Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[CH2:16][N:15]([C@H:22]1[C@H:27]([OH:28])[CH2:26][CH2:25][O:24][CH2:23]1)[C:14]2=[O:29])[C:5]#[N:6].C(=O)([O-])[O-:31].[K+].[K+].OO>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[CH2:16][N:15]([C@H:22]1[C@H:27]([OH:28])[CH2:26][CH2:25][O:24][CH2:23]1)[C:14]2=[O:29])[C:5]([NH2:6])=[O:31]
Reactant: Cc1c(Cc2ccc(C#N)cc2F)cc2c(c1C)CN([C@@H]1COCC[C@H]1O)C2=O
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(Cc2ccc(C(N)=O)cc2F)cc2c(c1C)CN([C@@H]1COCC[C@H]1O)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
To a mixture of rac-3-fluoro-4-((2-(trans-4-hydroxytetrahydro-2H-pyran-3-yl)-6,7-dimethyl-3-oxoisoindolin-5-yl)methyl)benzonitrile (0.08 g) and potassium carbonate (0.08 g) in DMSO (2.00 mL) was added 35% aqueous hydrogen peroxide (0.17 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate-THF. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (0.07 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([CH3:29])[C:19]=1[O:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[CH:15]=O.S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[CH3:29][C:18]1[CH:17]=[C:14]([C:15]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:1]=2)[CH:13]=[C:12]([CH3:11])[C:19]=1[O:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: NC(=O)c1ccccc1N
Reactant: Cc1cc(C=O)cc(C)c1OCCN1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3ccccc3c(=O)[nH]2)cc(C)c1OCCN1CCOCC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 2-amino benzamide (136 mg, 1.0 mmol) in N,N-dimethyl acetamide (5 mL) were added 3,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)benzaldehyde (263 mg, 1.0 mmol), sodium hydrogen sulphite (58.5%) (196 mg, 1.1 mmol) and p-toluenesulfonic acid (19 mg, 0.1 mmol). The reaction mixture was stirred at 150° C. overnight. Water (40 mL) was added. The formed solid was filtered off, washed with water and a small amount of methanol and dried under vacuum to give the title compound (190 mg, 50%) as an off-white solid. To a solution of the above compound (174 mg, 0.458 mmol) in 2:1 anhydrous CH2Cl2-methanol (15 mL) was added 1.0 M solution of hydrogen chloride in ether (1.5 mL) and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was triturated with 10% methanol in anhydrous ether to give the hydrochloride of 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one (187 mg, 98%), as an off-white solid. Selected data: MS (ES) m/z: 380.10; MP 300-302° C. (hydrochloride).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[C:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:12]([N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (5 g, 29 mmol), 1-acetylpiperazine (29 mmol), and K2CO3 (4.0 g, 29 mmol) in DMF (20 mL) was stirred at 120° C. for 4 h. The reaction mixture was cooled to room temperature and poured into ice cold water (100 mL). The crude solid product was collected by filtration, air dried, and purified by flash chromatography (silica gel, 4×15 cm, eluted with CHCl3) to yield the product as orange crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[N:5]=1)([O-:3])=[O:2]
Reactant: CC(C)CCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 70.5 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-bromo-3-methyl-butane (0.133 mL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-iso-pentyl-1H-pyrazole (115 mg, 59%) as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[N:23]1[C:32]2[C:27](=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:27]=3[CH:26]=[CH:25][CH:24]=[N:23]4)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: OB(O)c1cccc2ncccc12
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Product: CC(On1ccc2ncc(-c3cccc4ncccc34)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and quinolin-5-ylboronic acid according to the procedure described in example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:28])[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[N:16]2[C:20]([CH2:21]O)=[C:19]([CH3:23])[N:18]=[C:17]2[CH2:24][N:25]([CH3:27])[CH3:26])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12.N(C(OCC)=O)=NC(OCC)=O>>[F:15][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[C:20]([CH2:21][N:52]3[C:48](=[O:58])[C:49]4=[CH:57][CH:56]=[CH:55][CH:54]=[C:50]4[C:51]3=[O:53])=[C:19]([CH3:23])[N:18]=[C:17]2[CH2:24][N:25]([CH3:26])[CH3:27])=[C:9]([C:8](=[O:28])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:14]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc(CN(C)C)n(-c2ccc(F)cc2C(=O)c2cccc(Cl)c2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(CN(C)C)n(-c2ccc(F)cc2C(=O)c2cccc(Cl)c2)c1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 3, 3'-chloro-5-fluoro-2-[2-[(dimethylamino)methyl]-4-methyl-5-hydroxymethylimidazol-1-yl]benzophenone, triphenylphosphine, phthalimide and thereafter diethyl azodicarboxylate are reacted together to give N-[[1-[4-fluoro-2-(m-chlorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][NH2:8])=[CH:2]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[C:2]3[S:1][CH:5]=[CH:4][C:3]=3[CH2:6][CH2:7][NH:8]2)=[CH:12][CH:11]=1
Reactant: NCCc1ccsc1
Reactant: O=Cc1ccc(Cl)cc1
Product: Clc1ccc(C2NCCc3ccsc32)cc1

