Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[CH:43]1([NH:46][CH3:47])[CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:46]([CH:43]1[CH2:45][CH2:44]1)[CH3:47])=[O:25]
Reactant: CNC1CC1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)C1CC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and cyclopropyl-methylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)[CH3:2].[OH-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:15]1([S:21]([N:10]2[C:7]3=[N:8][CH:9]=[C:4]([S:3][CH2:1][CH3:2])[CH:5]=[C:6]3[CH:12]=[CH:11]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCSc1cnc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: CCSc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.4 %

Procedure:
To a mixture of 5-ethylsulfanyl-1H-pyrrolo[2,3-b]pyridine (2.7 g, 15.2 mmol), sodium hydroxide (1.82 g, 45.6 mmol) and tetrabutylammonium bromide (150 mg, 0.46 mmol) in dichloromethane (30 mL) at 0° C. was added benzenesulfonyl chloride (4.0 g, 22.8 mmol) dropwise. After stirring for 12 h at room temperature, the mixture was washed with water (2×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 50% dichloromethane/hexanes) to afford 1-benzenesulfonyl-5-ethylsulfanyl-1H-pyrrolo[2,3-b]pyridine (2.68 g, 63%): LC/MS m/e calcd for C15H14N2O2S2 [M+H]+ 319.42, observed 319.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+].[CH3:61][O:62][C:63]1[CH:64]=[C:65]([CH:68]=[C:69]([O:73][CH3:74])[C:70]=1[O:71][CH3:72])[CH2:66][NH2:67]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[CH3:24][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[N:8]=[C:5]3[CH:6]=[CH:7][C:2]([NH:67][CH2:66][C:65]4[CH:68]=[C:69]([O:73][CH3:74])[C:70]([O:71][CH3:72])=[C:63]([O:62][CH3:61])[CH:64]=4)=[N:3][N:4]3[CH:10]=2)=[CH:16][C:15]=1[NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1NC(=O)C(C)(C)C
Reactant: COc1cc(CN)cc(OC)c1OC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1cc(CNc2ccc3nc(-c4ccc(C)c(NC(=O)C(C)(C)C)c4)cn3n2)cc(OC)c1OC
Temperature: 100 °C
Yield: 40 %

Procedure:
A 40-mL vial is charged with N-[5-(6-chloroimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (1.0285 g, 3 mmol), tert-butyl xphos (0.255 g, 0.6 mmol), sodium tert-butoxide (0.577 g, 6 mmol), and bis(dibenzylideneacetone)palladium(0) (0.172 g, 0.3 mmol) and the vial is purged with N2. Toluene (16 mL) and 3,4,5-trimethoxybenzylamine (1.54 mL, 9 mmol) is added and the mixture heated at 100° C. for 1 hr. The reaction mixture is filtered through celite, washed with 1:1:0.1 CH2Cl2:EtOAc:MeOH and concentrated onto celite, and purified by silica gel chromatography (0-100% 1:1:0.1 CH2Cl2:EtOAc:MeOH) to afford the title compound (0.604 g). LCMS (m/z)=504.6 [M+H]+, tR=2.31 min.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][N:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])[C:17](=[O:28])[CH2:16]2)=[CH:11][C:10]=1[O:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)C1C=CC=CC=1>CCO.CCOC(C)=O.[Pd]>[CH:30]1([O:29][C:10]2[CH:11]=[C:12]([CH:15]3[CH2:19][N:18]([C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[C:23]#[N:24])[C:17](=[O:28])[CH2:16]3)[CH:13]=[CH:14][C:9]=2[OH:8])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: N#Cc1cccc(N2CC(c3ccc(OCc4ccccc4)c(OC4CCCC4)c3)CC2=O)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#Cc1cccc(N2CC(c3ccc(O)c(OC4CCCC4)c3)CC2=O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.4 %

