Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].Br[CH2:3][CH2:4][CH2:5][S:6]([O-:9])(=[O:8])=[O:7].C[O-].[Na+].[CH2:13]([SH:16])[CH2:14][SH:15].Cl>CCO.O>[CH2:13]([S:16][CH2:3][CH2:4][CH2:5][S:6]([OH:9])(=[O:8])=[O:7])[CH2:14][S:15][CH2:3][CH2:4][CH2:5][S:6]([OH:9])(=[O:8])=[O:7]
Reactant: O=S(=O)([O-])CCCBr
Reactant: SCCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)(O)CCCSCCSCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromopropane sulfonic acid sodium salt (24.7 g, 110 mmol) and sodium methoxide (7.06 g, 131 mmol) in EtOH (300 mL) at ambient temperature was added, dropwise, 1,2-ethanedithiol (4.4 mL, 52.3 mmol) in ethanol (25 mL). Allowed to stir at room temperature for one hour, and then heated to reflux overnight. Cooled to room temperature and acidified with 2 N HCl to pH 1-2. The resulting suspension was heated to 75° C. and water was slowly added in small portions until a clear solution was obtained. Cooled to room temperature, and then to 5° C. The resulting white precipitate was filtered off, washed with cold EtOH and dried, giving 11.9 g (67.4%) as a white powder. 1H NMR (400 MHz, D2O) δ 3.10 (t, J=7.2 Hz, 4H), 2.92 (s, 4H), 2.82 (t, J=7.2 Hz, 4H), 2.11 (m, 4H). 13C NMR (101 MHz, D2O) δ 52.26, 33.38, 32.27, 26.80.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)=[O:32])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:32])[C:33]2[CH:34]=[CH:35][CH:36]=[C:37]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=5)[O:10][C:3]=34)[CH:38]=2)=[CH:28][CH:29]=1
Reactant: O=C(Nc1ccc(F)cc1)c1cccc(B(O)O)c1
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Product: COc1cc(-c2cc3nccc(-c4cccc(C(=O)Nc5ccc(F)cc5)c4)c3o2)cc(OC)c1OC

Procedure:
The title compound was prepared by procedure C using 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine (45.00 mg; 0.14 mmol; 1.00 eq.) instead of 7-chloro-2-iodo-furo[3,2-b]pyridine, and 3-(4-fluorophenyl)aminocarbonyl-phenylboronic acid (40.10 mg; 0.15 mmol; 1.10 eq.) instead of 4-fluorophenylboronic acid and was obtained as a white solid (57 mg, 81%). (HPLC (method F): 87%, RT: 4.33 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 10.51 (s, 1H), 8.96 (s, 1H), 8.67-8.58 (m, 1H), 8.34 (d, J=7.4, 1H), 8.15 (d, J=7.4, 1H), 7.88-7.74 (m, 5H), 7.38 (s, 2H), 7.24 (t, J=7.8, 2H), 3.87 (s, 6H), 3.77-3.68 (m, 3H); MS (m/z) 499 [M+H]+, RT: 4.3 min.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[N:5]1)([CH3:3])[CH3:2]>CCO.[Pd]>[CH:1]([N:4]1[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CC(C)n1cc(N)cn1
Yield: 75.7 %

Procedure:
A solution of 1-isopropyl-4-nitro-1H-pyrazole (3 g, 19 mmol) in EtOH (30 mL) was stirred under a hydrogen atmosphere for 2 h in the presence of 10% Pd/C (300 mg). The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to afford 1-isopropyl-1H-pyrazol-4-ylamine (1.8 g, 75% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.99 (s, 1 H), 6.84 (s, 1 H), 4.23 (m, 1 H), 3.70 (s, 2 H), 1.28 (d, J=6.8 Hz, 6 H); MS (ESI) m/z: 126.2[M+H]+.
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([C:20]([NH:22][C:23]3[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:26]([O:28]C)=[O:27])=[O:21])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:6][CH2:5]1.CO>C1COCC1>[OH:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[C:12]([C:20]([NH:22][C:23]3[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:26]([OH:28])=[O:27])=[O:21])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(O)CC3)cc3ccccc23)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)O)c(C)c1NC(=O)c1cc(N2CCC(O)CC2)cc2ccccc12
Reaction time: 12 h
Yield: 29.1 %

