Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([NH2:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[S:21]>C(O)(=O)C.C(OCC)(=O)C.CCOCC>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:7](=[O:9])[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=2)[NH:11][C:20]1=[S:21]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: S=C=Nc1ccccc1Cl
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=c1c2cc(F)ccc2[nH]c(=S)n1-c1ccccc1Cl
Yield: 71.9 %

Procedure:
A solution of 1.04 g (6.71 mmol) of 5-fluoroanthranilic acid and 1.13 g (6.71 mmol) of 2-chlorophenylisothiocyanate in 10 ml of glacial acetic acid was refluxed for 2.5 hours. The reaction mixture was cooled and the acetic acid was evaporated to give a yellow solid residue, which was taken up in ethyl acetate and ether. The solid was filtered off and washed with ether and air dried to give 1.48 g (72%) of the desired product, m.p. 295-297° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH3:24])[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[CH3:24][C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC1(NC(=O)OC(C)(C)C)CCNC1
Yield: 96 %

Procedure:
Benzyl 3-(tert-butoxycarbonylamino)-3-methylpyrrolidine-1-carboxylate (2.00 g, 5.98 mmol) and 10% Pd/C (0.32 g, 0.30 mmol) in MeOH (20 mL) were stirred under 1 atmosphere of H2 for 1 hour. The catalyst was removed by filtration and washed with methanol. The filtrate was concentrated to give tert-butyl 3-methylpyrrolidin-3-ylcarbamate (1.15 g, 96%) as a solid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[S:24][CH:25]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4cccnc4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4cccnc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.6 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-[2-(3-pyridyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionate (655 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 6 hours, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(3-pyridyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionic acid (537 mg, yield: 92%). This was recrystallized from ethanol. Melting point: 118–119° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:15][S:12]([C:9]1[CH:10]=[CH:11][C:2]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5])(=[O:14])=[O:13]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1Cl
Reactant: C1COCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1N1CCOCC1
Reaction time: 8 h

Procedure:
To a solution of methyl 2-chloro-5-methanesulfonylbenzoate (23.4 g, 94 mmol) in toluene (250 ml) were added morpholine (9.8 ml, 113 mmol), cesium carbonate (40 g, 122 mmol), palladium acetate (380 mg, 1.4 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.06 g, 1.7 mmol). After stirring overnight with heating under reflux, ethyl acetate (250 ml) was added. The organic layer was washed successively with water (200 ml×2) and saturated brine (200 ml), and dried over magnesium sulfate. Filtration and concentration gave methyl 5-methanesulfonyl-2-(morpholin-4-yl)benzoate as a crude product. The obtained compound was used for Step 4 without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20][C:21]1[C:22]([F:31])=[C:23]([C:27]([O:29][CH3:30])=[O:28])[S:24][C:25]=1Br.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.[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>[Br:20][C:21]1[C:22]([F:31])=[C:23]([C:27]([O:29][CH3:30])=[O:28])[S:24][C:25]=1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([C:18]#[N:19])[CH:11]=1
Reactant: COC(=O)c1sc(Br)c(Br)c1F
Reactant: N#Cc1cc(B(O)O)ccc1OCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccc(OCc3ccccc3)c(C#N)c2)c(Br)c1F

