Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([O-])(O)=O.[Na+].O.[Br:24]Br>ClCCl>[Br:24][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:17]2
Reactant: BrBr
Reactant: CCCCCCCCC1Cc2ccccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCC1Cc2cc(Br)ccc2O1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
In a 50 ml-three-necked flask, 2.00 g (8.61 mM) of 2-octylcoumaran and 3.2 ml of dichloremethane were placed and mixed to obtain a solution. To the solution, 0.73 (8.69 mM) of NaHCO3 and 3.2 ml of water were added. To the mixture, a solution of 0.44 ml (0.54 mM) of bromine in 1 ml of dichloromethane were added dropwise in 17 minutes under stirring on an ice bath, followed by stirring for 3 hours and 25 minutes at room temperature. After the reaction, the reaction mixture was poured into ice water and subjected to extraction with dichloromethane, followed by two times washing with a common salt aqueous solution and drying with mirabilite. The resultant mixture was concentrated under reduced pressure to obtain 2.58 g of 5-bromo-2-octylcoumaran (Yield: 96.3%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].[CH:20]1([CH2:23][N:24]([C:31]2[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=2)[C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:22][CH2:21]1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:34]1[CH:35]=[CH:36][C:31]([N:24]([CH2:23][CH:20]2[CH2:21][CH2:22]2)[C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:30]=2)=[CH:32][CH:33]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: Ic1ccc(N(CC2CC2)c2ncccn2)cc1
Product: COC(=O)C(C/C=C/c1ccc(N(CC2CC2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 69.1 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (139 mg) was reacted with N-(cyclopropylmethyl)-N-(4-iodophenyl)pyrimidin-2-amine (162 mg) to obtain (E)-5-[4-(cyclopropylmethyl-pyrimidin-2-ylamino)phenyl]-2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (167 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=1/1) was used for purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(NCC)C>[CH3:15][Si:16]([C:19]#[C:20][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)([CH3:18])[CH3:17]
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1ccc(-c2ccc(C#C[Si](C)(C)C)cc2)cc1

Procedure:
In a flask having its atmosphere completely displaced with nitrogen were charged 19 g of 4,4'-diiodobiphenyl, 1.31 g of bis(triphenylphosphine)palladium dichloride, 0.094 g of cuprous iodide and 500 ml of diethylamine. The temperature was elevated to 30° C. under stirring, and 11.04 g of trimethylsilylacetylene was added to the mixture, followed by allowing the mixture to react for 4.5 hours to obtain 4,4'-di(trimethylsilylethynyl)biphenyl. Hydrolysis of this product yielded 4,4'-diethynylbiphenyl.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[S:29]([C:33]1[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=1)(=[O:32])(=[O:31])[NH2:30]>>[S:29]([C:33]1[CH:34]=[C:35]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:28])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:36]=[CH:37][CH:38]=1)(=[O:31])(=[O:32])[NH2:30]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(N)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Light yellow solid. MS (ISP) 554.0 [(M−H)−]; mp 254° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])(O)[CH3:26])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])=[CH2:26])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C(C)(O)c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1)c1ccccc1OC
Yield: 78 %

