Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:5]([OH:7])=O)([CH3:3])[CH3:2].[C:22](Cl)(=[O:26])[C:23](Cl)=O>>[CH:1]([CH:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:5]([N:19]1[CH2:16][CH2:15][CH2:14][C@H:23]1[CH2:22][OH:26])=[O:7])([CH3:2])[CH3:3]
Reactant: CC(C)C(CCCCCc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Product: CC(C)C(CCCCCc1ccc([N+](=O)[O-])cc1)C(=O)N1CCC[C@H]1CO
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (10 ml) was added to 2-isopropyl-7-(p-nitrophenyl)heptanoic acid (200 mg; prepared in reference example 6). The solution was stirred for 10 mins, and concentrated to dryness. Methylene chloride (10 ml) was added to this residue followed by the addition of 2-hydroxymethylpyrrolidine (0.087 ml). The solution was cooled with ice. Triethylamine (0.143 ml) was added to this reaction solution. The solution was stirred for 30 mins. Subsequently, the reaction solution was evaporated. The residue was purified by column chromatography on silica gel to give the title compound (150 mg) having the following physical data:
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:29])OC(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.CN1CCCC1>O1CCOCC1>[C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:29])[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Reactant: C1COCCN1
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)cn1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A mixture of Example C2 (0.145 g, 0.351 mmol), morpholine (0.092 g, 1.052 mmol) and N-methylpyrrolidine (2.99 mg, 0.035 mmol) in dioxane (3 mL) was heated at 80° C. overnight, cooled to RT, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)morpholine-4-carboxamide (80 mg, 52%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.43 (s, 1H), 9.29 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.13 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 6.62 (dd, J=5.7, 2.4 Hz, 1H), 3.53 (m, 4H), 3.39 (m, 4H), 1.21 (s, 9H); MS (ESI) m/z: 443.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8](COCC[Si](C)(C)C)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[SH:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[C:3]2[C:10]([S:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccccc1S
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1Sc1c[nH]c2ncnc(Cl)c12
Temperature: 50 °C
Yield: 87.6 %

Procedure:
4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (110 mg, 0.27 mmol) was treated with 2-methoxybenzenethiol (49 μl, 0.40 mmol), copper(I) iodide (77 mg, 0.40 mmol) and potassium carbonate (74 mg, 0.54 mmol) in 2.2 mL dimethylformamide according to the method described in Preparation 86 but heating the reaction mixture at 50° C. overnight. The residue was purified using SP1® Purification System (0% to 15%, hexane-ethyl acetate) to give 69 mg (60% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.C(N(CC)CC)C.C([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:37]2[CH:42]=[CH:41][C:40]([O:43]C(=O)C)=[CH:39][CH:38]=2)[C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](Cl)=[O:31])=[CH:23][CH:22]=1)(=O)C.O>C(Cl)Cl>[OH:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:37]2[CH:38]=[CH:39][C:40]([OH:43])=[CH:41][CH:42]=2)[C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:31])=[CH:23][CH:22]=1
Reactant: CC(=O)Oc1ccc(C(c2ccc(OC(C)=O)cc2)c2ccccc2C(=O)Cl)cc1
Reactant: COc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1cccc(NC(=O)c2ccccc2C(c2ccc(O)cc2)c2ccc(O)cc2)c1
Reaction time: 0.5 h