Procedure:
(4-Benzyloxy-3-cyanophenyl)boronic acid and methyl 4,5-dibromo-3-fluorothiophene-2-carboxylate were dissolved in a mixed solution of toluene and a 1 M aqueous sodium carbonate solution and the whole was heated at 110° C. for 2.5 days in the presence of tetrakis(triphenylphosphine)-palladium to obtain methyl 4-bromo-5-(4-benzyloxy-3-cyanophenyl)-3-fluorothiophene-2-carboxylate. Methyl 4-bromo-5-(4-benzyloxy-3-cyanophenyl)-3-fluorothiophene-2-carboxylate and triethylamine were stirred at room temperature in 1,4-dioxane under a hydrogen atmosphere at normal pressure in the presence of palladium-carbon to obtain methyl 5-(3-cyano-4-hydroxyphenyl)-3-fluorothiophene-2-carboxylate. FN: 276.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[C:6]([O:11]C)=[CH:5][C:4]=1[CH:13]=[O:14].B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1>[OH:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[C:6]([OH:11])=[CH:5][C:4]=1[CH:13]=[O:14]
Reactant: COc1cc(C=O)c(OC)cc1C=O
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: O=Cc1cc(O)c(C=O)cc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.5 g of 2,5-dimethoxybenzene-1,4-dicarboaldehyde (AD) and 25 mL of boron tribromide were dissolved in 150 mL of chlorobenzene and stirred at room temperature for 12 hours. After complete reaction, the reacted mixture was neutralized with sodium carbonate, followed by extraction with water and dichloromethane and recrystallization within dichloromethane, thereby obtaining 2,5-dihydroxybenzene-1,4-dicarboaldehyde. The obtained product exhibited yield, property and NMR analysis result as follows.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:17]=[C:16]([I:18])[CH:15]=[C:14](Cl)[N:13]=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:3]([O:10][C:14]1[CH:15]=[C:16]([I:18])[CH:17]=[C:12]([Cl:11])[N:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cc(I)cc(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium hydride (1.24 g, 31.0 mmol, 60 wt % in mineral oil) in THF (30.4 mL) at 0° C. was added benzyl alcohol (2.09 mL, 20.1 mmol) dropwise via syringe. After stirring at 0° C. for 30 mins, 2,6-dichloro-4-iodopyridine (5.00 g, 18.3 mmol) in THF (5 mL) was added dropwise via syringe. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction was cooled down to 0° C., and saturated aqueous ammonium chloride was slowly added to quench the reaction. The reaction mixture was allowed to warm to room temperature, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate. The organic layer was separated and the aqueous layer was back extracted two times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/ioshexane gradient) to give 2-(benzyloxy)-6-chloro-4-iodopyridine. LRMS (ESI) calculated for C12H10ClINO [M+H]+, 345.9; found 345.8.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9](F)=[C:8]2C=1C=[C:5]([C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[N:6]=[CH:7]2.CC1(C)C(C)(C)OB(C2C(N)=NC=CC=2)O1.ClC1[S:38]C2C=CC=CC=2N=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:38]1[C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=[C:5]1[C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1nc2ccccc2s1
Reactant: Nc1ncccc1-c1cc2c(Cl)ccc(F)c2cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)OB(c2cccnc2N)OC1(C)C
Agent: O=C([O-])[O-]
Product: Nc1ncccc1-c1nc2ccccc2s1

Procedure:
The title compound was prepared following the procedure for 3-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-2-ylamine, using 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (30.0 g, 136 mmol), 2-chlorobenzothiazole (16.5 g, 97 mmol), Pd(PPh3)4 (3.3 g, 3 mol %), and Cs2CO3 (72.6 g, 223 mmol). 1H NMR (CDCl3, 300 MHz): δ=6.71 (dd, J=6.8, 3.6 Hz, 1H), 7.13 (brs, 2H), 7.38 (t, J=8.4 Hz, 1H), 7.47 (t, J=8.4 Hz, 1H), 7.87 (d, J=6.0 Hz, 1H), 7.95 (dd, J=6.2, 1.5 Hz, 1H), 7.99 (d, J=6.0 Hz, 1H), 8.18 (dd, J=6.2, 1.2 Hz, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]#[N:37])=[CH:30][C:29]=2[CH2:38][CH:39]([CH3:41])[CH3:40])[CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:49][C:50]#[N:51].[Cl-].[Na+].O.O>CC(C)=O>[CH2:1]([C:8]1[CH:9]=[C:10]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]#[N:37])=[CH:30][C:29]=2[CH2:38][CH:39]([CH3:41])[CH3:40])[CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:49][C:50]#[N:51])=[C:16]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCCl
Reactant: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(-c2ccc(O)c(Cc3ccccc3)c2)c(Cc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(-c2ccc(OCC#N)c(Cc3ccccc3)c2)c(Cc2ccccc2)c1
Temperature: 55 °C
Reaction time: 40 h
Yield: 96.2 %

