Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([CH3:23])[CH:5]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[N+]=[N-]>CCO.[Pd]>[NH2:1][CH:4]([CH3:23])[CH:5]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(N=[N+]=[N-])C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(N)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of azide 109 (35 mg, 0.10 mmol) in EtOH (1 mL), under argon, 10% Pd/c (7 mg) was added. The reaction was purged with H2 and stirred overnight under H2 atmosphere (1 atm). The mixture was filtered through Celite®. The filtrate was concentrated to yield the amine 110 (29 mg, 90%). The crude residue was used without further purification in the next step. 1H-NMR (500 MHz, CDCl3): 0.05 (s, 6H), 0.90 (s, 9H), 1.12 (d, J=6.7 Hz, 3H), 1.47 (s, 9H), 3.21-3.31 (m, 1H), 3.42-3.48 (m, 1H), 3.63-3.82 (m, 2H), 5.01-5.10 (m, 1H). 13C-NMR (125 MHz, CDCl3): −5.1, 19.1, 21.3, 26.2, 28.8, 47.1, 56.9, 64.5, 176.5.
Reaction SMILES: [CH2:1]([C@H:3]1[NH:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:4]1)[CH3:2].C1C=CC2N(O)N=NC=2C=1.[C:27]([NH:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1/[CH:38]=[CH:39]/[C:40](O)=[O:41])(=[O:29])[CH3:28]>C(Cl)Cl>[Cl:37][C:35]1[CH:34]=[CH:33][C:32](/[CH:38]=[CH:39]/[C:40]([N:8]2[CH2:7][CH2:6][N:5]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH2:4][C@H:3]2[CH2:1][CH3:2])=[O:41])=[C:31]([NH:30][C:27](=[O:29])[CH3:28])[CH:36]=1
Reactant: CC(=O)Nc1cc(Cl)ccc1/C=C/C(=O)O
Reactant: CC[C@@H]1CN(Cc2ccc(F)cc2)CCN1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)/C=C/c1ccc(Cl)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
(R)-3-Ethyl-1-(4-fluorobenzyl)-piperazine (44.4 mg, 0.2 mmol), EDC1 (76 mg, 0.4 mmol), HOBT (55 mg, 0.4 mmol) and (E)-3-(2-Acetylamino-4-chloro-phenyl)-acrylic acid (47.8 mg, 0.2 mmol) were dissolved in 5 ml DCM and this mixture was stirred at room temperature overnight. The mixture was diluted with 50 ml DCM and extracted 3 times with water and once with saturated sodium chloride solution. The title compound, purified by chromatography (SiO2, ethyl acetate/MeOHINH3conc, 98/2/0.2) and was isolated as pale solid (81 mg, 91%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)=[CH2:10])=[CH:5][C:4]=1[CH3:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br>CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH:12]=2)=[CH2:10])=[CH:5][C:4]=1[CH3:18]
Reactant: C=C(c1cccc(O)c1)c1ccc(OC)c(C)c1
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C(c1cccc(OCc2cccc(OC)c2)c1)c1ccc(OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-[1-(4-methoxy-3-methyl-phenyl)-vinyl]-phenol (400 mg, 1.67 mmol, 1.0 eq) in 3 mL of dry N,N-dimethylformamide, anhydrous cesium carbonate was added (1.08 g, 3.33 mmol, 2.0 eq.) and the mixture was stirred for 20 min at room temperature. After this time, 3-methoxybenzylbromide (167 mg, 0.832 mmol, 1.2 eq.) was added and the resulting mixture was further stirred for 16 hours at 50° C. The reaction mixture was examined LC-MS which showed>90% conversion to the desired product. The reaction mixture was cooled to room temperature, 10 mL of water was added and the mixture was extracted with DCM. The organic fraction was dried over sodium sulfate and the crude product was purified by flash chromatography eluting with cyclohexane/ethylacetate (100:0 to 90:10). 408 mg of clean product was obtained as colorless liquid (yield: 95%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].[CH3:20][CH2:21][O:22][C:23]([CH3:25])=[O:24].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:2]1[CH2:3][CH2:4][C:23]2([O:24][CH2:20][CH2:21][O:22]2)[CH2:25][CH:7]=1
Reactant: CCOC(C)=O
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Product: Fc1ccc(C2=CCC3(CC2)OCCO3)c(F)c1

