Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f15) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8](C)(C)[C:9]([O:11]CC)=O)=O)=[CH:4][CH:3]=1.[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:18]1([N:24]2[C:9](=[O:11])[CH2:8][C:6]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:17][CH:16]=3)=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccc(C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C2=NN(c3ccccc3)C(=O)C2)cc1
Yield: 93.6 %

Procedure:
A mixture of 15 g (64 mmol) of ethyl α-(4-methylbenzoyl)isobutyrate, 10 g (93 mmol) of phenyl-hydrazine and 100 ml of toluene was dehydrated under reflux in the presence of p-toluenesulfonic acid monohydrate (catalytic amount) for 18 hours. The reaction solution was washed successively with 1N sodium hydroxide, 1N hydrochloric acid and saturated brine solution, and dried over anhydrous magnesium sulfate. Then the solvent was evaporated under reduced pressure. The obtained crude product was recrystallized from methanol to give 15 g of the object compound as white crystals (yield 84%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>Cl.CCO>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COc1ccccc1OC(c1ccccc1)C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1OC(c1ccccc1)C1CCNC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-[(2-Methoxyphenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester was dissolved in a solution of HCl in EtOH (1.25M, 8 mL) and stirred at room temperature for 18 hours, and then evaporated to dryness. The residue was purified by reverse phase preparative HPLC to afford the TFA salt of the RS/SR mixture of enantiomers of the title compound as a TFA salt (90 mg, 95% purity). MS m/z: [M+H]+ calcd for C18H21NO2, 284.16. found 284.4. 1H NMR (CD3OD, 400 MHz) δ (ppm): 7.40-7.35 (m, 4H), 7.32-7.28 (m, 1H), 7.00-6.98 (m, 1H), 6.92-6.88 (m, 1H), 6.71-6.65 (m, 2H), 5.32 (d, J=5.2, 1H), 3.90 (s, 3H), 3.62-3.55 (m, 1H), 3.36-3.30 (obscure, 3H, overlap with solvent), 2.97-2.92 (m, 1H), 2.28-2.21 (m, 1H), 2.13-2.07 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][C:21]3[N:25]5[N:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]5=[N:23][N:22]=3)=[CH:15][CH:14]=4)[CH:7]=[N:6]2)[CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl.O>[CH3:30][C:27]1[CH:28]=[CH:29][C:24]2[N:25]([C:21]([CH2:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[N:12]=[CH:11][C:10]([C:8]3[CH:7]=[N:6][N:5]([CH:3]5[CH2:4][N:1]([C:38](=[O:40])[CH3:39])[CH2:2]5)[CH:9]=3)=[CH:19]4)=[N:22][N:23]=2)[N:26]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(C6CNC6)c5)cc4c3)n2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CC(n2cc(-c3cnc4ccc(Cc5nnc6ccc(C)nn56)cc4c3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
To 3-(1-azetidin-3-yl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (25 mg, 0.063 mmol) in dichloromethane (1 mL) was added triethylamine (9.7 uL, 0.069 mmol) followed by acetyl chloride (5.0 uL, 0.069 mmol). The mixture was stirred at room temperature overnight. The reaction was diluted with water and the product extracted into dichloromethane. The reaction was diluted with water and extracted into dichloromethane and washed with water. The filtrate was concentrated in vacuo onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-90:10) to return the title compound (4.20 mg, 15% yield). Analytical data presented in Table 2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH:22]([F:32])[C:23]1[N:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[N:24][C:23]([CH:22]([F:32])[F:21])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(NC(=O)c3cnc(C(F)F)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(difluoromethyl)pyrazine-2-carboxylic acid [J. M. Ellard et al. WO2011009898 (2011)] following General Procedure F yielded the title compound as a colorless solid. MS: m/z=448.5 [M+H]+.
Reaction SMILES: [C:1]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)(=[O:3])[CH3:2].[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14].[BH4-].[Na+]>C(O)C.O>[OH:3][CH:1]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:2].[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14]
Reactant: CC(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(O)[c-]1cccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
A solution of 46.2 g (0.2 mol) of acetylferrocene in 200 ml of ethanol was added dropwise, at room temperature, to a solution of 30.4 g (0.8 mol) of sodium borohydride in 200 ml of water. The reaction mixture was stirred overnight at room temperature poured into water and the solid material which was obtained was filtered off. The product was washed and dried. 40 g of 1-hydroxyethylferrocene of melting point 69° C. were obtained in this manner.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:5]=1[O:6][CH2:7]C(O)=O)(=O)[CH3:2].C(OC(=O)C)(=O)C.C(O)(=O)C>O>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:5]2[O:6][CH:7]=[C:1]([CH3:2])[C:4]=2[CH:14]=1
Reactant: COc1ccc(OCC(=O)O)c(C(C)=O)c1
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2occ(C)c2c1
Temperature: 110 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
A mixture of (2-acetyl-4-methoxyphenoxy)acetic acid (10.0 g) synthesized above, acetic anhydride (18.3 g) and acetic acid (100 mL) was stirred at 110° C. for 5 hr, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to give the title object compound (5.87 g, 81%) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:23])[C:9]1[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][C:10]=1[O:21][CH3:22].[C:24]1(=O)[CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:1][CH:2]2[CH2:6][CH2:5][CH2:4][CH:3]2[NH:7][C:8](=[O:23])[C:9]2[C:14]([S:15][CH3:16])=[CH:13][C:12]([C:17]([F:19])([F:20])[F:18])=[CH:11][C:10]=2[O:21][CH3:22])[CH2:27][CH2:26][CH2:25]1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N
Reactant: O=C1CCC1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1NC1CCC1

