Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]O.[CH3:3][NH:4][C:5](=[O:37])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:22](=S)[N:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=3)[C:20](=[O:36])[C:16]32[CH2:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=1>C(O)(=O)C>[CH3:3][NH:4][C:5](=[O:37])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:22](=[O:1])[N:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=3)[C:20](=[O:36])[C:16]32[CH2:19][CH2:18][CH2:17]3)=[CH:11][CH:10]=1
Reactant: OO
Reactant: CNC(=O)CCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Solvent: CC(=O)O
Product: CNC(=O)CCCc1ccc(N2C(=O)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
Hydrogen peroxide (30%, 0.4) was added dropwise to a solution of N-methyl-4-{4-[7-(4-Cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}butanamide (42e) (0.032 g, 0.064 mmol) in glacial acetic acid (0.5 ml). The mixture was stirred at room temperature for 5 hours and then washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and chromatographed (dichloromethane:acetone, 80:20) to yield N-methyl-4-{4-[7-(4-cyano-3-trifluoromethylphenyl)-6,8-dioxo-5,7-diazaspiro[3.4]oct-5-yl]-phenyl}butyramide (42g) [RD158] (0.029 g, 0.06 mmol, 94%), the structure of which is illustrated in Formula 9, as a white powder.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([CH:15]1[CH2:19][CH:18]([O:20][C:21]2[C:30]3[C:25](=[C:26]([CH3:33])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[N:24]=[C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]([CH3:42])[CH3:41])[N:35]=3)[CH:22]=2)[CH2:17][CH:16]1[C:43](=[O:55])[NH:44][C:45]1([C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:47][CH:46]1[CH:48]=[CH2:49])=[O:14])(C)(C)C.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:53]([O:52][C:50]([C:45]1([NH:44][C:43]([CH:16]2[CH2:17][CH:18]([O:20][C:21]3[C:30]4[C:25](=[C:26]([CH3:33])[C:27]([O:31][CH3:32])=[CH:28][CH:29]=4)[N:24]=[C:23]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]([CH3:42])[CH3:41])[N:35]=4)[CH:22]=3)[CH2:19][CH:15]2[C:13]([OH:14])=[O:12])=[O:55])[CH2:47][CH:46]1[CH:48]=[CH2:49])=[O:51])[CH3:54]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3cccc(C(C)C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3cccc(C(C)C)n3)nc3c(C)c(OC)ccc23)CC1C(=O)O)C(=O)OCC
Reaction time: 2 h

Procedure:
TFA (5 mL) was added at room temperature to a solution of 2-(1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-[2-(6-isopropyl-pyridin-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-cyclopentanecarboxylic acid tert-butyl ester (109, 590 mg, 0.90 mmol) and triethylsilane (280 mg, 2.5 eq) in CH2Cl2 (5 mL). After 2 h, the reaction mixture was concentrated under reduced pressure to afford the desired product 110, which was used in the next step without further purifications.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.CN(C)CCCN=C=NCC.[C:33]([O:36][CH:37]1[C:41]2=[N:42][C:43]3[C:44](=[N:45][CH:46]=[C:47]([NH2:49])[CH:48]=3)[N:40]2[CH2:39][CH2:38]1)(=[O:35])[CH3:34]>CN(C)C=O>[C:33]([O:36][CH:37]1[C:41]2=[N:42][C:43]3[C:44](=[N:45][CH:46]=[C:47]([NH:49][C:19]([C:6]4[N:7]([CH2:11][C:12]5[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=5)[C:8]5[C:4]([CH:5]=4)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=5)=[O:20])[CH:48]=3)[N:40]2[CH2:39][CH2:38]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC1CCn2c1nc1cc(N)cnc12
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCn2c1nc1cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc12
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 61.9 %

