Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[NH:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=1)=[O:3].C(N=[C:37]=[S:38])(=O)C1C=CC=CC=1>C(Cl)Cl>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=[C:11]2[CH2:10][N:9]1[C:5]2[N:6]=[CH:7][NH:8][C:4]=2[C:2](=[O:3])[NH:1][C:37]1=[S:38]
Reactant: CC(C)(C)OC(=O)n1cc(CNc2nc[nH]c2C(N)=O)c2cc(Cl)ccc21
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(Cn2c(=S)[nH]c(=O)c3[nH]cnc32)c2cc(Cl)ccc21
Temperature: 80 °C
Yield: 44.5 %

Procedure:
A solution of tert-butyl 3-({[5-(aminocarbonyl)-1H-imidazol-4-yl]amino}methyl)-5-chloro-1H-indole-1-carboxylate (0.30 g, 0.78 mmol, obtained from Example 10(b)) and benzoyl isothiocyanate (0.13 mL, 0.94 mmol) in CH2Cl2 (5 mL) was stirred for 2 h and then evaporated. Ammonia (7 M in MeOH, 3 mL) was added to the residue and the mixture was heated to 80° C. for 2 h and then evaporated. Purification by flash chromatography using MeOH (2%) in CHCl3 gave the title compound (0.15 g, 50%). 1H1NMR (DMSO-d6) δ ppm 13.92 (1H), 12.57 (1H), 8.23 (1H), 8.12 (1H), 7.99 (1H), 7.81 (1H), 7.37 (1H), 5.81 (2H), 1.61 (9H); MS (ESI) m/z 430 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C@:5]([OH:11])([CH3:10])[C:6]([F:9])([F:8])[F:7])[CH3:2].[H-].[Na+].[Br:15][C:16]1[N:21]=[C:20]([C:22]2([CH3:37])[CH2:24][N:23]2[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N+:34]([O-:36])=[O:35])(=[O:27])=[O:26])[C:19]([F:38])=[CH:18][CH:17]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:12])[C@:5]([O:11][CH2:37][C:22]([C:20]1[C:19]([F:38])=[CH:18][CH:17]=[C:16]([Br:15])[N:21]=1)([NH:23][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35])(=[O:26])=[O:27])[CH3:24])([CH3:10])[C:6]([F:7])([F:8])[F:9])[CH3:2]
Reactant: CCOC(=O)[C@@](C)(O)C(F)(F)F
Reactant: CC1(c2nc(Br)ccc2F)CN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@](C)(OCC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1nc(Br)ccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid ethyl ester (715 mg, 3.84 mmol) in DMF (4 ml) was added NaH (55%) (154 mg, 3.84 mmol) at room temperature and the reaction mixture was stirred for 30 minutes at room temperature. A solution of 6-bromo-3-fluoro-2-[2-methyl-1-(2-nitro-benzenesulfonyl)-aziridin-2-yl]-pyridine (800 mg, 1.922 mmol) in DMF (9 ml) was added and the reaction mixture was stirred at room temperature for hours. The reaction mixture was poured onto a mixture of ice/2N HCl/t-butyl-methylether. The organic layer was washed with sat. sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated. Silica gel chromatography (cyclohexane/ethyl acetate) afforded the title compound as a mixture of 2 diastereoisomers. 300 mg (26% yield). TLC (cyclohexane/ethyl acetate 2:1) Rf=0.42; LCMS RtH5=1.25 min (100%, TIC ES+602, 604).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](/[C:7](/[CH3:17])=[CH:8]/[CH2:9][CH2:10][C:11]([CH2:15][CH3:16])([OH:14])[CH2:12][CH3:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:32][CH3:33])(=O)=O.O>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[S:6][C:5](/[C:7](/[CH3:17])=[CH:8]/[CH2:9][CH2:10][C:11]([CH2:15][CH3:16])([CH2:12][CH3:13])[O:14][Si:31]([CH2:36][CH3:37])([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:4][CH:3]=1
Reactant: CCC(O)(CC)CC/C=C(\C)c1ccc(Br)s1
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCC(CC)(CC/C=C(\C)c1ccc(Br)s1)O[Si](CC)(CC)CC
Temperature: 0 °C

Procedure:
