Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1>C(N(CC)CC)C>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1ccccc1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and benzoyl chloride in substantially the same manner as described in Example 61 with one change: pyridine was used as a base instead of triethylamine; off-white solid: MS (EI) m/z 497.2 (M+H)+; 1H NMR (DMSO-d6): δ 7.03 (d, J=7.6 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 7.39 (t, J=8.0 Hz, 2H), 7.50-7.95 (m, 10H), 8.05 (d, J=7.7 Hz, 1H), 8.36 (d, J=7.0 Hz, 1H), 9.16 (s, 1H), 10.33 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:12][CH2:13][F:14])[CH2:7][NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C(#N)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH2:12][CH2:13][F:14])[CH2:7][N:8]([C:27]([NH:26][CH2:24][CH3:25])=[O:28])[S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: CCN=C=O
Reactant: O=S1(=O)NCN(CCF)c2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNC(=O)N1CN(CCF)c2ccc(Cl)cc2S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 500 mg of the compound of Example 1 dissolved in 2.5 ml of acetonitrile there are added 0.5 ml of triethylamine and 2.5 ml of ethyl isocyanate. The reaction mixture is stirred at ambient temperature for 5 hours. The solvent is then removed under reduced pressure. The residue is taken up in 10 ml of acetone; charcoal is added to the resulting solution, which is then filtered; water is then added to the filtrate. The precipitate obtained is collected by filtration, washed with water and dried.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][C:13]([Cl:15])=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(Cl)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCCCCl)cc1
Yield: 75.5 %

Procedure:
A solution of 4-hydroxybenzaldehyde (100 mmol, 12.2 g), 3-bromopropionyl chloride (101 mmol, 20 mL) and potasium carbonate (20.7 g, 150 mmol) in acetone (250 mL) was heated at reflux for overnight. The salt was filtered off. The solvent was evaporated. Reduced pressure distillation provided the title compound (15 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]([CH3:11])[CH2:5]2.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.O>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]([F:14])([F:13])[F:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2
Reactant: CC1Cc2c(ccc(Br)c2C(F)(F)F)N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2c(C(F)(F)F)c(Br)ccc2[nH]1
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a solution of 5-bromo-2-methyl-4-(trifluoromethyl)-2,3-dihydro-1H-indole (0.09 g, 0.320 mmol; step C above) in 1,4-dioxane (5 mL) at rt was added DDQ (0.110 g, 0.48 mmol) in one portion. After 1 h, the mixture was poured into water and extracted with Et2O (×3). Combined organics were washed (1 N NaOH, H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.056 g of the title compound as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.07 (bs, 1H), 7.36 (m, 1H), 7.25 (d, J=5.0 Hz, 1H), 6.47 (s, 1H), 2.48 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][CH:5]1[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=2[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]1=2
Reactant: Cc1ccccc1C=C1c2ccccc2CCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccccc1CC1c2ccccc2CCc2ccccc21
Reaction time: 17 h