Procedure:
A solution of 0.25 g (0.87 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid, prepared in step 1.1, 0.166 g (0.87 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide and 0.117 g (0.87 mmol) of N-1-hydroxybenzotriazole in 3 ml of dimethylformamide is stirred at 20° C. for 15 minutes. The reaction mixture is subsequently admixed with 0.245 g (1.04 mmol) of 6-acetoxy-7,8-dihydro-6H-pyrrolo[2′,1′:2,3]imidazo[4,5-b]pyridin-3-amine (compound IV-b), in solution in 3 ml of dimethylformamide. The reaction mixture is subsequently stirred at 20° C. for 16 hours and then concentrated under reduced pressure, poured into 50 ml of water and extracted with three times 50 ml of ethyl acetate. The organic phases are combined, then washed with twice 20 ml of saturated sodium hydrogen carbonate solution, once with 20 ml of water and then once with 50 ml of saturated sodium chloride solution, dried over sodium sulfate and then concentrated under reduced pressure. The product obtained is purified by chromatography on a silica column, eluting with a mixture of dichloromethane and methanol. The product thus purified is finally triturated in hot diisopropyl ether and filtered while hot to give 0.27 g of the expected product.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([CH2:23][CH3:24])[N:10]=1)C1C=CC=CC=1.C1COCC1.[H][H]>[C].[Pd].C(O)C>[CH2:23]([C:11]1[C:12]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:9]([OH:8])[N:10]=1)[CH3:24]
Reactant: CCc1nc(OCc2ccccc2)c(C(=O)OC)cc1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1nc(O)c(C(=O)OC)cc1C(=O)OC
Yield: 72.6 %

Procedure:
A mixture of dimethyl 2-(benzyloxy)-6-ethylpyridine-3,5-dicarboxylate (2.37 g), 10% palladium carbon (containing 55% water, 2.00 g), THF (20 mL), and ethanol (20 mL) was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was filtered off, and then, the obtained filtrate was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to obtain the title compound (1.25 g).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[C@H:29]1[CH2:32][C@@H:31]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:30]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:35]([O:34][CH2:33][C@H:31]1[CH2:32][C@H:29]([N:16]2[C:17]3=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]3[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)=[N:15]2)[CH2:30]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](COCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@H](COCc2ccccc2)C1

Procedure:
A solution of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.452 g, 0.00149 mol) in N,N-dimethylformamide (10 mL) was reacted with cis 3-[(benzyloxy)methyl]cyclobutyl methanesulfonate (0.483 g, 0.00179 mol) and cesium carbonate (0.582 g, 0.00179 mol) at 70° C. for two days. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (2×20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica using dichloromethane/methanol (98:2). The solvent was removed in vacuo to give trans 1-{3-[(benzyloxy)methyl]cyclobutyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.325 g, 0.000681 mol) as a tan solid.
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/B(O)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH:20]=1)[CH:18]=[O:19]>>[CH:1]1(/[CH:7]=[CH:8]/[C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH:20]=2)[CH:18]=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)/C=C/C1CCCCC1
Reactant: O=Cc1cncc(Br)c1
Product: O=Cc1cncc(/C=C/C2CCCCC2)c1

Procedure:
Coupling of (E)-(2-cyclohexylvinyl)boronic acid with 5-bromonicotinaldehyde following the method used in Example 3 gave (E)-5-(2-cyclohexylvinyl)nicotinaldehyde as a yellow oil. Yield (0.8 g, 69%); 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.32 (s, 1H), 8.75 (s, 1H), 8.28 (s, 1H), 6.51-6.38 (m, 2H), 2.26-2.13 (m, 1H), 1.88-1.58 (m, 5H), 1.42-1.18 (m, 5H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C@H:9]([CH2:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])[C@H:8]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]1=[O:29].OP([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[O:29]=[C:7]1[C@@H:8]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:9]([CH2:10][N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])[NH:6]1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2ccccc2=O)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1ccccc1=O)OCc1ccccc1
Temperature: 90 °C
Yield: 77.1 %