Procedure:
2-(3-Thienyl)ethanamine (3.15 g) and 4-chlorobenzaldehyde (3.5 g) were mixed without solvent resulting in dissolution af the crystals of the amine followed by precipitation of slightly yellow crystals. The mixture was left at RT for 4 h. Trifluoroacetic acid (20 ml) was added and the mixture stirred overnight at RT.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:44]([NH:46][C:47]3[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=3[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.[NH:57]1[CH:61]=[CH:60][CH:59]=[C:58]1[C:62]([OH:64])=O>>[NH:57]1[CH:61]=[CH:60][CH:59]=[C:58]1[C:62]([NH:18][C@H:19]([C:44]([NH:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[O:55][CH3:56])=[O:45])[CH2:20][CH2:21][C:22](=[O:43])[NH:23][C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:64]
Reactant: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)c1
Reactant: O=C(O)c1ccc[nH]1
Product: COc1ccc(OC)c(NC(=O)[C@H](CCC(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)c2ccc[nH]2)c1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-trityl-L-glutaminyl]-2,5-dimethoxyaniline (988 mg, 1.33 mmol, example 82, step A) as described for example 82 (step B) using pyrrole-2-carboxylic acid (222 mg, 2.0 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using successively 10%, 15% and 20% EtOAc/CH2Cl2. The title compound was obtained as white crystals (497 mg, 61%).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[F:18])(=[O:7])[CH3:6]>CN(C)C=O.C1C=CC=CC=1>[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:3])=[O:14])=[CH:11][C:10]=1[F:18])(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1F
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1F
Temperature: 25 °C

Procedure:
2.90 ml of thionyl chloride was added to 2.50 g (12.6 mM) of 4-acetoxy-3-fluorobenzoic acid. Under stirring at room temperature, two drops of N,N-dimethylformamide (DMF) was added thereto, followed by refluxing for 40 minutes. After the reaction, dry benzene was added to the reaction mixture, followed by two times of distilling-off of excessive thionyl chloride under reduced pressure to obtain 4-acetoxy-3-fluorobenzoyl chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[Cl:14][C:15]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:16]=1[NH2:17]>ClC1C=CC=CC=1>[ClH:14].[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]([NH:17][C:16]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:15]=2[Cl:14])=[NH:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(N(C)C#N)c1
Reactant: Nc1cc(Cl)ccc1Cl
Agent: Cl
Solvent: Clc1ccccc1
Product: CCc1cccc(N(C)C(=N)Nc2cc(Cl)ccc2Cl)c1

Procedure:
A mixture of N-(3-ethylphenyl)-N-methylcyanamide (520 mg, 3.3 mmol), 2,5-dichloroaniline hydrochloride (600 mg, 3 mmol), and chlorobenzene (2 mL) were combined in a dry round bottom flask equipped with a water cooled condenser under nitrogen and placed in a preheated oil bath (150-160° C.). The reaction mixture was heated for 4 hours. After cooling, the crude reaction product was purified by crystallization from chlorobenzene/diethylether. The resulting crystals were collected by filtration, washed with diethylether, and dried in a vacuum oven (40° C., 15 hours) to yield the title compound, N-(3-ethylphenyl)-N-methyl-N'-(2,5-dichlorophenyl)guanidine hydrochloride, as a white solid (760 mg, 72% yield).
Reaction SMILES: [Br-].[F:2][C:3]([F:8])([F:7])[C:4]([Zn+])=[CH2:5].[Br:9][C:10]1[C:11]([O:17][CH:18]([F:20])[F:19])=[C:12](I)[CH:13]=[CH:14][CH:15]=1>O1CCCC1.Cl>[Br:9][C:10]1[C:11]([O:17][CH:18]([F:20])[F:19])=[C:12]([C:4]([C:3]([F:8])([F:7])[F:2])=[CH2:5])[CH:13]=[CH:14][CH:15]=1
Reactant: C=C([Zn+])C(F)(F)F
Reactant: FC(F)Oc1c(Br)cccc1I
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1OC(F)F)C(F)(F)F

