrogenated either by sulfur or by bromine in acetic acid. Yields of 4-methylphthalic anhydride of 59 percent to 87 percent are claimed for the former method, while the latter gives only a 16 percent yield [see Izv. Akad. Nauk. SSSR, Ser. Khim., 6, 1315 (1973) English translation, page 1271 and D. Craig, Journal of American Chemical Society, Vol. 72, page 3732, (1950)].
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.[H][H]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)O
Yield: 85.6 %

Procedure:
2.0 g (4.66 mmoles) of Z-Glp-Leu-pyrrolidine are dissolved in 40 ml of methanol, 0.4 g of a 10% palladium-on-carbon catalyst are added to the solution, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, the oily residue is dissolved in ether, and the solution is allowed to stand at a cool place overnight. The separated crystals are filtered off to obtain 1.25 g (91%) of Glp-Leu-pyrrolidine; m.p.: 103°-104° C., Rf5 =0.65, [α]D25 =-31.6° (c=1%, in acetic acid). Analysis for amino acids: Glu=1.00 (1.0), Leu=1.00 (1.0).
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[CH3:11][NH:12][C:13]([NH:15][CH3:16])=[O:14].C1(C)C=CC=CC=1>O>[Cl-:10].[O:14]=[C:13]1[N:15]([CH3:16])[CH2:6][P+:3]2([CH2:1][N:15]([CH3:16])[C:13](=[O:14])[N:12]([CH3:11])[CH2:4]2)[CH2:8][N:12]1[CH3:11]
Reactant: CNC(=O)NC
Reactant: OC[P+](CO)(CO)CO
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C[P+]2(CN(C)C1=O)CN(C)C(=O)N(C)C2
Yield: 88.9 %

Procedure:
A mixture of THPC (19.06 g, 0.1 mol), 1,3-dimethylurea (17.62 g, 0.2 mol), and toluene (150 ml) was heated to reflux in an apparatus fitted with a mechanical stirrer and a Dean-Stark trap for azeotropic removal of the water. The mixture was held at reflux unitl the evolution of water ceased (4 hr); this condensation, as might be expected, required a longer reflux period and more efficient stirring to displace the last of the water than that of Example 1. Half of the 7.2 ml (100.0%) of water was collected during the first 15 min. The product, which separated during the reaction as a mass of white solids, was broken up, triturated under acetonitrile to remove a resinous by-product (4.09 g), filtered, rinsed with acetonitrile and dried, giving 26.21 g (86.3%) of 3,9-dioxo-2,4,8,10-tetramethyl-2,4,8,10-tetraaza-6-phosphoniaspiro[5.5]undecane chloride (II, R=R'=CH3, X=Cl) as a white, crystalline solid. Two recrystallizations from 2-propanol (12 ml/g) gave pure product, mp 161°-162° C. and resolidifying, then mp 217° C. dec.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[CH3:12][NH:13][CH3:14].C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:12][N:13]([CH3:14])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CN(C)c1ccc([N+](=O)[O-])cn1
Temperature: 80 °C

Procedure:
2-Chloro-5-nitropyridine (3.57 g, 22.5 mmol), dimethylamine hydrochloride (5.50 g, 67.5 mmol) and diisopropylethylamine (13.7 mL, 78.7 mmol) were combined in DMSO (15 mL) and the reaction mixture was heated at 80° C. for 4 h. After cooling to RT, water was added and the desired N,N-dimethyl-5-nitropyridin-2-amine was isolated by filtration and used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[C:8]1([Mg]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[C:8]1([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cnccn1
Reactant: Br[Mg]c1ccccc1
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(-c2cnccn2)cc1
Reaction time: 1.33 h
Yield: 39 %

Procedure:
Chloropyrazine (20.68 gram, 177 mmol) and [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride (41.08 gram, 77.8 mmol) in dry THF (1.5 liter) were mixed and stirred for 80 minutes in a flask (cooled with a water bath) under nitrogen. A solution of phenylmagnesium bromide (3M in Et2O) (103 ml, 309 mmol) was added slowly through a dropping funnel into the cooled brick-red slurry at room temperature under nitrogen over 3.5 hours. After stirring at room temperature overnight, TLC showed that the reaction was complete. 3 N HCI (100 ml) was added slowly through a dropping funnel under nitrogen and the mixture was stirred for one hour. The THF layer was separated from the aqueous layer. The aqueous layer was adjusted to pH 12 with 6 N NaOH and extracted with EtOAc (100 ml, 3×). The organic fractions (THF and EtOAc) were combined and dried over MgSO4, filtered and concentrated to give a solid. The product was purified by flash chromatography on 300 g of flash grade silica gel in 2.5% EtOAc/CH2Cl2 to give 10.79 gram (69 mmol, 39%) of 2-phenylpyrazine, m.p. 69°-70° C.; FAB mass [M+1]+ 157;
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].O.[C:7]1([CH3:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH3:1][O:2][CH2:13][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:9][CH2:8]1
Reactant: Cc1ccccc1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COC[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 25 °C