Procedure:
To a suspension of 136.8 mg (0.26 mmol) 3-(3′,3″-Dibenzyl-4″-hydroxy-2-isobutyl-1,1′:4′,1″-terphenyl-4-yl)propanenitrile (28) and 184.9 mg (1.34 mmol, 5.2 eqv) K2CO3 in 12 ml acetone, 0.17 ml (2.69 mmol, 10.3 eqv) chloroacetonitrile was added. The resulting mixture was stirred for 40 h at 55° C. and then added to 40 ml of a mixture of brine/water (1+1). After extraction with EtOAc the combined org. fractions were washed with brine, dried over MgSO4 and evaporated. Column chromatography (Hexanes/EtOAc (2+1)) yielded 144.9 mg (0.25 mmol, 97%) 29 as a colorless oil: Rf (Hexanes/EtOAc (2+1)) 0.33; 1H NMR (500 MHz, CDCl3) δ 0.70 (d, 6H, J=6.62 Hz), 1.64 (m, 1H), 2.44 (d, 2H, J=7.41 Hz), 2.62 (t, 2H, J=7.41 Hz), 2.94 (t, 2H, J=7.41 Hz), 3.92 (s, 2H), 3.94 (s, 2H), 4.71 (s, 2H), 6.92 (m, 3H), 7.03-7.18 (m, 14H), 7.20-7.26 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 19.38, 21.04, 22.39, 29.53, 31.33, 35.96, 39.11, 42.02, 53.96, 111.86, 115.18, 119.18, 125.39, 125.79, 126.07, 127.27, 128.27, 128.41, 128.52, 128.64, 128.76, 129.86, 129.94, 130.31, 130.55, 131.64, 132.33, 136.32, 136.78, 137.69, 139.77, 140.19, 140.88, 140.89, 141.40, 149.00, 153.60; LRMS (EI) m/z 575 (2), 574 (5), 535 (1), 501 (1), 446 (2), 409 (15), 408 (50), 369 (13), 91 (100); HRMS (EI) Calcd. for C41H38N2O: 574.298413. Found: 574.298309.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:6]2>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH:7]=[CH:6]2)=[O:1]
Reactant: CC(C)(C)OC(=O)Nc1ccc2cc(CO)ccc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc2cc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
The tert-butyl 6-(hydroxymethyl)-2-naphthylcarbamate (1.00 g, 3.66 mmol) obtained in the above 2) was dissolved in dichloromethane (18 ml), manganese dioxide (1.59 g, 18.3 mmol) was added thereto, and the mixture was stirred at room temperature for 4 hours. The insolubles were filtered, the filtrate was concentrated under reduced pressure., and crystallized from diisopropyl ether to obtain tert-butyl 6-formyl-2-naphthylcarbamate (889 mg) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]([CH3:17])[CH2:15][N:14](CC2C=CC(C#N)=C(NC(C3C=CC=CC=3)C3C=CC=CC=3)C=2)[C:13](=[O:41])[C@@H:12]1[CH3:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH:16]([CH3:17])[CH2:15][NH:14][C:13](=[O:41])[CH:12]1[CH3:42])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccc(C#N)c(NC(c3ccccc3)c3ccccc3)c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1CNC(=O)C(C)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 148.5 %