Procedure:
In 20 ml of methylene chloride were dissolved 0.62 g of m-anisidine and 5 ml of triethylamine. To this solution was added dropwise under ice cooling 20 ml of methylene chloride containing 2.64 g of 2-[bis(4-acetoxyphenyl)methyl]benzoyl chloride as obtained in Reference Example 2. After stirring for 30 minutes, water was added thereto. The organic layer was separated off, and the water layer was extracted with chloroform. The chloroform layer was combined with the organic layer, and the combined organic layer was washed with 2N aqueous hydrochloric acid solution and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was suspended in a mixture of 50 ml of saturated aqueous sodium hydrogencarbonate solution and 50 ml of methanol, and the resulting suspension was heated under reflux for 2 hours. The suspension was concentrated under reduced pressure, and water was added to the residue. The resulting mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, and was recrystallized to afford 1.54 g of the desired product.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)=[N:5][C:4]=1[S:25][CH3:26])#[N:2].[Cl:27][S:28](O)(=[O:30])=[O:29]>C(Cl)(Cl)Cl>[C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:11]=[CH:12][C:13]([S:28]([Cl:27])(=[O:30])=[O:29])=[CH:14][CH:15]=2)[C:6]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH3:24])=[CH:20][CH:21]=2)=[N:5][C:4]=1[S:25][CH3:26])#[N:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1ccc(-c2nc(SC)c(C#N)c(=O)n2-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(-c2nc(SC)c(C#N)c(=O)n2-c2ccc(S(=O)(=O)Cl)cc2)cc1
Yield: 64.1 %

Procedure:
A solution of 5-cyano-2-(4-ethoxyphenyl)-1-phenyl-4-(methylthio)-6-oxo-1,6-dihydropyrimidine (1 g, 2.7 mmol) in chlorosulfonic acid (6.14 g, 53 mmol) and chloroform (30 ml) was refluxed 1 hr and then poured on to ice. The chloroform layer was collected and dried over Na2SO4 and concentrated under vacuo to yield title compound (0.8 g, yield 62.9%). 1H-NMR (DMSO):δ 1.21-1.24 (t, 3H), 2.6 (s, 3H), 3.94-3.99 (q, 2H), 6.7-6.72 (d, 1H), 7.03-7.05 (q, 1H), 7.33-7.39 (m, 5H), 8.04-8.05 (1H). MS m/z:463.7 (M+).
Reaction SMILES: [CH2:1]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl>C(O)CCC>[CH2:1]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([C:22]([O:24][CH2:13][CH2:1][CH2:2][CH3:3])=[O:23])=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1cc2cc(C(=O)O)ccc2[nH]1
Agent: Cl
Solvent: CCCCO
Product: CCCCCCCCCCCCc1cc2cc(C(=O)OCCCC)ccc2[nH]1
Yield: 109.4 %

Procedure:
A solution of 2-(n-dodecyl)indole-5-carboxylic acid (15.0 g) in n-butanol (100 ml) containing aqueous hydrochloric acid (10ml of strength 36.5% w/v) was heated on a steam bath for 8 hours. The solution was concentrated in vacuo to about one half of its volume, diethyl ether (300 ml) was added, and the solution was washed with water and was dried over magnesium sulphate. Evaporation of the solvent in vacuo gave a residue which was recrystallised from methanol to give n-butyl 2-(n-dodecyl)indole-5-carboxylate (9.6 g), in the form of an off-white powder, m.p. 74°-76° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([OH:24])=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:16]=4)[C:4]=2[C:3]=1[CH3:28])[CH:12]=[CH:11][CH:10]=[CH:9]3.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([O:24][C:29](=[O:31])[CH3:30])=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:16]=4)[C:4]=2[C:3]=1[CH3:28])[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: CC(=O)OC(C)=O
Reactant: Cc1sc2cc3ccccc3c(-c3cc(C(C)C)c(O)c(C(C)C)c3)c2c1C
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C(C)C)cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C(C)C