Procedure:
Add the 5-(2-methyl-benzylidene)-10,11-dihydro-5H-dibenzo [a,d]cycloheptene (0.19 g, 0.64 mmol) to a mixture of 10% Pd/C (0.075 g) suspended in absolute ethanol (4.0 mL) and ethyl acetate (2.0 mL) and hydrogenate under a balloon of hydrogen at room temperature and pressure. Stir for 17 h, remove the catalyst via filtration through a pad of Celite, evaporate the filtrate and pass through a plug of silica gel equilibrated with hexanes. Concentrate the filtrate to give the title product: MS (m/e) 298 (M+). Analysis for C23H22: Calcd: C, 91.99 H, 7.39. Found: C, 91.95 H, 7.39.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4].I[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:14][CH3:15])[N:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: CCI
Reactant: COC(=O)c1cc([N+](=O)[O-])n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (525, 2.50 g, 0.0146 mol) in N,N-dimethylformamide (62.5 mL) were added iodoethane (1.2 mL, 0.016 mol) and potassium carbonate (4.17 g, 0.0301 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (526, 1.3 g, 44.7%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC>C1(C)C=CC=CC=1.O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=c1[nH]cnc2cc(-c3ccccn3)ccc12
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a solution of 7-bromo-3H-quinazolin-4-one (100 mg, 0.444 mmol) in toluene/dioxane (3:1), add 2-tributylstannanyl-pyridine (162 mg, 0.444 mmol) followed by tetrakis-(triphenylphosphine)-palladium(0) (26 mg, 0.022 mmol). Bubble dry nitrogen through the solution for 10 minutes then heat the stirring solution to 115° C. under a nitrogen atmosphere. After several minutes the reaction mixture becomes homogeneous. After 16 hours, cool the reaction vessel and collect the precipitate via filtration. Wash the solid with 25% EtOAc/hexanes followed by hexanes to give 7-pyridin-2-yl-3H-quinazolin-4-one as a beige solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:23])[C:9]3[CH2:14][CH:13]([CH3:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[F:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]2)=[CH:27][CH:26]=1>>[CH3:15][CH:13]1[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]2[C:5]3[C:6]([N:8]([CH3:23])[C:9]=2[CH2:14]1)=[N:7][C:2]([N:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][C:28]2[CH:38]=[CH:39][C:25]([F:24])=[CH:26][CH:27]=2)[CH2:32][C:33]1=[O:37])=[CH:3][CH:4]=3
Reactant: O=C1CN(CCc2ccc(F)cc2)CCN1
Reactant: CC1Cc2c(c3ccc(Br)nc3n2C)CN1C(=O)OC(C)(C)C
Product: CC1Cc2c(c3ccc(N4CCN(CCc5ccc(F)cc5)CC4=O)nc3n2C)CN1C(=O)OC(C)(C)C
Yield: 73 %

Procedure:
tert-Butyl 2-bromo-7,9-dimethyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (2-((4 mg, 0.640 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (141 mg, 0.640 mmol) were reacted following the procedure for Example 2 (step e) to provide the title compound (245 mg, 73%) as a colorless oil: ESI MS m/z 522 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([CH3:28])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:17]4[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]5[CH:27]=[CH:26][N:25]=[CH:24][N:23]=5)(=[O:19])=[O:20])=[CH:15][CH:16]=4)[CH:11]=[CH:10][N:9]=3)=[C:4]([CH3:28])[CH:3]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Reactant: OB(O)c1cccc(F)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1cc(-c2cccc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 100 °C
Yield: 42 %

Procedure:
A vial was charged with 1-(4-chloro-2-methylphenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (EXAMPLE 357; 61.66 mg, 0.150 mmol) (3-fluorophenyl)boronic acid (42.0 mg, 0.300 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (3.08 mg, 7.50 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (11.37 mg, 0.015 mmol) and potassium phosphate (96 mg, 0.450 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (682 μl) and water (68.2 μl) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h 45 min at 100° C. The mixture was extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 3% MeOH/DCM) to give 1-(3′-fluoro-3-methyl-[1,1′-biphenyl]-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (29.49 mg, 0.063 mmol, 41.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.08 (br. s., 1H), 8.77-8.67 (m, 2H), 8.58 (s, 1H), 8.24 (br. s., 1H), 8.15 (d, J=5.6 Hz, 1H), 7.98 (dd, J=1.8, 8.9 Hz, 1H), 7.80-7.72 (m, 2H), 7.71-7.61 (m, 3H), 7.55 (dt, J=6.2, 8.0 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.28-7.19 (m, 1H), 7.03 (br. s., 1H), 2.06 (s, 3H). m/z (ESI) 471.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:9](=[S:11])[NH2:10])=[CH:4][CH:3]=1.[CH2:21](OC(OCC)CBr)[CH3:22]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:9]2[S:11][CH:21]=[CH:22][N:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(CBr)OCC
Reactant: NC(=S)C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(C(c2ccc(Cl)cc2)c2nccs2)cc1

