Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[O:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([O:39][CH3:40])[CH:38]=1)[CH:34]=O>C1(C)C(C)=CC=CC=1>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:9][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][Br:1])[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=1
Reactant: [Br-]
Reactant: C(=C1CCCCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1
Solvent: Cc1ccccc1C
Product: COc1cc(C=CC(=O)CCCCCBr)cc(OC)c1
Temperature: 25 °C

Procedure:
1.13 parts of [(2-oxepanylidene)methyl] triphenylphosphonium bromide having the formula ##STR11## was suspended and 0.83 part of 3,5-dimethoxybenzaldehyde was dissolved in 45 parts of xylene as the aprotic medium. This mixture was maintained under a nitrogen atmosphere and was refluxed for 24 hours and was then cooled to room temperature. Xylene was removed from the resulting clear solution at a temperature of about 60° C. and under reduced pressure. The remaining traces of xylene were removed in a drying oven at a temperature of about 50° C. and under a reduced pressure of about 0.5 millimeter of mercury. The resulting product mixture was separated chromatographically in a silica gel column using a benzene elution solvent, to isolate 1-(3,5-dimethoxyphenyl)-8-bromo-1-octen-3-one which, after recrystallization from benzene, melted at about 73°-76° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:23][C:24]=3[CH3:25])=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a mixture of ethyl 3-[2-ethoxy-4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (1.20 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (5.0 mL) and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (1.09 g, 97%) of 3-[2-ethoxy-4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:41][CH2:40][CH2:39]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[C:45]([F:50])[CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:52](Cl)[CH2:53]Cl.C(O)C>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:51])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][CH2:28][C:29]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[C:36](=[O:42])[NH:37][CH:38]3[CH2:39][CH2:40][CH2:41]3)=[O:30])[N:24]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[C:45]([F:50])[CH:44]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][CH2:52][CH3:53])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccc(F)c(F)c3)n2)CC1
Reactant: ClCCCl
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccc(F)c(F)c2)n1)C(=O)N1CCN(C(=O)OCC)CC1

Procedure:
To a solution of 1.50 g 4-((S)-4-Carboxy-2-{[5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-(3,4-difluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 25 ml dichloromethane were added 481 mg EDC, 306 mg DMAP and 617 μl ethanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 520 mg MS (ES+): m/e=746.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].[CH3:13][NH:14][CH2:15][CH:16]=[O:17]>C1C=CC=CC=1>[CH3:13][N:14]([CH2:15][CH:16]=[O:17])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12]
Reactant: CNCC=O
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(S(C)(=O)=O)s1

Procedure:
A mixture of 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-methylsulfonyl-1,3,4-thiadiazol-2-yl)ureido] acetaldehyde.
Reaction SMILES: CC([N:5]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)[C:6](=[O:8])[O-:7])(C)C.[Li][C:18]([CH3:21])([CH3:20])[CH3:19].CCCCC.[CH3:27][O:28][C:29](Cl)=[O:30].[Cl-].[NH4+]>O1CCCC1>[CH3:19][C:18]([O:7][C:6]([NH:5][C:9]1[C:10]([C:29]([O:28][CH3:27])=[O:30])=[C:11]([F:16])[C:12]([F:15])=[CH:13][CH:14]=1)=[O:8])([CH3:21])[CH3:20]
Reactant: COC(=O)Cl
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)N(C(=O)[O-])c1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: COC(=O)c1c(NC(=O)OC(C)(C)C)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
To a solution of 1,1-dimethylethyl(3,4-difluorophenyl)carbamate (8.0 g, 35 mmol) in tetrahydrofuran (250 mL) at −78° C. was slowly added tBuLi as a 1.7M solution in pentane (46 mL, 78.60 mmol, 2.25 equiv., Aldrich). The resulting bright yellow solution was maintained at −78° C. for 3 hours, at which time methylchloroformate (3.24 mL, 42 mmol, 1.20 equiv.) was added dropwise. After 45 minutes, aqueous ammonium chloride (100 mL) was added and the reaction was warmed to room temperature. The organic layer was washed with brine, taken to a residue under reduced pressure, and purified by chromatography on SiO2 (10 to 30% ethyl acetate/hexanes) to afford methyl 6-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2,3-difluorobenzoate as a pale yellow oil (5.8 g, 20.2 mmol, 58% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9 H), 3.94 (s, 3 H), 7.21-7.28 (m, 1 H), 8.08 (ddd, J=9.25, 4.12, 2.20 Hz, 1 H), 9.44 (s, 1 H).
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][NH:24][CH2:25][CH2:26][NH:27][CH3:28]>C(O)CCC>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([N:24]([CH3:23])[CH2:25][CH2:26][NH:27][CH3:28])[N:12]=2)=[CH:16][CH:17]=1
Reactant: CNCCNC
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: Cl
Solvent: CCCCO
Product: CNCCN(C)c1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1
Yield: 79.8 %

