Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[I:12][C:13]1[C:14]([O:23][CH3:24])=[N:15][C:16]([S:21][CH3:22])=[C:17]([CH:20]=1)[C:18]#[N:19].C(OCC)(=O)C>ClCCl>[I:12][C:13]1[C:14]([O:23][CH3:24])=[N:15][C:16]([S:21]([CH3:22])=[O:9])=[C:17]([CH:20]=1)[C:18]#[N:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1nc(SC)c(C#N)cc1I
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1nc(S(C)=O)c(C#N)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
1.42 g (1.1 eq) of 70% 3-chloroperbenzoic acid is added to a solution of 1.6 g (5.23 mmol) of 5-iodo-6-methoxy-2-(methylthio)nicotinonitrile in 20 ml of dichloromethane. The reaction medium is stirred at room temperature for 1 hour. Ethyl acetate is added and the organic phase is washed with saturated sodium bicarbonate solution, dried on magnesium sulfate, filtered and evaporated to yield 1.63 g (97%) of 5-iodo-6-methoxy-2-(methylsulfinyl)nicotinonitrile in the form of a white powder which may also contain 5-iodo-6-methoxy-2-(methylsulfonyl)nicotinonitrile in small proportions (<20%). If necessary, the mixture is used as-is in the following steps.
Reaction SMILES: [C:1]([CH2:5][C:6]1([CH2:16][CH3:17])[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:8][C:7]1=O)([O:3][CH3:4])=[O:2].[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26]N)[CH3:19].C(Cl)(C)=O>CO>[CH3:4][O:3][C:1](=[O:2])[CH2:5][C:6]1([CH2:16][CH3:17])[C:7]2[NH:26][C:21]3[C:22](=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:18][CH3:19])[C:8]=2[CH:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH2:11]1
Reactant: CCC1(CC(=O)OC)CCC(C2CC2)CC1=O
Reactant: CCc1ccccc1NN
Solvent: CO
Solvent: CC(=O)Cl
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)CCC3C1CC1
Temperature: 0 °C
Yield: 33.8 %

Procedure:
The mixture of diastereomeric ketones (40 mmol, 9.52 g) prepared in Step (d) and 2-ethylphenylhydrazine (40 mmol, 5.45 g) were heated at reflux in 172 ml of MeOH for 60 hours, cooled to 0° C. and treated with 80 mmol (6.28 g, 5.7 ml) of AcCl. The reaction was refluxed an additional 45 minutes followed by removal of solvent in vacuo. Flash chromatography afforded 4.58 g (13.5 mmol, 34%) of orange oil containing a mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][C:13]1[N:17]=[CH:16][NH:15][N:14]=1.O.O.O.P([O-])([O-])(O)=O.[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:14]1[C:13]([CH3:12])=[N:17][CH:16]=[N:15]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1nc[nH]n1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ncnn1-c1ccc([N+](=O)[O-])cc1F
Yield: 22.3 %