Procedure:
A solution of aqueous 2N NaOH (3.00 ml) is added to a stirred solution of methyl 3-(3-(4-hydroxypiperidin-1-yl)-1-naphthamido)-2,4-dimethylbenzoate (0.10 g, 0.23 mmol) in THF:MeOH (3 ml:1 ml). After 12 hours at room temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with aqueous 1N HCl and extracted with dichloromethane (2×20 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as a white solid (0.028 g, 29%). Mass spectrum (m/z): 419.2 (M+1).
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[C:22]([C:25]1[CH:32]=[C:31]([Cl:33])[C:28]([C:29]#[N:30])=[C:27](I)[C:26]=1[O:35][CH2:36][CH3:37])(=[O:24])[CH3:23].[Cl-].[NH4+]>CN(C)C(=O)C.[Zn].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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[C:22]([C:25]1[C:26]([O:35][CH2:36][CH3:37])=[C:27]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[C:28]([C:29]#[N:30])=[C:31]([Cl:33])[CH:32]=1)(=[O:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1I
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
Zinc (4.60 g, 70.3 mmol) and oven dried Celite (870 mg) was added to a flask and the flask was heated with a heat gun while under high-vac for 5 min and then back-filled with nitrogen. N,N-Dimethylacetamide (57 mL) was added, followed by 1,2-dibromoethane (430 μL, 5.0 mmol) and the mixture was heated at 70° C. for 10 min and then cooled to room temperature. The reaction mixture was treated with chlorotrimethylsilane (630 μL, 5.0 mmol) dropwise and stirred at room temperature for 1 h. The reaction mixture was treated with a solution of tert-butyl 3-iodoazetidine-1-carboxylate (18 g, 62 mmol) in N,N-dimethylacetamide (28 mL) dropwise (internal temperature was kept below 40° C. with a water bath) and heated at 40° C. for 2 h. The zinc-iodo reagent (transferred via canula) was filtered through a plastic filter (that was appropriately sealed to avoid atmospheric exposure) directly into a clean, dry flask that was flushed with nitrogen. The reaction mixture was treated with tris(dibenzylideneacetone)dipalladium(0) (720 mg, 0.79 mmol) and tri-(2-furyl)phosphine (370 mg, 1.6 mmol) and degassed with nitrogen for a few minutes. The reaction mixture was treated with a solution of 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile (14 g, 41 mmol) in N,N-dimethylacetamide (130 mL) (degassed with nitrogen) quickly and heated at 70° C. for 2 h. The reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water (4×500 mL) and brine (1×500 mL), dried with magnesium sulfate, filtered, and concentrated to a crude dark oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (5%-45%) to give the desired product (14 g, 88%). 1H NMR (300 MHz, CDCl3) δ 7.46 (s, 1H), 4.42-4.20 (m, 5H), 3.80 (q, J=7.0 Hz, 2H), 2.59 (s, 3H), 1.44 (s, 9H), 1.37 (t, J=7.0 Hz, 3H). LCMS for C15H16ClN2O4 ([M-(t-Bu)+H]+H)+: m/z=323.1; Found: 323.0.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (4 g, 28.35 mmol, 1.00 equiv), 4-fluorophenol (3.177 g, 28.34 mmol, 1.00 equiv) and potassium carbonate (7.83 g, 56.24 mmol, 1.98 equiv) in N,N-dimethylformamide (50 mL) was stirred overnight at 120° C. The reaction was cooled to room temperature and then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate. The combined organic layers was washed with 3×150 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to yield 6.4 g (97%) of 1-fluoro-4-(4-nitrophenoxy)benzene as a yellow solid. 1H-NMR (400 MHz, CDCl3): δ 8.22-8.18 (m, 2H), 7.16-7.04 (m, 4H), 7.00-6.97 (m, 2H) ppm.
Reaction SMILES: Cl([O-])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([O:31][CH2:32][CH:33]=[O:34])[CH:9]=[N:10][C:11]=1[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[NH:23][C:24]1[CH:29]=[N:28][C:27]([CH3:30])=[CH:26][N:25]=1.CC(=CC)C.P([O-])(O)(O)=[O:41].[Na+].Cl>CC(O)(C)C.O>[Cl:5][C:6]1[CH:7]=[C:8]([O:31][CH2:32][C:33]([OH:41])=[O:34])[CH:9]=[N:10][C:11]=1[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[NH:23][C:24]1[CH:29]=[N:28][C:27]([CH3:30])=[CH:26][N:25]=1
Reactant: O=P([O-])(O)O
Reactant: Cc1cnc(Nc2ncnc3ccc(Oc4ncc(OCC=O)cc4Cl)cc23)cn1
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cnc(Nc2ncnc3ccc(Oc4ncc(OCC(=O)O)cc4Cl)cc23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Sodium chlorite (30 mg, 0.33 mmol) was added to a water (0.3 ml)/2-methyl-2-propanol (1.2 ml) mixed solution of {[5-chloro-6-({4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}acetaldehyde (50 mg, 0.11 mmol) obtained in Example 32, 2-methyl-2-butene (0.051 ml, 0.48 mmol) and sodium dihydrogenphosphate (13 mg, 0.11 mmol), and the reaction solution was stirred at room temperature for 1 hour. Aqueous 1 N hydrochloric acid solution was added to the reaction solution, and extracted with chloroform/methanol (9:1). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to obtain the entitled compound (37 mg, yield: 77%) as a yellow solid.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]2[C:13](=[O:23])[N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:16])[CH:10]2[CH2:9]1)C1C=CC=CC=1.Cl.[OH-].[Na+]>C(O)C.[Pd]>[C:17]1([N:14]2[C:13](=[O:23])[CH:11]3[CH:10]([CH2:9][NH:8][CH2:12]3)[C:15]2=[O:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1C2CN(Cc3ccccc3)CC2C(=O)N1c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1C2CNCC2C(=O)N1c1ccccc1
Reaction time: 12 h

