Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH:10]2[N:22]([C:25](=[O:42])[CH:26]([NH:31][C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:24][CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.CO>C(Cl)Cl>[CH2:35]([O:34][C:32](=[O:33])[NH:31][CH:26]([C:25]([N:22]1[CH2:23][CH2:24][CH:9]2[NH:8][CH2:12][CH:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)[CH:10]12)=[O:42])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21
Temperature: 0 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
The Boc-containing compound 23 (1.0 g, 1.70 mmol) was dissolved in DCM (4 mL) and cooled to 0° C. before TFA (2 mL) was added and the reaction stirred at 0° C. for 1 h. TLC analysis (10:1 DCM/MeOH) indicated the starting material had all been consumed and the product had formed. The reaction mixture was concentrated at low pressure on the rotary evaporator. The crude residue was dissolved in DCM and washed successively with saturated aqueous NaHCO3 (3×), and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to afford 845 mg of 24 as a white foam. Mass spectrum, m/z [488.3] (M+H)+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[C:8]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:22][CH:21]=1)(=O)=O.[CH3:37][C:38]1[S:42][C:41](B(O)O)=[CH:40][CH:39]=1.[F-].[Cs+].C(=O)(O)[O-].[Na+].[ClH:53]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[ClH:53].[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:22][CH:21]=1)=[C:7]([C:41]1[S:42][C:38]([CH3:37])=[CH:39][CH:40]=1)[CH:16]=[CH:15]2
Reactant: Cc1ccc(B(O)O)s1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C)s3)ccc2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Suspend 6-methoxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-yl trifluoromethanesulfonate (398.8 g; 758.8 mmol), 5-Methyl-2-thiopheneboronic Acid (224 g; 1.58 mol), and cesium fluoride (300 g; 1.97 mol) in acetonitrile (12 L). Degas the resulting suspension via gas inlet tube for 30 minutes while heating to 50° C. Treat the mixture with tricyclohexylphosphine (8 g; 28.5 mmol) and degas for 10 minutes, then treat with palladium (II) acetate (4 g; 17.8 mmol), degas for an additional 5 minutes, and stir overnight at 80° C. Add tricyclohexylphosphine (8 g; 28.5 mmol) and palladium (II) acetate (4 g; 17.8 mmol) and heat the mixture for an additional 8 hours, then allow the solution to slowly cool overnight. Filter the cooled solution through a large glass frit and concentrate the filtrate. Slurry the residue and filter cake in water (4 L) and ethyl acetate (8 L), then transfer to a separatory funnel and treat with saturated aqueous sodium bicarbonate (300 g; 3.57 mol). Stir vigorously for 10 minutes, then separate the layers. Wash the organic layer with saturated aqueous sodium bicarbonate, brine, and dry over MgSO4 overnight. Filter the mixture, and treat the filtrate with HCl (4N in dioxane, 200 mL, 800 mmol). Stir the resulting slurry 60 minutes; then filter to obtain the title compound (352 g; 690.06 mmol). LRMS (m/z): 474 (M+1-HCl).
Reaction SMILES: [I:1]I.[C:3]([O:7][C:8](=[O:33])[NH:9][CH2:10][CH2:11][CH:12]1[N:17]2[CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=3)[CH:20]=[C:16]2[C:15](=[O:32])[NH:14][CH2:13]1)([CH3:6])([CH3:5])[CH3:4]>C(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[C:3]([O:7][C:8](=[O:33])[NH:9][CH2:10][CH2:11][CH:12]1[N:17]2[C:18]([I:1])=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:29])([F:30])[F:31])[CH:22]=3)[CH:20]=[C:16]2[C:15](=[O:32])[NH:14][CH2:13]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: II
Reactant: CC(C)(C)OC(=O)NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)cn21
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC1CNC(=O)c2cc(-c3cccc(OC(F)(F)F)c3)c(I)n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Iodine (450 mg 1.77 mmol) was added portion wise to a solution of tert-butyl(2-{1-oxo-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}ethyl)carbamate (780 mg 1.77 mmol) and silver trifluoroacetate (392 mg, 1.77 mmol) in dry DCM (100 ml), at 5° C. The reaction mixture was stirred at the same temperature for 1 hour, then the ice bath removed and left to warm to rt (1 h). The solid was filtered, the organic phase washed with Na2S2O5 (5% aq. solution) until decolouration occurred and finally washed with water. The organic was dried over Na2SO4 to obtain the title compound 1.0 g (99%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13].Cl[CH2:16][S:17]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18].CC(C)([O-])C.[K+].Cl>C1COCC1>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH2:16][S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:19])[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: O=S(=O)(CCl)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1OCCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cc(F)cc1OCCCl
