Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][CH2:2][CH2:3][OH:4].Cl[C:6]([O:8][CH2:9][CH3:10])=[O:7].N1C=CC=CC=1>C1C=CC=CC=1>[C:6](=[O:7])([O:8][CH2:9][CH3:10])[O:4][CH2:3][CH2:2][I:1]
Reactant: OCCI
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)OCCI
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a well-stirred solution consisting of 34.40 g. (0.20 mole) of 2-iodoethanol dissolved in 25 ml. of benzene precooled to 0° C. with the aid of an ice/water bath, there is added in a dropwise manner a solution consisting of 19.1 ml. (0.20 mole) of ethyl chloroformate dissolved in 25 ml. of benzene. Upon completion of this step, the reaction mixture is treated with 19.1 ml. (0.20 mole) of pyridine which is also added in a dropwise manner. The resulting suspension is then stirred for a period of one hour at 0° C. (while under a nitrogen atmosphere) and for six hours at room temperature (~20° C.). At the end of this time, the pyridine hydriodide is removed by filtration and the organic filtrate is washed twice with 50 ml. of 3N hydrochloric acid and once with 50 ml. of brine, followed by drying over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there is obtained 2-iodoethyl ethyl carbonate as the residual material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][C:3]=1[NH2:18].N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][C:3]=1[NH:18][S:26]([CH3:25])(=[O:28])=[O:27]
Reactant: COc1cncc(C#Cc2ccc(F)c(N)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cncc(C#Cc2ccc(F)c(NS(C)(=O)=O)c2)c1
Temperature: 0 °C
Reaction time: 14 h
Yield: 57.4 %

Procedure:
Dissolve 2-fluoro-5-(5-methoxypyridin-3-ylethynyl)-phenylamine, (prepared as described in EXAMPLE 111), (330 mg, 1.36 mmol) in dichloromethane (10 mL) under nitrogen and cool to 0° C. Add pyridine (0.240 ml, 2.99 mmol) followed by methanesulfonyl chloride (0.106 mL, 1.36 mmol) dropwise via syringe. Stir 14 h while allowing to warn to room temperature. Concentrate and purify by silica gel chromatography, eluting with 80:20 ethyl acetate:hexanes to 100% ethyl acetate, to give the title compound as a white solid (250 mg, 57%).
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[CH3:33][N:34]([CH3:39])[S:35](Cl)(=[O:37])=[O:36]>>[CH3:33][N:34]([CH3:39])[S:35]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH2:4][CH:3]([F:2])[F:32])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)(=[O:37])=[O:36]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)N(C)C)CC2)n3CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and dimethylsulfamoyl chloride. Light-yellow solid. MS (m/z): 542.3 (M+H)+.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)=[C:2]=[O:3].Cl.[NH2:10][C:11]1[N:16]=[C:15]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]([C:27]([O:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[C:13]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[N:12]=1>>[NH2:10][C:11]1[N:16]=[C:15]([C:17]2[CH:26]=[C:25]3[C:20]([CH2:21][CH2:22][N:23]([C:27]([O:29][CH:30]4[CH2:35][CH2:34][N:33]([C:2]([NH:1][CH:4]5[CH2:8][CH2:7][CH2:6][CH2:5]5)=[O:3])[CH2:32][CH2:31]4)=[O:28])[CH2:24]3)=[CH:19][CH:18]=2)[CH:14]=[C:13]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[N:12]=1
Reactant: O=C=NC1CCCC1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCNCC3)CC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)OC3CCN(C(=O)NC5CCCC5)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 67, Step 4 starting from isocyanatocyclopentane and piperidin-4-yl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate HCl salt. Analytic LCMS (M+H)+: m/z=563.3.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]=2[S:14][C:13]=1[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[OH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:20]2[C:19](=[O:21])[N:18]([CH3:22])[C:17](=[O:23])[N:16]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]=2[S:14][C:13]=1[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(OCCCOC3CCCCO3)c(Cc3cccnc3)sc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(OCCCO)c(Cc3cccnc3)sc21
Reaction time: 5 h
Yield: 21.5 %