Procedure:
3,4-Difluoronitrobenzene (514 mg, 3.23 mmol), 3-methyl-1H-1,2,4-triazole (325 mg, 3.72 mmol) and di-potassium hydrogen phosphate trihydrate (1.49 g, 6.46 mmol) in dimethyl sulfoxide (1.5 mL) were stirred for 6 hours at 70° C. The mixture was concentrated in vacuo; the residue was diluted in water and extracted three times with ethyl acetate. The combined organic layers were washed four times with water, twice with brine, dried with magnesium sulfate and evaporated. Column chromatography (30 g silica, heptane/ethyl acetate 1:1 v/v) afforded the title compound (160 mg, 22%) as white crystals MS ISP (m/e): 223.2[(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.22 (m, 2H), 8.04 (s, 1H), 7.74 (dd, 1H), 2.48 (d, 3H). Mp 56-58° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(N([CH2:14][CH3:15])CC)C.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]([S:24]([C:15]2[CH:14]=[CH:18][C:17]([F:16])=[CH:22][C:21]=2[F:23])(=[O:26])=[O:25])[S:24]([C:18]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=2[F:16])(=[O:26])=[O:25])[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)cc1F)N(c1cncc(Br)c1)S(=O)(=O)c1ccc(F)cc1F
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
A solution of 5-bromo-3-pyridinamine (104 mmol) in dichloromethane (55 mL) was added dropwise over ˜60 min to a stirred solution of triethylamine (230 mmol) and 2,4-difluorobenzenesulfonyl chloride (235 mmol) in dichloromethane (300 mL). After 1.5 h, additional 2,4-difluorobenzenesulfonyl chloride (53.4 mmol) was added, and after 2 days, more 2,4-difluorobenzenesulfonyl chloride (47.0 mmol) and triethylamine (108 mmol) were added. After 1 h, the resulting mixture of mono- and bis-sulfonylation products was concentrated in vacuo and the residue was suspended in methanol (500 mL) and then filtered to provide N-(5-bromo-3-pyridinyl)-N-[(2,4-difluorophenyl)sulfonyl]-2,4-difluorobenzenesulfonamide as a white solid (54.4 mmol, 52%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([N:9](C2C=CC(OC)=C(OC3CCCC3)C=2)[C:10](=O)C)[C:3]=1[OH:27]>C1(C)C=CC=CC=1.P(Cl)(Cl)(Cl)=O>[O:27]1[C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[CH:10]1
Reactant: COc1ccc(N(C(C)=O)c2cc(Cl)cc(Br)c2O)cc1OC1CCCC1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2ocnc2c1
Reaction time: 1 h
Yield: 261.4 %

Procedure:
A suspension of 32.9 g (72.4 mM) of the 2-Bromo-4-chloro-6-(3-cyclopentyloxy-4-methoxy-phenyl-acetylamino)-phenol in 400 ml of toluene and 39.7 ml (434 mM) of phosphorus oxychloride was refluxed for 1.5 hr. Some solid material was filtered off and the filtrate evaporated to dryness in vacuo. The honey-like residue was suspended in 200 ml of sodium bicarbonate solution for 1 hr. The solid was collected, washed and dried at 25° C. to give 22.53 g (71.2%) of crude benzoxazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH:5]=[N+]=[N-])[CH3:2].[Sn](Cl)Cl.[CH3:12][CH:13]([CH3:18])[CH2:14][CH2:15][CH:16]=[O:17]>ClCCl>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:16](=[O:17])[CH2:15][CH2:14][CH:13]([CH3:18])[CH3:12])[CH3:2]
Reactant: CC(C)CCC=O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: Cl[Sn]Cl
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCC(C)C
Temperature: 25 °C
Yield: 55.4 %

Procedure:
A solution of diazo-acetic acid ethyl ester (555 mg, 4.86 mmol) in dichloromethane (8 mL) was treated with tin (II) chloride (88 mg, 0.463 mmol) and stirred vigorously at 25° C. A solution of 4-methyl-pentanal (464 mg, 4.63 mmol) in dichloromethane (2 mL) was added to the mixture dropwise over 10 min resulting in gas evolution. After the nitrogen evolution ceased (approximately 1 h), the reaction was extracted with brine and diethyl ether (2×80 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (ISCO RediSep column, 0 to 7% ethyl acetate in hexanes) to afford the desired product, 6-methyl-3-oxo-heptanoic acid ethyl ester (478 mg, 55%), as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.89 (6H, d, J=6.3 Hz), 1.26-1.29 (4H, m), 1.48-1.57 (2H, m), 2.53 (2H, t, J=7.4 Hz), 3.42 (2H, s), 4.18 (2H, quartet, J=7.6 Hz).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[CH:11]=3)[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:25])C(=O)C1>C(Cl)Cl>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:15])([CH3:16])[C:12](=[O:17])[C:11]=3[Br:25])[CH:7]=[CH:6][C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(c2ccc3nonc3c2)=CC1=O
Solvent: ClCCl
Product: CC1(C)OC(c2ccc3nonc3c2)=C(Br)C1=O
Reaction time: 3 h
Yield: 59.6 %