Procedure:
A mixture of intermediate I-25 (6.11 g, 89% pure, 18.86 mmol), 2,4-difluorophenyl-boronic acid (4.55 g, 28.86 mmol), LiCl (3.26 g, 1.41 mmol), Na2CO3 (8.1 g, 76.46 mmol), in DME (70.2 mL) and H2O (38 mL) was deoxygenated with a nitrogen flow. Then, tetrakis(triphenylphosphine)palladium (0) (1.63 g, 1.41 mmol) was added and the mixture was stirred under nitrogen atmosphere, at reflux for 5 hours. After cooling, the mixture was diluted with EtOAc/H2O and filtered off over diatomaceous earth. The filtrate was washed with saturated NaHCO3 and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by two flash column chromatographies (silica; EtOAc in heptane 0/100 to 5/95, then silica; CH2Cl2 100%). The desired fractions were collected and concentrated in vacuo to yield intermediate I-26 (1.56 g, 32.7%) as oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.3 %

Procedure:
(5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (40 mg, 0.098 mmol) was dissolved in tetrahydrofuran (2 mL). Methanesulfonyl chloride (18 mg, 0.127 mmol) was added to the reaction mixture followed by triethylamine (136 uL, 0.977 mmol). The suspension was stirred at rt overnight. The compound was triturated with 1:1 ether-hexanes to yield desired product (14 mg, 29%). 1H NMR (300 MHz, dichloromethane-d2) δ 7.95 (1d, 1 H), 7.80 (1s, 1 H), 7.69-7.97.64 (m, 3 H), 7.27-7.25 (m, 4 H), 7.13 (d, 1 H), 6.54 (s, 1 H) 5.61 (bs, 2 H), 5.61 (bs, 2 H), 5.52 (s, 2H), 4.05-3.90 (m, 2H), 3.60-3.35 (m, 3 H), 2.75 (s, 3 H), 2.45 (m, 1 H), 2.20 (m, 1 H); ES-MS m/z 488.3 [M+H]+, HPLC RT (min) 2.72.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[CH:13]1([NH:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH2:23])[CH2:15][CH2:14]1>CC#N>[CH:13]1([N:16]2[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[NH:23][C:6]2=[O:7])[CH2:15][CH2:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cnccc1NC1CC1
Solvent: CC#N
Product: O=c1[nH]c2cnccc2n1C1CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
CDI (CAS 530-62-1) (151.8 g, 936 mmol) was added to a solution of the intermediate 5-c (133 g, 891.4 mmol) in CH3CN (1800 mL) at 0° C. The reaction was allowed to warm to 10° C. and stirred for 1 hour. The solid was collected by filtration, then washed with CH3CN (200 mL) to afford compound 5-d as a white powder (101 g, 65%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:22]=[C:21]2[CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)=O)(C)(C)C>ClCCl>[NH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:22]=[C:21]2[CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)CCn1cc(Cc2cccnc2)c2cc(CCNC(=O)OC(C)(C)C)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCn1cc(Cc2cccnc2)c2cc(CCN)ccc21
Reaction time: 3 h
Yield: 65.1 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a stirred solution of methyl 5-(2-t-butoxycarbonylaminoethyl)-3-(3-pyridylmethyl)-1H-indole -1-propanoate (5.0 g) in dry dichloromethane (50 ml) and the solution was stirred for 3 hours. An additional 5 ml of trifluoroacetic acid was then added and stirring was continued for a further 2 hours. The solution was evaporated and the residue was partitioned between dichloromethane and dilute aqueous ammonia. The aqueous layer was separated and extracted withdichloromethane. The organic layers were combined and evaporated. Water (ca50 ml) was added followed by sufficient acetic acid to adjust the pH to ca4. The solution was washed twice with ethyl acetate and then made basic with concentrated aqueous ammonia solution. The mixture was extracted twice with dichloromethane and the combined extracts were dried (MgSO4) and evaporated to give the title compound as a gum (2.51 g), Rf. 0.15(SS3).
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[C:24](N1C=CN=C1)=[O:25])[CH2:4][CH3:5])[CH3:2].C[Mg]Br.C(OCC)C>C(Cl)Cl>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])[C:8]=1[CH:24]=[O:25])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)n1ccnc1
Agent: C[Mg]Br
Solvent: ClCCl
Solvent: CCOCC
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C=O