Procedure:
(2S,6RS)-4-[3-(Benzhydryl-amino)-4-cyano-benzyl]-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (2.6 g, 5.21 mmol) is dissolved in 100 mL of ethyl acetate and cooled to 0° C. A 12N solution of hydrochloric acid (0.5 ml, 6.0 mmol) is added dropwise. The deprotection is complete in thirty minutes. The reaction mixture is washed with 10% sodium bicarbonate. The ethyl acetate layer is dried with magnesium sulfate, filtered and condensed. The resulting residue is purified by flash colunm (SiO2, 60% ethyl acetate/hexane) to give the product (2S,6RS)-4-(3-amino)-4-cyano-benzyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (2.03 g, 99%).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[I-:32].[Cs+].COCCOC.N(OCCC(C)C)=O>CO.[Cu]I>[I:32][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1
Reactant: [I-]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: [Cs+]
Solvent: CO
Solvent: COCCOC
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4I)ncn3)cccc2s1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To N-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 151), (0.25 g, 0.56 mmol) was added CsI (0.15 g, 0.56 mmol, Aldrich), 12 (0.071 g, 0.28 mmol, Aldrich), CuI (0.032 g, 0.17 mmol, Aldrich) and ethylene glycol dimethyl ether (6 mL). To the mixture was added isoamyl nitrite (0.45 mL, 3.4 mmol, Aldrich) and the reaction was stirred for 1 h at room temperature, at 65° C. for 3 h, and then at room temperature for 18 h. The reaction mixture was diluted with MeOH (2 M in NH3) and concentrated. The residue was taken up in MeOH and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 0.4 to 1.3% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a white solid. Mp: 242-243° C. MS (ESI, pos. ion) m/z: 557.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[N+:12]([O-])([O-:14])=[O:13].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1ccc2cnccc2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: Cc1ccc2cnccc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
6-Methylisoquinoline (2.00 g, 14 mmol) was taken up in sulfuric acid (25.0 mL) and the mixture cooled down to 0° C. The reaction was treated with potassium nitrate (2.8 g, 28 mmol) which was added in portions. After addition was complete, the reaction was stirred for about 1.5 h at 0° C. The reaction was poured onto crushed ice and basified with 5N NaOH. The solid that precipitated was collected by suction filtration, washed with water and dried to give the product (2.5 g, 95%) as a tan solid. MS (ESI, pos. ion) m/z: 189.1 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].Cl.Cl[C:13]([NH2:15])=[NH:14]>COCCOCCOC>[NH2:15][C:13]1[N:14]=[C:4]([NH2:5])[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:10])[N:1]=1
Reactant: N=C(N)Cl
Reactant: Cc1cccc(N)c1C#N
Agent: Cl
Solvent: COCCOCCOC
Product: Cc1cccc2nc(N)nc(N)c12
Yield: 86.9 %

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 1, using 10.0 grams (0.076 mole) of 2-amino-6-methylbenzonitrile (prepared as in Example 1, Step B), and 10.0 grams (0.087 mole) of chloroformamidine hydrochloride in 40 mL of 2-methoxyethyl ether, yielding 11.5 grams of 2,4-diamino-5-methylquinazoline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:17][O:16]3)[C:14]3[CH:13]=[C:12]([Cl:18])[N:11]=[C:10]([F:19])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[N:20]([Si](C)(C)C)=[N+:21]=[N-:22]>CN(C=O)C.CCOC(C)=O.O>[N:20]([C:15]1([CH2:17][OH:16])[C:14]2[CH:13]=[C:12]([Cl:18])[N:11]=[C:10]([F:19])[C:9]=2[O:8][C:5]2[C:4]1=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[N+:21]=[N-:22]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Fc1nc(Cl)cc2c1Oc1ccc(Br)cc1C21CO1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1(CO)c2cc(Br)ccc2Oc2c1cc(Cl)nc2F
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.7 %

Procedure:
To a solution of 7-bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,2′-oxirane] (23.5 g, 68.6 mmol) in DMF (600 mL) was added azidotrimethylsilane (54.6 mL, 412 mmol). The reaction mixture was stirred at RT for 6 hours. Additional azidotrimethylsilane (54.6 mL, 412 mmol) was added and the reaction was stirred at RT for 18 hours. The reaction mixture was diluted with EtOAc and water. The organic layer was separated, washed sequentially with a saturated aqueous LiCl solution and brine before drying over sodium sulfate. The solution was concentrated under reduced pressure to afford (5-azido-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methanol (26.12 g, 67.7 mmol, 99% yield).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[OH:17])[CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1>C(OC(=O)CC)(=O)CC.N1C=CC=CC=1>[C:18]1([C:7]2[C:6]3[C:15](=[C:2]([O:1][C:12](=[O:17])[CH2:11][CH3:10])[CH:3]=[CH:4][CH:5]=3)[C:14]([O:16][C:14](=[O:16])[CH2:13][CH3:8])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[C:12]3[O:17][C:2](=[O:1])[CH2:3][CH3:4])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1c2c(O)cccc2C(c2ccccc2)c2cccc(O)c21
Agent: CCC(=O)OC(=O)CC
Solvent: c1ccncc1
Product: CCC(=O)Oc1cccc2c(-c3ccccc3)c3cccc(OC(=O)CC)c3c(OC(=O)CC)c12
Yield: 56.5 %