Procedure:
To a stirred solution of 5-(benzo[c][1,2,5]oxadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.25 g, 1.086 mmol) CHCl3 (15 mL), NBS (0.29 g, 1.630 mmol) was added portionwise at RT. The reaction mixture was then stirred for 3 h and diluted with DCM (10 mL). The organic layer was then washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(benzo[c][1,2,5]oxadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.2 g, 60%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH:14]C(=O)OC(C)(C)C)[CH3:13])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C@@H:3]([CH3:22])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:10][CH:11]=1
Reactant: CO[C@@H](C)COc1ccc(C(C)NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@@H](C)COc1ccc(C(C)N)cc1

Procedure:
tert-Butyl [1-(4-{[(2S)-2-methoxypropyl]oxy}phenyl)ethyl]carbamate (0.29 g, 0.94 mmol) was treated with trifluoroacetic acid (2 mL) in dichloromethane (18 mL) for 25 minutes, the volatiles removed under reduced pressure and the residue purified by silica gel column chromatography using dichloromethane:methanol:triethylamine 98:1:1 giving the title compound in 0.12 g (59%) yield 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (s, 2 H) 7.34-7.41 (m, J=8.78 Hz, 2 H) 6.97-7.03 (m, 2 H) 4.35 (q, J=6.78 Hz, 1 H) 3.93 (d, J=5.02 Hz, 2 H) 3.60-3.70 (m, 1 H) 3.30 (s, 3 H) 2.96 (q, J=7.11 Hz, 1 H) 1.45 (d, J=6.78 Hz, 3 H) 1.16 (d, J=6.27 Hz, 3 H)
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][CH2:27][O:28]C2CCCCO2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O>O1CCCC1.CO.Cl>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][CH2:27][OH:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CCOC3CCCCO3)[nH]c2c1
Agent: Cl
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CCO)[nH]c2c1
Yield: 66.2 %

Procedure:
A solution of methyl 3-cyclohexyl-2-{2-[2-(tetrahydropyran-2-yloxy)ethyl]phenyl}-1H-indole-6-carboxylate (2.21 g, 4.80 mmol) in tetrahydrofuran (10 ml), methanol (10 ml) and 6N hydrochloric acid (20 ml) was stirred at room temperature for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1-2:1) to give methyl 3-cyclohexyl-2-[2-(2-hydroxyethyl)phenyl]-1H-indole-6-carboxylate (1.20 g, yield 66.7%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[NH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1.N1C2C(=CC=CC=2)C=C1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](OC)=[O:35])=[CH:26]1>>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[NH:10][C:34]([C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:25]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)[CH:26]=1)=[O:35]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Nc1nccs1
Reactant: Fc1ccc(CBr)cc1
Agent: c1ccc2[nH]ccc2c1
Product: O=C(Nc1nccs1)c1cn(Cc2ccc(F)cc2)c2ccccc12

Procedure:
R5X=1-Bromomethyl-4-fluoro-benzene; NH2A=2-aminothiazole; Indole starting material=methyl indole 3-carboxylate
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:17]([CH:19]=[CH2:20])=O.S(=O)(=O)(O)O.N1CCCCC1>[Cl-].[Al+3].[Cl-].[Cl-].C(O)(=O)C>[C:13]([C:12]1[C:7]2[C:8](=[CH:17][CH:19]=[CH:20][CH:6]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:15])[C:14]1[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: C=CC=O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C(c1ccccc1)c1cccc2ccccc12

Procedure:
It has been known to produce benzanthrone by the following processes. (1) Anthraquinone is dissolved into sulfuric acid and a mixture of metallic powder and glycerin is added to the solution to reduce anthraquinone and simultaneously, the reaction product is further reacted with the compound resulted by dehydration of glycerin in an addition-reaction (B10S 987 and F1AT 1313). (2) Benzanthrone is produced by reacting an anthrahydroquinone ester such as acetate and sulfate which is obtained by reducing and esterifying anthraquinone, with acrolein in the presence of a dehydration catalyst such as sulfuric acid and piperidine in a solvent of acetic acid. (DRP 720,467). (3) Benzanthrone is produced by condensing α-benzoylnaphthalene at higher than 150° C. in the presence of aluminum chloride catalyst or at 120° C. in the presence of iron chloride catalyst. (DRP 239,761).
Reaction SMILES: [N:1]1([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:36]([O:39][CH2:40][C:41](Cl)=[O:42])(=[O:38])[CH3:37]>C(Cl)Cl.[Cl-].[Na+].O>[C:36]([O:39][CH2:40][C:41]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)=[O:42])(=[O:38])[CH3:37]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)n1C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OCC(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Reaction time: 1.25 h