Procedure:
5-{3-[(tetrahydro-2H-pyran-2-yl)oxy]propoxy}-3-methyl-1-(2-methylpropyl)-6-[(3-pyridinyl)methyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (230 mg) was dissolved in methanol (3 ml). Toluenesulfonic acid (190 mg) was added and the mixture was stirred for 5 h. The methanol was evaporated, sodium bicarbonate (aqueous) and ethyl acetate were added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate, the ethyl acetate layers were combined, washed with brine, dried, filtered and evaporated. The residue was purified by chromatography (ethyl acetate) and HPLC (dichloromethane:ethanol 100-90:0-10) then dissolved in aqueous ethanol and precipitated by addition of water to give the title compound (41 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Ce+3].C(=O)([O-])[O-].C(=O)([O-])[O-].[Ce+3]>O1CCOCC1.[Cu](I)I>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Fc1ccccc1S
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Ce+3]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Sc3ccccc3F)cn2)CC1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5.0 g, 14.6 mmol), 2-fluorobenzenethiol (9.3 g, 73 mmol), 1,10-Phenanthroline (7.9 g, 43.8 mmol), copper iodide (13.9 g, 73 mmol) and cerium carbonate (28.6 g, 87.6 mmol) in dioxane (100 mL) was refluxed for 3 days. The reaction mixture was cooled to RT and concentrated. The residue was directly purified by silica gel chromatography to give the title compound. MS (ES+) C19H23FN4O2S requires: 390. found: 391 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.CCCCNC(N(CCCC)CCCC)=S.C(N(C(C)C)C(C)C)C>O1CCCC1.O>[CH3:11][C:4]1[CH:3]=[C:2]([Br:1])[CH:10]=[CH:9][C:5]=1[C:6]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:8]
Reactant: C1CCNC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: CCCCNC(=S)N(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 2a from 4-bromo-2-methylbenzoic acid, pyrrolidine, tBtU and N-ethyl-diisopropylamine in tetrahydrofuran/water 9:1
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([CH2:15][C:16]#[N:17])[CH2:6][C:5]2=1.N>C(O)C.[Rh]>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([CH2:15][CH2:16][NH2:17])[CH2:6][C:5]2=1
Reactant: N#CCC1CCc2[nH]c3ccc(F)cc3c2C1
Agent: [Rh]
Agent: N
Solvent: CCO
Product: NCCC1CCc2[nH]c3ccc(F)cc3c2C1
Reaction time: 24 h

Procedure:
To a solution of (6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)acetonitrile (0.423 g, 1.857 mmol) in ethanol (55 mL) kept under nitrogen was added concentrated aqueous ammonia (38 mL) followed by 5% rhodium on alumina catalyst (40% by weight). The mixture was hydrogenated at room temperature and 50 psi for 24 hours. Following TLC, additional catalyst (1.130 g) was added and the hydrogenation was resumed. After 6 hours the catalyst was filtered off over Celite, the cake washed with ethanol and the filtrate evaporated to dryness at reduced pressure. The residue was treated with a small amount of ethanol and evaporated. The procedure was performed three times. The residual oil was purified by flash chromatography on silica gel Merck-60 using a gradient from 2:248 to 10:90 of ammonia saturated methanol in dichloromethane. The desired title compound was obtained as a pale yellow foam (0.405 g). MS (ES): [M−H]− @231.1.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:17]Br>C(O)(=O)C>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([Br:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CCN(C(C)=O)CC2
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc2c(cc1Br)CCN(C(C)=O)CC2

Procedure:
A solution of 3-acetyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (2.3 g, 0.01 m) in acetic acid (20 ml) was treated with a solution of bromine (1.8 g, 0.011 m) in acetic acid (10 ml). The mixture was warmed to 70° for 1.5 hours, concentrated in vacuo and partitioned between water and ethyl acetate. The ethyl acetate phase was washed, dried with sodium sulfate and concentrated in vacuo to give 3-acetyl-8-bromo-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine. NMR (CDCl3) 6.7, 7.3; aryl protons.
Reaction SMILES: [CH2:1]([C:6]1([CH:13]=[O:14])[CH2:11][CH:10]2[CH2:12][CH:7]1[CH:8]=[CH:9]2)[CH2:2][CH2:3][CH2:4][CH3:5].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([CH:6]1[CH2:11][CH:10]2[CH2:9][CH:8]([CH:7]=[CH:12]2)[C:13]1=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1(C=O)CC2C=CC1C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCC1CC2C=CC(C2)C1=O
Temperature: 0 °C
Yield: 46.1 %