Procedure:
A solution of crude 37 (2.23 mmol) in toluene (80 mL) was treated with p-toluenesulfonic acid (100 mg) and refluxed under a Dean-Stark trap for 3 hr. After cooling, the reaction mixture was diluted with ethyl acetate (150 mL) and washed with saturated sodium bicarbonate (150 mL) and water (2×100 mL). The organic extract was dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator and the crude product was purified by chromatography on silica (75 g) with 2% ethyl acetate in heptane (4 L) to afford 38 (0.78 g, 78%).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[CH3:23][C:24]1([CH3:30])[CH2:29][O:28][CH2:27][CH2:26][NH:25]1.CCN(C(C)C)C(C)C>>[CH3:23][C:24]1([CH3:30])[N:25]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:26][CH2:27][O:28][CH2:29]1
Reactant: CC1(C)COCCN1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COCCN1c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 100 °C
Yield: 12 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 65 mg, 0.230 mmol), 3,3-dimethylmorpholine hydrochloride (69.8 mg, 0.461 mmol, Tyger Scientific, Ewing, N.J.), and DIPEA (201 μl, 1.151 mmol), heating at 100° C. for 3 h. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(3-(3,3-dimethylmorpholino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (12% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (s, 6H) 2.92 (t, J=6.85 Hz, 2H) 3.46-3.50 (m, 2H) 3.51 (s, 2H) 3.74-3.79 (m, 2H) 3.90-3.94 (m, 2H) 7.00 (br. s., 1H) 7.12 (d, J=2.15 Hz, 1H) 7.59 (t, J=7.82 Hz, 1H) 7.81 (dd, J=8.12, 1.27 Hz, 1H) 7.96 (dd, J=7.53, 1.27 Hz, 1H) 8.91 (s, 1H) 11.69 (br. s., 1H). MS (ESI, pos. ion) m/z: 378.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:25][CH2:24][CH2:23][C:10]3([C:14](=[O:15])[N:13]([C@H:16]4[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28].C(N(CC)CC)C.C(Cl)Cl>>[OH:22][C@H:19]1[CH2:18][CH2:17][C@H:16]([N:13]2[CH2:12][CH2:11][C:10]3([CH2:23][CH2:24][CH2:25][N:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:27](=[O:28])[O:29][CH:30]([CH3:32])[CH3:31])=[CH:3][CH:4]=4)[CH2:9]3)[C:14]2=[O:15])[CH2:21][CH2:20]1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1ccc(N2CCCC3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)Nc1ccc(N2CCCC3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(4-aminophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg, 0.00006 mol), isopropyl chloroformate (11 mg, 0.000087 mol), and triethylamine (20 μL, 0.0002 mol) in methylene chloride (300 μL, 0.005 mol) was stirred at rt for 2 h. The crude reaction mixture was purified by prep.-HPLC to afford 17.4 mg of the desired product. LC-MS: 430.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[CH3:18][C:19]([S@:22]([NH:24][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][C:2]([F:17])([F:1])[C:3]([F:6])([F:5])[F:4])=[CH:9][CH:10]=1)[CH3:15])=[O:23])([CH3:21])[CH3:20]
Reactant: CC(=O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OC(F)(F)C(F)(F)F)cc1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (812 mg, a yellow oil) from 1-(4-(perfluoroethoxy)phenyl)ethanone (737 mg, 2.90 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[CH:16][CH:15]=1>C(O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[O:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[N:1]=2)=[CH:16][CH:15]=1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: S=C=Nc1ccc(Br)cc1
Solvent: CCO
Product: FC(F)(F)c1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
2-Amino-4-(trifluoromethyl)phenol (250 mg, 1.41 mmol) and 1-bromo-4-isothio-cyanatobenzene (302 mg, 1.41 mmol) were stirred in ethyl alcohol at ambient temperature for 18 h. The flask was charged with 1-[3-(dimethylamino)propyl]-3-ethylcarhodiimide hydrochloride (EDCI) (405 mg, 2.12 mmol), and the mixture was stirred for 2 h before being heated at reflux overnight. The reaction was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 2 N aqueous hydrochloric acid solution and water, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 85:15 hexanes/ethyl acetate to provide the title compound (315 mg, 62%). LC-MS m/z 357.1 (MH+), retention time 4.20 minutes.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][CH2:9]C(O)=O)=[CH:6][CH:5]=1)#[N:2].[Br:15]Br>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:9][CH2:8][C:7]1[CH:13]=[CH:14][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: N#CCc1ccc(CCC(=O)O)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#CCc1ccc(CCBr)cc1

Procedure:
A mixture of p-cyanomethylhydrocinnamic acid (18.9 g., 0.1 mole), red mercuric oxide (17.2 g., 0.08 mole), and carbon tetrachloride (180 ml.) is stirred at room temperature while bromine (16.0 g., 0.1 mole) is added dropwise during 40 minutes. The resulting mixture is heated at reflux for 1 hour. The mixture is then cooled, filtered, washed with dilute hydrochloric acid and water, and dried over magnesium sulfate. The solution is evaporated to leave the product as a yellow residual oil. It is purified by column chromatography on silica gel with benzene elution.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]#[N:13].[NH3:14]>CCO>[NH2:14][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]#[N:13]
Reactant: N#Cc1c(F)cccc1C(F)(F)F
Reactant: N
Solvent: CCO
Product: N#Cc1c(N)cccc1C(F)(F)F