Procedure:
200 mg of Pd—C was added to 3-[4-(4-benzyloxy-3-cyclopentyloxyphenyl)-2-oxo-pyrrolidin-1-yl]-benzonitrile (1.7 g. 3.8 mmol) in EtOH/EtOAc and flushed with H2 three times. The mixture was then stirred under H2 at r.t. for 72 h. The mixture was filtered through celite and then concentrated under reduced pressure. The residue was then dissolved in EtOAc and washed with 2N HCl, sat. NaHCO3, and sat. NaCl. Purification by silica gel gave 350 mg of the desired product. Yield: 26%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2O.S(=O)(=O)(O)O>O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2
Reactant: OC1CCc2c(Br)cccc21
Agent: O=S(=O)(O)O
Solvent: O
Product: Brc1cccc2c1C=CC2
Yield: 69.2 %

Procedure:
Compound 3 (150 g, 704 mmol, 1 equiv) was suspended in a mixture of concentrated sulfuric acid (250 mL) and water (1.25 L). The mixture was refluxed overnight. The reaction was cooled and extracted with 1.5 L of dichloromethane. The organic layer was washed with saturated sodium bicarbonate (1.5 L), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified over silica gel (800 g), eluting with heptanes to give compound 4 (95 g, 69% yield) as a light yellow oil.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1.[CH2:12]([CH:15]([C:18]#[N:19])[C:16]#[N:17])[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([C:15]([CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1)([C:18]#[N:19])[C:16]#[N:17])[CH:13]=[CH2:14]
Reactant: C=CCC(C#N)C#N
Reactant: COC(=O)c1cnn(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C#N)(C#N)Cn1cc(C(=O)OC)cn1
Yield: 45.2 %

Procedure:
0.79 g of 1-(chloromethyl)-4-methoxycarbonyl-1H-pyrazole and 0.49 g of allyl malononitrile were dissolved in 15 ml of N,N-dimethylformamide. 1.26 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and then recrystallized from hexane-chloroform to obtain 0.50 g of allyl [{4-(methoxycarbonyl)-1H-pyrazole-1-yl}methyl]malononitrile (referred to as the compound of the present invention (24), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[CH:5]2[CH2:11][CH:12]=1.[S]>[O-2].[Zn+2]>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: CC1=CCC2C(=O)OC(=O)C2C1
Agent: [O-2]
Agent: [S]
Agent: [Zn+2]
Product: Cc1ccc2c(c1)C(=O)OC2=O

Procedure:
reacting the 4-methyl-1,2,3,6-tetrahydrophthalic anhydride with sulfur in the presence of zinc oxide and 2-mercaptobenzothizole as a catalyst to form 4-methylphthalic anhydride and a thio derivative;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:28])[C:10]1[N:14]([CH2:15][CH2:16][CH2:17]O)[C:13]2[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:12]=2[N:11]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH:20]=[CH:21][CH:22]=3)[N:14]2[CH2:15][CH2:16][CH2:17][O:28]1
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCN(CC)c1cccc2nc3n(c12)CCCOC3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a stirred solution of 3-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propan-1-ol (Reference example 207, 1.37 g, 3.24 mmol) in pyridine (16 mL) was added methanesulfonyl chloride (502 μL, 6.49 mol) at 0° C. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in dimethylformamide (32 mL) and potassium carbonate (897 mg, 6.49 mmol) was added. After being stirred for 12 h at 80° C., the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (341 mg, 0.844 mmol, 26%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:13]=2[CH3:21])[N:7]=1)=[O:5])[CH3:2].[NH2:22][C:23]1[C:24]([O:38][CH3:39])=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[C:16]([C:18](=[O:20])[NH:22][C:23]3[CH:28]=[C:27]([C:29]([CH3:31])([CH3:32])[CH3:30])[CH:26]=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:24]=3[O:38][CH3:39])[CH:15]=[CH:14][C:13]=2[CH3:21])[N:7]=1)=[O:5])[CH3:2]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CCOC(=O)c1cc(N)n(-c2cc(C(=O)O)ccc2C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(N)n(-c2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)ccc2C)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 47.4 %

