Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11][CH2:12][CH2:13]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCBr)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.5 %

Procedure:
A mixture of 4-nitrophenol (1.0 g, 1.0 eq., 7.19 mmol), 1,2-dibromoethane (3.85 mL, 6.0 eq, 43.1 mmol), and anhydrous K2CO3 (3.0 g, 3 eq, 21.5 mmol) in dry acetone (36 mL) was stirred at RT for 16 h. The reaction mixture was filtered, and the filtrate was condensed. Condensed mass was again dissolved in ethyl acetate and washed with aq. sodium bicarbonate solution. Organic layer was dried (Na2SO4), condensed, and the residue was chromatographed using ethyl acetate and hexanes to obtain the title compound as solid (540 mg, 32%).
Reaction SMILES: [N+]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:17])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[Cl:20]C1C=CC(C(Cl)=O)=CC=1>>[Cl:20][C:4]1[CH:19]=[CH:18][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:17])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C1CCCCCN1C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C1CCCCCN1C(=O)c1ccc(Cl)cc1

Procedure:
Synthesized as for N-(4-nitrobenzoyl)caprolactam (Example XXIII) using 4-chlorobenzoylchloride (Aldrich) in place of 4-nitrobenzoyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[S:18][C:17]([C:19]4[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=4)=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1.[OH:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[S:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:26][CH2:27][CH2:28][N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:21][CH:20]=4)=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCCN1CCOCC1
Reactant: COc1cccc(Nc2ncnc3cc(-c4ccc(Br)cc4)sc23)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cccc(Nc2ncnc3cc(-c4ccc(OCCN5CCOCC5)cc4)sc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 28.4 %

Procedure:
N-(3-methoxyphenyl)-6-(4-bromophenyl)thieno[3,2-d]pyrimidine-4-amine (0.26 g, 0.76 mmol) was dissolved in 5 ml of degassed dimethylformamide and added with 4-(2-hydroxyethyl)morpholine (0.12 ml, 0.92 mmol) and triphenylphosphine (241 mg, 0.92 mmol). The mixture was further added with DIAD (0.18 ml, 0.92 mmol) at 0° C. and stirred at room temperature for 15 hours. It was extracted with 50 ml saturated sodium bicarbonate and 50 ml of ethylacetate and the organic layer was washed with 50 ml of water twice, dried with magnesium sulfate and filtered. After concentration under vacuum, column chromatography (dichloromethane/methanol, 15/1) was done. The title compound (100 mg, 29%) was obtained as ivory colored solid.
Reaction SMILES: [O:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C(=O)N([Br:38])C(=O)C1>C(Cl)Cl>[Br:38][C:7]1[C:8]2[O:1][CH:2]=[CH:3][C:4]=2[NH:5][C:6]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2occc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: COC(=O)c1[nH]c2ccoc2c1Br
Reaction time: 8 h

