Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].[OH-].[K+].ClC(Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>O.C1(C)C=CC=CC=1>[NH:10]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3](=[O:4])[O:2][C:1]1=[O:16]
Reactant: COC(=O)c1sccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccsc2c(=O)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
40 g (250 mmol) 3-Amino-thiophene-2-carboxylic acid methyl ester were suspended in 250 ml water with 21.0 g (374 mmol) potassium hydroxide. The mixture was boiled in a microwave oven (500 W) for 30 min and afterwards it was cooled to 0° C. A solution of 37.1 g (125 mmol) triphosgene in 200 ml toluene was added drop wise and the reaction mixture stirred for 2 h at room temperature. The residue was isolated by filtration. The product was washed with water and sodium bicarbonate solution. For further purification it can be washed with ethyl ether and methanol after drying.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:13]([OH:41])[C@@H:14]([N:24](CC1C=CC=CC=1C)CC1C=CC=CC=1C)[CH2:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:13]([OH:41])[C@@H:14]([NH2:24])[CH2:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1CN(Cc1ccccc1C)[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1

Procedure:
Add 2-(R)-[2-(S)-[bis-(2-methylbenzyl)-amino]-3-(3,5-difluorophenyl)-1-(S)-hydroxypropyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.116 g, 0.205 mmol), 20% palladium on carbon (0.069 g) and methanol (3 mL) and hydrogenate at one atmosphere hydrogen gas for 18 h. Add filter agent and filter and concentrate to give the title compound as a residue (0.069 g, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].C[O-].[Na+].CS(C)=O.[Cl:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=2[CH2:32]Cl>O>[Cl:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=2[CH2:32][O:7][C:6]([C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])=[O:8]
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(OCc1c(Cl)ccc2cc(Cl)cnc12)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
33 parts by weight of 2-nitrobenzoic acid, 40 parts by weight of 30% strength sodium methylate solution and 440 parts by weight of dimethylsulfoxide are stirred for 2 hours at 100° C. Thereafter, 49 parts by weight of 3,7-dichloro-8-chloromethylquinoline are introduced and the reaction mixture is stirred for a further 2 hours at 100° C. The solution is then cooled, water is added and the precipitated solid is filtered off under suction and recrystallized from toluene. 69 parts by weight (92% of theory) of 3,7-dichloro-8-[(2-nitrophenyl)-carbonyloxymethyl]-quinoline of melting point 152° C. are obtained.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([F:23])=[C:11]([CH:22]=1)[CH2:12][C:13]1[C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=[CH:15][CH:14]=1>>[Cl:6][C:7]1[C:22]2[C:19](=[O:21])[C:18]3[CH:17]=[N:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:2])[C:11]=2[C:10]([F:23])=[CH:9][CH:8]=1
Reactant: O=C(O)c1cnccc1Cc1cc(Cl)ccc1F
Reactant: O=S(=O)(O)O
Product: O=C1c2ccncc2C(=O)c2c(Cl)ccc(F)c21
Temperature: 130 °C
Yield: 82 %

