Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:12][CH:11]=1.Cl.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.CC(O)C>[CH2:17]([N:14]([CH2:15][CH3:16])[C:13]1[CH:19]=[CH:20][C:10]([NH:9][C:2]2[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)=[CH:11][CH:12]=1)[CH3:18]
Reactant: Nc1cc(Cl)ncn1
Reactant: CCN(CC)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCN(CC)c1ccc(Nc2cc(N)ncn2)cc1
Temperature: 90 °C
Reaction time: 36 h

Procedure:
A mixture of 6-chloro-pyrimidin-4-ylamine (0.65 g, 5 mmol), 4-amino-N,N-diethylaniline (0.82 mL, 5 mmol), 2-propanol (5 mL) and HCl conc. (0.225 mL, ˜2.5 mmol) is shaken for 36 h at 90° C. After cooling to room temperature, the reaction mixture is distributed between half-saturated K2CO3-solution and ethyl acetate. The precipitate thus formed is filtered off, washed with H2O and ethyl acetate and dried in vacuo to afford the title compound. Greyish solid, HPLC: tR=2.37 min (gradient F), ESI-MS: 258.3 [MH]+.
Reaction SMILES: N1C(C)=CC=CC=1C.[CH2:9]([C:11]([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([OH:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:32]([CH3:45])[CH:31]=1)([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)[CH2:12][CH3:13])[CH3:10].O([Si:54]([CH3:57])([CH3:56])[CH3:55])S(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([C:11]([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:25])([CH3:26])[C:22]([CH3:27])([CH3:28])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([O:44][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
2,6-Lutidine (0.16 g, 1.49 mmol) was added to a solution of 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-cyclohexanol (Example 35-(3); 0.15 g, 0.29 mmol) in dichloromethane (1.5 mL). Trimethylsilyl triflate (0.13 mL, 0.71 mmol) was added at 0° C., and the mixture was stirred at the same temperature for one hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% ethyl acetate/hexane) to give the title compound (0.16 g, 93%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C-:9]#[N:10].[Na+]>CS(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: [C-]#N
Reactant: Cc1ccc(F)nc1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(C#N)nc1
Temperature: 150 °C
Reaction time: 72 h
Yield: 249.2 %

Procedure:
2-Fluoro-5-methylpyridine (CAN 2369-19-9, 50 g, 90 mmol) and sodium cyanide (CAN 143-33-9, 70 g, 1.43 mol) were dissolved in DMSO (200 mL), the mixture was stirred for 3 days at 150° C. The mixture was cooled to room temperature, ice water (200 mL) was added and the product was obtained as red solid (26.5 g, 50%) by filtration and drying; MS (EI): m/e 119.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=O>>[F:23][C:18]1[CH:17]=[C:16]([C:14]2[C:6]3[C:7]([O:9][CH3:10])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[O:11][CH:13]=2)[CH:21]=[C:20]([F:22])[CH:19]=1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Reactant: COc1cc(O)cc(OC)c1
Product: COc1cc(OC)c2c(-c3cc(F)cc(F)c3)coc2c1
Yield: 68 %

Procedure:
This compound was prepared using Method B from 3,5-dimethoxyphenol and 2-bromo-1-(3,5-difluorophenyl)ethanone: Yield 68% following procedures B.2 and B.3; m.p. 102-103° C.; IR 2937, 1591, 1501, 1444, 1354, 1217, 1113 cm−1; 1H-NMR (300 MHz, δ ppm, CDCl3) 7.49 (s, 1H), 7.20-7.11 (m, 2H), 6.75 (tt, J=9.0 Hz, 2.3 Hz, 1H), 6.66 (d, J=1.9 Hz, 1H), 6.36 (d, J=1.9 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H); 13C-NMR (75 MHz, δ ppm, CDCl3) 162.8 (dd, J=246.5 Hz, 13.3 Hz), 159.7, 158.2, 154.6, 140.7, 135.8 (t, J=10.6 Hz), 121.5, 112.2 (dd, J=8.1 Hz, 17.4 Hz), 109.2, 102.4 (t, J=25.5 Hz), 95.0, 88.6, 55.9, 55.5.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=2)[CH2:3][CH2:2]1>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([C:15]([F:16])([F:17])[F:18])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(OCC2CC2)cc1C(F)(F)F
Solvent: CCO
Product: Nc1ccc(OCC2CC2)cc1C(F)(F)F
Temperature: 70 °C
Yield: 50.5 %