Procedure:
A solution of 5-benzyl-2-phenyltetrahydropyrrolo[3,4-c]pyrrole-1,3-dione, freed of its hydrochloride beforehand by treatment with 4 N sodium hydroxide (93.2 g; 304 mmol), in absolute ethanol (1200 ml) is placed in a 5000 ml autoclave and palladium-on-charcoal at 5% (11 g) is then added. After having purged with nitrogen, the autoclave is placed under 64 bar of hydrogen at 70° C. for 12 hours. After returning to 20° C., the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The compound obtained is triturated in diisopropyl ether (500 ml) and the solid obtained is filtered off, washed with diisopropyl ether and, finally, dried under reduced pressure at constant weight. 2-Phenyltetrahydropyrrolo[3,4-c]pyrrole-1,3-dione, (6.6 g; 92%) is isolated, the characteristics of which are as follows:
Reaction SMILES: C(O[C:6](=[O:13])[NH:7][C@@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)(C)(C)C.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[NH2:7][CH2:8][CH2:9][NH:10][C:6]([NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:9]1)=[O:13]
Reactant: Clc1ccccn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: NCCNC(=O)N[C@@H]1CCN(c2ccccn2)C1

Procedure:
The titled compound is prepared analogously to Intermediate D by replacing (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester and replacing 2-bromopyridine with 2-chloropyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22](Br)=[N:21][C:20]=1[CH3:25])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[O:8])=[N:21][C:20]=1[CH3:25])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: Oc1ccc(Cl)cn1
Product: Cc1nc(-n2cc(Cl)ccc2=O)sc1C(=O)NCc1ccccc1
Yield: 39 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 5-chloro-2-hydroxypyridine in place of 4-aminopyridin-2(1H)-one to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a white solid in 39% yield: mp 173-174° C.; 1H NMR (300 MHz, CDCl3) δ 8.79 (d, J=2.4 Hz, 1H), 7.36-7.23 (m, 6H), 6.61 (d, J=9.9 Hz, 1H), 6.43 (s, 1H), 4.55 (d, J=5.4 Hz, 2H), 2.66 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.9, 158.8, 152.4, 152.0, 141.0, 131.7, 128.7, 128.5, 127.8, 127.6, 123.8, 121.9, 115.5, 44.1, 17.2; MS (ES+) m/z 360.1 (M+1), 362.1 (M+1).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH:29]([N:32]=[C:33]=[O:34])([CH3:31])[CH3:30]>C(Cl)Cl>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:33]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:34])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: Fc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: CC(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)NC(=O)N1CC(OC(c2ccc(F)cc2)c2ccccc2C(F)(F)F)C1