2.2 g (6.9 mmol) of (E)-7-(5-bromo-2-thienyl)-3-ethyloct-6-en-3-ol are dissolved in 50 mL of dichloromethane. 25 mg (0.2 mmol) of 4-dimethylaminopyridine and 4.8 mL of triethylamine (34.8 mmol) are added and the reaction medium is cooled to 0° C. 3.9 mL (17.4 mmol) of triethylsilyl trifluoromethanesulphonate are added dropwise. After the addition, the reaction medium is warmed to room temperature and then treated with water and extracted with dichloromethane. After separation of the phases by settling, drying and concentration of the organic phases under reduced pressure, the residue obtained is purified by chromatography on a column of silica. A yellow oil is obtained (m=2.3 g; Y=97%).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[CH3:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20](Cl)=[O:21]>CN(C1C=CN=CC=1)C>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:20]([C:16]1[S:17][CH:18]=[CH:19][C:15]=1[CH3:14])=[O:21])[CH2:3][CH2:4][CH3:5]
Reactant: Cc1ccsc1C(=O)Cl
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1sccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 3-methylthiophene-2-carbonyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.95 (t, 3 H) 1.34-1.43 (m, 2 H) 1.60-1.71 (m, 2 H) 2.17 (s, 3 H) 2.20 (s, 3 H) 2.47 (s, 3 H) 3.92-3.98 (m, 2 H) 6.13 (s, 1 H) 6.91-6.96 (m, 1 H) 7.46-7.52 (m, 1 H); MS (ESI) m/z 308 (M+H)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1>C(OC(=O)C)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([N+:1]([O-:4])=[O:2])[C:9]2[O:13][CH2:12][CH2:11][C:10]=2[CH:14]=1
Reactant: Fc1ccc2c(c1)CCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cc(F)cc2c1OCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of nitric acid (100%, 1.5 ml, 36 mmol) in acetic anhydride (18 ml) was maintained at room temperature for 0.5 hour. The mixture was added to a solution of 5-fluoro-2,3-dihydrobenzofuran (2.5 g, 18 mmol) in 10 ml acetic anhydride at 10° C. The reaction mixture was stirred at room temperature for 2 hours then poured into ice-water. The mixture was extracted with methylene chloride (3×60 ml), washed with 1N sodium hydroxide (5×100 ml) and brine (200 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was removed under vacuum to afford a yellow solid: mp 113-114° C.
Reaction SMILES: [C:1](O)(=O)C.C(N)=N.COCCO.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:23]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH:22]=1.C(OCC)(=O)C>O>[N:20]1([C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:23]([NH:34][C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:1]1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2N)cc1Nc1ccc(F)cc1
Agent: N=CN
Solvent: COCCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-n2cnc3ccccc32)cc1Nc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 104 %

Procedure:
Formamidine acetate 0.10 g was added to ethylene glycol monomethyl ether 3.0 mL solution of tert-butyl 4-((2-aminophenyl)amino)-2-(4-fluoroanilino)benzoate 0.15 g at room temperature, and it was stirred at 80° C. for 6 hours. After the reaction mixture was cooled to room temperature, and ethyl acetate and water were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution, the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=2:1] to give tert-butyl 4-(1H-benzimidazol-1-yl)-2-(4-fluoroanilino)benzoate 0.16 g of a pale red solid.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([Br:22])[C:13]=1[NH2:23]>>[Br:22][C:14]1[CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=[C:12]2[C:13]=1[NH:23][C:2](=[O:4])[C:1](=[O:8])[NH:11]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(C(F)(F)F)cc(Br)c1N