Procedure:
To a cold solution (ice-water bath) of methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (1.0 g, 6.05 mmol) in DCM (10 mL) was added TBAF (1.0 M in THF, 9.0 mL, 9.0 mmol) and NBS (1.5 g, 7.9 mmol). The resulting dark colored solution was stirred from 0° C. to rt overnight. The reaction mixture was diluted with 50 mL of CH2Cl2 and washed with water (100 mL) and brine (100 mL) and dried (Na2SO4). After filtration, the filtrate was concentrated by evaporation and the crude product was purified by silica gel chromatography (0-5% EtOAc/hexane) to afford a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.84 (broad, 1H, NH), 7.54 (d, J=2.2 Hz, 1H), 6.48 (d, J=1.83 Hz, 1H), 3.92 (s, 3H) ppm; m+/z 244 (100%), 246 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([F:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[I:22]I>C1COCC1.S([O-])([O-])(=O)=S.[Na+].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([I:22])=[C:10]([F:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: COc1cc(F)cc(-c2cccc(Cl)c2)c1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(Cl)c2)cc(F)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A RBF was charged with 3′-chloro-3-fluoro-5-methoxy-1,1′-biphenyl (577.6 mg, 2.441 mmol) and THF (8135 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 10 min, then n-butyllithium (1.8M in hexanes) (1627 μl, 2.93 mmol) was added dropwise. After 30 min, a solution of iodine (929 mg, 3.66 mmol) in THF (3 mL) was added dropwise. TLC after 5 min showed conversion to a slightly lower spot. The mixture was diluted with saturated aq. sodium thiosulfate solution and warmed to room temperature. The mixture was diluted with water and extracted with EtOAc (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Ultra SNAP column, 0-5% EtOAc/Heptane) to give 3′-chloro-3-fluoro-4-iodo-5-methoxy-1,1′-biphenyl (687 mg, 1.895 mmol, 78% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) □=7.87 (td, J=1.0, 1.8 Hz, 1 H), 7.74 (td, J=1.8, 7.0 Hz, 1 H), 7.55-7.43 (m, 2 H), 7.25 (dd, J=1.8, 9.1 Hz, 1 H), 7.14-7.07 (m, 1 H), 3.97 (s, 3 H).
Reaction SMILES: [CH:1]1[CH:2]=C[C:4]2[N:9](O)N=[N:7][C:5]=2[CH:6]=1.[N:11]1([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:23]([CH:27]=2)[C:24]([OH:26])=O)=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.N1C=CC=C(N)C=1.C(Cl)CCl>CN(C)C=O.O>[N:11]1([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:23]([CH:27]=2)[C:24]([NH:7][C:5]2[CH:4]=[N:9][CH:2]=[CH:1][CH:6]=2)=[O:26])=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccccc1
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(C(=O)N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Neat HOBT (90 mg, 0.59 mmol) was added in one charge to a stirred solution of 5-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 57; 200 mg, 0.59 mmol), 3-pyridinamine (55.1 mg, 0.59 mmol) and EDC (112 mg, 0.59 mmol) in N,N-dimethylformamide (5 ml) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The organic phase was washed with sodium hydroxide solution (1 mol/l, 25 ml), saturated brine (25 ml), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was washed with ether (5 ml) and dried to yield the title compound as a white solid. 67 mg.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=O.COC(C1CCNC1C1C=CC(F)=CC=1)=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.B.[Na]>CO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH:6]2[CH:5]([CH2:3][OH:2])[CH2:9][CH2:8][N:7]2[S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:25][CH:24]=1
Reactant: COC(=O)C1CCN(S(=O)(=O)c2ccc(C)cc2)C1c1ccc(F)cc1
Agent: B
Agent: COC(=O)C1CCNC1c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC(CO)C2c2ccc(F)cc2)cc1

Procedure:
Reduction of (2RS,3RS)-2-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-3-carboxylic acid methyl ester, prepared from (2RS,3RS)-2-(4-fluoro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester and toluene-4-sulfonyl chloride in accordance with the general method of example 1e, with sodium boron hydride in MeOH yielded after aqueous work-up and purification by column chromatography on silica gel (ethyl acetate/hexane 1:1) the title compound as a pale yellow oil, MS: m/e=348 (M−H+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)=[O:3].[N+:13]([O-])([OH:15])=[O:14].CCOC(C)=O>C(O)(=O)C.CCCCCC>[CH3:1][C:2]([C:4]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc2c(c1)OCO2
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 0 °C