Procedure:
Fuming sulfuric acid (30% SO3 ; 0.31 mL) is added to 4-(5-chloro-2-fluorobenzyl)nicotinic acid of Preparative Example 19. The dark mixture is heated quickly to 130° C. for 10 min in a flask fitted with a cotton filled drying tube. After cooling to room temperature, the reaction mixture is quenched with ice (3 g) and extracted with methylene chloride (4×7 mL). The combined extracts are dried with Na2SO4 and the solvent is removed by roto-evaporation to yield 9-chloro-6-fluorobenzo[g]isoquinoline-5,10-dione as a yellow solid (0.045 g; 82% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5](=[O:8])[NH:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[Br:13]N1C(=O)CCC1=O>ClCCl>[Br:13][C:6]1[C:5](=[O:8])[NH:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]([CH3:1])[N:7]=1
Reactant: COC(=O)c1[nH]c(=O)cnc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1[nH]c(=O)c(Br)nc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate (2.0 g, 11.89 mmol) was dissolved in dichloromethane (30 mL) and N-bromosuccinimide (2.12 g, 11.89 mmol) was added. The reaction was allowed to stir at room temperature for 16 h. On completion, the reaction mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The solid was washed with ether to afford methyl 5-bromo-3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate (2) as light brown solid. Yield: 1.25 g, 42%; MS (ESI) m/z 247.04 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 12.92 (brs, 1H), 3.87 (s, 4H), 2.50 (s, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[Cl:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][CH2:20][NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=3[C:10]([F:13])([F:12])[F:11])=[CH:25][CH:24]=2)=[CH:31][CH:32]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C(F)(F)F)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a stirred solution of the 4-fluoro-3-(trifluoromethyl)benzaldehyde (177 μL, 1.30 mmol) and N-(4-chlorophenethyl)-4-hydroxybenzamide (359 mg, 1.30 mmol) in DMSO (3 ml) was added K2CO3 (270 mg, 1.95 mmol). The reaction was stirred at 95° C. for 2 hours and then directly purified by silica gel chromatography to give N-(4-chlorophenethyl)-4-(4-formyl-2-(trifluoromethyl)phenoxy)benzamide (0.541 g).
Reaction SMILES: [CH3:1]O.[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([OH:14])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10].S(=O)(=O)(O)O>ClCCCl>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH3:1])=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: COC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98 %

Procedure:
Methanol (59 mL, 3.0 equivalent amounts) was added to a 1,2-dichloroethane (400 mL) solution of 2-(3,4-dichlorophenyl)acetic acid (100 g, 0.488 mol). The solution was heated to 50° C., and then concentrated sulfuric acid (10 mL) was dropwise added over a period of 15 minutes, followed by stirring at 50° C. for 1.5 hours. The reaction solution was cooled to room temperature, followed by liquid separation to remove a sulfuric acid layer, and the obtained organic layer was sequentially washed with water, a saturated sodium hydrogencarbonate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a colorless oil (105 g, yield: 98%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-])=O.FC(F)(F)C1C=CC=CC=1N=C=O.[CH3:27][S:28]([CH3:30])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[S:28]([CH3:30])[CH3:27]
Reactant: CS(C)=O
Reactant: O=[N+]([O-])c1ccccc1C(F)(F)F
Agent: O=C=Nc1ccccc1C(F)(F)F
Product: CS(C)=Nc1ccccc1C(F)(F)F

Procedure:
The process of claim 18 in which 2-trifluoromethylnitrobenzene is carbonylated to 2-trifluoromethylphenyl isocyanate, which is reacted with dimethylsulfoxide to obtain N-(2-trifluoromethylphenyl)-S,S-dimethylsulfilimine, rearranged to a 2-(methylthiomethyl)-6-trifluoromethylaniline, and desulfurized to 2-methyl-6-trifluoromethyl aniline.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1.[CH:16]1[CH:17]=[CH:18][N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22][CH2:21][C:20]=12.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH2:25][N:19]4[CH:18]=[CH:17][CH:16]=[C:20]4[CH2:21]3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cn(-c2ccc(C(=O)Cl)cc2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
The 4-(4-methylimidazol-1-yl)benzoyl chloride (0.99 g) was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.64 g) and diisopropylethylamine (0.60 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of hydrous sodium magnesium silicate, and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the title compound (0.52 g) was obtained as a solid, m.p. 140-145° C.; MS, m/z: 369 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(N(CC)C(C)C)(C)C.[I-].[Na+].[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>C(O)C>[CH3:37][O:38][CH2:39][CH2:40][NH:41][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=1)[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: COCCN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COCCNCCNc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 90 °C