Procedure:
The title compound was prepared by reacting [4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-imidazol-1-yl-methanone with methylmagnesium bromide/ethyl ether in methylene chloride. 1H NMR(CDCl3) d 9.7(d,1H), 6.88(s,2H), 6.10(s,1H), 3.32(m,1H), 2.73(s,3H), 2.31(s,3H), 2.10(s,3H), 2.09(s,6H), 1.5-1.7(m,4H), 0.95(t,6H) ppm.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[C:34]2[N:33]=[CH:32][N:31]([CH3:35])[C:30]=2[CH:29]=[CH:28][CH:27]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[C:34]3[N:33]=[CH:32][N:31]([CH3:35])[C:30]=3[CH:29]=[CH:28][CH:27]=2)[CH:6]=1
Reactant: Cn1cnc2c(Nc3cc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nnc3C(N)=O)cccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc2c(Nc3cc(N[C@@H]4CCCC[C@@H]4N)nnc3C(N)=O)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (132 mg, 275 μmol) in CH2Cl2 (5 mL) was treated with TFA (4.08 g, 2.76 mL, 35.8 mmol) and the reaction mixture stirred to room temperature for 18 h. The solvent was evaporated and the residue purified by chromatography (spherical silica 20-45 μM, 80 g, Versaflash Supelco, 0 to 10% of a 9:1 MeOH:NH4OH solution in CH2Cl2, 30 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazine-3-carboxamide (70 mg, 67%) as an off-white solid. 1H NMR (DMSO-d6) δ: 11.06 (s, 1H), 8.23 (br. s., 1H), 8.16 (s, 1H), 7.50 (br. s., 1H), 7.15-7.37 (m, 3H), 6.75 (s, 1H), 6.70 (d, J=7.6 Hz, 1H), 4.09 (br. s., 1H), 3.84 (s, 3H), 3.08 (br. s., 1H), 1.54 (br. s., 6H), 1.26 (d, J=17.0 Hz, 2H); LC-MS 381.1 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]3[C:16](=[O:27])[NH:15][C:14](=[O:28])[N:13]([CH2:29][CH2:30][CH2:31][CH3:32])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br[CH2:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=1[F:45].N12CCCN=C1CCCCC2>C(#N)C.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][C:10]2[N:18]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:24])([CH3:25])[CH3:23])[C:17]3[C:16](=[O:27])[N:15]([CH2:36][C:37]4[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=4[F:45])[C:14](=[O:28])[N:13]([CH2:29][CH2:30][CH2:31][CH3:32])[C:12]=3[N:11]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCCn1c(=O)[nH]c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Reactant: COc1ccc(F)c(CBr)c1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCn1c(=O)n(Cc2cc(OC)ccc2F)c(=O)c2c1nc(Cc1ccc(NC(C)=O)cc1)n2COC(=O)C(C)(C)C
Temperature: 25 °C
Yield: 20.4 %