Procedure:
A solution of 2-(4-chlorophenyl)-2-(4-nitrophenyl)ethanethioamide (800 mg, 2.608 mmol, 1 equip) and bromoacetaldehyde diethyl acetal (2.055 g, 10.431 mmol, 4 equip) in acetic acid (12.09 mL) and water (0.47 mL) was heated at 100° C. for 45 minutes. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, saturated sodium bicarbonate, and then dried over Na2SO4, filtered, and concentrated. The residue was purified by MPLC using ethyl acetate-heptane as eluent to yield 2-((4-chlorophenyl)(4-nitrophenyl)methyl)thiazole as a viscous brown oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:10][C:11]2[C:17]([Cl:18])=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[Cl:19])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Cl:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([O:10][C:11]2[C:12]([Cl:19])=[CH:13][C:14]([NH:15][C:26]([NH:25][C:23](=[O:24])[C:22]3[C:28]([Cl:32])=[CH:29][CH:30]=[CH:31][C:21]=3[Cl:20])=[O:27])=[CH:16][C:17]=2[Cl:18])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Cc1cc(C#N)cnc1Oc1c(Cl)cc(N)cc1Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)cnc1Oc1c(Cl)cc(NC(=O)NC(=O)c2c(Cl)cccc2Cl)cc1Cl
Yield: 71.1 %

Procedure:
To a 100 mL flask equipped with magnetic stirrer, condenser, under nitrogen atmosphere was added 4-(3-methyl-5-cyano-2-pyridinoxy)-3,5-dichloroaniline (1.7 g, 5.78 mmol) and toluene (15 mL). The resulting mixture was heated up to 90° to form a solution. A solution of 2,6-dichlorobenzoylisocyanate (2.0 g, 9.25 mmol) in 2 mL of toluene was added to the above solution. The resulting mixture was heated at 90° for 1.5 hours and then cooled. The cold reaction mixture was filtered and the solid was washed with cold toluene. The solid was vacuum dried to afford an orange solid (2.1 g, 4.11 mmol). m.p. 245°-246°
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[C:4]([C:11]([O:13]CC)=[O:12])=[CH:3]1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([F:9])([F:10])[F:8])[C:4]([C:11]([OH:13])=[O:12])=[CH:3]1
Reactant: CCOC(=O)c1cn(C)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 1-methyl-4-(trifluoromethy1)pyrrole-3-carboxylate (4.4 g, 0.02 mol) and 4N sodium hydroxide (5 ml, 0.02 mol) in ethanol is stirred for 24 hours at room temperature, diluted with water and extracted with ether. The aqueous phase is acidified with 10% HCl and filtered. The filter cake is washed with water and dried in vacuo at 45° C. to afford the title compound as an off-white solid, 2.4 mp 210° to 212° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:17]3)=[C:9]([NH:31][CH2:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:8]=2)[CH2:3]1.[CH:46]1[N:50]=[CH:49][N:48]([C:51](N2C=NC=C2)=[O:52])[CH:47]=1>C(Cl)Cl>[CH3:24][C:22]1([CH3:25])[O:23][C@@H:19]2[C@@H:18]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:17][C@@H:16]([N:13]3[CH:12]=[N:11][C:10]4[C:14]3=[N:15][C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:51]([N:48]5[CH:47]=[CH:46][N:50]=[CH:49]5)=[O:52])[CH2:3]3)=[N:8][C:9]=4[NH:31][CH2:32][CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:20]2[O:21]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)n5ccnc5)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21

Procedure:
A mixture comprising N-{(3aR,4S,6R,6aS)-6-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-yl}-propionamide (see preparation of intermediates) (0.24 g, 0.39 mmol) and CDI (0.275 g, 1.7 mmol) in DCM is stirred at room temperature for 3 hours. Purification of the resulting mixture by chromatography on silica eluting with 0-5% MeOH in DCM yields the titled compound as a yellow oil. The compound exists as a mixture of the imidazole-urea intermediate together with variable amounts of the corresponding isocyanate and imidazole which are equally suitable as precursors to ureas.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:11])[C:9]=1[CH3:10].Cl[C:13]1[C:22]2[C:17](=[C:18]([O:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:11])[C:9]=1[CH2:10][C:13]1[C:22]2[C:17](=[C:18]([O:25][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc2c(Cl)nncc2c1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OC1CCCC1
Reaction time: 8 h
Yield: 57.1 %