Procedure:
5-Amino-1-(5-carboxy-2-methyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (46 mg, 0.159 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) (67 mg, 0.175 mmol) were combined in DMF (500 μL) and stirred for 5 min at room temperature N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (48 mg, 0.175 mmol) was added to the reaction mixture followed by i-Pr2NEt (83 μL, 0.477 mmol). The solution was stirred at room temperature for 48 h then poured onto saturated NaHCO3. The aqueous layer was extracted with CH2Cl2 and the combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by semi-prep HPLC provided the title compound (41 mg, 48%) as a yellow solid (TFA salt): mp 104-111° C. (dec.); ESI MS m/z 544 [C26H33N5O6S+H]+; HPLC>98%, tR=20.79 min.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7](=S)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH2:22]>C(O)CCC>[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH2:21][NH:22][C:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH:10][C:4]2[CH:3]=[C:2]([Cl:1])[CH:17]=[CH:16][C:5]=2[N:6]=1
Reactant: COC(CN)OC
Reactant: S=C1Nc2ccc(Cl)cc2Nc2ccccc21
Solvent: CCCCO
Product: COC(CNC1=Nc2ccc(Cl)cc2Nc2ccccc21)OC

Procedure:
In the manner given in Example 1, 7-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepine-11-thione is treated with aminoacetaldehyde dimethyl acetal in n-butanol to give 7-chloro-[(5H-dibenzo[b,e][1,4]diazepin-11-yl)amino]-acetaldehyde dimethyl acetal.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:45])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]([CH2:34][C:35]([OH:37])=[O:36])[N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:45])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]([CH2:34][C:35]([OH:37])=[O:36])[NH:29][CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:17])[CH3:18]
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCNC2CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
Trifluoroacetic acid (1.0 ml, 13.0 mmol) was added dropwise at 25° C. under nitrogen to a solution of (6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2-{[(1,1-dimethylethyl)oxy]carbonyl}-5-methyl-1,2,3,4-tetrahydro-1-isoquinolinyl)acetic acid (Preparation 22; 75 mg, 0.138 mmol) in dichloromethane (3 ml) and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue co-evaporated with toluene, dried for 20 min under vacuum then triturated with diethyl ether to give a pale brown solid (45 mg). Purification by MDAP gave the title compound (8.2 mg) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][N:7]=1.Cl[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C>O1CCCC1>[CH3:21][O:20][C:18]([NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][N:7]=1)=[O:19]
Reactant: NCCOc1cc(-c2ccccc2)on1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NCCOc1cc(-c2ccccc2)on1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
3-(2-Aminoethoxy)-5-phenylisoxazole hydrochloride (240 mg) was suspended in anhydrous tetrahydrofuran (5 ml), and the suspension was cooled to 5° C. Then, methyl chloroformate (113 mg) and triethylamine (243 mg) were added thereto, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the reaction mixture was added to ice-cold water (40 ml) and extracted with ethyl acetate (40 ml×2). Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The crystals thus obtained were recrystallized from a mixture of ethyl acetate and ether to obtain the title compound (233 mg, 89%) as colorless crystals.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]3[CH:18]=[N:19][CH:20]=[C:13]23)[CH2:9]1)C1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[NH:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]3[CH:18]=[N:19][CH:20]=[C:13]23)[CH2:9]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCC3(CCCn4cncc43)C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1ncn2c1C1(CCC2)CCNC1

Procedure:
A solution of 1.00 mmol of 1′-benzyl-6,7-dihydro-5H-spiro[imidazo[1,5-a]pyridine-8,3′-pyrrolidine] in 5 ml of methanol is admixed with 1 mmol of 2M aqueous hydrochloric acid and 0.10 g of 10% Pd/C. The reaction mixture is hydrogenated with 1 bar of hydrogen at 22° C. for 18 hours. The reaction mixture is filtered over Hyflo and the filtrate is evaporated. The residue is taken up in ethyl acetate and the amine is liberated with saturated aqueous sodium carbonate solution. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [I:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[OH-].[Na+]>CN(C=O)C>[I:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:9]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(I)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cnc(OCC(F)(F)F)c(I)c1
Reaction time: 20 h
Yield: 64 %