Procedure:
Slices of metal Na (17.4 g, 0.755 mol) were added in small portions to methyl alcohol (250 ml) agitated at room temperature to prepare sodium methoxide. After metal Na pieces disappeared, a solution obtained by dissolving the compound (IV) (200.0 g, 0.581 mol) obtained above, in dry toluene (600 ml), was gradually added through a dropping funnel so that the inner temperature could keep within a range of 50° to 60° C. After completion of the addition, the mixture was refluxed for 4 hours, followed by cooling, adding water (20 ml), transferring into a separating funnel, washing the resulting toluene layer with water until the aqueous layer became neutral, distilling off toluene under reduced pressure, distilling under reduced pressure and collecting fractions of boiling points of 105°~108° C./1.5 mmHg to obtain trans-4-methyloxymethyl-1-phenylcyclohexane (V) (100.0 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[OH:19])([O-])=O.NCCCN.O>C1(C)C(C)=CC=CC=1>[OH:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: NCCCN
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1

Procedure:
To a 1000-ml. round-bottomed, three-neck flask fitted with a gas inlet tube, stirrer and reflux condenser is added 20.0 grams (0.08 mol) of 2-nitro-2'-hydroxy-5'-methylazobenzene (99.7% pure) dissolved in a solution of 200 ml of xylene. To this solution is added with stirring a mixture of 23.0 grams (0.32 mol) of 1,3-diaminopropane, 100 ml of water and 4 grams (0.02 mol) of cupric acetate. Carbon monoxide gas is then bubbled through the stirred reaction mixture for 15-20 hours with the temperature being maintained at 85°-90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[N:10]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH3:19][C:20](=[O:25])[CH2:21][C:22](=[O:24])[CH3:23]>Cl.O.C(O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][N:10]=[C:21]([C:20](=[O:25])[CH3:19])[C:22](=[O:24])[CH3:23])=[CH:3][CH:4]=1
Reactant: O=N[O-]
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(NN=C(C(C)=O)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
4-Amino-anisole (15 g, 0.12 mol) was dissolved in a mixture of concentrated hydrochloric acid (36 ml) and water (36 ml). To the resulting mixture was added dropwise at 5° C. a solution of sodium nitrite (9.2 g, 0.13 mol) in water (45 ml). The resulting diazonium salt was added to a mixture of sodium acetate (30 g, 0.37 mol), ethanol (125 ml) and pentane-2,4-dione (12.2 g, 0.12 mol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The precipitate was filtered off and washed with water (2×150 ml), ethanol (2×50 ml) and dried in vacuo at 50° C. for 18 h affording 17 g (60%) of 3-[(4-methoxy-phenyl)-hydrazono]-pentane-2,4-dione as a solid.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1.O1CCCC1.N1C=CC=CC=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[C:6](=[O:16])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:9](=[N:17][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cnccn1
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)C1=CC(=Nc2cnccn2)C=C(C(C)(C)C)C1=O
Temperature: 25 °C