Procedure:
2-Pentylbicyclo[2.2.1]hept-5-ene-2-carbaldehyde (217 g, synthesized as above) was loaded into a 2-L round bottom flask fitted with an overheard stirrer and a condenser, followed by CH2Cl2 (1 L). The resulting mixture was cooled to 0° C. using a dry ice bath. AlCl3 (153 g) was then added in one portion. After GC analysis showed the completion of the reaction, the reaction mixture was poured onto ice, and the organic layers were separated and washed once with sodium hydroxide solution (10%). The solvent (CH2Cl2) was then removed under reduced pressure, and the resulting crude product was purified by distillation to yield 3-pentylbicyclo[3.2.1]oct-6-en-2-one (100 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12](C4CN(C(OC(C)(C)C)=O)C4)[C:11]=3[C:10](=[O:28])[N:9]2[C:29]2[CH:30]=[C:31]([CH3:39])[C:32]3[N:33]([C:35]([CH3:38])=[N:36][N:37]=3)[CH:34]=2)=[CH:4][CH:3]=1.CO.ClC1C=CC(C2C3C(C4CC4)=NNC=3C(=O)N2C2C=C(C)C3N(C(C)=NN=3)C=2)=CC=1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:15]3[C:14]([CH3:16])=[N:13][NH:12][C:11]=3[C:10](=[O:28])[N:9]2[C:29]2[CH:30]=[C:31]([CH3:39])[C:32]3[N:33]([C:35]([CH3:38])=[N:36][N:37]=3)[CH:34]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Agent: Cc1cc(N2C(=O)c3[nH]nc(C4CC4)c3C2c2ccc(Cl)cc2)cn2c(C)nnc12
Solvent: CCOCC
Solvent: CO
Product: Cc1n[nH]c2c1[C@@H](c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O

Procedure:
The title compound (133 mg, 44% yield) was obtained enantiomerically pure (>99% ee) after chiral preparative SFC (system: Thar SFC200; column: Chiralpak OD-H, 30×250 mm; mobile phase: scCO2/MeOH 70:30; flow: 120 g/min; detection UV: 265 nm) of the racemic mixture of 4-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 129) and subsequent trituration in diethyl ether.
Reaction SMILES: C(O)C.[CH:4]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])OCC.[CH3:14][C:15]([CH3:19])=[CH:16]C=O.C(=O)([O-])[O-].[K+].[K+]>S([O-])(O)(=O)=O.[K+]>[CH2:12]([O:11][CH:4]([O:8][CH2:9][CH3:10])[CH:14]=[C:15]([CH3:19])[CH3:16])[CH3:13]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)=CC=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Product: CCOC(C=C(C)C)OCC
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
Under an argon atmosphere, a 250-mL, round-bottomed flask equipped with a stir bar was charged with abs. ethanol (52 mL, 892 mmol, 5.0 eq). The flask was cooled to 4° C. (internal) in an ice bath. Triethyl orthoformate (29.7 mL, 178 mmol, 1.0 eq) was added followed by 3-methyl-2-butenal (17.2 mL, 178 mmol, 1.0 eq). The resulting clear, colorless solution was further cooled to 2° C. (internal). Potassium hydrogen sulfate (1.277 g, 9.38 mmol, 0.05 eq) was then added in one portion, resulting in an immediate exotherm to 10° C. The heterogeneous mixture was allowed to warm to 21° C. (internal) over 45 minutes (within 20 minutes, the mixture became slightly cloudy) and then stirred for an additional 15 minutes. The reaction mixture was then filtered and the remaining solid rinsed with abs. ethanol (5 mL). To the resulting clear, colorless solution was added anhydrous potassium carbonate (2.615 g, 18.92 mmol). The mixture was stirred for one hour before filtering off the potassium carbonate. The solid was rinsed with abs. ethanol (5 mL) and the filtrate was vacuum distilled (172 mm Hg) through a Vigereux column (13.5 cm) to produce 24.14 g (85% yield) of the title compound (boiling point 115°-119° C.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:15]3([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:11]=2[N+:12]([O-])=O)[CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[NH2:12][C:11]1[CH:10]=[CH:9][C:8]([C:15]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(c2ccc([N+](=O)[O-])c(OCC3CC3)c2)CCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C1(c2ccc(N)c(OCC3CC3)c2)CCC1
Reaction time: 6 h
Yield: 94.6 %