Procedure:
2-[4-(Piperazin-1-yl)anilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 20; 330 mg 0.88 mmol) was stirred in DCM (6 ml) at room temperature. Triethylamine was added (153 mg 1.51 mmol) followed by dropwise addition of acetoxyacetylchloride (143 mg 1.05 mmol). After stirring for 1.25 hours, DCM (10 ml) and brine (5 ml) were added. The reaction was stirred vigorously for 10 minutes then the organic layers were separated, dried and evaporated under reduced pressure to give the title compound as a yellow foam. Quantitative yield. The solid was triturated with ether and re-evaporated. NMR: 1.40 (d, 6H), 2.08 (s, 3H), 2.48 (s, 3H), 3.05 (b d, 4H), 3.54 (b d, 4H), 4.81 (s, 2H), 5.70 (septuplet, 1H), 6.92 (d, 2H), 6.95 (d, 1H), 7.40 (s, 1H), 7.48 (d, 2H), 8.31 (d, 1H), 9.18 (s, 1H); m/z 478.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]2[C:23]3[C:24](=[C:26]([O:42][CH3:43])[CH:27]=[CH:28][C:29]=3[C:30](OC3C=CC([N+]([O-])=O)=CC=3)=[O:31])[O:25][C:19]=2[CH2:18]1)=[O:16])[CH3:13].O>CN(C=O)C>[Cl:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[NH:1][C:30]([C:29]1[CH:28]=[CH:27][C:26]([O:42][CH3:43])=[C:24]2[O:25][C:19]3[CH2:18][N:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH2:22][CH2:21][C:20]=3[C:23]=12)=[O:31]
Reactant: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c23)C1
Reactant: Nc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCc2c(oc3c(OC)ccc(C(=O)Nc4c(Cl)cncc4Cl)c23)C1

Procedure:
To a solution of 4-amino-3,5-dichloro pyridine (0.125 g, 0.765 mmol) in dry DMF, sodium hydride (0.0162 g, 0.675 mmol) was added at 0° C. followed by 4-nitrophenyl 2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxylate (0.197 g, 0.45 mmol). Water was added to RM. Solid filtered out and purified on Silica Gel column with CHCl3: EtOAc to yield N-(3,5-dichloropyridin-4-yl)-2-(ethoxycarbonyl)-8-methoxy-1,2,3,4-tetrahydro[1]benzofuro[2,3-c]pyridine-5-carboxamide.
Reaction SMILES: [BH3:1].[C:2]1([PH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.Br[C:21]1[CH:22]=[C:23]([CH3:29])[C:24]([CH3:28])=[CH:25][C:26]=1[Br:27]>C1COCC1>[BH3:1].[Br:27][C:26]1[CH:25]=[C:24]([CH3:28])[C:23]([CH3:29])=[CH:22][C:21]=1[P:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: Cc1cc(Br)c(Br)cc1C
Agent: B
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(Br)c(P(c2ccccc2)c2ccccc2)cc1C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of diphenylphosphine borane (V-a) (0.17 g, 0.83 mmol) in dry THF (2 mL) was added dropwise under argon at −78° C. n-BuLi (0.83 mmol). The resulting solution was stirred at this temperature during one hour and 4,5-dibromo-o-xylene (VI-b) (0.31 g, 1.16 mmol) was then added dropwise followed by n-BuLi (0.17 mmol). After one hour at −78° C., the reaction mixture was quenched with water (10 mL) and extracted with methylene chloride (3×10 mL). The organic phases were dried over MgSO4, filtered and the solvent evaporated giving a residue which was purified by column chromatography on silica gel using petroleum ether/methylene chloride 3:1 as eluent. Analytical pure sample can be obtained by recrystallization in methylene chloride/hexane. White solid; yield 56%; Rf 0.45 (petroleum ether/ethyl acetate 3:1); IR (neat) 3050, 2986, 2946, 2917, 2417, 2388, 2357, 1588, 1481, 1471, 1436, 1343, 1136, 1125, 1102, 1062, 1028, 999, 923, 877, 749, 734, 701, 692 cm−1; 1H NMR (300MHz, CDCl3) δ 2.17 (s, 3H, CH3), 2.29 (s, 3H, CH3), 7.21 (d, J=12.3 Hz, Harom), 7.43-7.56 (m, 7H, Harom), 7.65-7.72 (m, 4H, Harom); 13C NMR (75.5 MHz, CDCl3) δ 19.4 (CH3), 19.5 (CH3), 124.7 (d, J=4.4 Hz, Carom), 131.1 (d, J=2.5 Hz, Carom), 133.2 (d, J=9.6 Hz, Carom), 135.9 (d, J=6.1 Hz, Carom), 136.3 (d, J=9.9 Hz, Carom), 137.8 (d, J=11.8 Hz, Carom), 142.6 (d, J=2.2 Hz, Carom); 31P NMR (121 MHz, CDCl3) δ 25.5; HRMS calcd for C20H21PBBrNa (M+Na)+ 405.0553, found 405.0563; Anal calcd for C20H21PBBr: C, 62.71; H, 5.53; found: C, 62.86; H, 5.58.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[C:10]([I:11])[C:3]=12.S(O[CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:23]3[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]3)[CH:9]=[C:10]([I:11])[C:3]=12
Reactant: Cc1ccc(S(=O)(=O)OC2CN(C(=O)OC(C)(C)C)C2)cc1
Reactant: Brc1ccnc2[nH]cc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(n2cc(I)c3c(Br)ccnc32)C1
Temperature: 95 °C
Yield: 32.8 %