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]azetidine hydrochloride (162) (150 mg, 0.42 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (2.62 mmol/g; 475 mg, 1.26 mmol), molecular sieves and iso-propyl isocyanate (42 μL, 0.42 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (24 mL), then evaporated to afford the desired product as a colourless glass which gave a white solid on scratching (126 mg, 74%).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6]([NH:11][CH2:12][C@H:13]([OH:18])[C:14](OC)=[O:15])[CH:5]=1)(=[O:3])[NH2:2].[NH3:19].CO>>[NH2:19][C:14](=[O:15])[C@@H:13]([OH:18])[CH2:12][NH:11][C:6]1[N:7]=[C:8]([Cl:10])[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=1
Reactant: COC(=O)[C@@H](O)CNc1cc(C(N)=O)nc(Cl)n1
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(NC[C@H](O)C(N)=O)nc(Cl)n1
Temperature: 50 °C
Yield: 94 %

Procedure:
A mixture of the (S)-methyl 3-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)-2-hydroxypropanoate (0.421 g, 1.53 mmol) and 7M ammonia in MeOH (10 mL, 70 mmol) were heated in a sealed tube at 50° C. overnight. The precipitated solid was filtered off from the warm reaction mixture, rinsed once with 5 mL MeOH, and air-dried to give (S)-6-((3-amino-2-hydroxy-3-oxopropyl)amino)-2-chloropyrimidine-4-carboxamide as a light tan powder (0.372 g, 1.43 mmol, 94% yield). LC/MS: m/z=260.1 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][S:11]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=O)(C)(C)C.[ClH:24].CCOCC>ClCCl.O1CCOCC1>[ClH:24].[NH2:8][CH2:9][CH2:10][S:11]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: COC(=O)c1ccc(S(=O)(=O)CCNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)CCN)cc1

Procedure:
A solution of methyl 4-(2-tert-butoxycarbonylaminoethanesulfonyl)benzoate (2.86 g, 8.33 mmol) in dichloromethane (20 ml) was treated with 4M HCl in dioxane (20 ml) for 2 h. Ether (200 ml) was added and the suspension was filtered, washed with ether (2×50 ml), hexane (50 ml) and pumped dry to give methyl 4-(2-aminoethylsulfonyl)benzoate hydrochloride (2.23 g) which was coupled with benzofuran 2-carboxylic acid as described above to afford the title compound. MS (M+1): 388.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:26])[C:22]=1[N+:23]([O-:25])=[O:24])[C:17]([OH:19])=O.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCCC1>[CH3:26][C:21]1[CH:20]=[C:16]([C:17]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:19])[CH:15]=[C:14]([CH3:13])[C:22]=1[N+:23]([O-:25])=[O:24]
Reactant: C1COCCN1
Reactant: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N2CCOCC2)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1′-Carbonyldiimidazole (1.66 g) is added to a solution of 3,5-dimethyl-4-nitrobenzoic acid (1 g) in tetrahydrofuran (10 mL). The mixture is stirred for 3 hours at room temperature, morpholine (0.9 mL) is added and the mixture is stirred for further 30 minutes. After concentration the mixture is diluted with ethyl acetate and washed with hydrochloric acid (0.2 M), saturated aqueous NaHCO3 solution and brine. The organic phase is dried (Na2SO4) and concentrated to give the title compound. Yield: 1.3 g; LC (method 20): tR=5.10 min; Mass spectrum (ESI+): m/z=265 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1ccncc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccncc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 3-bromoisonicotinaldehyde (2.5 g, 13.44 mmol) in MeOH (Volume: 100 ml) was added sodium borohydride (1.017 g, 26.9 mmol) and the reaction mixture was stirred at that temperature for 1 hour. The reaction mixture was then quenched with satd. NaHCO3, filtered, and evaporated to remove MeOH. The aqueous layer was extracted with EtOAc (2×). The combined organics were washed with satd. NaHCO3 and brine, dried, and concentrated to give Intermediate 65A as a white solid. MS (ES): m/z=189.9 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:25](OC4C=CC([N+]([O-])=O)=CC=4)=[O:26])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.[NH:37]1[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:25]([N:37]4[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38]4)=[O:26])[CH2:10]3)[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: OC1CCNC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Product: O=C(N1CCC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
100 mg (0.20 mmol) of the compound from Example 184A and 52 mg (0.6 mmol) of 3-pyrrolidinol were reacted according to the General Method 6. Yield: 50 mg (55% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:33]=[CH:32][C:20]([CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:18]=1.C1C(=O)N([Cl:41])C(=O)C1>CN(C=O)C>[Cl:41][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:33]=[CH:32][C:20]([CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1
Yield: 55.9 %