Procedure:
Stannous chloride (4.75 g, 21 mmol) was added to a solution of 4-cyclopropylmethoxy-1-nitro-2-trifluoromethylbenzene (1.1 g, 4.2 mmol) in ethanol (12 mL). The reaction temperature was raised to 70° C. for 1.5 hour. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (20 mL). Water (15 mL) was added and sodium hydrogen carbonate was added until pH 7. The mixture was filtered and the organic phase collected. The aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (38 g) using heptane and ethyl acetate (9:1) as eluent to give 0.49 g of 4-cyclopropylmethoxy-2-trifluoromethylphenylamine.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[N:10]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccccc1F
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2ccccc2F)n1
Yield: 66 %

Procedure:
using the procedure in Example 161A Step 3, 2-fluorophenylhydrazine hydrochloride (1.30 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) were reacted to give 3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-amine (1.23 g, 5.28 mmol, 66%). 1H NMR (300 MHz, DMSO-d6) δ 7.46-7.29 (m, 4H), 5.31 (s, 1H), 5.05 (br s, 2H), 1.20 (s, 9H); LC-MS (ESI) m/z 234 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:21]=1>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:19][C:20]3[N:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=3)=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Reactant: CCOC(=O)c1ccc(N)nc1
Product: CCOC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2OC(C)C)nc1
Yield: 5.4 %

Procedure:
Following a procedure analogous to Example 12, 5-methoxy-3-(1-methyl ethoxy)benzo[b]thiophene-2-carboxylic acid (1.07 g, 4 mmol ) and ethyl 6-aminonicotinate (690 mg, 4.2 mmol) provides 90 mg (6%) of product; mp 131°-133° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:26][C@H:27]1[CH2:32][O:31][CH2:30][CH2:29][O:28]1)(=O)=O>O1CCOCC1>[O:28]1[CH2:29][CH2:30][O:31][CH2:32][C@@H:27]1[CH2:26][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CS(=O)(=O)OC[C@H]1COCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC1(C)OB(c2cnn(C[C@H]3COCCO3)c2)OC1(C)C
Yield: 100 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.5 g) was added to a suspension of cesium carbonate (2.50 g) in 1,4-dioxane (30 ml). After stirring, (2R)-1,4-dioxan-2-ylmethyl methanesulfonate (2.78 g) was added and the mixture was stirred at 90° C. for four hours. After leaving to cool, the reaction solution was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography [chloroform:methanol=19:1 (v/v)] to give 3.79 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH:8]=[C:7]([OH:17])[C:6]=2[CH:18]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[CH2:8][C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: OC1=Cc2ccccc2C=Cc2ccc(Br)cc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1Cc2ccccc2C=Cc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.3 %

Procedure:
To a solution of 3-bromo-5-hydroxy-dibenzo[a,e]cyclooctene (0.75 g) in dry dichloromethane (60 ml) was added pyridinium dichromate (2.1 g) and crushed 4 A molecular sieves (1.3 g). After stirring at room temperature for 14 h, diethyl ether (150 ml) Was added and the reaction mixture was filtered through a plug of celite. The solvent was removed and the residue purified by chromatography on flash silica with 5% ethyl acetate in hexane as eluent to give, as a colorless solid, the title compound (0.7 g). δ(360 MHz, CDCl3) 4.04 (2H, s, CH2 --C=O), 6.95 (1H, d, J=12.8 Hz, CHA =CHB), 7.09 (1H, d, J=12.8 Hz, CHA =CHB), 7.22-7.59 (6H, m, ArH), 8.36 (1H, d, J=2.2 Hz, C(O)--C=CH--CBr).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])[CH:18]=[C:17]([Cl:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.[Cl-].[NH4+].[N-:30]=[N+:31]=[N-:32].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])[CH:18]=[C:17]([Cl:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[N:30]=[N:31][NH:32][N:14]=2)=[CH:15][CH:16]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCOc2ccc(-c3nn[nH]n3)cc2)c(Cl)c1