Procedure:
2-Fluoro-6-trifluoromethylbenzenecarbonitrile was heated at 100° C. in a saturated solution of NH3 in EtOH overnight. The reaction mixture was concentrated and the residue was purified by column chromatography on silicagel (EtOAc/Hexanes 1:5), to obtain the title compound as a white solid. GC/MS m/z 186.1 (M+), Rt 10.1 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:11][C:12](Cl)=[CH2:13])=[C:4]([OH:10])[C:5]([Cl:9])=[CH:6][C:7]=1[F:8].FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:3]2[CH:11]=[C:12]([CH3:13])[O:10][C:4]=2[C:5]([Cl:9])=[CH:6][C:7]=1[F:8]
Reactant: C=C(Cl)Cc1c(N)c(F)cc(Cl)c1O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(N)c(F)cc(Cl)c2o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
3-Amino-6-chloro-2-(2-chloro-2-propenyl)-4-fluorophenol (4.8 g) was dissolved in chloroform (20 ml), and trifluoromethanesulfonic acid (4.6 g)was dropwise added thereto at 5° C. for 5 minutes, followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into a 5% NaOH solution (30 ml) at 5° C. and extracted with ethyl acetate. The organic layer was dried and concentrated to give 4-amino-7-chloro-5-fluoro-2-methylbenzo[b]furan (3.5 g; yield, 86%).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:19][CH3:20])(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO>[CH2:19]([C:11]1[NH:10][C:18]2[C:13]([CH:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:20]
Reactant: CCc1cc2ccccc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc2ccccc2[nH]1

Procedure:
1.2 g (4.2 mmol) 1-benzenesulphonyl-2-ethyl-1H-indole in 10 mL EtOH were combined with 5 mL of a (20 mmol) 4 N aqueous sodium hydroxide solution and refluxed for 8 h. Then the solvent was eliminated using the rotary evaporator and the residue was diluted with ice water. After acidifying with semi-concentrated aqueous hydrochloric acid the grease precipitated was extracted with ethyl acetate. The organic phase was dried on sodium sulphate, filtered off, evaporated down and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][N:31]=1)[C:16]([NH:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:17].[CH:32]1(O)CCCC1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:10][CH2:32][CH2:11][CH2:12]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][N:31]=1)[C:16]([NH:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:17]
Reactant: Nc1ccc(OC2CCC2)cc1-c1cc(C(=O)N[C@H]2CCCc3ccccc32)ccn1
Reactant: OC1CCCC1
Product: Nc1ccc(OC2CCCC2)cc1-c1cc(C(=O)N[C@H]2CCCc3ccccc32)ccn1

Procedure:
This intermediate was prepared according to the procedure described for the synthesis of (S)-2-(2-amino-5-cyclobutoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide Example 132, using cyclopentanol in place of cyclobutanol.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[N:36]2>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:44]3[CH2:45][CH2:46][N:41]([C:35]4[CH:34]=[CH:33][C:32]5[C:37](=[CH:38][CH:39]=[CH:40][C:31]=5[Cl:30])[N:36]=4)[CH2:42][CH2:43]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Clc1cccc2nc(N3CCNCC3)ccc12
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCN(c3ccc4c(Cl)cccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 5-chloro-2-piperazin-1-yl-quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[CH:30](OC)[N:31]([CH3:33])[CH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:20]=[CH:30][N:31]([CH3:33])[CH3:32])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N=CN(C)C
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of 6.0 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl benzoic acid amide synthesized in Step 1 of Synthetic Example 19 and 50 mL of N,N-dimethylformamide dimethylacetal were stirred at 120° C. for 1.5 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure. The residual solid was washed with ethyl acetate-hexane mixture (1:20) to obtain 6.2 g of the aimed product as pale yellow crystal.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[OH:9].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>>[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:9][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]2[O:2][CH3:1])[C:12]=1[C:13]#[N:14]
Reactant: COC1CCCCC1O
Reactant: N#Cc1c(N)cccc1F
Product: COC1CCCCC1Oc1cccc(N)c1C#N