Procedure:
5-Iodo-6-(2,2,2-trifluoroethoxy)nicotinic acid (1 g, 2.88 mmol) was dissolved in DMF (10.0 mL); 3-amino-pyridine (285 mg, 3.03 mmol), TBTU (981 mg, 3.05 mmol) and N,N-diisopropylethylamine (1.8 g, 14.4 mmol) were added and the reaction mixture was stirred for 20 hours. The mixture was poured into 5 mL 1 M NaOH solution and extracted with i-propyl acetate (2×50 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo to give a light yellow solid. Crystallization from dichloromethane afforded the title compound (0.78 g, 64%) as white solid; MS (ESI) 423.9 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.Cl[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:19]>N1C=CC=CC=1>[CH3:15][C:14]1[C:13](=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:4][NH:3][C:18](=[O:19])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCOC(=O)Cl
Reactant: Cc1c(CN)[nH]c2ccccc2c1=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCOC(=O)NCc1[nH]c2ccccc2c(=O)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.1 %

Procedure:
To a solution of 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (160 mg) in pyridine (8 mL) was added pentyl chloroformate (100 mg), followed by stirring at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: chloroform/methanol) to obtain pentyl [(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl]carbamate (104 mg).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([NH:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:3]3[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=3[I:1])[NH:11]2)=[CH:16][CH:15]=1)=[O:25]
Reactant: COc1nccc(I)c1-c1cc2ccc(N)cc2[nH]1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1nccc(I)c1-c1cc2ccc(NC(=O)c3cccc(Cl)c3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of 2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (50 mg, 0.14 mmol) in CH2Cl2 (5 mL) was added 3-chlorobenzoic acid (21 mg, 0.14 mmol) and HATU (52 mg, 0.14 mol). The solution was stirred at 25° C. for 1 h and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded 3-chloro-N-[2-(4-iodo-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-benzamide (56 mg, 81%) as a white solid. MH+ 503.8.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([S:14](Cl)(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CN(C)C(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[C:10]([S:14]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[F:18])(=[O:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(S(=O)(=O)Cl)c(F)cc1Cl
Reactant: Nc1ccccc1F
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(S(=O)(=O)Nc2ccccc2F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To Ethyl 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoate (1.0 g, 3.32 mmol) in N,N-dimethylacetamide (5 mL) was added 2-fluoroaniline (1.48 g, 13.28 mmol) dropwise over 30 seconds at room temperature. The mixture was stirred at room temperature for 2 hours, and then it was diluted with ethyl acetate (33 mL). The organic solution was washed with 1 N HCl (2×13 mL) and saturated NaCl (13 mL). The organic layer was concentrated, ethanol (8 mL) was added, and the mixture concentrated to give ethyl 2-chloro-4-fluoro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoate.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH3:16][O:15][N:13]1[CH:14]=[C:10]2[CH:9]=[N:8][C:7]3[CH:2]=[C:3]([CH3:20])[CH2:4][N:5]([CH2:17][CH2:18][CH3:19])[C:6]=3[N:11]2[CH2:12]1
Reactant: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCN1CC(C)=CC2=C1N1CN(OC)C=C1C=N2
Temperature: 30 °C
Reaction time: 4 h

Procedure:
2 g of intermediate A1 are suspended in 50 ml ethanol. 1 ml triethylamine and 1 g palladium catalyst are added. An autoclave is used as reaction vessel. Hydrogen is pressed in up to 20 bar pressure. Now, the mixture is stirred at 30° C. for 4 hours. After filtration the solvent is removed. The crude product is dissolved in 100 ml dichloromethane. This solution is washed with 50 ml water. The solvent is removed to isolate pure product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[C:22]([CH3:38])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[F:37])=[CH:25][CH:26]=1.O>CN(C)C=O>[F:37][C:28]1[CH:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:27]=1[C:24]1[N:23]=[C:22]([CH3:38])[C:21]([CH2:20][O:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)=[CH:15][CH:14]=2)=[CH:26][CH:25]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1CCl
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A solution of 359 mg (1.65 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 20.0 ml N,N-dimethylformamide was treated at 0° C. with 66 mg (1.65 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 500 mg (1.65 mmol) 3-Chloromethyl-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridine were added and stirred continued at r. t. over night. After addition of 40 ml water, the precipitate was isolated, washed thoroughly with water and diisopropylether. The residue was dried at 40° C. to give 618 mg (77%) of the title compound as light brown powder.