Procedure:
Using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenol (5.0 g, 13.7 mmol), acetic anhydride (1.68 mL, 17.8 mmol), and pyridine (85 mL) the title compound was prepared according to the procedure in Example 2, step 3 to give 5.37 g (91%) as a white solid, mp 243-245° C.; NMR (DMSO-d6) δ 8.49 (s, 1 H), 7.98 (d, 1 H), 7.49-7.39 (m, 3 H), 7.16 (s, 2 H), 3.01 (septet, 2 H), 2.43 (s, 3 H), 2.41 (s, 3 H), 1.56 (s, 3 H), 1.16 (d, 12 H). MS(EI), [M+] 430; Anal. Calc. for C28H30O2S: C, 78.10, H, 7.02, N, 0.00. Found: C, 77.95, H, 7.04, N, 0.07.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19]N[CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30][C:29]=2[CH:36]=1.C([OH:40])(C)C>Cl.O1CCOCC1.O>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][O:40][CH2:19][CH2:20]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30][C:29]=3[CH:36]=2)=[N:3][CH:4]=1
Reactant: CC(C)O
Reactant: Nc1ccc2c(c1)CCC(=O)CC2
Reactant: COc1cc(N2CCNCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCC(=O)CC3)ncc1Cl
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
Into a microwave vial was added (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-piperazin-1-yl-phenyl)-amine (60 mg, 0.0002 mol) and 2-amino-5,6,8,9-tetrahydro-benzocyclohepten-7-one (38 mg, 0.00022 mol) in isopropyl alcohol (5 mL, 0.06 mol) with 3-4 drops of 4M HCl in dioxane-water. The mixture was subjected to microwaves at 130° C. for 10 minutes. Trace starting materials were present so the reaction mixture was resubjected to the same conditions. The resulting solid was collected by filtration and washed with cold methylene chloride and dried in a vacuum oven at 50° C. overnight to give 50 mg of 2-[5-chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-5,6,8,9-tetrahydro-benzocyclohepten-7-one as an off-white solid. MP: 212-215° C.; 1HNMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.11 (s, 1H), 8.04 (s, 1H), 7.54 (s, 1H), 7.50 (d, 1H, J=8 Hz), 7.25 (d, 1H, J=9, 17 Hz), 6.99 (d, 1H, J=8 Hz), 6.68 (d, 1H, J=9 Hz), 6.51 (d, 1H, J=9 Hz), 3.77 (s, 7H), 3.15 (m, 4H), 2.75 (m, 2H), 2.60 (m, 2H), 2.47 (m, 4H); MS (m/e) 494 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:28])[CH2:25][CH2:26][OH:27])=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]([CH2:25][CH2:26][OH:27])[CH3:28])=[CH:22][CH:23]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN(CCO)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CCO)c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Yield: 63 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.17 g, 0.61 mmol) and 2-[(4-amino-phenyl)-methyl-amino]-ethanol (0.10 g, 0.61 mmol) were stirred in N,N-dimethylformamide (3 mL) and triethylamine (0.16 mL) at 60-70° C. The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-[({4-[(2-hydroxyethyl)(methyl)amino]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione (0.16 g, 64%) as a rust colored powder.
Reaction SMILES: [F:1][C:2]([F:23])([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1)[C:3]1[N:12]=[C:11](SC)[C:10]2[C:5](=[CH:6][C:7]([CH3:15])=[CH:8][CH:9]=2)[N:4]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH3:35][C:36]1[NH:40][N:39]=[C:38]([NH2:41])[CH:37]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:23])([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=1)[C:3]1[N:12]=[C:11]([NH:41][C:38]2[CH:37]=[C:36]([CH3:35])[NH:40][N:39]=2)[C:10]2[C:5](=[CH:6][C:7]([CH3:15])=[CH:8][CH:9]=2)[N:4]=1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2cc(C)ccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 35.7 %

Procedure:
To a solution of 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methyl-4-(methylthio)quinazoline (152 mg, 0.454 mmol) in DCM (3 mL) at 0° C. was added 70% meta-chloroperoxybenzoic acid (168 mg, 0.681 mmol), and the mixture was stirred for 40 min at 0° C. DCM (15 mL) was added and the mixture was washed with saturated aq NaHCO3 (20 mL) and saturated aq sodium thiosulfate (20 mL), dried over Na2SO4, and concentrated under reduced pressure. To the residue (154 mg) was added 5-methyl-1H-pyrazol-3-amine (132 mg, 1.36 mmol) in THF (4 mL), and the mixture was stirred at rt overnight and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Varian Diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/5% ACN/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (62.3 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ 12.08-12.20 (m, 1H), 10.53-10.66 (m, 1H), 8.66 (s, 1H), 8.57 (d, J=8.7 Hz, 1H), 7.93-8.03 (m, 2H), 7.66 (s, 1H), 7.48 (d, J=7.5 Hz, 1H), 5.99 (s, 1H), 2.51 (s, 4H), 2.18 (s, 3H). LCMS (ESI) m/z 386 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][CH2:12][CH3:13])[CH:5]=[C:4]([CH:14]([CH3:16])[CH3:15])[N:3]=1>CO.[Pd]>[ClH:1].[CH2:12]([NH:11][C:6]1[CH:5]=[C:4]([CH:14]([CH3:16])[CH3:15])[N:3]=[CH:2][C:7]=1[NH2:8])[CH3:13]
Reactant: CCNc1cc(C(C)C)nc(Cl)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCNc1cc(C(C)C)ncc1N
Product: Cl
Reaction time: 3.5 h