Procedure:
The title compound, white solid, MS: m/e=403.4 [(M+H)+], was prepared in accordance with the general method of example 11 from N-((1RS,2SR)-2-amino-cyclopentyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate O) and cyclobutanone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([OH:22])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22][CH3:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(O)nc3N21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 0.5 h

Procedure:
To a solution of 0.25 g (0.82 mmol) (4R,9aR)-6-hydroxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 2 mL N,N-dimethylformamide, 40 mg (0.90 mmol) sodium hydride (55–65% dispersion in oil) was added. After 30 min., 0.10 mL (0.23 g, 1.64 mmol) methyl iodide was added. After 1 h the reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water, then brine and were dried over magnesium sulfate. After filtration and evaporation of the solvent the product was purified by column chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:5) as eluant.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15]CC2C=CC=CC=2)=[O:14])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:23][CH:24]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)COc1ccc(C(=O)O)cc1
Reaction time: 6 h
Yield: 98.8 %

Procedure:
A 500 mL high-pressure flask was charged with benzyl 4-(2-tert-butoxy-2-oxoethoxy)benzoate (2.06 g, 6.02 mmol) in methanol (100 ml). Palladium on carbon (0.320 g, 0.301 mmol) was added, the resulting suspension was allowed to shake under an atmosphere of hydrogen (47 Psi) at room temperature for 6 h. The mixture was filtered through Celite®), the colorless filtrate was concentrated to afford 4-(2-tert-butoxy-2-oxoethoxy)benzoic acid (1.5 g, 5.95 mmol, 99% yield) as pale yellow solid. LC/MS (Table 1, Method a) Rt=3.03 min.; MS m/z: 251.30 (M−H)−. 1H NMR (400 MHz, Solvent d-DMSO) ppm 7.88 (d, J=8.99 Hz, 2H), 6.98 (d, J=9.00 Hz, 2H), 4.75 (s, 2H), 1.43 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18](O)=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.C1N=C[N:28](C(N2C=NC=C2)=O)C=1.[NH4+].[Cl-].O>CS(C)=O>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:28])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cccc2c(NCc3cccc(C(F)(F)F)c3)ncnc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cccc2c(NCc3cccc(C(F)(F)F)c3)ncnc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 4-{[3-(trifluoromethyl)benzyl]amino}quinazoline-8-carboxylic acid (68 mg, 0.19 mmol) in 2 mL of anhydrous DMSO, CDI (47 mg, 0.29 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at 50° C. for 3 h. After cooling down to rt, NH4Cl (22 mg, 0.29 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was poured into water. The white precipitate was collected as the desired product by filtration, followed by washed with water in 92% yield. 1HNMR (In DMSO): 4.90 (d, J=5.9 Hz, 2H), 7.56-7.69 (m, 4H), 7.74 (s, 1H), 7.86 (d, J=3.7 Hz, 1H), 8.51 (dd, J=1.5 and 8.0 Hz, 1H), 8.58 (dd, J=1.5 and 7.7 Hz, 1H), 8.59 (s, 1H), 9.24 (t, J=5.9 Hz, 1H), 10.33 (d, J=3.7 Hz, 1H). Mass: M+H+: 347.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([N:18]3[CH2:23][CH2:22][CH:21]([N:24]4[C:33](=[O:34])[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([CH3:35])[CH:31]=5)[N:26]([CH3:36])[C:25]4=[O:37])[CH2:20][CH2:19]3)=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:38][CH3:39])=[O:5])C.[OH-].[Na+].Cl>CO>[C:4]([CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([N:18]3[CH2:19][CH2:20][CH:21]([N:24]4[C:33](=[O:34])[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([CH3:35])[CH:31]=5)[N:26]([CH3:36])[C:25]4=[O:37])[CH2:22][CH2:23]3)=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:38][CH3:39])([OH:5])=[O:3]
Reactant: CCOC(=O)COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2cc1OCC(=O)O
Yield: 32.7 %