Procedure:
In 10 ml of a solution of 1-trifluoromethylethenyl zinc bromide prepared according to the method described in documents in 1M tetrahydrofuran, 1.0 g of 3-bromodifluoromethoxy-1-iodobenzene and 0.05 g of dichlorobis(triphenylphosphine) palladium (II) were added, and stirred under reflux with heat for 2 hours. After the completion of the reaction, the reaction mixture was poured in 20 ml of diluted hydrochloric acid, extracted with ethyl acetate (50 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in hexane, and high polar impurities were excluded by treating with silica gel to obtain 0.77 g of crude aimed product as colorless oily substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.C(O)(=O)C.[CH:18](N)=[NH:19]>C(O)(=O)C>[CH3:10][N:8]([C:5]1[N:6]=[CH:7][C:2]2[N:1]=[CH:18][NH:19][C:11](=[O:13])[C:3]=2[CH:4]=1)[CH3:9]
Reactant: N=CN
Reactant: CN(C)c1cc(C(=O)O)c(N)cn1
Solvent: CC(=O)O
Product: CN(C)c1cc2c(=O)[nH]cnc2cn1
Yield: 44.1 %

Procedure:
5-Amino-2-(N,N-dimethylamino)-pyridine-4-carboxylic acid (0.54 g) was treated with formamidine acetate (3.12 g) in glacial acetic acid (20 ml) and heated at reflux for 16 hours. The mixture was cooled, evaporated to dryness in vacuo and partitioned between ethyl acetate and water. The organic phase was separated, dried over magnesium sulphate and concentrated in vacuo to give, after chromatography on silica, the title compound (0.25 g); δH CDCl3 9.10(1H,d), 8.80(1H,s), 8.31(1H,s), 7.07(1H,s), 3.20(6H,s); m/z (M+1+) 191.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])([O-:3])=[O:2].OS(O)(=O)=O.[CH3:24]O>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH:14]([CH3:18])[C:15]([O:17][CH3:24])=[O:16])([O-:3])=[O:2]
Reactant: CC(Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 81 %

Procedure:
To a solution of 3-(2,4-dinitrophenyl)-2-methylpropanoic acid (1.6 g, 5.0 mmol) in MeOH (10 mL) was added H2SO4 (0.85 mL, 16 mmol) and the mixture was heated to reflux overnight. The solvent was removed under reduced pressure and the residue was dissolved in DCM (100 mL). The organic solution was washed with saturated aqueous NaHCO3 and the layers were separated. The organic solution was dried over anhydrous Na2SO4 and filtered. The organic solution was directly purified by preparative TLC (1.0 mm plate), eluting with 5:1 pet ether/EtOAc to give methyl 3-(2,4-dinitrophenyl)-2-methylpropanoate (1.1 g, 81%): LC/MS (Table 2, Method f) Rt=1.95 min; MS m/z: 267 (M−H)−.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CO>[CH2:1]([CH:8]1[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCC3(CC2)OCCO3)cc1
Solvent: CO
Solvent: O
Product: O=C1CCC(Cc2ccccc2)CC1
Yield: 105.8 %

Procedure:
A mixture of 28 g of 8-benzyl-1,4-dioxa-spiro[4.5]decane, 100 mL of water, 10 mL of methanol and 20 g of Amberlite™ IR-120+ was heated to reflux for 5 h. After cooling, removal of solvents under reduced pressure gave 24 g of 4-benzyl-cyclohexanone as an oil.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.Cl[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN1CCCC1=O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: Clc1ccccn1
Reactant: Nn1ccc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: c1ccc(Nn2ccc3ccccc32)nc1
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (3.4 g) was added to a room temperature solution of N-aminoindole (2.0 g) in 1-methyl-2-pyrrolidinone (40 ml). After stirring for one hour, 2-chloropyridine (1.6 ml) was added and the resulting solution was stirred for forty-eight hours. The reaction mixture was then quenched with water, diluted with ethyl acetate (250 ml) and washed with brine (3×250 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give an oil. Purification of the residue by flash chromatography (silica, 0-5% ethyl acetate/dichloromethane) gave the title compound as a solid (2.0 g), m.p. 109°-110° C.
Reaction SMILES: C[N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1C=CC=CC=1.C(OCC)C>[C:21]([N:2]1[CH2:19][CH2:18][N:5]2[C:6]3[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=3[CH2:8][N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[CH:4]2[CH2:3]1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)Cl
Reactant: CN1CCN2c3ccccc3Cn3cccc3C2C1
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)N1CCN2c3ccccc3Cn3cccc3C2C1