Procedure:
To a solution of 2-chloro-5-(2-chloroethylamino)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (WO 99/29661) (0.2 g) and N,N-diisopropylethylamine (0.27 ml) in ethanol (5 ml) was added sodium iodide (0.08 g) and 2-methoxyethylamine (0.11 g). The reaction vessel was sealed and the reaction mixture heated at 90° C. for 15 h before concentration under reduced pressure. The residue was partitioned between ethyl acetate and sodium hydrogencarbonate solution, and the aqueous phase extracted with additional ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by NPHPLC (eluting with 0-25% ethanol in dichloromethane) to afford 5-(N-(2-methoxyethyl)-2-aminoethyl)amino-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide as a semi-solid. This was converted to the hydrochloride salt by stirring with 4M HCl in dioxane and concentrated under reduced pressure to leave the title compound as a white solid (0.085 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][Si](C)(C)C)[CH:10]=2)[C:5](=[O:18])[CH2:4][CH2:3]1.CC1(C)C2C(=CC=C([Si](C)(C)C)C=2)C(=O)C(C#C)C1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:18])[CH2:4][CH2:3][C:2]2([CH3:19])[CH3:1])#[CH:13]
Reactant: CC1(C)CCC(=O)c2ccc(C#C[Si](C)(C)C)cc21
Agent: C#CC1CC(C)(C)c2cc([Si](C)(C)C)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A solution of 4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydronaphthalene-1-one (Intermediate 12, 0.28 g, 1.03 mmol) in methanol (10 mL was treated with potassium carbonate (0.74 g, 5.35 mmol) and stirred at ambient temperature for 4 h. The volatiles were distilled off in vacuo and the residue was diluted with water and extracted with diethyl ether (×2). The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (0.19 g, 89%) as an oil that solidified on standing.
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:5]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=12.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)CCC>O1CCOCC1.C(Cl)Cl.[Pd](Cl)Cl.C1(P(C(C)C(P(C2C=CC=CC=2)C2C=CC=CC=2)C)C2C=CC=CC=2)C=CC=CC=1.[Ag]=O>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([N:4]=[C:3]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:2]=2[C:24]2[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(N)(=O)=O)cc1
Reactant: Fc1ccc(-c2nn3cc(Cl)ccc3c2Br)cc1
Agent: Cl[Pd]Cl
Agent: O=[Ag]
Agent: CC(C(C)P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(Cl)ccc23)cc1
Yield: 33.7 %

Procedure:
3-Bromo-6-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (397 mg, 1.22 mmol), 4-(tri-n-butylstannyl)phenylsulfonamide (1.09 g), bis(diphenylphosphino)butane palladium(II) dichloride (100 mg) and silver oxide (283 mg) were stirred in anhydrous dioxan (15 ml) at reflux for 24 h. After cooling, the concentrated reaction mixture was taken up in DCM and concentrated onto silica gel which was loaded onto an SPE column and eluted with cyclohexane:ethyl acetate (8:1). This gave a white solid which was triturated with cyclohexane and filtered to give the title compound as a white solid (165 mg, 34%). MH+ 400 1H NMR (DMSO) δ 7.27 (2H, t, J 8 Hz); 7.4 (3H, m); 7.52 (4H, m); 7.7 (1H, d, J 9 Hz); 7.87 (2H, d, J 8 Hz); 9.18 (1H, s); Tlc SiO2 cyclohexane:ethyl acetate (3:1) Rf 0.12 detection uv254.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[C:9]([O:10][CH2:11][O:12][CH3:13])=[CH:8][C:7]([O:14][CH2:15][O:16][CH3:17])=[C:6]([CH2:18][CH3:19])[C:5]=1[CH2:20][C:21]([O:23]C)=[O:22].[OH-].[Li+].O.Cl>CO>[C:21]([CH2:20][C:5]1[C:6]([CH2:18][CH3:19])=[C:7]([O:14][CH2:15][O:16][CH3:17])[CH:8]=[C:9]([O:10][CH2:11][O:12][CH3:13])[C:4]=1[C:3]([OH:25])=[O:2])([OH:23])=[O:22]
Reactant: CCc1c(OCOC)cc(OCOC)c(C(=O)OC)c1CC(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1c(OCOC)cc(OCOC)c(C(=O)O)c1CC(=O)O
Temperature: 60 °C
Reaction time: 30 h
Yield: 92.4 %