Procedure:
In 10 ml of methanol was dissolved 250.0 mg (0.47 mmol) of Compound 93 obtained in Example 84, and 5 ml of a 2N aqueous solution of sodium hydroxide was added thereto, followed by heating under reflux for 6 hours. After cooling, the reaction mixture was neutralized by addition of 4N hydrochloric acid, and extracted with chloroform. The organic layer was washed and dried, and the solvent was distilled off under reduced pressure. To the residue was added ether, and the precipitated crystals were collected by filtration and dried to give 77.8 mg (yield: 33%) of Compound 95 as white crystals.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:29](N1C=C[N+](C)=C1)=[O:30]>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:29]([N:21]3[CH2:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20]3)=[O:30])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: C[n+]1ccn(C(=O)N2Cc3ccccc3C2)c1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(1,3-dihydro-isoindole-2-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was recrystallized (ethanol) (≈100). HPLC-MS m/z=401.1 (M+1), Rt: 5.1 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:28])[C:3]=1[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31].Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][N:25]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:28])[C:3]=1[CH2:29][C:30]([OH:32])=[O:31]
Reactant: COc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)OC(C)(C)C)c(F)c3)CC2)nc1
Agent: Cl
Solvent: ClCCl
Product: COc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)nc1
Temperature: 35 °C
Reaction time: 5 h

Procedure:
Tert-butyl 2-(2,6-difluoro-4-(2-((1S,2R)-2-(1-(5-methoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethoxy)phenyl)acetate (1.87 g, 3.71 mmol) was dissolved in DCM (10 ml) and hydrochloric acid (9.28 ml, 4 M solution in dioxane, 37.1 mmol) was added. The mixture was stirred at 35° C. for 5 h. The volatiles were removed under reduced pressure to afford the titled compound. LC/MS (m/z): 448 (M+H)+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:1]([N:14]1[CH2:17][CH:16]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 8 h

Procedure:
To a solution of 1-benzhydrylazetidin-3-ol (20 g, 0.835 mol) in pyridine (167 mL) was added DMAP (12.24 g, 0.1 mM) and p-toluene sulphonylchloride at −40° C. The reaction mixture was stirred overnight. The reaction mixture was partitioned between dichloromethane (200 mL) and water. Solvent was evaporated off, purified by column chromatography using silica gel, 100-200 mesh) and 10% ethyl acetate hexane as eluent to obtain 1-benzhydryl-3-(toluene-4-sulfonyl)-azetidine. 1H-NMR (400 MHz, CDCl3,), δ ppm 7.76-7.74 (m, 2H), 7.34-7.15 (m, 12H), 4.89-4.85 (m, 1H), 4.32 (s, 1H), 3.47-3.43 (m, 2H), 3.06-3.03 (m, 2H), 2.43 (s, 3H).
Reaction SMILES: C(OC(N1[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])C1)=O)(C)(C)C.NCCC1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1>>[N:37]1[CH:38]=[CH:39][C:12]([CH2:11][CH2:10][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])=[CH:35][CH:36]=1
Reactant: NCCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCc1ccncc1)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 4-(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.) 10.25 (1H, s) 8.40-8.46 (2H, m) 8.21 (1H, t, J=5.54 Hz) 8.02 (1H, d, J=5.32 Hz) 7.77 (1H, d, J=5.47 Hz) 7.47 (1H, d, J=5.42 Hz) 7.32 (1H, dd, J=3.49, 2.56 Hz) 7.21-7.27 (2H, m) 6.81 (1H, d, J=5.47 Hz) 6.43 (1H, dd, J=3.49, 1.88 Hz) 3.47-3.55 (2H, m) 2.85 (2H, t, J=7.15 Hz)
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH2:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1.[H-].[Na+].[Li+].[Br-].I[CH3:24]>CN(C=O)C.C1COCC1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]([CH2:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[C:6](=[O:17])[N:5]([CH3:24])[C:4](=[O:18])[CH:3]=1
Reactant: N#Cc1ccccc1Cn1c(Cl)cc(=O)[nH]c1=O
Reactant: CI
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1c(=O)cc(Cl)n(Cc2ccccc2C#N)c1=O
Reaction time: 0.33 h
Yield: 72.5 %