Procedure:
Under stirring, 55% sodium hydride (3.73 g, 85.56 mmoles) was added to a solution, under nitrogen, of 3,5-dichloro-4-methyl-pyridine (13.86 g, 85.56 mmoles) in anhydrous DMF (100 ml). The mixture was kept under stirring for 1 hour then added with a solution of 1-chloro-5-cyclopentyloxy-6-methoxy-phthalazine (7.95 g, 28.52 mmoles), obtained as described in example 7, in anhydrous dimethylformamide (70 ml). After resting overnight, the mixture was quenched with water, diluted with water and extracted with ethyl acetate. The extract was washed with water and dried on sodium sulphate, then evaporated to dryness. The residue was flash chromatographed (eluent petrolatum/ethyl acetate 1:1) to give 6.58 g of the title compound (yield: 57%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]([NH2:16])=[S:15].CC([O-])=O.[Na+]>CCO>[NH2:16][C:14]1[S:15][CH:2]=[C:3]([C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[N:13]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2csc(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(2-Bromo-acetyl)-benzonitrile (2.9 g, 12.9 mmol) was combined with 1.0 g (12.9 mmol) of thiourea. This mixture was suspended in 60 mL of EtOH. To this suspension was added NaOAc (1.4 g, 16.8 mmol). This suspension was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[NH:6][NH:5][C:4](=[O:7])[C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1[CH3:19].O=[C:21]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH2:22][C:23](OCC)=[O:24].Cl.O1CCOCC1>C(O)C>[CH3:19][C:10]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:3]1[C:4]([OH:7])=[N:5][N:6]2[C:23]([OH:24])=[CH:22][C:21]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:1][C:2]=12
Reactant: Cc1c(Cc2c(N)[nH][nH]c2=O)cccc1C(F)(F)F
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1c(Cc2c(O)nn3c(O)cc(C4CCOCC4)nc23)cccc1C(F)(F)F

Procedure:
To a suspension of 5-amino-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1,2-dihydro-3H-pyrazol-3-one (136 mg, 0.5 mmol) in ethanol (1 mL) were added ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (100 mg, 0.5 mmol) and 4 M HCl solution in dioxane (25 uL, 0.1 mmol). The reaction mixture was irradiated (microwave) at 110° C. for 30 minutes. Reaction was cooled down. The precipitate was collected by filtration. It was washed with acetic acid (1 mL), then methanol (1 mL) and dried. The titled compound was obtained. (52 mg, 25%); LC/MS: MS (ES+) m/e 408 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.69 (dd, J=12.51, 4.17 Hz, 1H) 1.73-1.80 (m, 3H) 2.46 (s, 3H) 2.72 (s, 1H) 3.34-3.45 (m, 2H) 3.83 (s, 2H) 3.93 (br. s., 2H) 5.51 (s, 1H) 7.15 (d, J=7.58 Hz, 1H) 7.29 (t, J=7.71 Hz, 1H) 7.54 (d, J=8.34 Hz, 1H) 11.46 (s, 1H).
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][NH2:15])[CH2:11][C@H:10]2[C:16]([NH:18][CH2:19][CH:20]([OH:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])=[O:8])=[CH:3][CH:2]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[C:34]([NH:15][N:14]=[C:12]1[CH2:13][N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:6][CH:5]=2)=[O:8])[C@H:10]([C:16]([NH:18][CH2:19][CH:20]([OH:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:17])[CH2:11]1)(=[O:36])[CH3:35]
Reactant: NN=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NN=C1C[C@@H](C(=O)NCC(O)c2ccccc2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reaction time: 8 h