Procedure:
The above-obtained 3-ethyl-2-(methoxycarbonylmethyl)-4,6-bis(methoxymethoxy)benzoic acid methyl ester (1.1 g, 3.0 mmol) was dissolved in methanol (3 mL) and the obtained solution was added with 4.0 mol/L aqueous lithium hydroxide solution (15 mL, 60 mmol) followed by stirring at 60° C. for 30 hours. The reaction mixture was added with water and 6.0 mol/L hydrochloric acid and the pH value was adjusted to 3. Then, the mixture was extracted with ethyl acetate 3 times. The organic layers were combined and dried over anhydrous sodium sulfate. Then, the solvent was evaporated under reduced pressure to obtain 2-(carboxymethyl)-3-ethyl-4,6-bis(methoxymethoxy)benzoic acid (0.91 g, 94%).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)[CH:12]=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:35](=[O:36])[CH2:34][NH:33][C:32]2=[S:37])=[CH:27][CH:26]=1>C(O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)/[CH:12]=[C:34]1/[C:35](=[O:36])[N:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)[C:32](=[S:37])[NH:33]/1
Reactant: COc1ccc(N2C(=O)CNC2=S)cc1
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(N2C(=O)/C(=C/c3ccc(-n4cnc(C)c4)c(OC)c3)NC2=S)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.3 %

Procedure:
Piperidine (0.019 mL) was added to an ethanol (2 mL) solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (20 mg) obtained in Example 1 and 3-(4-methoxyphenyl)-2-thioxoimidazolidine-4-one (21 mg), and heat-refluxing of the reaction solution was carried out for 12 hours. The reaction solution was allowed to be cooled to room temperature and the solid deposited was separated by filtering, and 18 mg (47%) of the title compound was obtained by washing with ethanol and ether. The physical properties of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][CH:19](C2C3C(=CC=CC=3)N=CC=2)[CH3:20])=[CH:5][CH:4]=1.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][C:39]=2C(N)C)[CH:34]=[CH:33][CH:32]=1.COC1C(C2C=CC(OC)=CC=2)=CC(C=O)=CC=1.C([BH3-])#N.[Na+]>>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][CH:19]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:40]=2[N:31]=[CH:32][CH:33]=[CH:34]3)[CH3:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(CNC(C)c3ccnc4ccccc34)ccc2OC)cc1
Reactant: CC(N)c1cccc2cccnc12
Agent: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(-c2cc(CNC(C)c3cccc4cccnc34)ccc2OC)cc1
Yield: 72 %