Procedure:
A 47 g quantity of 2,6-di-tert-butyl-1,4-benzoquinone and 20 g of aminopyrazine were added to 300 ml of tetrahydrofuran and dissolved therein with heating. To the solution was added a yellow suspension (whichhad been prepared by adding 12 ml of titanium tetrachloride dropwise with ice-cooling and stirring to a solution of 35 ml of pyridine in 200 ml of dichloroethane), and the mixture was refluxed with heating for 1 hour. To the reaction mixture was added a suspension of 70 ml of pyridine, 24 ml oftitanium tetrachloride and 200 ml of dichloroethane. The resulting mixture was refluxed with heating for 2 hours. Again a suspension of 17 ml of pyridine, 6 ml of titanium tetrachloride and 100 ml of dichloroethane was added thereto and the resulting mixture was refluxed with heating for 30 minutes. Then, the reaction mixture was cooled to room temperature and filtered through a Celite pad and the insoluble materials were washed there with ethyl acetate. The filtrate was concentrated and the resulting crude product was purified by silica gel column chromatography (eluent: diethyl ether-hexane=1:10→1:1), and washed with cold hexane, thereby giving 58 g of 2,6-di-tert-butyl-4-pyrazinylimino-2,5-cyclohexadien-1-one (Compound 1a) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH2:21].[NH4+].[OH-]>>[CH3:17][O:18][C:19](=[O:34])[C@H:20]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[NH:21][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and Nε-(tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=119-121° C.). The reaction was monitored by tlc (Rf=0.46 in 90:10:1 CH2Cl2MeOH\NH4OH).
Reaction SMILES: O1CCC(C(O)=O)CC1.[CH2:10]([O:13][CH2:14][CH2:15]Cl)[CH2:11]Cl.[Na].[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[O:13]1[CH2:14][CH2:15][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:18]([O:26][CH2:27][CH3:28])=[O:25])[CH2:11][CH2:10]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCCOCCCl
Agent: O=C(O)C1CCOCC1
Agent: [Na]
Product: CCOC(=O)C1(C(=O)OCC)CCOCC1

Procedure:
According to the statements in J. Chem. Soc., 2525-30 (1930) esters of tetrahydropyran-4-carboxylic acid can be prepared by treating 2,2'-dichlorodiethyl ether with the sodium salt of diethyl malonate to form diethyl tetrahydropyran-4,4-dicarboxylate, hydrolyzing to obtain tetrahydropyran-4,4-dicarboxylic acid, decarboxylating to tetrahydropyran-4-carboxylic acid, and finally esterifying.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:29][CH2:30][CH3:31])[CH:28]=1)[CH:24]=O)[CH3:19].O>CO>[CH2:30]([O:29][C:27]1[CH:26]=[C:23]([CH:22]=[C:21]([O:20][CH2:18][CH3:19])[CH:28]=1)[CH2:24][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4])[CH3:31]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1
Solvent: O
Solvent: CO
Product: CCOc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OCC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 53.5 %

Procedure:
To a solution of the amine (4) (127 mg, 0.486 mmol) and 3,5-diethoxybenzaldehyde (123 mg, 0.632 mmol) in methanol (3.3 mL) was added borane-pyridine complex (155 μL, 1.46 mmol) at 40° C. and the resulting mixture was stirred for 2.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (10) as a yellow solid (114 mg, Yield: 54%).
Reaction SMILES: [F:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]([F:15])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]>[Pd].CCO>[NH2:12][C:11]1[C:2]([F:1])=[C:3]([C:8]([F:15])=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)ccc([N+](=O)[O-])c1F
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1c(F)ccc(N)c1F
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
10% (wt.) Pd on activated carbon (4.46 g, 4.19 mmol) was added to a 1 L flask charged with methyl 2,6-difluoro-3-nitrobenzoate (18.2 g, 83.8 mmol) under a nitrogen atmosphere. EtOH (350 mL, 0.25 M) was added, and then H2 was passed through the reaction mixture for 15 minutes. The reaction mixture was stirred under two H2 balloons overnight. The following day the reaction mixture was re-flushed with fresh H2 balloons and stirred an additional 4 hours. Upon consumption of the starting material and intermediate hydroxylamine as determined by TLC, N2 gas was flushed through the reaction mixture. The mixture was then filtered through glass microfibre filter (“GF/F”) paper twice. The volatiles were removed to afford methyl 3-amino-2,6-difluorobenzoate as an oil (15.66 g, 99%). The material was taken directly onto the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:10][C:6]1[C:5]([F:8])=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:7]=1
Reactant: Oc1cc(F)ccc1F
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Oc1cc(F)c(Br)cc1F
Reaction time: 3 h

Procedure:
To 2,5-difluorophenol (594, 5.50 g, 0.0423 mol) in chloroform (110.0 mL), bromine (2.18 mL, 0.0423 mol) was added slowly. After 3 hours, the reaction was poured into a solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a colorless oil (595, 6.20 g, 70.2%).
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>>[O:19]1[CH2:18][CH:17]1[CH2:15][O:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Reactant: ClCC1CO1
Product: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12

Procedure:
deprotection of 9-benzenesulfonyl-9H-carbazol-4-ol to give 4-hydroxy-carbazole reaction of 4-hydroxy-carbazole with epichlorohydrin under basic conditions to give 4-oxiranylmethoxy-9H-carbazole;