Procedure:
A solution of 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (100 mg, 0.21 mmol) and 2-bromomethyl-1-fluoro-4-methoxy-benzene (56 mg, 0.25 mmol) in acetonitrile (2.0 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.06 mL, 0.45 mmol). The reaction was stirred at 25° C. The reaction was diluted with ethyl acetate and was washed with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1:1 ethyl acetate/petroleum ether) afforded 2,2-dimethyl-propionic acid 8-(4-acetylamino-benzyl)-3-butyl-1-(2-fluoro-5-methoxy-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl ester (26 mg, 20%) as a yellow solid. This material was taken on without further purification or characterization.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:9][C:10]1[CH:11]=[C:12]([C:14](I)=[CH:15][CH:16]=1)[NH2:13]>>[F:9][C:10]1[CH:11]=[C:12]2[C:14]([CH:2]=[C:1]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[NH:13]2)=[CH:15][CH:16]=1
Reactant: C#Cc1cccnc1
Reactant: Nc1cc(F)ccc1I
Product: Fc1ccc2cc(-c3cccnc3)[nH]c2c1

Procedure:
3-Ethynylpyridine and 3-fluoro-6-iodoaniline are processed according to the method described in Example 86 to give 6-fluoro-2-pyridin-3-yl-1H-indole. MS (ESI) m/z 213.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[C:2]1C=CC=CC=1.C(=O)([O-])[O-:28].[Na+].[Na+].ClCC(Cl)=O.O>C(Cl)Cl>[CH2:20]([N:8]1[CH2:9][CH2:10][N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[C:2](=[O:28])[CH2:1]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1NCCN(Cc1ccccc1)Cc1ccccc1
Agent: O=C(Cl)CCl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1N1CCN(Cc2ccccc2)CC1=O
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a stirred solution of 21.6 g of N,N-dibenzyl-N'-(2-methoxyphenyl)-ethylenediamine in 400 ml methylene chloride was added 12.9 g of sodium carbonate. To this mixture, a solution of 8.42 g of chloroacetylchloride in 100 ml methylene chloride was added dropwise over 30 minutes and stirred for 1 hour. Water (500 ml) was added, the organic phase separated, washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue (27.9 g) in a flask was immersed in a 180° oil bath and the formed benzylchloride removed by distillation. The crude material was chromatographed on 250 g silica gel using ether for elution. The appropriate fractions were evaporated to dryness and the solid recrystallized from isopropylether to yield 11.0 g 4-benzyl-1-(2-methoxyphenyl)-2-piperazinone in the form of yellowish crystals, mp 109°-111°, pure by TLC (ether on silica gel).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[S:33][C:34]([CH3:37])=[CH:35][N:36]=4)[C:28](=[O:38])[N:27]([CH3:39])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[S:33][C:34]([CH3:37])=[CH:35][N:36]=4)[C:28](=[O:38])[N:27]([CH3:39])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)s1
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To a solution of 120c (98 mg, 0.18 mmol) in methanol/dichloromethane(3/3 mL) was added NaBH4 (21 mg, 0.55 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. The mixture was quenched with water (5 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×15 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 120 (30 mg, 31%) as a white solid. MS-ESI: [M+H]+ 546.7. 1H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.58 (d, J=5.5 Hz, 1H), 8.56 (d, J=2.5 Hz, 1H), 8.54 (d, J=2.0 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.78 (d, J=13.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 6.96 (d, J=1.0 Hz, 1H), 4.91 (bs, 1H), 4.42-4.41 (m, 2H), 3.60 (s, 3H), 2.28 (d, J=1.0 Hz, 3H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:11]=[C:10]([C:12]([NH:14][C@H:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=3[N:18]=2)[CH3:16])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.CN(C(O[N:37]1N=NC2C=[CH:41][CH:42]=[CH:43][C:38]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.N1CC=CC1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:26][C:24]1[CH:23]=[CH:22][C:20]2[NH:21][C:17]([C@@H:15]([NH:14][C:12](=[O:13])[C:10]3[CH:9]=[CH:8][C:4]([C:5]([N:37]4[CH2:38][CH:43]=[CH:42][CH2:41]4)=[O:7])=[C:3]([C:2]([F:28])([F:1])[F:27])[CH:11]=3)[CH3:16])=[N:18][C:19]=2[CH:25]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: C1=CCNC1
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 55 %