Temperature: -78 °C
Yield: 88.3 %

Procedure:
A mixture of 2-(2-chloroethoxy)-4-fluoro-1-nitro-benzene (1.3 g, 6 mmoles) and 1-chloromethane-sulfonyl-naphthalene (2.16 g, 9 mmoles) in THF, under nitrogen, was stirred at −78° C., treated dropwise with a solution of 1M potassium t-butoxide (18 ml, 18 mmoles) over a 30 min. period, allowed to warm to −40° C., stirred at −40° C. for 5 hours, poured into cold 2N HCl and extracted with EtOAc. The extracts were combined, dried over Na2SO4, and concentrated under vacuum. The resultant residue was recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid (2.25 g, 5.3 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: C([O:3][C:4](=[O:24])[C@H:5]([OH:23])[CH2:6][C@H:7]([NH2:22])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)C.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Li+].[OH-]>CN(C=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([NH:22][C:31]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:32])[CH2:6][C@@H:5]([OH:23])[C:4]([OH:3])=[O:24])=[CH:10][CH:11]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C1CCCCO1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O)C1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
(2R,4R)-4-Amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (50 mg, 144 μmol) was added to a solution of tetrahydro-pyran-2-carboxylic acid (1.2 eq., 165 mmol) and HATU (71.1 mg, 187 mmol) in DMF (250 μL), followed by the addition of DIPEA (75 μL, 431 mmol). The resulting mixture was stirred at room temperature for 1 hour. 10 M aqueous LiOH (115 μL, 1.2 mmol) was added and the mixture was stirred for an additional 1 hour. The mixture was washed with DCM (1 mL) and the aqueous layer was acidified with concentrated HCl (250 μL) and extracted with DCM (2×1 mL). The DCM extracts were combined and concentrated in vacuo, and the resulting crude liquid was purified by reverse phase preparative HPLC to yield the title compound (32.6 mg). MS m/z [M+H]+ calc'd for C23H26ClNO5, 432.15; found 432.2.
Reaction SMILES: C1(CO[C:9]2[CH:10]=[CH:11][CH:12]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:13]3[C:17]=2[N:16]=[C:15]2[CH2:18]CC[CH2:21][C:14]=32)C=CC=CC=1.C([O:33][CH2:34][CH3:35])(=O)C>C(O)C.[Pd]>[CH2:22]([CH:12]1[C:13]2=[C:14]3[CH2:21][CH2:35][CH:34]([OH:33])[CH2:18][C:15]3=[N:16][C:17]2=[CH:9][CH:10]=[CH:11]1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCOC(C)=O
Reactant: CCCCCCCCC1C=CC(OCc2ccccc2)=C2N=C3CCCCC3=C21
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCC1C=CC=C2N=C3CC(O)CCC3=C21
Yield: 98.5 %

Procedure:
The hydrogenation of 1,2,3,4-tetrahydro-6-phenylmethoxy-9-octyl-9H-dibenzo[b,d]pyrrole from Example 63 was carried out at atmospheric pressure and at room temperature. Thus, 12.5 g of this material dissolved in 125 mL of absolute ethanol and 75 mL of ethyl acetate was hydrogenated in the presence of 0.6 g of 10% Palladium on carbon. The mixture was filtered on celite, the solvents evaporated in vacuo and the residue was chromatographed on silica gel to give 9.5 g (98.5%) of 1,2,3,4-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrol-3-ol as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:7]=1.[C:23]([CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])#[N:24].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([CH2:26][CH2:25][C:23]#[N:24])[CH:28]=4)[CH:3]=[CH:4][C:5]=3[CH3:22])[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: N#CCCc1cccc(C(=O)O)c1
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(N)ccc3C)nc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)c4cccc(CCC#N)c4)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of N-{5-[(5-amino-2-methylphenyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (120 mg, 382 μmol) produced in Example D35(v), 3-(2-cyanoethyl)benzoic acid (74 mg, 420 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (160 mg, 420 μmol) in pyridine (4 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=30/70→0/100), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran and ethyl acetate to give the title compound (117 mg, 65%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])OC4C=CC=CC=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[C:37](OCC)=[O:38].O1CCOCC1>CN(C)C1C=CN=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:37](=[O:38])[CH:32]5[CH2:33][CH2:34][CH2:35][CH2:36][N:31]5[C:22]4=[O:30])=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3)CC2)cc1
Reactant: CCOC(=O)C1CCCCN1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(c3ccc(N4C(=O)C5CCCCN5C4=O)cc3)CC2)cc1
Reaction time: 5 h
Yield: 47.5 %

Procedure:
A mixture of 50 parts of phenyl [4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]carbamate, 22.7 parts of ethyl 2-piperidinecarboxylate, 4 parts of N,N-dimethyl-4-pyridinamine and 300 parts of 1,4-dioxane was stirred for 5 hours at reflux temperature. After saturation with water, the reaction mixture was heated for 30 minutes. After cooling, the precipitated product was filtered off, washed with 2-propanol and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1-butanol. The product was filtered off and dried, yielding 24.8 parts (47.5%) of 5,6,7,8-tetrahydro-2-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]imidazo[1,5-a]pyridine-1,3(2H,8aH)-dione; mp. 223.4° C. (int. 17).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=O.Cl.[NH2:17][OH:18]>C(O)C.O>[Br:1][C:2]1[C:3]([S:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[N:17][OH:18]
Reactant: NO
Reactant: CC(C)(C)Sc1c(C=O)ccc(I)c1Br
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)Sc1c(C=NO)ccc(I)c1Br
Yield: 70 %

Procedure:
A mixture of 3-bromo-2-tert-butylsulfanyl-4-iodo-benzaldehyde (1.5 g, 3.8 mmol) and hydroxylamine hydrochloride in ethanol (20 mL) and water (4 mL) was heated to reflux for 2 h. The reaction mixture was cooled and concentrated. The residue was treated with water (40 mL) and then saturated aqueous sodium bicarbonate solution until the pH was ˜8.0. The mixture was extracted with ethyl acetate (2×40 mL). The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (25% ethyl acetate:hexanes) afforded 1.1 g (70%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.34 (s, 9H), 7.41 (d, J=8.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 8.47 (s, 1H), 8.51 (br. s, 1H); MS (ESI): 414, 416 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[OH:17].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>C(#N)C>[CH2:15]([C:13]1[CH:12]=[CH:11][C:10]([O:17][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[C:28]([F:29])([F:30])[F:31])=[C:9]([O:8][CH3:7])[CH:14]=1)[CH3:16]
Reactant: CCc1ccc(O)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1ccc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)c(OC)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a suspension of K2CO3 (2 mmol; 276 mg) in anhydrous acetonitrile (1 mL) under argon, was added 2-methoxy-4-ethylphenol (0.285 mL; 2 mmol) followed by 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (418 mg; 2 mmol). The reaction mixture was stirred at 80° C. overnight. Concentrated under argon, washed with NaOH (0.1N; 3 mL), the mixture was extracted with ethyl acetate (2*3 mL). Combined organic phases were dried over MgSO4, concentrated in vacuo, to give the title product as a light brown oil (651 mg; 95%), used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([OH:3])=O.S(Cl)(Cl)=O.Cl.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C=O)C.O1CCCC1>[F:25][C:21]1[CH:20]=[C:19]([N:18]([CH3:17])[C:1](=[O:3])[C:4]2[CH:11]=[CH:10][CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CNc1cccc(F)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1cccc(C=O)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-carboxybenzaldehyde (Fluka; 12.01 g, 80 mmol) was slurried in 80 mL of dry toluene and thionyl chloride (7 mL, 96 mmol) and 5 drops of DMF. A reflux condenser with a calcium sulfate drying tube attached was placed on the flask. The mixture was refluxed for 1 hour after the solution went clear, and then allowed to cool. The volatiles were removed on the rotovap. The residue was pumped on briefly on a vacuum pump. The crude acid chloride was then dissolved in 150 mL of dry tetrahydrofuran, and cooled in an ice/water bath. N-methyl-3-fluoroaniline hydrochloride (13.05 g, 80.8 mmol) was added. Triethylamine (35 mL, 250 mmol) in 50 mL of dry tetrahydrofuran was then added dropwise via an addition funnel. The cloudy solution was allowed to warm to room temperature over 1 hour, and allowed to stir overnight. To remove the copious amount of precipitate, 100 mL of diethyl ether was added and the reaction mixture was filtered. After rinsing the salts with more ether, the solvents were removed under reduced pressure. The residue was extracted with ethyl acetate, washed with 1N HCl twice, then with water, sodium carbonate solution, and saturated NaCl solution. The organic layer was dried over sodium sulfate/magnesium sulfate, and the solvent removed by evaporation at reduced pressure. Crude N-(3-fluorophenyl)-3-formyl-N-methylbenzamide as a light golden oil was obtained, 19.92 g (96% unchromatographed yield) [NMR (300 MHz, DMSO-d6): δ 3.38 (s, 3H); 6.94-7.02 (m, 2H); 7.18-7.29 (m, 2H); 7.46 (t, J=7.7 Hz, 1H) 7.55 (d, J=7.6 Hz, 1H); 7.81 (m, 2H); 9.90 (s, 1H)].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:34][C:35]1[CH:47]=[CH:46][C:38]([C:39]([NH:41][CH:42]2[CH2:45][O:44][CH2:43]2)=[O:40])=[CH:37][C:36]=1[O:48][CH3:49].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:30]1([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]([C:15](=[O:16])[NH:17][CH3:18])=[CH:13][CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:34][C:35]3[CH:47]=[CH:46][C:38]([C:39]([NH:41][CH:42]4[CH2:43][O:44][CH2:45]4)=[O:40])=[CH:37][C:36]=3[O:48][CH3:49])[N:3]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCC4)c23)cc1