Procedure:
A solution of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine hydrochloride (120 mg, 0.36 mmol) and N,N′-dimethylethylenediamine (0.14 mL, 1.26 mmol) in 2 mL of 1-butanol was heated at 100° C. overnight with stirring. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (101 mg, 80%). 1H NMR (CDCl3, 400 MHz) δ 7.42 (d, 1H, J=8.4 Hz), 7.31 (t, 1H, J=6.8 Hz), 7.09 (d, 2H, J=8.8 Hz), 6.86 (m, 3H), 6.64 (t, 1H, J=6.8 Hz), 3.90 (t, 2H, J=6.4 Hz), 3.82 (s, 3H), 3.50 (s, 3H), 3.30 (s, 3H), 2.92 (t, 2H, J=6.4 Hz), 2.50 (s, 3H); ESI-MS m/z 352 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=3)[C:11]2=[O:24])[CH2:2]1.[Cl:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]2[O:36][CH2:37][O:38][C:32]=2[CH:31]=1>>[ClH:25].[CH2:37]1[O:36][C:33]2[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][CH2:26][N:1]3[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][N:10]4[CH2:19][CH2:18][C:17]5[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=5)[C:11]4=[O:24])[CH2:2]3)=[CH:31][C:32]=2[O:38]1
Reactant: COc1cc2c(cc1OC)C(=O)N(CCCC1CCCNC1)CC2
Reactant: ClCCCOc1ccc2c(c1)OCO2
Product: COc1cc2c(cc1OC)C(=O)N(CCCC1CCCN(CCCOc3ccc4c(c3)OCO4)C1)CC2
Product: Cl

Procedure:
Prepared from 2-[3-(piperidin-3-yl)-propyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-3-(3,4-methylenedioxy-phenoxy)-propane analogously to Example 1.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][N:5]([C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].O.O.[OH-].[Li+].Cl>O1CCOCC1.CCOC(C)=O>[F:33][C:30]([F:31])([F:32])[C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=1)[C:19]([N:5]([CH2:4][C:3]([OH:35])=[O:2])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:34]
Reactant: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {(3,5-bis-trifluoromethyl-benzoyl)-[4-(2-chloro-phenyl)-pyridin-3-yl]-amino}-acetic acid methyl ester (109 mg, 211 μmol, example 88) in dioxane (2 mL) was added water (2 mL) and lithium hydroxide hydrate (11.1 mg, 264 μmol). The reaction mixture was stirred at room temperature for 2 hours and then poured on 30 mL 1M aqueous HCl and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and evaporated to give a yellow solid which was pure enough for the next step (119 mg, 112%). MS (ESI): m/z=503.060 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:16])[CH2:12][C:13]([CH3:15])=O)[CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:8]([O:10][C:11](=[O:16])[CH:12]=[C:13]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(C)Nc1ccccc1
Reaction time: 1 h

Procedure:
Aniline (0.20 mol) and ethylacetoacetate (0.20 mol) are mixed in toluene (200 ml) containing 0.04 g of p-toluenesulfonic acid-hydrate and heated at reflux under a water separator for 1 hour. The toluene is removed under vacuum to afford the ethyl-3-phenylaminobut-2-enoate which can be used as is for the preparation of the 3-quinolinecarboxylic acid, 2-methyl-, ethyl ester.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[CH:24]=[CH:23][C:11]2[O:12][C:13]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:14]=3[C:15](=O)[CH2:16][C:10]=2[CH:9]=1.[CH2:25]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:29])[CH3:26].C(=O)(O)[O-].[Na+]>[Ti](Cl)(Cl)(Cl)Cl.O>[CH2:25]([O:27][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:15]2[C:14]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:13]=3[O:12][C:11]3[CH:23]=[CH:24][C:8]([CH3:7])=[CH:9][C:10]=3[CH:16]=2)[CH2:34][CH2:35]1)=[O:29])[CH3:26]
Reactant: Cc1ccc2c(c1)CC(=O)c1cc(C)ccc1O2
Reactant: CCOC(=O)N1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN(C2=Cc3cc(C)ccc3Oc3ccc(C)cc32)CC1