Procedure:
To a stirred solution of ethyl 1-(3-(cyclopropylmethoxy)-4-nitrophenyl)cyclobutanecarboxylate (2.8 g), in dry MeOH (100 mL), Pd(OH)2 (1.2 g) was added and the reaction mixture was reduced under an atmosphere of H2 for 6 h at room temperature. The reaction mixture was filtered through a pad of Celite™ washing with MeOH. The combined filtrates were concentrated under reduced pressure to yield ethyl 1-(4-amino-3-(cyclopropylmethoxy)phenyl)cyclobutanecarboxylate (2.4 g) as a thick liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([C:21]4[N:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][N:22]=4)[CH:17]=[N:18][C:19]=3F)=[CH:10][CH:9]=2)[C@H:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[O:36]1CCOCC1.Cl>O>[CH3:1][C:2]1([CH3:35])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19](=[O:36])[NH:18][CH:17]=[C:16]([C:21]4[N:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][N:22]=4)[CH:15]=3)=[CH:10][CH:9]=2)[C@H:3]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1(C)OC(=O)N(c2ccc(-c3cc(-c4nccc(C#N)n4)cnc3F)cc2)[C@H]1c1ccccc1
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: CC1(C)OC(=O)N(c2ccc(-c3cc(-c4nccc(C#N)n4)c[nH]c3=O)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A resealable tube was charged with (S)-2-(5-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)phenyl)-6-fluoropyridin-3-yl)pyrimidine-4-carbonitrile (0.055 g, 0.12 mmol), dioxane (3.0 mL) and water (1.00 mL). Concentrated hydrochloric acid (37%)(0.25 mL) was added, the system was flushed with argon, the tube was sealed, and the reaction mixture stirred at 100° C. for 1 hour. The reaction mixture was then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford (S)-2-(5-(4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)phenyl)-6-oxo-1,6-dihydropyridin-3-yl)pyrimidine-4-carbonitrile (0.044 g, 0.095 mmol, 80% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (s, 3H), 1.65 (s, 3H), 5.49 (s, 1H), 7.22-7.45 (m, 5H), 7.50-7.61 (m, 2H), 7.63-7.76 (m, 2H), 7.93 (d, J=4.89 Hz, 1H), 8.28-8.47 (m, 2H), 9.11 (d, J=4.99 Hz, 1H), 12.33 (br.s., 1H). m/z (ESI) 464 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1>CN(C=O)C>[CH2:1]([NH:8][C:9](=[O:12])[CH2:10][NH:27][C:26]1[CH:28]=[CH:29][C:23]([F:22])=[CH:24][C:25]=1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)NCc1ccccc1
Reactant: Cc1cc(F)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1NCC(=O)NCc1ccccc1
Temperature: 100 °C
Reaction time: 40 h

Procedure:
A mixture of N-benzyl-2-chloroacetamide (17.8 g), DIPEA (19.5 mL) and 4-fluoro-2-methyl-aniline (10.6 mL) in anhydrous DMF (174 mL) was stirred at 100° C. for 40 hours under a Nitrogen atmosphere. After cooling to r.t., the dark solution was partitioned between AcOEt (200 mL) and water (200 mL). The separated aqueous phase was extracted with further AcOEt (3×200 mL). The combined organic extracts were washed with water (200 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography (CH/AcOEt 2:8) to give a dark solid, which was triturated with CH to give the title compound as a beige solid (16.2 g).
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17]>C(#N)C>[CH2:20]([O:19][C:15]([NH:16][NH:17][C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1)=[O:18])[CH3:21]
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1Cl
Reactant: CCOC(=O)NN
Solvent: CC#N
Product: CCOC(=O)NNc1nc2cc(Cl)c(Cl)cc2[nH]c1=O
Temperature: 24 °C
Yield: 85 %