Procedure:
A solution of (2-chloro-6-isopropyl-3-nitro-pyridin-4-yl)-ethyl-amine (0.56 g, 2.30 mmol) in MeOH (20 mL) containing 10% Pd/c (˜50 mg) is stirred under and atmosphere of H2 for 3.5 h. The reaction mixture is then filtered through a pad of Celite using MeOH. The filtrate is concentrated in vacuo. Toluene is added to the residue and then removed in vacuo. This is repeated once more, yielding N4-ethyl-6-isopropyl-pyridine-3,4-diamine hydrochloride as a dark solid. 1H NMR (CD3OD, 400 MHz) δ 7.46 (s, 1H), 6.60 (s, 1H), 3.43 (q, J=7.4 Hz, 2H), 3.03 (sept, J=6.8 Hz, 1H), 1.35 (t, J=7.4 Hz, 3H), 1.33 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9](Br)=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1.[CH:18]1(B(O)O)[CH2:20][CH2:19]1.[F-].[Cs+]>O1CCOCC1>[CH3:1][O:2][CH2:3][C:4]1[C:9]([CH:18]2[CH2:20][CH2:19]2)=[CH:8][CH:7]=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]1
Reactant: OB(O)C1CC1
Reactant: COCc1c(Br)cccc1-n1nnn(C)c1=O
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Temperature: 90 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
A mixture of 1-(2-methoxymethyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 8) 30.1 g, cyclopropylboronic acid 12.9 g, cesium fluoride 46.2 g, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct 8.2 g and dioxane 680 ml was stirred at 90° C. for four hours. After cooling the reaction mixture, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(2-methoxymethyl-3-cyclopropylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 26.0 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CC(C)=O>[C:22]([O:21][C:19](=[O:20])[CH2:18][O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Br:1])([CH3:25])([CH3:24])[CH3:23]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(C#N)cc1Br
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
A solution of 3-bromo-4-hydroxybenzonitrile (Lancaster; 3.00 g; 15.2 mmol) in acetone (30 mL) was treated with potassium carbonate (2.30 g; 16.7 mmol), stirred for 10 minutes then treated with tert-butyl bromoacetate (2.24 mL; 15.2 mmol). The reaction mixture was stirred at 65° C. for 18 hours, then the mixture was filtered, the solid was washed with acetone and the filtrate was concentrated to dryness under vacuum to give the title compound as a yellow sticky solid (4.75 g, quant).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=3)[CH2:33][CH2:32]1)=[O:20])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Reactant: Brc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(F)c(F)cc2nc1NC(=O)N1CCN(c2cccc(Br)c2)CC1
Yield: 58 %

Procedure:
Ethyl N-(6,7-difluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-bromophenyl)piperazine were reacted by the same way with the example 169 to obtain the titled compound (yield, 58%). 1H NMR (300 MHz, CDCl3) 3.30 (m, 4H), 3.76 (m, 4H), 4.15 (s, 3H), 6.85-6.87 (m, 1H), 7.02-7.03 (m, 2H), 7.06-7.07 (m, 1H), 7.13-7.16 (m, 1H), 7.30 (br s, 1H), 7.51-7.53 (m, 1H), 7.60 (br s, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]1=[O:15])(=O)=O.[CH3:16][NH:17][CH3:18]>O1CCCC1>[CH3:16][N:17]([CH3:18])[CH2:6][CH2:7][N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]1=[O:15]
Reactant: CNC
Reactant: CC1(C)CN(CCOS(C)(=O)=O)C(=O)N1
Solvent: C1CCOC1
Product: CN(C)CCN1CC(C)(C)NC1=O
Yield: 81.2 %