Procedure:
To the solution of 1.9 g of 2-methyl-1,3,4,14b-tetrahydro-10H--pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine in 50 ml of benzene, 2.14 g of ethyl chloroformate are added and the mixture is refluxed for 3 days. It is diluted with diethyl ether, washed with N hydrochloric acid and with both saturated aqueous sodium chloride and sodium bicarbonate, dried and evaporated, to yield the 2-carbethoxy-1,3,4,14b-tetrahydro-10H--pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine showing in the NMR-spectrum peaks at 8.55(t), 6.60(m), 5.65(q) and 3.90(d) ppm, and in the mass-spectrum a molecular ion of 311.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)=[O:23])[N:21]=2)[CH:18]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 4-(trifluoromethyl)aniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]2[CH:30]=[C:31]([CH3:39])[C:32]3[O:36][C:35]([CH3:37])=[N:34][C:33]=3[CH:38]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][C:35]1[O:36][C:32]2[C:31]([CH3:39])=[CH:30][C:29]([NH:28][C:24]3[N:25]=[CH:26][N:27]=[C:22]([N:17]4[CH2:18][CH2:19][CH:14]([N:10]5[CH2:9][CH2:8][C:7]6[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=6[NH:12][C:11]5=[O:13])[CH2:15][CH2:16]4)[CH:23]=3)=[CH:38][C:33]=2[N:34]=1
Reactant: Cc1nc2cc(Nc3cc(Cl)ncn3)cc(C)c2o1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Nc4cc(C)c5oc(C)nc5c4)ncn3)CC1)C(=O)N2
Temperature: 150 °C
Reaction time: 2.5 h

Procedure:
70 mg (0.25 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 55 mg (0.20 mmol) (6-chloro-pyrimidin-4-yl)-(2,7-dimethyl-benzoxazol-5-yl)-amine and 0.15 mL (0.87 mmol) DIPEA were combined in 1.5 mL DMF and stirred for 2.5 h at 150° C. The reaction mixture was purified by preparative HPLC. The product-containing fractions were combined and freeze-dried. The residue was stirred with MeOH and DMF, left to stand for 1 h and filtered. The precipitate was washed with MeOH and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]2)=[CH:10][CH:9]=1.Br[C:20]1[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][N:21]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH:18][C:20]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][N:21]=3)[N:14]=[CH:15]2)=[CH:10][CH:9]=1
Reactant: OCc1ccnc(Br)c1
Reactant: Cc1ccncc1-c1ccc2cc(N)ncc2c1
Product: Cc1ccncc1-c1ccc2cc(Nc3cc(CO)ccn3)ncc2c1
Yield: 44 %

Procedure:
The title compound was prepared following the procedures described for Example 13, using 7-(4-methylpyridin-3-yl)isoquinolin-3-amine and 2-bromopyridine-4-methanol, to yield 26.2 mg (44%) of (2-(7-(4-methylpyridin-3-yl)isoquinolin-3-ylamino)pyridin-4-yl)methanol. LCMS (ESI): RT (min)=2.759, M+H=343.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.12 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.23 (d, J=5.2 Hz, 1H), 8.00 (s, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.38 (d, J=4.9 Hz, 1H), 7.29 (s, 1H), 6.81 (d, J=5.1 Hz, 1H), 5.35 (t, J=5.7 Hz, 1H), 4.50 (d, J=5.6 Hz, 2H), 2.34 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)(O)[CH:9]=[CH2:10])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C(Cl)Cl>[Cl:19][CH2:10][CH:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: C=CC(O)(c1ccc(Cl)cc1)c1cccnc1
Solvent: ClCCl
Product: ClCC=C(c1ccc(Cl)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of crude 1-(4-chlorophenyl)-1-(3-pyridyl)-2-propen-1-ol (40 mmol) in 100 ml methylene chloride was added dropwise to a suspension of phosphorus pentachloride (12.4 g, 60 mmol) at 10° C. After stirring for 1 h at room temperature the solution was washed with 50 ml water at 0° to 10° C. The solution of the crude title compound was used in the following aminations, i.e. Example 2 and 3.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([CH3:13])=[C:4]([CH3:14])[CH:3]=1.[CH3:15][O:16]C(Cl)Cl>ClCCl>[Cl:1][C:2]1[C:10]2[O:9][C:8]([CH3:11])([CH3:12])[CH2:7][C:6]=2[C:5]([CH3:13])=[C:4]([CH3:14])[C:3]=1[CH:15]=[O:16]
Reactant: COC(Cl)Cl
Reactant: Cc1cc(Cl)c2c(c1C)CC(C)(C)O2
Solvent: ClCCl
Product: Cc1c(C)c2c(c(Cl)c1C=O)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 20 g of the 7-chloro-2,3-dihydro-2,2,4,5-tetramethylbenzofuran in 200 ml of absolute dichloromethane was added 27.3 ml of titanium chloride(IV) and 18.75 ml of α,α-dichloromethyl methyl ether at 0° C. With stirring at room temperature for 45 minutes and refluxing for 15 minutes, the reaction mixture was quenched with 200 ml of ice-water and stirred for 30 minutes and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 14 g of 7-chloro-2,3-dihydro-2,2,4,5-tetramethylbenzofuran-6-carboxaldehyde.