Procedure:
2 g of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-benzonitrile, 1.2 g of ammonium chloride and 1.5 g of sodium azide are stirred for 48 hours at 100° C. in 50 ml of dimethylformamide. The reaction mixture is poured onto cold dilute hydrochloric acid and extracted with ethyl acetate. Concentration of the organic phase and crystallisation from diethyl ether/hexane yield 5-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-2H-tetrazole having a melting point of 159-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=O.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[CH:16][C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)[C:7]#[N:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccco1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC(=Cc1ccco1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a flask was added 22.65 g. (0.15 mole) of 4-chlorobenzyl cyanide in 75 ml. of methanol and 14.4 g. (0.15 mole) of 2-furaldehyde in 50 ml. of methanol. While stirring at room temperature, 12.0 g. (0.15 mole) of aqueous 50% sodium hydroxide was added dropwise. Within 30 minutes, a precipitate formed and 50 ml. of additional methanol was added. After one hour, the solid was filtered and dried to give 27.5 g. (91.2% yield) of 2-(4-chlorophenyl)-3-(2-furyl)acrylonitrile as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])/[CH:11]=[CH:24]/[N:25]([CH3:27])[CH3:26])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc(C(C)=O)c(C(F)(F)F)cc1NC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)/C=C/N(C)C)c(C(F)(F)F)cc1NC(C)=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 5-acetyl-2-acetylamino-4-trifluoromethyl-benzoic acid methyl ester (2.46 g, 8.1 mmol) and N,N dimethyl formamide dimethyl acetal (1.1 mL, 8.1 mmol) was stirred at 90° C. for 4 h. The mixture was diluted with AcOEt. The organic phase was washed with water, dried (Na2SO4) and concentrated in vacuo to afford a yellow paste. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (50:50 to 100:0)) to provide the title compound as a beige paste (1.12 g, 39%). ES-MS: m/z 359.3 [M+H]+, rt 4.77 min.
Reaction SMILES: C1([O:6][C:7](=[O:35])[C@@H:8]([NH:13][C:14](=[O:34])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](=[O:32])[NH:30][OH:31])=[CH:17][CH:16]=2)[CH2:9][CH:10]([CH3:12])[CH3:11])CCCC1.[OH-].[Na+].N#N>C1COCC1>[OH:31][NH:30][C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][C@@H:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7]([OH:35])=[O:6])=[O:34])=[CH:20][CH:19]=1)=[O:33])=[O:32]
Reactant: CC(C)C[C@H](NC(=O)c1ccc(NC(=O)CCCCCCC(=O)NO)cc1)C(=O)OC1CCCC1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)c1ccc(NC(=O)CCCCCCC(=O)NO)cc1)C(=O)O
Yield: 28.7 %

Procedure:
Compound (98) (21 mg, 0.043 mmol) was dissolved in THF (1 ml) and 2M NaOH (1 ml) added. The reaction vial was shaken for 16 h before THF removal by blowing a stream of N2 gas at the surface of the solution. The aqueous residue was purified by preparative HPLC to yield compound (99) (5.2 mg). LCMS purity 92%, m/z 422 [M++H]+, 1H NMR (400 MHz, MeOD), δ: 0.95-1.05 (6H, m, 2×CH3), 1.30-1.50 (4 H, m, alkyl), 1.55-1.85 (7H, m, alkyl), 2.10 (2H, t, CH2), 2.40 (2H, t, CH2), 4.65 (1 H, m, CH), 7.65 (2H, d, Ar), 7.80 (2H, d, Ar).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1.S(Cl)(C)(=O)=O.C(N(CC)CC)C.S([O-])(=O)(=O)C.[N-:28]=[N+:29]=[N-:30].[Na+]>C(Cl)Cl.CN(C=O)C.O>[N:28]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CO)cn1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(CN=[N+]=[N-])cn1
Yield: 82.7 %