Procedure:
Prepared in an analogous manner to example 4, step 2 using Benzyl ((3S,4R)-1-(2,4-dimethoxybenzyl)-2-oxo-4-((2-oxopyridin-1(2H)-yl)methyl)azetidin-3-yl)carbamate (361 mg, 0.622 mmol), K2S2O8 (225 mg, 0.833 mmol) and K2HPO4 (135 mg, 0.773 mmol) in ACN:water (2:1, 9.9 mL) while heating for 1.5 h at 90° C. More K2S2O8 (45 mg, 0.17 mmol) and K2HPO4 (26.9 mg, 0.155 mmol) were added and heated for another 30 min, whereupon it was concentrated, redissolved in EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-10%) to afford the title compound (157 mg, 81%). LCMS: Rt=0.56 min, m/z=328.2 (M+1) Method 2m_acidic.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]([OH:21])[CH2:10][C:11](=[O:20])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].[Cl-].[Ti+4]>[C:1]1([CH:7]=[CH:8][CH:9]([OH:21])[CH2:10][CH:11]([OH:20])[CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)C=Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Product: CC(C)(C)OC(=O)CC(O)CC(O)C=Cc1ccccc1
Yield: 55 %

Procedure:
By carrying out the reaction as in Example 9 but starting from 1.0 g of t-butyl 7-phenyl-5-hydroxy-3-oxo-6-heptenoate (3.42 mmol) and using 0.95 cm3 of titanium chloride triisopropoxide (3.77 mmol) and 261.8 mg of sodium cyanoborohydride (3.95 mmol), there is obtained, after reacting for 3 hours 10 minutes, with a yield of 55%, 550 mg of t-butyl 7-phenyl-3,5-dihydroxy-6-heptenoate for which the syn/anti ratio is equal to 90/10.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([O:20]C)=[O:19])[CH:15]=[CH:14][C:13]=1[F:22].[OH-].[Na+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][C:13]=1[F:22]
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(S(C)=O)cc2F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Methyl 6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxylate (37.0 mg, 0.112 mmol) was dissolved in THF (0.12 mL) and MeOH (0.12 mL), and 1.0 M aq. NaOH (0.56 mL, 0.56 mmol) was then added. The reaction mixture was stirred at room temperature for 50 min. The mixture was then neutralized with HCl (12 M) to pH=7 and concentrated under reduced pressure to remove all the solvents. The residue was dissolved in THF, dried, filtered and concentrated under reduced pressure to give the sub-title compound as a white powder. LCMS calc. for C13H9F3NO3S (M+H)+: m/z=316.0. Found: 316.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([CH2:29]Br)[CH:23]=1>>[Br:21][C:22]1[CH:23]=[C:24]([CH:25]=[C:26]([F:28])[CH:27]=1)[CH2:29][N:11]1[C:10](=[O:13])[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12]1
Reactant: Fc1cc(Br)cc(CBr)c1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Product: O=c1n(Cc2cc(F)cc(Br)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
219 mg (0.71 mmol) of the compound from Example 5A and 191 mg (0.71 mmol) of 1-bromo-3-(bromomethyl)-5-fluorobenzene were reacted analogously to the preparation of Example 101A. This gave 181 mg (51% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])(C)(C)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)=[CH:20][CH:19]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Brc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a stirred solution of 4.14 g (20.0 mmol) of 2-bromonaphthalene in 50 mL of THF at -78° C. under nitrogen was added a solution of 23.5 mL (40.0 mmol, 1.7M in pentane) of t-butyllithium over 10 minutes. The resulting slurry was stirred for 30 minutes and then warmed to 0° C. for 15 minutes. To this deep indigo solution was added a solution of 3.50 g (25.6 mmol) of thrice-fused zinc chloride in 25 mL of THF. The resulting light yellow solution was warmed to room temperature and stirred for 1 hour. After cooling to -78° C., a solution of 5.66 g (20.0 mmol) 1-bromo-4-iodobenzene and 300 mg (0.26 mmol) of tetrakis(triphenylphosphine)palladium in 20 mL of THF was added over the course of 15 minutes. After an additional 20 min, the cooling bath was removed, the reaction stirred at room temperature for 16 hours and then quenched with 50 mL of 2M hydrochloric acid. The mixture was extracted thrice with ether, the extracts combined, washed once with saturated sodium bicarbonate solution and once with 10% sodium thiosulfate. The organic extract was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel (5×25 cm column, hexanes as elutent) to give 4.05 g (72%) of title compound as a white solid, mp 121°-123° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N)(=[S:24])C.Cl.[OH-].[Na+]>O.CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[S:24])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: CC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=S)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C