Product: O=c1[nH]c2cc(C(F)(F)F)cc(Br)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962). A mixture of diethyl oxalate (1.15 g, 7.91 mmol) and 1,2-diamino-3-bromo-5-trifluoromethylbenzene (200 mg, 0.95 mmol) was heated to reflux under N2 for 2 h. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with EtOH (15 mL). This white solid was dried in a drying pistol (0.05 torr, 78° C.) to yield 148.3 mg (60.7%). mp 301-304 (dec). 1H NMR (d6 -DMSO) δ7.28 (s, 1H, ArH), 7.56 (s, 1H, ArH), 11.7 (br s, 2H, NH). 19F NMR (C6F6 external standard, δ-162.9) δ-57.97 (s). EIHRMS calc. for C9H4BrF3N2O2 307.9408, found 307.9411.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Cl.[N:22]1([CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)[CH:26]=[N:25][CH:24]=[N:23]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[F:1][C:2]1[C:3]([N:29]2[CH2:30][CH2:31][CH:27]([N:22]3[CH:26]=[N:25][CH:24]=[N:23]3)[CH2:28]2)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: c1ncn(C2CCNC2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1COc2c(N3CCC(n4cncn4)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
A suspension of 70.25 mg (0.25 mmol) of (-) -9,10-difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-benzoxazine-6-carboxylic acid and 87 mg (0.5 mmol) of 3-(1,2,4-triazol-1-yl)pyrrolidine hydrochloride in 3 ml of acetonitrile in the presence of 76 mg (0.5 mmol) DBU was stirred under nitrogen at reflux condition overnight. The yellow solution was then evaporated to dryness and to the residue, water was added and solid collected. The off-white solid was dissolved in chloroform and the small amounts of the suspension were filtered off. The supernatant was evaporated and to the residue, water was added and solid collected (60 mg), m.p. 229°-231° C. 1H NMR (CDCl3) δ: 8.59 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.7 (d, 13.5Hz, 1H), 5.17-5.00 (m, 1H), 4.6-3.73 (m, 7H), 2.67-2.4 (m, 2H), 1.61 (d, 6.7Hz, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:12]=2[C:11]([O:20][CH2:21][C:22](OCC)=O)=[CH:10][CH:9]=1.[OH2:27].[OH-].[Na+]>C(OCC)C>[Cl:7][C:8]1[C:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18][C:12]=2[C:11]([O:20][CH:21]([OH:27])[CH3:22])=[CH:10][CH:9]=1
Reactant: CCOC(=O)COc1ccc(Cl)c2c1CCN(C)CC2
Reactant: O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(O)Oc1ccc(Cl)c2c1CCN(C)CC2
Yield: 91 %

Procedure:
Lithium aluminum hydride (1.53 g, 40 mmol) in ethyl ether (80 ml) was stirred, heated to reflux and treated with a solution of ethyl [(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)oxy]acetate (4.0 g, 13.5 mmol) in ethyl ether (60 ml). The mixture was stirred at reflux for 3.5 hours, cooled, and carefully treated with water (1.5 ml), 10% sodium hydroxide (4.5 ml) and water (1.5 ml). The mixture was filtered and the filtrate dried with magnesium sulfate and concentrated to give 3,2 g (91%) of [(9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepin-6-yl)oxy]ethanol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.Br[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[CH:15]1([CH2:14][O:1][C:2]2[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrCC1CCCCC1
Reactant: COc1cc(O)cc(C(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OCC2CCCCC2)cc(C(C)=O)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 56.2 %

Procedure:
1-(3-Hydroxy-5-methoxyphenyl)ethanone (O3.033; 1.5 g) and bromomethylcyclohexane (1.76 g) were dissolved in DMF (20 ml), and sodium hydride (260 mg) was added. After stirring at 50° C. for 24 h, the DMF was drawn off. The residue was taken up in EA, washed with water, dried, filtered and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA 0-50% within 30 min). 1.33 g of the title compound were obtained.