Procedure:
To a mixture of 4-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (D6) (500 mg, 1.548 mmol) and tert-butyl 3-(tosyloxy)azetidine-1-carboxylate (D100) (558 mg, 1.703 mmol) in DMSO (10 mL) was added cesium carbonate (1513 mg, 4.64 mmol). The final mixture was heated at 80° C. for 4 hours after which the temperature is increase to 95° C. and the mixture heated overnight. The reaction mixture was diluted with water (50 mL) and then extracted with ethyl acetate (50 mL×3). The combined organics were dried over magnesium sulfate and concentrated. The crude was purified on normal phase silica eluting with ethyl acetate and cyclohexane (0-50%) to give the title compound (243 mg). LCMS (A): m/z (M+H)+ 478/480, C15H17BrIN3O2 requires 477/479 (acidic).
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC=C(O)C=2)C(F)=CN=1.[S:43]1[C:47]2C=CC=CC=2[C:45](CN)=[CH:44]1>>[S:43]1[C:44]2[CH:45]=[CH:21][CH:22]=[CH:23][C:24]=2[C:25]([CH2:20][NH:19][C:14]2[N:13]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=3)[C:17]([F:18])=[CH:16][N:15]=2)=[CH:47]1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: NCc1csc2ccccc12
Agent: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Oc1cccc(Nc2nc(NCc3csc4ccccc34)ncc2F)c1
Yield: 53 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine (50 mg, 0.21 mmol) and benzothiophen-3-ylmethylamine (100 mg, 0.61 mmol) gave N2-(benzothiophen-3-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 53%). 1H NMR (CDCl3): δ 4.82 (d, J=6.0 Hz, 2H), 6.45 (dd, J=8.1 Hz, 1H), 6.70 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.03 (t, J=8.1 Hz, 1H), 7.22 (m, 1H), 7.34 (s, 1H), 7.39-7.46 (m, 2H), 7.82 (m, 1H), 7.89-7.92 (m, 2H); 19F NMR (282 MHz, CDCl3): 6-170.02; LCMS: ret. time: 21.29 min.; purity: 92.97%; MS (m/e): 367.03 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:13]=2)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[N:3]=[C:4]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[CH:13]=4)[C:5]4[S:10][CH2:9][CH2:8][C:6]=4[N:7]=3)[CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: Clc1nc2c(c(Nc3cccc(CN4CCOCC4)c3)n1)SCC2
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(N2CCN(c3nc4c(c(Nc5cccc(CN6CCOCC6)c5)n3)SCC4)CC2)cc1
Temperature: 160 °C
Yield: 74.5 %