Procedure:
20.0 g (67 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile and 10.06 g (134 mmol) of thioacetamide are heated to 90° together with 100 ml of dry N,N-dimethylformamide, whereupon the mixture is saturated with dry hydrogen chloride at this temperature for 5 hours. The mixture is cooled to room temperature and poured into 2.5 l of water. The mixture is neutralized to pH 7 with sodium hydroxide solution and the precipitated product is filtered off under suction. The material on the suction filter is taken up in methylene chloride, insoluble material is filtered off and the filtrate is washed with water, dried over magnesium sulphate and concentrated in half. By suction filtration and recrystallization from ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbothioamide of melting point 247°-248°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]3[N:24]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[CH:30][CH:29]=[CH:28]5)[N:23]=[C:22]([CH:35]([CH3:37])[CH3:36])[CH:21]=3)=[O:18])=[C:12]([F:38])[CH:11]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].C([NH:42][C@H](C(O)=O)CS)(=O)C.C([O-])(=O)C.[NH4+].C([O-])([O-])=O.[K+].[K+]>CO.O>[C:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]3[N:24]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[CH:30][CH:29]=[CH:28]5)[N:23]=[C:22]([CH:35]([CH3:36])[CH3:37])[CH:21]=3)=[O:18])=[C:12]([F:38])[CH:11]=2)[CH:6]=[CH:5][N:4]=1)(=[NH:42])[NH2:2]
Reactant: CC(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(C#N)c3)cc2F)n(-c2ccc3ncccc3c2)n1
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(C(=N)N)c3)cc2F)n(-c2ccc3ncccc3c2)n1
Temperature: 60 °C
Yield: 16.4 %

Procedure:
1-(4-(2-Cyanopyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (0.108 g, 0.221 mmol) and N-acetylcysteine (0.072 g, 0.441 mmol) were dissolved in MeOH (0.3 mL). Ammonium acetate (0.041 g, 0.0.529 mmol) was added and the reaction mixture was heated at 60° C. under N2 overnight. The completed reaction was diluted with H2O (10 ml), basified by K2CO3, extracted with EtOAc (2×30 mL) and THF (20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography to afford 1-(4-(2-carbamimidoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (0.019 g, 17% yield) as a white solid. This was converted to corresponding HCl salt by reacting with HCl (4.0 M HCl/dioxane, 1.0 eq.). 1H NMR (DMSO-d6) δ 9.57 (s, 2H), 9.36-9.34 (m, 2H), 9.20 (d, J=1.2 Hz, 1H), 9.09 (dd, J=4.4, 1.2 Hz, 1H), 8.74 (d, J=8.0 Hz, 1H), 8.68 (d, J=5.2 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.28 (d, J=9.2 Hz, 1H), 8.18-8.10 (m, 2H), 7.92 (d, J=2.4 Hz, 1H), 7.80 (dd, J=8.4, 4.8 Hz, 1H), 7.32-7.26 (m, 2H), 7.05 (dd, J=8.8, 1.2 Hz, 1H), 6.44 (s, 1H), 2.97-2.93 (m, 1H), 1.28 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 525.3 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:15]1[N:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[C:18]([N+:25]([O-:27])=[O:26])=[CH:17][CH:16]=1.O>CS(C)=O>[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[N:20]=2)[CH2:10][CH2:9]1
Reactant: CN1CCNCC1
Reactant: CC(C)Oc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1nc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 73.4 %