Procedure:
To a cold (0° C.) solution of benzylated 6-chlorouracil 2 (10 g, 38 mmol) in DMF-THF (1:1, 300 mL) under nitrogen, was added NaH (60%, 1.6 g, 39.9 mmol) in portions, followed by adding LiBr (2 g). The mixture was stirred at r.t for 20 min. After adding iodomethane (5.4 mL, 76 mmol), the flask was sealed and stirred at this temperature for 10 min, rt for 2 h, and 35° C. overnight, and then concentrated in vacuo. It will be understood that alkylation of the amine may be performed under standard conditions known in the art, including the use of a base such as NaH, LiH or the like in an organic solvent or mixture of solvents. The solvent may include DMSO, THF, DMF and the like, or mixtures thereof. In addition, additives may be used, including LiBr, LiI, NaI and the like. For example, the alkylation can be performed using methyliodide and KsCO3 in acetone. The reaction may be performed at about 15-45° C., preferably at about 20-43° C., and more preferably at about 35-41° C. until the reaction is complete. The residue was dissolved in CHCl3 and washed with water and brine, dried (Na2SO4), and filtered then concentrated in vacuo. The crude product was crystallized from THF-Hexanes to give 7.6 g (72%) of the title compound 3. It will also be understood by those skilled in the art that the benzonitrile may be purified in a variety of organic solvents or solvent mixtures. For example, the benzonitrile can be purified by adding a mixture of dichloromethane and heptane. Optionally, the benzonitrile may be further purified in an organic solvent or mixture of solvents such as dichloromethane, chloroform, acetonitrile, THF, ethyl acetate, isopropyl acetate and the like. Preferably, the product is purified and washed with ethyl acetate. 1H NMR (400 MHz, DMSO): δ 7.87 (d, 1H, J=7.6 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.51 (t, 1H, J=7.6 Hz), 7.40 (d, 1H, J=8 Hz), 6.21 (s, 1H), 5.38 (s, 2H), 3.28 (s, 3H). MS (ES) [m+H] calc'd for C13H11ClN3O2, 276.1; found 276.1.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[C:33]([CH3:34])=[N:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH2:12][N:13]([C:24]3[C:33]([CH3:34])=[N:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH2:14][CH:15]2[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: Cc1nc2ccccc2nc1Cl
Product: Cc1nc2ccccc2nc1N1CC2CN(C(=O)c3ccccc3-c3ccccc3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-3-methyl-quinoxaline. MS (ESI) mass calcd. for C28H26N4O, 434.53; m/z found, 435.1 [M+H]+. 1H NMR (CDCl3): 7.85-7.72 (m, 1H), 7.65 (br s, 1H), 7.53-7.30 (m, 9H), 7.21 (d, J=10.5 Hz, 2H), 3.80-3.54 (br m, 3.5H), 3.44-3.28 (br m, 1.5H), 3.15-2.90 broad (m, 2.5H), 2.85-2.70 (br m, 1.5H), 2.65-2.50 (m, 4H)
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:8][CH2:7][CH:6]=[CH:5][CH2:4][O:3]1.S(=O)(=O)(O)[OH:11].ClOC(C)(C)C.S(=O)(O)[O-].[Na+].[OH-].[Na+]>C(O)(C)(C)C>[CH3:1][C:2]1([CH3:9])[O:8][CH2:7][CH:6]2[CH:5]([O:11]2)[CH2:4][O:3]1
Reactant: O=S(=O)(O)O
Reactant: CC1(C)OCC=CCO1
Agent: CC(C)(C)OCl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC1(C)OCC2OC2CO1
Temperature: 0 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To an ice-cold (5°), stirred solution of the dioxepin (II) (12.81 g, 0.1 mole) in aqueous t-butanol (50%; 50 ml) adjusted to pH 6.0 with dilute sulfuric acid, was added t-butyl hypochlorite (11.3 g, 0.105 mole), while the pH was maintained at 6.0. The reaction mixture was allowed to rise to room temperature and stirred for 4 hrs with protection from light. Sodium bisulfite (200 mg) was added to the reaction mixture, followed by 50% aqueous sodium hydroxide to bring the pH to 12. The reaction mixture was heated at 100° for 1 hr and then cooled. The upper t-butanol layer was separated and the aqueous layer was extracted with t-butanol (3×20 ml). The combined organic layers were dried (Na2CO3). Solvent removal, followed by fractional distillation, gave the epoxide product (III) as a colorless oil in ≃80% yield.