Procedure:
A hydrazono pyrrolidine derivative obtained by the general method outlined in Example 17, e.g. (2S,4EZ)-1-([1,1′-biphenyl]-4ylcarbonyl)-4-hydrazono-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide (51 mg, 0.111 mmol) was dissolved in pyridine (1 mL). Acetic anhydride (3 eq, 32 μl, 0.35 mmol) was added, and the mixture was stirred overnight. The solvent was evaporated and the resultant crude reaction mixture was purified by column chromatography using DCM/MeOH (20:1) to collect the desired product, e.g. (2S,4EZ)-4-(acetylhydrazono)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-[(2RS)-2-hydroxy-2-phenylethyl]-2-pyrrolidinecarboxamide as a mixture of two isomers as a colorless solid in 73% yield (98.4% purity by HPLC).
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:1][N:2]1[C:6]([O:7][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:4]([CH3:16])=[N:3]1
Reactant: Cc1nn(C)c(O)c1Sc1ccccc1Cl
Reactant: Fc1ccccn1
Product: Cc1nn(C)c(Oc2ccccn2)c1Sc1ccccc1Cl
Yield: 25.6 %

Procedure:
A mixture of 0.5 g (2 mmol) of 1,3-dimethyl-4-(2-chlorophenylthio)-5-hydroxypyrazole and 0.97 g (10 mmol) of 2-fluoropyridine was refluxed with heating for 8 hours. After completing the reaction, the reaction mixture was purified by means of silica gel column chromatography (developing solution: ethyl acetate-hexane (3:2 v/v)) to give 0.17 g of 1,3-dimethyl-4-(2-chlorophenylthio)-5-(pyridine-2-yloxy)pyrazole.
Reaction SMILES: C([N:3]1[C:12]2[C:7](=[C:8](N)[C:9](F)=[C:10](F)[C:11]=2F)[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)C.C(OC(NC1CCNC1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[O:17]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:3][CH:4]=[C:5]1[C:18]([OH:20])=[O:19]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(N)c(F)c(F)c(F)c21
Agent: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C

Procedure:
A suspension of 3.02 g (10 mmole) of 1-ethyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydro quinoline-3-carboxylic acid, 2.79 g (15 mmole) of 3-(t-butoxycarbonylamino)pyrrolidine, 3.0 g (30 mmole) of triethylamine and 100 ml of acetonitrile is refluxed for 18 hours. The reaction mixture is cooled to room temperature and the precipitate is removed by filtration, washed with acetonitrile, ether, and dried in vacuo to give 1-ethyl-5-amino-6,8-difluoro-7-[3-(t-butoxycarbonylamino)-1-pyrrolidinyl[-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:16](=[CH:17][CH:18]=1)[C:8]1[N:9]([CH2:12][CH:13]([NH2:15])[CH3:14])[N:10]=[CH:11][C:7]=1[CH2:6]2.[B-](Br)(Br)(Br)[S+](C)C.C1COCC1.C([O-])(O)=O.[Na+]>ClCCCl>[NH2:15][CH:13]([CH3:14])[CH2:12][N:9]1[C:8]2[C:16]3[C:5]([CH2:6][C:7]=2[CH:11]=[N:10]1)=[CH:4][C:3]([OH:2])=[CH:18][CH:17]=3
Reactant: COc1ccc2c(c1)Cc1cnn(CC(C)N)c1-2
Agent: C[S+](C)[B-](Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(N)Cn1ncc2c1-c1ccc(O)cc1C2
Yield: 13.3 %

Procedure:
To a solution of the product from Step D (0.56 g, 0.23 mmol) in 1,2-dichloroethane (10 mL) was added boron tribromide-methylsulfide complex in THF solution (1.0M, 0.5 mL, 0.5 mmol) and the solution heated to reflux for 16 h. The solution was allowed to cool, poured into aqueous NaHCO3, extracted with chloroform (2×20 mL), dried (Na2SO4) and concentrated. The crude product was purified by chromatography (silica, 20% methanol in dichloromethane) to give a solid (0.007 g, 13%): 1H NMR (CDCl3) δ 7.39 (m, 2H), 7.00 (s, 1H), 6.79 (dd, J=8.4, 2.4 Hz, 1H), 4.30 (dd, J=13.8, 4.8 Hz, 1H), 4.14 (dd, J=13.8, 7.8 Hz, 1H), 3.55 (m, 1H), 3.48 (bm, 4H), 1.19 (d, J=6.6 Hz, 3H); MS m/z 230 [M+H]+.