Procedure:
Prepared as in Example 22b from 2-methoxycyclohexanol and 2-amino-6-fluorobenzonitrile as a yellow oil (34%). MS 247 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([C:15](=[O:17])[CH3:16])[C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[C:13]#[N:14].C[O-].[Na+]>[Ni].C(Cl)Cl.CO>[C:15]([N:5]1[C:6]2[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=2[CH2:13][NH:14][C:3](=[O:2])[CH2:4]1)(=[O:17])[CH3:16]
Reactant: COC(=O)CN(C(C)=O)c1cc(N)ccc1C#N
Agent: [Ni]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CC(=O)NCc2ccc(N)cc21
Reaction time: 12 h
Yield: 34.4 %

Procedure:
A mixture of [acetyl-(5-amino-2-cyano-phenyl)-amino]-acetic acid methyl ester (0.4 g, 1.6 mmol), sodium methoxide (87 mg, 1.6 mmol) and Raney nickel (50 mg) was shaken for 12 hours under a 50 psi H2 atmosphere. The catalyst was removed by filtration and the filtrate was concentrated. Silica gel chromatography (DCM/MeOH 9:1) gave 1-acetyl-8-amino-1,2,4,5-tetrahydro-benzo[e][1,4]diazepin-3-one (120 mg, 0.55 mmol, 34%): 1H NMR (300 MHz, CD3OD) δ 7.12 (d, 1H), 6.7 (m, 2H), 5.35 (d, 1H), 4.37 (d, 1H), 3.80 (d, 1H), 3.49 (d, 1H), 1.93 (s, 3H); MS (m/e) 220 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7](NC(=O)C)=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1.[N:13]1C=CC=C[CH:14]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:7]([C:14]#[N:13])=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: c1ccncc1
Reactant: CC(=O)Nc1ccc(Cl)nc1Cl
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a mixture of 2,6-dichloro-3-acetamidopyridine (6.3 g, 55% pure) and pyridine (4.93 ml, 61 mmole) in dichloromethane (100 ml), trifluoroacetic anhydride (4.23 ml, 30 mmole) was added. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The crude product was purified by flash chromatography, eluting with 85% hexane:15% ethyl acetate to give a pale yellow product (1.77 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24](C)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:42]=[N:41][C:40]([NH2:43])=[CH:39][CH:38]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncnc(N)c1-c1ccc(N)nc1)c1nn2cccc2c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.21 mmol) were added 70 mg (0.32 mmol) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine, 19 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex and 317 μl of a 2M aqueous solution of sodium carbonate in dioxane. The mixture was stirred under argon atmosphere at 80° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified first by flash chromatography (0% to 15% MeOH/DCM) and then by reverse phase chromatography (C-18 silica from Waters®, water/1:1 acetonitrile-methanol as eluents [0.1% v/v formic acid buffered] 0% to 100%) to give 28 mg (30% yield) of the title compound as a white solid.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][CH:27]([CH2:30][CH3:31])[CH2:28]N.S>C(O)C>[CH3:26][CH:27]([CH2:30][CH3:31])[CH2:28][NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CCC(C)CN
Agent: S
Solvent: CCO
Product: CCC(C)CNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 115 °C

Procedure:
A stirred suspension of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2 g) and 2-methylbutylamine (3 cc) in anhydrous ethanol (15 cc) is saturated with hydrogen sulphide and the mixture is heated for 1 hour to a temperature in the region of 115° C. After being cooled, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residual yellow paste is taken up with ethyl acetate (30 cc) and distilled water (20 cc). The organic phase is separated, washed with saturated aqueous sodium chloride solution (20 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual viscous yellow oil (2.2 g) is purified by chromatography on a column (height: 40 cm; diameter: 3.2 cm) of silica gel (0.04-0.063 mm), eluting with a mixture (92:8 by volume) (300 cc) of ethyl acetate and methanol and collecting 25-cc fractions. Fractions 6 to 11 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-[(2RS)-2-Methylbutyl]-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (1.8 g) is thereby obtained in the form of a viscous yellow oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH3:15][O:16][C:17]1[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>ClCCl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: COc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Yield: 37 %

Procedure:
A solution of 5-chlorosulfonyl-2-oxindole (3 g), o-anisidine (1.8 mL) and pyridine (2.1 mL) in dichloromethane (20 mL) was stirred at room temperature for overnight at which time the red color solid was present. The solid was filtered, washed with ethanol and dried under vacuum to yield 1.5 g (37%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid (2-methoxy-phenyl)-amide.