Procedure:
Prepared analogously to Example 1g from (1S)-2-trifluoromethyl-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and 3-pyrroline in tetrahydrofuran. Yield: 55%; Rf value: 0.50 (silica gel: dichloromethane/ethanol=9:1); C22H18ClF3N4O2 (462.863); mass spectrum: (M+H)+=463/465 (chlorine isotope) and (M−H)−=461/463 (chlorine isotope).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[N+:21]([O-])=O>C(OCC)(=O)C.C(O)C>[NH2:21][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(Nc2nccc(-c3cccnc3)n2)cc1N
Temperature: 25 °C
Yield: 104.9 %

Procedure:
N-(4-methyl-3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (34 g, 0.11 mol) and stannous chloride dihydrate (124.5 g, 0.55 mol) were dissolved in a solvent mixture of ethyl acetate and ethanol (300 ml, 10/1, v/v) and reacted under reflux for 26 hours. The reaction mixture was cooled to room temperature, washed with 10% aqueous hydrochloric acid solution, concentrated, and subjected to column chromatography (chloroform/methanol=9/1, v/v) to give N-(3-amino-4-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (32 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](=[O:11])[N:8]([CH3:10])[CH:9]=1)([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7](=[O:11])[N:8]([CH3:10])[CH:9]=1
Reactant: Cn1cc([N+](=O)[O-])ccc1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1cc(N)ccc1=O
Reaction time: 8 h

Procedure:
To a suspension of 5-nitro-1-methyl-2(1H)-pyridone (154 mg, 0.999 mmol) in ethyl acetate (3 mL) and ethanol (3 mL) was added 5% Pd—C (36 mg), and the resulting mixture was stirred under hydrogen atmosphere overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain the title compound as light-green oil. 1H NMR (CD3OD 400 MHz): δ=3.53 (s, 3H), 6.49 (d, 1H, J=9.6 Hz), 7.07 (d, 1H, J=3.2 Hz), 7.28 (dd, 1H, J=2.8 & 9.6 Hz). MS (ES+): m/z 125.04 (100) [MH+]. HPLC: tR=0.43 min (ZQ2000, polar—5 min).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][C:3]=1[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N)ccc1I
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NS(C)(=O)=O)ccc1I
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A solution of 4-iodo-3-methylaniline (4.37 g, 18.75 mmol) in CH2Cl2 (25 ml) was treated with pyridine (6.07 ml, 75 mmol) followed by drop wise addition of methanesulfonyl chloride (1.607 ml, 20.63 mmol) to give a reddish/orange mixture. The mixture was stirred for 2 h, concentrated and diluted with EtOAc. The EtOAc layer was washed with 1M HCl, water, saturated NaCl, dried (Na2SO4) and filtered. The EtOAc filtrate was treated with activated charcoal for 30 min at 50° C. and filtered through a 10 g silica plug and concentrated to give the title compound as a light yellow solid (5.5 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].O>C1(C)C=CC=CC=1>[CH3:3][C:2]1[C:11]([CH3:10])=[N:1][C:2]2[C:11](=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[N:12]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2nc(C)c(C)nc2c1

Procedure:
55.8 g (0.354 mole) of methyl 3,4-diaminobenzoate and 30.5 g (0.354 mole) of diacetyl are heated under reflux in 500 ml of toluene for 3 hours, using a water separator. The toluene is distilled off in vacuo and the residue is dissolved in ethyl acetate under the influence of heat, active charcoal being added, the active charcoal is separated off via a Seitz filter and the filtrate is concentrated to dryness.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:27])[CH:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:27])[CH:19]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:13][CH:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:16]
Reactant: Oc1ccc(C2=CCCCCC2)cc1
Reactant: CCCCCCC(Br)C(=O)OCC
Product: CCCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)OCC

Procedure:
Analogously to the process described in Example 1, 11.5 g of p-(1-cycloheptenyl)-phenol and 26.4 g of 2-bromooctanoic acid ethyl ester give α-[p-(1-cycloheptenyl)-phenoxy]-octanoic acid ethyl ester as a colourless oil of boiling point 155°-160° C/0.04 mm Hg.