Procedure:
The title compound was prepared by the same procedure for (6,4′-dimethoxy-biphenyl-3-ylmethyl)-(1-quinolin-4-yl-ethyl)-amine from 1-quinolin-8-yl-ethylamine (510 mg, 3.0 mmol), 6,4′-Dimethoxy-biphenyl-3-carbaldehyde (242 mg, 1.0 mmol) and sodium cyanoborohydride (1.0 g, 16 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, ethyl acetate) in form as white solid in 72% yield (287 mg, 0.72 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[C:26]([N:34]=[C:35]=[S:36])(=O)[C:27]1C=CC=C[CH:28]=1.C([O-])([O-])=O.[K+].[K+].BrC(C)C=O>CC(C)=O>[CH:14]1([N:13]([CH:17]2[CH2:19][CH2:18]2)[C:11]([C:9]2[N:8]([CH2:20][CH3:21])[C:6]3=[N:7][C:2]([NH:1][C:35]4[S:36][C:27]([CH3:28])=[CH:26][N:34]=4)=[C:3]4[N:24]=[CH:23][N:22]([CH3:25])[C:4]4=[C:5]3[CH:10]=2)=[O:12])[CH2:16][CH2:15]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Agent: CC(Br)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C)s3)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
4-Amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 86.3 mg, 0.255 mmol) was dissolved in acetone and benzoyl isothiocyanate (37.8 μL, 0.281 mmol) was added. The reaction was stirred at room temperature for 2 h. The solvent was removed in vacuo. The residue was taken up in ethanol (1500 μL) and K2CO3 (49.3 mg, 0.357 mmol) was added. The reaction mixture was warmed to 60° C. for 3 h. 2-Bromopropanal (45.4 mg, 0.332 mmol) was added. After 3 h, additional 2-bromopropanal (˜100 mg) was added. Stirred at 60° C. for 16 h. Additional 2-bromopropanal was added and the reaction mixture was stirred at 60° C. 3 h. The ethanol was removed by concentration in vacuo. The crude residue was purified by flash chromatography using an Isco 12 g column eluting with 2-10% MeOH/CH2Cl2). Additional purification was accomplished via preparative HPLC. N,N-dicyclopropyl-6-ethyl-1-methyl-4-(5-methylthiazol-2-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (20 mg, 17.47% yield) was isolated as a white solid.
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:24]=2)[CH3:22])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:24]=2)[CH3:22])[N:15]=1)[CH3:7]
Reactant: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1cccc(Oc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)O)n1)c1cccc(Oc2ccccc2)c1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of (R)-4-((R)-1-tert-butoxyethyl)-3-(2-((S)-1-(3-phenoxyphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (70.1 mg, 0.147 mmol) in DCM (1.1 ml) was treated with TFA (368 ul) at room temperature. The resulting solution was let sit for 30 min, then concentrated. The crude material was purified by reverse phase HPLC. Product fractions were combined and lyophilized to afford (R)-4-((R)-1-hydroxyethyl)-3-(2-((S)-1-(3-phenoxyphenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (41.3 mg, 0.097 mmol, 66% yield) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 0.64 (br. s., 3H) 1.42 (d, J=6.90 Hz, 3H) 3.70 (br. s., 1H) 4.32-4.48 (m, 3H) 4.67-4.75 (m, 1H) 5.08 (br. s., 1H) 6.78 (d, J=7.87 Hz, 1H) 6.91 (d, J=7.87 Hz, 2H) 7.00-7.18 (m, 3H) 7.22-7.37 (m, 4H) 8.14 (br. s., 1H). LCMS m/z 421.3 (M+H)+, Rt 0.72 min. HRMS(A) m/z 421.1873 (M+H)+, Rt 1.84 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N+:10]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CCN)cc1F
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 2-fluoro-1-methoxy-4-(2-nitro-vinyl)benzene (1.5 g, Intermediate (2)] in THF (50 mL) is treated dropwise with a solution of lithium aluminum hydride in ether (23 mL, 1M). The mixture is heated at 40° C. for 3 hours, cooled to room temperature, diluted with ether and quenched with Na2SO4.10H2O (104 g). After standing at room temperature overnight the reaction mixture is filtered and the filtrate is evaporated. The residue is subjected to chromatography on silica gel eluting with EtOAc to give 2-(3-fluoro-4-methoxy-phenyl)-ethylamine [0.81 g, Intermediate (3)] as an oil. MS: 170 (M+H); 1H NMR (CDCl3): 6.9-7 (3H, m); 3.85 (3H, s); 2.95 (2H, t); 2.7 (2H, t).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][CH:30]([C:33](O)=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24]1>>[C:1]([O:5][C:6](=[O:22])[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH:23]3[CH2:25][CH2:24]3)[CH2:28][CH2:29]2)=[O:34])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(CC2CC2)CC1
Product: CN(C(=O)OC(C)(C)C)C1CN(C(=O)C2CCN(CC3CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound [(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester was prepared from [(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester instead of N-[(3RS,4SR)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 1-cyclopropylmethyl-piperidine-4-carboxylic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a dark brown oil, which was directly used without further characterisation.