Procedure:
463 mg of potassium carbonate and 224 mg of 1-methylpiperazine are added to a solution of 484 mg of 6-chloro-3-nitro-2-(propan-2-yloxy)pyridine in 4.45 ml of DMSO. The reaction medium is heated for 1 hour at 105° C. After cooling, the mixture is run into water and extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is taken up in diisopropyl ether and the insoluble material is filtered off and dried under vacuum, so as to give 460 mg of 1-methyl-4-[5-nitro-6-(propan-2-yloxy)pyridin-2-yl]piperazine in the form of a yellow solid.
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[O:34])[C:21](=[O:33])[N:22]2[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O1C2C=CC(O)=CC=2OC1.[O:45]1[C:49]2[CH:50]=[C:51]([OH:54])[CH:52]=[CH:53][C:48]=2[CH2:47][CH2:46]1>>[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]([OH:34])([C:52]1[C:51]([OH:54])=[CH:50][C:49]3[O:45][CH2:46][CH2:47][C:48]=3[CH:53]=1)[C:21](=[O:33])[N:22]2[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)CN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Oc1ccc2c(c1)OCC2
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with ethyl (4-bromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compound was obtained (68%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.66 (br, 1H), 7.31-7.19 (m, 3H), 6.73 (dd, 1H), 6.49-6.45 (m, 1H), 5.09-4.36 (m, 4H), 4.20 (q, 2H), 3.14-2.90 (m, 2H), 1.23 (t, 3H); MS (ES+) m/z 432.2 (M−17).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]#[N:25])[C:5]2[CH:6]=[CH:7][N:8]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=4)[N:14]=[C:13]([CH3:22])[C:12]=3[CH3:23])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)O1>>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:22])[C:12]([CH3:23])=[C:11]2[N:8]1[C:9]2[CH:10]=[C:2]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH:3]=[C:4]([C:24]#[N:25])[C:5]=2[CH:6]=[CH:7]1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: Cc1nc2ccc(Cl)cc2c(-n2ccc3c(C#N)cc(Br)cc32)c1C
Product: Cc1nc2ccc(Cl)cc2c(-n2ccc3c(C#N)cc(-c4ccncc4)cc32)c1C

Procedure:
Prepared according to procedure W using 6-bromo-1-(6-chloro-2,3-dimethylquinolin-4-yl)-1H-indole-4-carbonitrile (0.2 g, 0.243 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.06 g, 0.292 mmol) to give 1-(6-chloro-2,3-dimethyl-4-quinolinyl)-6-(4-pyridinyl)-1H-indole-4-carbonitrile as a: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (2H, d, J=5.9 Hz), 8.22 (1H, d, J=1.2 Hz), 8.12 (1H, d, J=9.0 Hz), 8.01 (1H, d, J=3.1 Hz), 7.70-7.79 (4H, m), 7.11 (1H, d, J=3.1 Hz), 6.91 (1H, d, J=2.3 Hz), 2.78 (3H, s), 2.02 (3H, s); Mass Spectrum (ESI) m/e=409.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O-])=[O:30])=[CH:24][CH:23]=1)([O-:21])=[O:20].O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:29](=[O:30])[CH2:28][C:25]1[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:27][CH:26]=1)[CH2:7][CH2:6]2
Reactant: CCCCCOc1c(OC)ccc2c1CCNC2
Reactant: O=C([O-])Cc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOc1c(OC)ccc2c1CCN(C(=O)Cc1ccc([N+](=O)[O-])cc1)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-Methoxy-5-pentyloxy-1,2,3,4-tetrahydroisoquinoline (116 mg, 0.465 mmol), (4-nitrophenyl)acetate (101.1 mg, 0.558 mmol) and 1-hydroxybenzotriazol hydrate (81.7 mg, 0.605 mmol) were dissolved in DMF (2 ml), and WSC hydrochloride (125 mg, 0.651 mmol) was added to this solution under ice-cooling. After stirring at room temperature for 3 hours, ethyl acetate (3 ml) and saturated aqueous sodium hydrogencarbonate solution (3 ml) were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure to give a crude product of 1-(6-methoxy-5-pentyloxy-3,4-dihydro-1H-isoquinolin-2-yl)-2-(4-nitrophenyl)ethanone. This product was used for the next reaction.