Procedure:
1.09 g (2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-yl)-(3-morpholin-4-ylmethyl-phenyl)-amine, 1.77 g 1-(4-chloro-phenyl)-piperazine and 1.03 ml diisopropylethylamine are placed in 12 ml dioxane, then heated in the microwave for 1 hour at 160° C. Then water is added and the mixture is extracted with dichloromethane. The organic phase is separated off using a phase transfer cartridge and evaporated to dryness. The residue is crystallised with methanol. 1.17 g of the product are obtained as a powder (m.p 177°-178° C.).
Reaction SMILES: [F:1][C:2]1(B(O)O)[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH:19]O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:4]([OH:19])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: CCCCCCOC1C=C(F)C=CC1(F)B(O)O
Reactant: OO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCOc1c(F)ccc(F)c1O
Reaction time: 0.75 h
Yield: 87 %

Procedure:
White crystals of 1,4-difluoro-2-hexyloxybenzene-1-boronic acid (48 g) were dissolved in warm toluene (150 ml) and hydrogen peroxide (43 ml, 30%) was added drop-wise. Heating was continued for 45 min at 100° C. Once the solution had cooled to room temperature water was added (50 ml) and the layers were separated. The toluene layer was washed with ferrous ammonium sulphate (10%, 2×50 ml) and water (2×50 ml). The combined organic extracts were dried with magnesium sulphate, filtered and the solvent was removed to yield crude 3,6-difluoro,2-hexyloxyphenol as a pale yellow oil (31.67 g, 100%). The crude product was dissolved in toluene (150 ml), extracted with sodium hydroxide solution (10%w/v in methanol, 3×50 ml). The purple, aqueous extract, containing the phenoxide anion of the product, was then re-acidified with concentrated HCl until all of the colour had been displaced (pH˜4). The phenol was then extracted with dichloromethane (3×100 ml), washed with water (3×50 ml), dried with magnesium sulphate and filtered. Removal of the solvent in vacuo yielded the required product as an orange/brown oil (27.2 g, 87%). Kugelrohr distillation was performed under reduced pressure (2 mbar), the colourless distillate collected when the oven temp was 100° C. was found to contain only 4 (26.5 g, 82%), (Found: C, 62.65; H, 6.9. C12H16O2F2 requires C, 62.6; H, 6.9; O, 13.91; F, 16.52%); vmax(film)/cm−1 3524 and 2932 (C—H aliph), 2300 (C═C); δH(300 MHz; CDCl3) 0.90 (3H, t, 3J(H,H)=7 Hz, —CH3), 1.32 (4H, m, 2×—CH2—), 1.34 (2H, septet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 1.76 (2H, quintet, 3J(H,H)=7 Hz, —CH2CH2CH2O—Ar), 4.17 (2H, t, 3J(H,H)=7 Hz, —CH2CH2O—Ar), 5.70 (1H, s, —OH, removed with D2O), 6.58 (1H, ddd, 3J(H,F)=13.3, 3J(H,H)=7.4, 4J(H,F)=4.5 Hz, C3H), 6.74 (1H, ddd, 3J(H,F)=18.3, 3J(H,H) 7.4, 4J(H,F)=4.6 Hz, C4H); δC(75 MHz 1H{BB}, INEPT; CDCl3) 14.31 (CH3), 22.91 (CH2), 25.78 (CH2), 30.34 (CH2), 31.87 (CH2), 74.90 (CH2), 106.65 (CH, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C4), 110.75 (CH, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C5), 135.67 (C, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C1), 138.42 (C, dd, 2J(C,F)=15.1, 3J(C,F)=8.4 Hz, C2), 147.65 (C, dd, 1J(C,F)=239, 4J(C,F)=2.6 Hz, C6), 151.7 (C, dd, 1J(C,F)=248, 4J(C,F)=2.6 Hz, C3); m/z 230 (M+, 10%), 146 (M+-alkoxy chain, 100%), 43 (50%).