Procedure:
5-(Hydroxymethyl)pyridine-2-carbonitrile (4 g, 0.03 mol; see step (ii) above) was dissolved in 25 mL of methylene chloride and cooled in an ice bath. Mesyl chloride (2.32 mL, 0.0300 mol) and then triethylamine (4.6 mL, 0.033 mol) were added dropwise. The reaction mixture was stirred and after work up the crude mesylate was treated with NaN3 (7.35 g, 0. 113mol) in 20 mL of DMF. The reaction mixture was stirred at 40° C. for 2 h, diluted with water and extracted with ethyl acetate. The organic layer was concentrated to yield 3.95 g (83%) of the crude azide.
Reaction SMILES: C([NH:8][C:9]([C:11]1[N:12]([CH3:32])[CH:13]=[C:14]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)[CH:15]=1)=[O:10])C1C=CC=CC=1.N[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:32][N:12]1[CH:13]=[C:14]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)[CH:15]=[C:11]1[C:9]([NH:8][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:10]
Reactant: Cn1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1C(=O)NCc1ccccc1
Reactant: Nc1ccccc1
Product: Cn1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)cc1C(=O)Nc1ccccc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 300 using the carboxylic acid intermediate from example 310 and aniline to provide 312. LC-MS (M+H=410, obsd.=410).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[CH2:29][CH2:28]2)[C:24]([CH3:40])=[CH:23][C:21]=1[NH2:22]>>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([C:6]2[C:5]([CH3:17])=[CH:4][N:3]=[C:2]([NH:22][C:21]3[CH:23]=[C:24]([CH3:40])[C:25]([N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)[CH2:29][CH2:28]4)=[CH:26][C:20]=3[O:19][CH3:18])[N:7]=2)=[CH:9]1
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(C)cc1N
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)c(C)cc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1) and 2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 26).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].N[C:13](N)=[O:14]>>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:13](=[O:14])[NH:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: NC(N)=O
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2o1

Procedure:
This was prepared in a similar manner as the 5-chloro-2-hydroxyphenyl analogue, by fusing 2-amino-4-nitrophenol and urea to form 5-nitrobenzoxazolinone (m.pt. 215° C. after recrystallisation from acetone), and then heating with alcoholic dimethylamine as above: it was not recrystallised.
Reaction SMILES: [F:1][C:2]1[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:34])=[O:33])=[CH:29][CH:28]=[C:27]([F:38])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([CH:16]=[CH2:17])=[CH:14][N:13](S(C3C=CC=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1)=[O:5].C([O-])([O-])=O.[K+].[K+]>CO.O>[F:1][C:2]1[C:30]([NH:31][S:32]([CH2:35][CH2:36][CH3:37])(=[O:33])=[O:34])=[CH:29][CH:28]=[C:27]([F:38])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:15]([CH:16]=[CH2:17])=[CH:14][NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: C=Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)CCC)c3F)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=Cc1c[nH]c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)CCC)c3F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
2,6-Difluoro-N-(1-(phenylsulfonyl)-3-vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.0061 g, 0.0109 mmol) was dissolved in MeOH (1.0 mL) and water (0.3 mL). K2CO3 (0.0150 g, 0.109 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The solution was partitioned between water and EtOAc. The organic portion was washed with water (3×), brine, dried over Na2SO4 and concentrated. The resulting residue was purified by column chromatography (1:1 hexane/EtOAc/1% HCO2H) to give 2,6-difluoro-3-(propylsulfonamido)-N-(3-vinyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (2.8 mg, 61.2%). 1H NMR (400 MHz, DMSO-d6) δ 11.81 (br s, 1H), 10.92 (s, 1H), 9.80 (br s, 1H), 8.61-8.62 (m, 1H), 8.44-8.45 (m, 1H), 7.65-7.67 (m, 1H), 7.52-7.58 (m, 1H), 7.24-7.29 (m, 1H), 6.81-6.88 (m, 1H), 5.56-5.61 (m, 1H), 5.11-5.14 (m, 1H), 3.10-3.14 (m, 2H), 1.74-1.80 (m, 2H), 0.98-1.02 (m, 3H); m/z (APCI-neg) M−1=419.3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C1(C)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[Cl:44][C:45]1[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:46]=1[C:47](Cl)=[O:48]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][N:8]([C:47](=[O:48])[C:46]3[C:45]([Cl:44])=[CH:53][CH:52]=[CH:51][C:50]=3[Cl:54])[C:5]2=[N:6][CH:7]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
Into a reaction flask under nitrogen, propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (9, 8.40 g, 18.3 mmol) is combined with 100 mL of toluene, 4-dimethylaminopyridine (447 mg, 3.7 mmol), diisopropylethylamine (4.74 g, 36.7 mmol) and 2,6-dichloro-benzoyl chloride (10, 4.34 g, 20.7 mmol). The reaction is stirred at room temperature overnight, then diluted with 300 mL of dichloromethane and washed with 200 mL of saturated aqueous sodium bicarbonate, then 200 mL of brine. The organic layer is dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of ethyl acetate:hexane. Appropriate fractions are combined to provide crude material that is further purified with additional chromatography, eluting with 1:1 hexane:dichloromethane up to 100% dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (11, 4.15 g, 36%).
Reaction SMILES: [Na+].C(OC([NH:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:20]3=[C:21]([CH2:23][CH2:24][CH2:25][N:19]3[CH:18]=[C:17]([C:26]([O-:28])=[O:27])[C:16]2=[O:29])[CH:22]=1)=O)(C)(C)C.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:20]3=[C:21]([CH2:23][CH2:24][CH2:25][N:19]3[CH:18]=[C:17]([C:26]([OH:28])=[O:27])[C:16]2=[O:29])[CH:22]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cc2c3c(c1)c(=O)c(C(=O)[O-])cn3CCC2
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: NCCCc1cc2c3c(c1)c(=O)c(C(=O)O)cn3CCC2