Reaction SMILES: [CH:1](=[N:19][OH:20])[C:2]1[CH2:3][O:4][C:5]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][C:6]=2[CH:7]=1.O.N.O.[OH-].[Na+]>C(Cl)Cl.FC(F)(F)C(O)=O>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:5]3[O:4][CH2:3][C:2]([CH2:1][NH:19][OH:20])=[CH:7][C:6]=3[CH:8]=2)[CH:14]=1
Reactant: ON=CC1=Cc2cc(Cc3cccnc3)ccc2OC1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: ONCC1=Cc2cc(Cc3cccnc3)ccc2OC1
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
13.1 ml of borane-pyridine complex was added dropwise to a mixture of 3.46 g (13.0 mmol) of 3-formyl-6-(3-pyridylmethyl)-2H-1-benzopyran oxime in methylene chloride (16 ml) and trifluoroacetic acid (16 ml) at −23° C. over 10 minutes and the mixture was stirred at the same temperature for 30 minutes, followed by addition of concentrated ammonia water to neutralize the acid. Then, water and an aqueous 10% sodium hydroxide solution were added to make the mixture basic, followed by extraction with ethyl acetate. After the organic layer was washed with water and brine, the solvent was evaporated in vacuo. The residue was purified by Florisil (Trademark) column chromatography (chloroform: methanol=50:1-15:1) to obtain 3.03 g (yield=86.9%) of the desired compound as an oil.
Reaction SMILES: C([S:4][CH2:5][C@H:6]([C:19]([F:22])([F:21])[F:20])[C:7]([NH:9][C@@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C:12]([OH:14])=[O:13])=[O:8])(=O)C.[OH-].[NH4+].C(OCC)(=O)C.CCCCCC>O.CO.C(O)(=O)C>[F:20][C:19]([F:21])([F:22])[C@@H:6]([CH2:5][SH:4])[C:7]([NH:9][C@@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C:12]([OH:14])=[O:13])=[O:8]
Reactant: CC(=O)SC[C@@H](C(=O)N[C@H](CC(=O)O)CC(C)C)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CC(C)C[C@@H](CC(=O)O)NC(=O)[C@H](CS)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A suspension of the (S,S) isomer product of Example 36 (0.91 g., 2.7 mmol.) in water maintained at 0° C. under argon was treated with ammonium hydroxide (5M solution, 10 mL, 50 mmol.) and stirred for 5 minutes. The reaction was quenched at 0° C. with 140 mL of 10% potassium bisulfate and then extracted with ethyl acetate (4 x). The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo to yield 1.0 g. of a yellow solid. The crude reaction product was triturated with hexane:ethyl acetate to yield 0.78 g. of the title (S,S) isomer product as an off white solid; m.p. 155°-156° C., TLC Rf =0.18 (ethyl acetate:hexane:acetic acid, 100:100:1). [α]D =+26.1° (c=0.81, methanol).
Reaction SMILES: C(O)C.[N:4]1([NH2:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[CH:17][N:16]=1.C(N(CC)CC)C>O>[C:21]([C:20]1[C:15]([NH:13][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5]2)=[N:16][CH:17]=[N:18][CH:19]=1)#[N:22]
Reactant: N#Cc1cncnc1Cl
Reactant: Nn1ccc2ccccc21
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#Cc1cncnc1Nn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 100 ml absolute ethanol, was added 5.0 g of 1H-indol-1-amine, 5.0 g of 4-chloro-5-cyanopyrimidine and 5 ml of triethylamine. After stirring at ambient temperature for 20 hours, the mixture was poured into 400 ml water, stirred for five minutes, then extracted with ethyl acetate. The organic layer was washed with water, then dried (saturated NaCl, anhydrous MgSO4).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.CN1CCOCC1.[CH3:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>C(Cl)Cl>[CH3:25][C:26]1[CH:27]=[C:28]([S:32]([NH:1][C:2]2[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C)n(CC(=O)OC(C)(C)C)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.42 g, 5.88 mmol), as prepared in step 3 of Example 1, and N-methylmorpholine (1.29 mL, 11.76 mmol) in methylene chloride (40 mL) was added 3-methylbenzenesulfonyl chloride (1.12 g, 5.88 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. Additional methylene chloride (60 mL) was added. The resulting methylene chloride solution was washed with saturated NaHCO3 (2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography (5 to 10% ethyl acetate in methylene chloride) to give the title compound as a white solid (2.1 g, 91%). 1H-NMR (300 MHz, CDCl3) δ 7.63 (m, 2H), 7.55 (br s, 1H), 7.42 (d, 1H, J=8 Hz), 7.32 (m, 2H), 6.01 (d, 1H, J=8 Hz), 4.64 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2/[CH:22]=[C:23]2\[C:24](=[O:33])[NH:25][C:26]3[C:31]\2=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)/[C:23](=[CH:22]/[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)/[C:24]1=[O:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CC1