Procedure:
Following General Procedure H, tert-butyl 4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenethyl(methyl)carbamate (200 mg, 0.43 mmol) in (DMF) was reacted with NCS (70 mg, 0.50 mmol) to afford the desired product (120 mg, 55%) as a yellow solid: ESI MS m/z 500 [C26H27ClN2O4S+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:11][C:12](O)=[O:13].S(C)C.Cl>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: O=C(O)CCc1cc(F)c(F)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: OCCCc1cc(F)c(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.2 %

Procedure:
3-(2,4,5-Trifluorophenyl)propionic acid (3.25 g, 16.0 mmol; from Step 1) was dissolved in THF (15 mL) and cooled to 0° C. To this solution was added Me2S.BH3 (3.2 mL, ˜32 mmol) dropwise under 30 min and the resulting mixture was then heated at 70° C. for 30 min. After cooling to 0° C., 6 M aqueous HCl (20 mL) was added dropwise. The mixture was heated at 70° C. for 1 h. After cooling to room temperature the mixture was extracted with ether (2×20 mL) and the combined organic layers were washed with brine and dried over Na2SO4. Evaporation and drying in vacuum gave the title compound as a colorless liquid (3.17 g, 97% pure by HPLC) that was used directly in the next step. *Previously reported in EP 369812.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH2:9]1)=O)(C)(C)C.N[CH2:32][CH2:33][C:34]1C=CC=CN=1>>[N:8]1[CH:9]=[CH:34][CH:33]=[CH:32][C:12]=1[CH2:11][CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: NCCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCc1ccccn1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(2-aminoethyl)pyridine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 364 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, br. s.) 10.24 (1H, s) 8.41-8.47 (1H, m) 8.24 (1H, t, J=5.56 Hz) 8.02 (1H, d, J=5.37 Hz) 7.77 (1H, d, J=5.47 Hz) 7.61-7.70 (1H, m) 7.46 (1H, d, J=5.37 Hz) 7.31 (1H, dd, J=3.32, 2.44 Hz) 7.25 (1H, d, J=7.81 Hz) 7.13-7.20 (1H, m) 6.79 (1H, d, J=5.37 Hz) 6.44 (1H, dd, J=3.42, 1.85 Hz) 3.53-3.68 (2H, m) 2.98 (2H, t, J=7.37 Hz)
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:13])=[C:5]([C:9]([F:12])([F:11])[F:10])[C:6]=1[C:7]#[N:8].[CH3:14]C(C)([O-])C.[K+].CI>O1CCCC1.O.CCOCC>[Br:1][C:2]1[N:3]([CH3:14])[C:4]([Br:13])=[C:5]([C:9]([F:10])([F:11])[F:12])[C:6]=1[C:7]#[N:8]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1c(Br)[nH]c(Br)c1C(F)(F)F
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CI
Product: Cn1c(Br)c(C#N)c(C(F)(F)F)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,5-dibromo-4-(trifluoromethyl)pyrrole-3-carbonitrile (0.10 g, 0.30 mmol) in tetrahydrofuran is treated with solid potassium t-butoxide (0.053 g, 0.49 mmol), stirred for 1 hour at 25° C., treated dropwise with methyl iodide (0.067 g, 0.47 mmol), stirred for 2 hours at 25° C. and for 1 hour at 50° C. and diluted with water and ether. The phases are separated and the organic phase is washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to afford the title compound as a white solid, 0.09 g, mp 101°-104° C.