Procedure:
A solution of 50 g (0.305 mole) 3,4-methylenedioxy-acetophenone (Aldrich) in 200 mL glacial acetic acid was added dropwise over 30 minutes to 700 mL of cold (2-4° C.) 70% HNO3 with stirring (NOTE: the reaction will overheat without external cooling from an ice bath, which can be dangerous and lead to side products). At temperatures below 0° C., however, the reaction can be sluggish. A temperature of 3-5° C. seems to be optimal). The mixture was left stirring for another 60 minutes at 3-5° C., and then allowed to approach ambient temperature. Analysis by TLC (25% EtOAc in hexane) indicated complete conversion of the starting material within 1-2 hr. When the reaction was complete, the mixture was poured into ˜3 liters of crushed ice, and the resulting yellow solid was filtered off, washed with water and then suction-dried. Yield ˜53 g (84%), used without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:46])([C:22]3[N:23]=[CH:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:26]=3)[CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[N:7]=1)=[O:5])[CH3:2].Cl.N1C=CC=CC=1>>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:46])([C:22]3[N:23]=[CH:24][NH:25][CH:26]=3)[CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)n1
Agent: Cl
Solvent: c1ccncc1
Product: CCNC(=O)c1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)n1
Yield: 51.2 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-ethyl-6-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-2-pyridinecarboxamide (1.82 g) and pyridine hydrochloride (570 mg), the title compound (560 mg) was obtained as colorless powder crystals.
Reaction SMILES: FC(F)(F)C(O)=O.C([CH:12]([C@H:16]1[CH2:22][CH2:21][C@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][N:18]([CH2:29][CH2:30][O:31][CH3:32])[C:17]1=[O:33])[C:13]([O-:15])=[O:14])(C)(C)C>ClCCl>[CH3:32][O:31][CH2:30][CH2:29][N:18]1[CH2:19][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22][C@H:16]([CH2:12][C:13]([OH:15])=[O:14])[C:17]1=[O:33]
Reactant: COCCN1C[C@@H](c2ccccc2)CC[C@H](C(C(=O)[O-])C(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCN1C[C@@H](c2ccccc2)CC[C@H](CC(=O)O)C1=O
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution (trans)-tert-butyl[1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-yl]acetate (170 mg, 0.47 mmol) in dichloromethane (3 mL). After 2 h, the solution was concentrated. MS 306 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Clc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(Oc2ccccn2)cc1
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
To a stirred solution of 4-bromophenol (200 mg) in DMF (3 mL) was added NaH (60% in oil, 46.2 mg) at room temperature. The mixture was stirred for 30 min, and 2-chloropyridine (131 mg) was added. The mixture was exposed to microwave irradiation at 230° C. for 1 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (76 mg).
Reaction SMILES: C([NH:8][C@@:9]([CH3:37])([CH2:35][CH3:36])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:29][CH:30]2[CH2:33][CH2:32][CH2:31]2)[C:21]([C:23]2[NH:27][N:26]=[C:25]([Cl:28])[CH:24]=2)=[O:22])=[C:15]([F:34])[CH:14]=1)=[O:11])(OC(C)(C)C)=O.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(#N)C>[NH2:8][C@@:9]([CH3:37])([CH2:35][CH3:36])[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:29][CH:30]2[CH2:31][CH2:32][CH2:33]2)[C:21]([C:23]2[NH:27][N:26]=[C:25]([Cl:28])[CH:24]=2)=[O:22])=[C:15]([F:34])[CH:14]=1)=[O:11]
Reactant: CC[C@](C)(NC(=O)OC(C)(C)C)C(=O)Oc1ccc(CN(CC2CCC2)C(=O)c2cc(Cl)n[nH]2)c(F)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC[C@](C)(N)C(=O)Oc1ccc(CN(CC2CCC2)C(=O)c2cc(Cl)n[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a solution of (S)-4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenyl 2-(Boc-amino)-2-methylbutanoate (0.020 g, 0.037 mmol) in ACN 2 mL was added 0.5 mL Et3SiH and 0.5 ml TFA, and then stirred at r.t. for overnight. After removed the solvent, chromatography on silica gel with 0-40% methanol in DCM give the crude product. Then, the crude product was purified one more time by preparative HPLC (Water/ACN, 5-100%, 15 mins, then 100%, 5 mins.) gave pure product (S)-4-((3-chloro-N-(cyclobutylmethyl)-1H-pyrazole-5-carboxamido)methyl)-3-fluorophenyl 2-amino-2-methylbutanoate (0.010 g, 0.023 mmol, 62% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:16]1[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:15]1)[CH3:27]
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Yield: 51 %