Reaction time: 2 h
Yield: 183.2 %

Procedure:
To a solution of E/Z-4-[4-Chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (2.44 g, 5 mmol) in DCM (10 mL) at r.t. was added diteret-butyl-dicarbonate (1.6 g, 7.5 mmol), followed by the addition of 4-dimethylaminopyridine (0.06 g, 0.5 mmol). The reaction mixture was stirred for 2 h and washed with 0.5N hydrochloric acid, dried over anhydrous Na2SO4, then the solvent was removed to give title compound (Yield: 2.7 g, 92%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=3)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=2[CH:23]=1.[Br:24][C:25]1[C:26](F)=[N:27][CH:28]=[CH:29][CH:30]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu](I)I.CN(C=O)C>[Br:24][C:25]1[C:26]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([CH2:10][O:11][C:12]4[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=4)[C:15]([O:17][CH3:18])=[O:16])[N:7]([CH3:22])[C:6]=3[CH:23]=2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1cccc(OCc2nc3ccc(O)cc3n2C)c1
Reactant: Fc1ncccc1Br
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCc2nc3ccc(Oc4ncccc4Br)cc3n2C)c1
Yield: 46.8 %

Procedure:
The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (3.12 g, 10 mmol), 3-bromo-2-fluoropyridine (1.94 g, 11 mmol), copper iodide (0.19 g, 1.0 mmol), 1,10-phenanthroline (0.18 g, 1.0 mmol), cesium carbonate (9.77 g, 30 mmol) and DMF (50 mL) to obtain the title compound (2.19 g, 47%) as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[CH:41]=[C:42]([CH:53]=[C:54]([O:56][CH3:57])[CH:55]=1)[CH2:43]B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:39][C:40]1[CH:41]=[C:42]([CH:53]=[C:54]([O:56][CH3:57])[CH:55]=1)[CH2:43][C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: COc1cc(F)cc(CB2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(F)cc(Cc2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 9 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (93 mg, 0.16 mmol) was treated with 2-(3-fluoro-5-methoxybenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130 mg, 0.38 mmol), sodium carbonate (40 mg, 0.38 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11 mg, 0.02 mmol) in a mixture of 1,2-dimethoxyethane (1.1 ml) and water (0.3 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 40%, hexane-ethyl acetate) to give 14 mg (9% yield, 68% purity) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][N:34]=[C:35]=[S:36])[CH2:28]2)=[CH:12][CH:11]=1>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:35]([NH:34][CH2:33][CH2:32][N:29]1[CH2:30][CH2:31][CH:27]([NH:26][C:18]2[N:17]([CH2:16][C:13]3[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=2)[CH2:28]1)=[S:36]
Reactant: Nc1ccncc1N
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)C3)nc3ccccc32)cc1
Solvent: C1CCOC1
Product: Nc1ccncc1NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)C1
Yield: 51 %

Procedure:
A mixture of 2.8 parts of 3,4-pyridinediamine, 10.7 parts of 1-[(4-fluorophenyl)methyl]-N-[1-(2-isothiocyanatoethyl)-3-pyrrolidinyl]-1H-benzimidazol-2-amine and 90 parts of tetrahydrofuran was stirred and refluxed for 7 hours. The precipitated product was filtered off while hot, washed with a small amount of tetrahydrofuran and dried, yielding 6.5 parts (51%) of N-(4-amino-3-pyridinyl)-N'-[2-[3-[[1-[(4-fluorophenyl) methyl]-1H-benzimidazol-2-yl]amino]-1-pyrrolidinyl]ethyl]thiourea; mp. 225° C. (compound 177).