Procedure:
In a sealed tube, a solution of 2-(4,4-dimethyl-2-oxoimidazolidin-1-yl)ethyl methanesulfonate (500 mg, 2.1 mmol) and dimethyl amine (4.6 mmol) in tetrahydrofuran (2.3 mL) was heated at 60° C. for 5 hours. Additional dimethylamine (1 mL of a 2M tetrahydrofuran solution) was added and the reaction was heated for 3 additional hours. The solution was concentrated to a crude residue under reduced pressure, then dissolved in 5 mL of 1 N HCl. The aqueous solution was washed with dichloromethane, then made basic (pH>8) with sodium carbonate and extracted with dichloromethane twice. The aqueous solution was further adjusted to pH>10 with NaOH, and extracted with twice with dichloromethane. The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure to give 316 mg of an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 1.30 (s, 6H), 2.27 (s, 6H), 2.41-2.45 (t, 6.8 Hz, 2H) 3.24 (s, 2H), 3.29-3.33 (t, J=6.8 Hz, 2H), 3.51-3.61 (m, 14H), 3.88 (br m, 2H), 7.27-7.29 (d, J=8.1 Hz, 2H), 7.58-7.60 (d, J=8.2 Hz, 2H); LRMS (ESI/APCI) m/z 186 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][CH2:41][CH2:42]O>>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:42][CH2:41][O:40][CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][O:34]3)[CH:26]=2)=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Reactant: OCCOC1CCCCO1
Product: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(OCCOC4CCCCO4)c3)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 61F and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (purchased from Fluka) were processed as described in Example 62A to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](SC)[C:5]([C:10]#[N:11])=[C:4]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[N:3]=1.[Na]>C1(O)CCCCC1>[NH2:1][C:2]1[N:7]=[C:6]([O:18][CH:16]2[CH2:17][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:5]([C:10]#[N:11])=[C:4]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[N:3]=1
Reactant: COc1cc(-c2nc(N)nc(SC)c2C#N)cc(OC)c1OC
Agent: [Na]
Solvent: OC1CCCCC1
Product: COc1cc(-c2nc(N)nc(OC3CCCCC3)c2C#N)cc(OC)c1OC

Procedure:
From 2-amino-4-methylsulfanyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile and sodium cyclohexoxide in cyclohexanol. ES-MS m/e (%): 407 (M+Na+, 15), 385 (M+H+, 50), 303 ([M+H—C6H10]+, 100).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:6][C:7]1=[N:8][C:9](=[O:19])[S:10]/[C:11]/1=[CH:12]\[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:4]#[CH:5].C(=O)([O-])[O-].[K+].[K+].C([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1)(=O)C.O>CN(C=O)C>[OH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][N:16]2[CH2:17][CH2:18][CH:13](/[CH:12]=[C:11]3/[C:7]([NH:6][CH2:3][C:4]#[CH:5])=[N:8][C:9](=[O:19])[S:10]/3)[CH2:14][CH2:15]2)=[C:32]([C:38]([F:39])([F:40])[F:41])[CH:31]=1
Reactant: CC(=O)Oc1ccc(CBr)c(C(F)(F)F)c1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of (5Z)-4-(prop-2-yn-1-ylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (2 g) in DMF (20 mL) were added potassium carbonate (3.45 g) and 4-(bromomethyl)-3-(trifluoromethyl)phenyl acetate (1.84 g). The reaction mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the residue in methanol (20 mL) was added potassium carbonate (858 mg), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the solid was recrystallized from ethyl acetate/heptane to give the title compound (0.75 g).