Procedure:
In analogy to the procedure described in intermediate 5B, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 5A) and ethyl bromoacetate gave, after purification on a SiO2-column (n-heptane/EtOAc 1:2 to 100% EtOAc), the titled compound in 51% yield as white foam. MS: 399.1 (MH+, 2Cl).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.C([Sn](Cl)(Cl)CCCC)CCC.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C1([SiH3])C=CC=CC=1>COCCOC.CO.O>[O:34]1[CH2:35][CH2:36][N:31]([CH:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][CH:8]=3)[CH2:3]2)[CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(=O)C2)cc1
Reactant: C1COCCN1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: CO
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(N3CCOCC3)C2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A mixture of ketone 267 (0.40 g, 1.53 mmol), dibutyltin dichloride (0.35 g) and morpholine (0.27 mL) in ethyleneglycol dimethylether (3.5 mL) was stirred at room temperature for 6 h, then cooled to 0° C. for the addition of neat phenyl silane (0.60 mL, 4.72 mmol). The reaction mixture was stirred at room temperature for 18 h then diluted with MeOH (3 mL) and H2O (0.5 mL), stirred for additional 4 h and concentrated. The residue was purified by flash chromatography (eluent: 5% MeOH in DCM) to provide title compound 268 (0.56 g, >100% yield, crude, used without additional purification).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8]1)=[O:6].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[CH3:3][O:4][C:5]([CH:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: COC(=O)C1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C1CCC(=O)N1Cc1ccccc1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a slurry of NaH (22 g of 60% NaH in mineral oil, 0.55 mol) in 400 mL benzene was added the product of Example 1A (0.387 mol) in 100 mL benzene dropwise via addition funnel. The mixture stirred for 30 minutes after the addition was complete, then was warmed to reflux and allowed to stir for 1.5 h. The reaction was cooled to 45° C. and stirred for 16 h. A portion of benzyl bromide (45 mL, 0.38 mol) was added, the mixture was warmed to reflux and an additional amount of benzyl bromide was added (45 mL, 0.38 mol). This solution stirred for 24 h at reflux, then was cooled to ambient temperature, filtered through Celite® diatomaceous earth and the residue was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and excess benzyl bromide was removed via distillation. The distillation residue was purified via column chromatography (SiO2, 75% hexanes-EtOAc) to give 46.6 g of the title compound (0.2 mol, 52% yield). MS (DCl/NH3) m/z 234 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[C:15]([CH3:21])([CH3:20])[CH2:14]1.CCN(C(C)C)C(C)C>C(O)(C)C>[OH:19][C@H:16]1[CH2:17][CH2:18][C@@H:13]([NH:12][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:14][C:15]1([CH3:21])[CH3:20]
Reactant: CC1(C)C[C@H](N)CC[C@@H]1O
Reactant: CSc1ncc(C#N)c(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@@H]2CC[C@H](O)C(C)(C)C2)n1
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (2.15 g, 11.6 mmol)), (1S,4R)-4-amino-2,2-dimethylcyclohexanol (1.51 g, 10.5 mmol) and DIEA (2.72 mg, 21.1 mmol) in isopropanol (30 mL) was heated at 100° C. for 3 h. After removal of the organic solvents under reduced pressure, the residue was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (15% ethyl acetate in petroleum) to afford the title compound, as a pale yellow solid (2.2 g, 7.53 mmol, 72% yield). MS (ESI) m/z 293.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([CH2:9][OH:10])=[CH:7][CH:6]=[CH:5][C:4]1=[O:11])[CH3:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>ClCCl>[CH2:1]([N:3]1[C:8]([CH2:9][O:10][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:7][CH:6]=[CH:5][C:4]1=[O:11])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1c(CO)cccc1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCn1c(COS(C)(=O)=O)cccc1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
1-Ethyl-6-(hydroxymethyl)-2-oxo-1,2-dihydropyridine (1.51 g, 9.86 mmol) obtained in Step 2 and triethylamine (2.06 mL, 14.8 mmol) were dissolved in dichloromethane (40 mL), and at 0° C., methanesulfonyl chloride (0.920 mL, 11.8 mmol) was added dropwise thereto, followed by stirring at 0° C. for 30 minutes. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure to afford 1-ethyl-6-(methanesulfonyloxymethyl)-2-oxo-1,2-dihydropyridine (2.29 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[CH:18]=[C:17](Cl)[N:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][C:9]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[CH:10][CH:11]=3)[N:6]=1.Cl.[F:30][C:31]1([F:36])[CH2:35][CH2:34][NH:33][CH2:32]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>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].C1COCC1>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[CH:18]=[C:17]([N:33]4[CH2:34][CH2:35][C:31]([F:36])([F:30])[CH2:32]4)[N:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][C:9]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[CH:10][CH:11]=3)[N:6]=1
Reactant: N#Cc1cccc(-c2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(Cl)ncc2O3)c1
Reactant: FC1(F)CCNC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(N4CCC(F)(F)C4)ncc2O3)c1
Temperature: 90 °C

Procedure:
To a mixture of (S)-3-(2′-amino-3-chloro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazole]-7-yl)benzonitrile (0.10 g, 0.257 mmol), 3,3-difluoropyrrolidine hydrochloride (0.111 g, 0.772 mmol), pd2(dba)3 (0.012 g, 0.013 mmol), and 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (0.015 g, 0.039 mmol) in a resealed tube was added THF (1 mL) and 1.0 M lithium bis(trimethylsilyl)amide (1.543 mL, 1.543 mmol). The resulting mixture was heated at 90° C. for 17 h. The mixture was cooled, concentrated and purified by reverse phase HPLC to afford (S)-3-(2′-amino-3-(3,3-difluoropyrolidin-1-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazole]-7-yl)benzonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[F:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]=1[NH:51][S:52]([CH3:55])(=[O:54])=[O:53].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[CH:41][C:36]([F:35])=[C:37]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:38]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:9]=2)[CH:12]=[N:13]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2ccc(F)c(NS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(F)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 26.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Step 1 example 71) (172 mg, 0.317 mmol) was coupled with N-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methanesulfonamide (Intermediate 65) (100 mg, 0.317 mmol) using sodium carbonate (101 mg, 0.952 mmol) and Pd(PPh3)2Cl2 (12 mg, 0.015 mmol) in DME/water (15/2 ml). This afforded 54 mg (26.2% yield). MS: m/z=652.0 (M+1).