Procedure:
To a mixture, stirred under an argon atmosphere, of 2.5 g of 1,8-dihydroxy-10-phenyl anthrone obtained at example 10 (1) in 25 cm3 of propionic anhydride, 0.100 cm3 of anhydrous pyridine is added. The reaction mixture is then brought for one hour to 70° C., at the end of which period all the initial reactant is transformed. The reactive excess is then removed by evaporation under a vacuum. The resulting solid is dissolved in a minimum of toluene, introduced into a silica gel column and then eluted with toluene. After evaporation of the eluant, 1.3 g of a solid are obtained which is then recrystallized in a toluene/hexane mixture, yielding 1.1 g white crystals having a melting point of 216° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[CH:9]=[N:10][C:5]2=[C:4]([NH:20][C:21](=O)[CH2:22][Cl:23])[CH:3]=1>C1COCC1>[Cl:23][CH2:22][CH2:21][NH:20][C:4]1[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]2[N:8]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[CH:9]=[N:10][C:5]=12
Reactant: Cc1cc(C)c(-n2cnc3c(NC(=O)CCl)cc(C)nc32)c(C)c1
Solvent: C1CCOC1
Product: Cc1cc(C)c(-n2cnc3c(NCCCl)cc(C)nc32)c(C)c1

Procedure:
Treat a solution of N-[5-methyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridin-7-yl]-2-chloroacetamide (0.04 g, 0.10 mmol) in THF (5 mL) with borane-methyl sulfide complex (0.03 mL, 0.30 mmol). Heat the mixture to reflux for 8 h and quench at ambient temperature with a large excess of MeOH, followed by 6 N HCl (2 mL). Re-heat the mixture to reflux for 1 h, then concentrate under reduced pressure to obtain the title compound as a yellow solid.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[NH:10]C(=O)C.O.[OH-].[Li+]>CO>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[NH2:10]
Reactant: CC(=O)Nc1nc2cnccc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1nc2cnccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-(thiazolo[4,5-c]pyridin-2-yl)acetamide, prepared in the previous step, in MeOH (200 mL) at room temperature was added lithium hydroxide hydrate (7.08 g, 169 mmol). The reaction mixture was stirred at room temperature for 30 min and then warmed to 40° C. After 3 h, additional lithium hydroxide hydrate (7.48 g) was added. The reaction mixture was heated to 50° C. for 20 h and concentrated. The reaction mixture was diluted with DCM/MeOH (˜10:1, 500 mL). The undissolved material was removed by filtration and the filtrate was concentrated. Purification by flash column chromatography on silica gel (eluted with 2% to 10% MeOH in DCM) gave thiazolo[4,5-c]pyridin-2-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH3:15])=[CH:5][C:6]2[O:10][CH:9]([C:11]#[N:12])[CH2:8][C:7]=2[CH:13]=1.Cl.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([O:14][CH3:15])=[CH:5][C:6]2[O:10][CH:9]([CH2:11][NH2:12])[CH2:8][C:7]=2[CH:13]=1
Reactant: COc1cc2c(cc1OC)OC(C#N)C2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)OC(CN)C2
Yield: 22.2 %

Procedure:
5,6-Dimethoxy-2,3-dihydrobenzofuran-2-carbonitrile (Method 16; 2.63 g, 12.94 mmol) was dissolved in ethanol (700 ml) and hydrochloric acid (conc, 2.3 ml) and Pd on charcoal (10%, 1 g) were added. The mixture was hydrogenated under 3.5 atmosphere of hydrogen at 72° C. for 3 days. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in water and washed once with diethyl ether. The pH of the aqueous phase was adjusted to 10–11 with NaOH(aq) and the resulting solution was extracted several times with diethyl ether, then with DCM. The organic layers were dried, filtered and evaporated under reduced pressure. The diethyl ether extraction gave 0.6 g (22%) of pure product and the DCM extraction gave 2.0 g (74%) of pure product. NMR (400 MHz) 2.80–2.87 (m, 3H), 3.21 (dd, 1H), 3.74 (s, 3H), 3.76 (s, 3H), 4.72–4.82 (m, 1H), 6.47 (s, 1H), 6.82 (s, 1H).