Procedure:
9-(3-tert-Butoxycarbonylamino-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid sodium salt (224 mg, 0.58 mmol) was dissolved in trifluoroacetic acid (3 mL). After 0.5 h at room temperature the reaction mixture was concentrated to provide the title compound as a beige solid. ESMS m/z 287 (MH+). NMR (MeOD-d4) δ 8.83 (s, 1H), 8.15 (d, 1H), 7.62 (d, 1H), 4.43 (t, 2H), 3.14 (t, 2H), 2.98 (t, 2H), 2.89 (t, 2H), 2.66 (tt, 2H), 2.05 (tt, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[NH:15][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>CC(O)C>[NH:13]1[C:12]2[CH:17]=[CH:18][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]5)=[N:32][CH:31]=4)[N:7]=3)=[CH:10][C:11]=2[NH:15][C:14]1=[O:16]
Reactant: O=c1[nH]c2ccc(Nc3nc(Cl)ncc3F)cc2[nH]1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3ncc(F)c(Nc4ccc5[nH]c(=O)[nH]c5c4)n3)cn2)CC1
Temperature: 85 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a vial with 5-(2-chloro-5-fluoropyrimidin-4-ylamino)-1H-benzo[d]imidazol-2(3H)-one (28.0 mg, 0.1 mmol) and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (38.4 mg, 0.2 mmol), i-PrOH (2 mL) was added, followed by TFA (10 μL, 0.13 mmol). The vial was tightly closed, and the solution was stirred at 85° C. for 2 days. The solvent was removed in vacuo, and the crude product was purified by RP-HPLC. Purified compound (as a trifluoroacetate salt) was dissolved in MeOH—H2O (1:4, 2 mL) and was passed through a PL-HCO3-MP-SPE column, washing with same solvents (1 mL). The filtrate was collected and the solvent was removed by lyophilization. N4-(Benzimidazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-fluoropyrimidine-2,4-diamine was obtained as a purple solid: 26.2 mg (60% yield); 1H NMR (300 MHz, DMSO) δ 10.56 (s, 1H), 10.52 (s, 1H), 9.16 (s, 1H), 8.85 (s, 1H), 8.27 (br d, J=2.3, 1H), 8.00 (br d, J=3.8, 1H), 7.84 (dd, J=2.3, 9.1, 1H), 7.30 (dd, J=1.7, 8.2, 1H), 7.17 (d, J=1.7, 1H), 6.86 (d, J=8.2, 1H), 6.73 (d, J=9.1, 1H), 3.40-3.37 (m, 4H, overlapped with H2O), 2.44-2.41 (m, 4H), 2.25 (s, 3H); LCMS (M+) m/z 436.50.