Reactant: COc1cc(C(=O)NC2COC2)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Nc4ccc(C(=O)NC5COC5)cc4OC)nc(OC4CCC4)c23)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a degassed mixture of 4-(2-chloro-4-cyclobutoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), 4-amino-3-methoxy-N-(oxetan-3-yl)benzamide (1.1 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.09 M) was added palladium acetate (0.1 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.3 equiv). The reaction was stirred at 100° C. for 2 h. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel chromatography (0-5% DCM in MeOH) to afford the title compound (crude) as a yellow solid which was used in the next step without further purification. MS (ESI) m/z 673.1 [M+1]+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.COC(C)(C)C.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>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[CH3:7])=[CH:12][CH:11]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1ccsc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: COc1ccc(-c2sccc2C)cc1
Temperature: 25 °C

Procedure:
2-Bromo-3-methyl-thiophene (0.53 g, 3.00 mmol) was dissolved in 1,4-dioxane (35 ml) under an argon atmosphere. To this solution were added Pd(PPh3)4 (0.33 g, 0.28 mmol), 4-methoxyphenyl boronic acid (0.50 g, 3.30 mmol) and 2 M Na2CO3 (6 ml). The resultant mixture was stirred at 100° C. for 2 hours. The reaction was cooled to rt diluted with tert.butyl methyl ether and poured into water and extracted with tert.butyl methyl ether (2×). The combined organic extracts were washed with water, brine, dried (MgSO4.2H2O), filtered and concentrated under reduced pressure to yield a yellow oil that was purified over silica gel (n-heptane) to yield an oil: 0.32 g (48%), GC-MS: M=204.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:2]2[S:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:4][C:3]=2[CH:6]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cc(C(F)(F)F)ccc2s1

Procedure:
Using 4.28 g (22.3 mmol) of 2-fluoro-5-trifluoromethylbenzaldehyde, 1.34 g (33.4 mmol) of sodium hydride (60% pure) and 2.6 g (24.5 mmol) of methyl mercaptoacetate, 4.93 g (80.0% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].S(Cl)(Cl)=O.C[N:20](C=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([NH2:20])=[O:9]
Reactant: CN(C)C=O
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccc([N+](=O)[O-])c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 5-methoxy-2-nitrobenzoic acid (7.5 g, 38.0 mmol) in anhydrous benzene (50 mL), was added thionyl chloride (3.8 mL, 52.05 mmol) followed by the addition of anhydrous DMF (0.4 mL). The resulting reaction mixture was refluxed for 5 h, upon which the volatiles were removed in vacuo. The residue was dissolved in anhydrous THF (60 mL) and added to an ice-cold saturated solution of ammonia in THF (60 mL). The resulting heterogeneous reaction mixture was allowed to warm room temperature and stirring was continued at RT for 48 h. The s volatiles were removed in vacuo and the residue was used without further purification for next step. HPLC retention time 3.29 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([OH:26])[CH2:14][O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[NH:22]C(=O)C)[CH2:8]2)=[CH:4][CH:3]=1.[ClH:29].CO>C(OCC)C>[ClH:1].[ClH:29].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][CH:13]([OH:26])[CH2:12][N:9]1[CH2:10][CH2:11][CH:7]([O:6][C:5]2[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:8]1
Reactant: CC(=O)Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)cc2)C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Nc1ccccc1OCC(O)CN1CCC(Oc2ccc(Cl)cc2)C1
Temperature: 102.5 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A mixture of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)acetamide (0.95 g, 2.34 mmol) and concentrated hydrochloric acid (25 mL) was heated (100-105° C.) for 3 hours then allowed to stand at room temperature overnight. The mixture was concentrated at reduced pressure to a third of its volume basified with saturated sodium hydrogen carbonate. The resulting suspension was extracted twice with ethyl acetate. The organic extracts were dried, the solvent was evaporated at reduced pressure to give a pale brown oil. This oil was dissolved in a to minimum amount of methanol, diluted with ethyl ether and the product precipitated by addition of HCl-saturated ethyl ether. The product was filtered to afford the subtitle product (0.93 g, 91.2%).