Procedure:
To a solution of 0.58 g (~2.3 mmol) 2,6,7-trichloroquinoxalin-3(4H)-one in 25 ml of acetonitrile was added 0.27 g (~2.6 mmol) of ethyl carbazate. The reaction mixture was refluxed for 3 h. Cooling to 24° C. gave the title compound (0.62 g; 84%) as a precipitate. M.p. >300° C. decomp.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:18]([O:22][C:23]([C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:26](O)=[O:27])=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:18]([O:22][C:23]([C@@H:25]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:27])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1cc(N)cc(-c2ccncc2)c1
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)[C@H](Cc2ccccc2)C(=O)OC(C)(C)C)cc(-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
To a solution of methyl 3-amino-5-(pyridin-4-yl)benzoate 45.1.C (4.70 g, 20.6 mmol) in DMF (50 mL) was added (S)-2-(tert-butoxycarbonyl)-3-phenylpropanoic acid (6.56 g, 24.7 mmol, available from Aldrich), diisopropylethylamine (5.40 mL, 30.9 mmol) and 2-(1H-Benzotriazole-1-yl)-1,1,3,3-Tetramethyluronium hexafluorophosphate (9.36 g, 24.7 mmol). The resulting mixture is stirred overnight at room temperature. The mixture was then partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with additional EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-100% EtOAc/hexane) to afford (S)-methyl 3-(2-(tert-butoxycarbonyl)-3-phenylpropanamido)-5-(pyridin-4-yl)benzoate 45.1.D (3.00 g, 31% yield).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O=P(Cl)(Cl)Cl>[C:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)#[N:16]
Reactant: NC(=O)C1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Step 1): A solution of 1-diphenylmethylpiperidine-4-carboxamide (14.79 g, 50 mmol) in POCl3 (300 ml) was refluxed for 3.5 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved into the mixture of sat. NaHCO3 aq. solution and AcOEt. After separation, the aqueous layer was extracted with AcOEt. The combined organic layer was washed with H2O and brine, dried over MgSO4 and then concentrated. The residue was recrystallized from iso-PrOH to give 4-cyano-1-diphenylmethylpiperidine, 12.36 g (89%): mp 219°-230° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]([C:18]2[CH:19]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][CH:23]=2)=[CH2:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[C:3]([CH:16]([C:18]2[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=2)[C:24]([O:26][CH3:27])=[O:25])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: C=C(c1cccc(C(=O)OC)c1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C(C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1

Procedure:
A solution of methyl 3-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)vinyl]phenylcarboxylate (2.5 g, 6.9 mmol) in ethyl acetate, in the presence of palladium-on-charcoal (700 mg) at a pressure of 6 bar of hydrogen, is stirred at room temperature for 4 h. The mixture is filtered through Celite and then concentrated on a rotary evaporator under vacuum at 40° C.
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[NH:8][C:9]([NH2:18])=[C:10]2[C:14]([N:15]=1)=[N:13][C:12]([O:16][CH3:17])=[N:11]2)[CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>CN(C=O)C>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][N:13]1[C:12]([O:16][CH3:17])=[N:11][C:10]2[C:14]1=[N:15][C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])=[N:8][C:9]=2[NH2:18]
Reactant: ClCCCCBr
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine (1 g, 2.74 mmol) and potassium carbonate (0.946 g, 6.84 mmol) in DMF (12.5 ml) were stirred under nitrogen and heated to 50° C. for 1 hour. The mixture was then allowed to cool to ambient temperature and 1-bromo-4-chlorobutane (0.315 ml, 2.74 mmol) was added and stirring was continued under nitrogen at ambient temperature overnight. The mixture was then partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate and the combined organic extracts were washed with saturated brine and passed through a hydrophobic frit and evaporated in vacuo. The residue (1.0322 g) was dissolved in dichloromethane and loaded onto an amino cartridge (70 g) and eluted using a 0-100% ethyl acetate in cyclohexane gradient over 40 minutes. Product fractions were combined and evaporated to give the title compound as an off-white solid (667 mg).