Procedure:
A solution of 11.35 ml. of titanium (IV) chloride in 135 ml. of benzene is added dropwise with stirring and cooling at 20°-25° C. to a solution of 30 g. of 10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-one and 80 ml. of N-ethoxycarbonylpiperazine in 300 ml. of benzene. Then, the mixture is stirred for 4 hours at reflux and cooled. The cooled mixture is poured into a solution of 12 g. of sodium bicarbonate in 300 ml. of water. The precipitated titanium dioxide is removed by filtration and washed well with benzene. The filtrate is washed four additional times with water. The aqueous phases are extracted again with benzene. The combined benzene extracts are dried over sodium sulfate and evaporated in vacuo, and there is obtained 4-[2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: C[O-].[Na+].O1CCCC1.[CH:9]1([CH2:13][N:14]([CH2:33][CH3:34])[C:15]2[C:24]([CH2:25][NH:26][C:27]3[CH:31]=[C:30]([CH3:32])[O:29][N:28]=3)=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:12][CH2:11][CH2:10]1.[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br>O.C(OCC)(=O)C>[F:35][C:36]([F:49])([F:50])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:46])[F:47])[CH:44]=1)[CH2:40][N:26]([CH2:25][C:24]1[C:15]([N:14]([CH2:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH2:33][CH3:34])=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:27]1[CH:31]=[C:30]([CH3:32])[O:29][N:28]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCN(CC1CCC1)c1nc2ccccc2cc1CNc1cc(C)on1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC1CCC1)c1nc2ccccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
Sodium methoxide (0.108 g, 2.0 mmol) was added to an anhydrous tetrahydrofuran (6 mL) solution of cyclobutylmethyl-ethyl-{3-[(5-methyl-isoxazol-3-ylamino)-methyl]-quinolin-2-yl}-amine (0.14 g, 0.4 mmol), with stirring, at ambient temperature. After this mixture was stirred for 15 minutes, 3,5-bis-trifluoromethybenzyl bromide (0.08 mL, 0.4 mmol) was added slowly, and stirring was continued overnight. Ethyl acetate (30 mL) and water (30 mL) were added, and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (2×30 mL), and the combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude residue was purified by chromatography on silica gel and eluted with 10-70% hexane in ethyl acetate to afford the title compound (0.045 g), yield: 20%.
Reaction SMILES: Br[CH:2]([CH3:14])[C:3]([C:5]1[CH:6]=[N:7][C:8]([CH:11]([F:13])[F:12])=[CH:9][CH:10]=1)=O.[C:15]([NH:18][C:19]([NH2:21])=[NH:20])(=[O:17])[CH3:16].O>CN(C=O)C>[F:12][CH:11]([F:13])[C:8]1[N:7]=[CH:6][C:5]([C:3]2[NH:21][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[N:20][C:2]=2[CH3:14])=[CH:10][CH:9]=1
Reactant: CC(Br)C(=O)c1ccc(C(F)F)nc1
Reactant: CC(=O)NC(=N)N
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(F)F)nc2)[nH]1
Temperature: 50 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
Dissolve 2-bromo-1-[6-(difluoromethyl)-3-pyridyl]propan-1-one (0.500 g, 1.89 mmol) and acetyl guanidine (0.514 g, 5.68 mmol) in DMF (12 mL). Heat the mixture to 50° C., and stir for 16 hours. Pour the mixture into water, and extract with EtOAc (3×20 mL). Dry the combined organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the resulting residue by flash chromatography (silca gel) eluting with a 40:1 ratio of DCM/MeOH to give the title compound as a white solid (0.229 g, 46% yield). LCMS (m/z) 267 (M+1).
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].CN(N=O)/C(/N)=N/[N+]([O-])=O.[OH-].[K+].[Br:16][CH2:17][CH2:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:20](Cl)=[O:21]>CCOCC>[Br:16][CH2:17][CH2:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)[C:20](=[O:21])[CH:3]=[N+:1]=[N-:2]
Reactant: O=C(Cl)C(CCBr)c1ccc(Cl)c(Cl)c1
Reactant: C=[N+]=[N-]
Agent: CN(N=O)/C(N)=N/[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)C(CCBr)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
Prepare a solution of diazomethane from 15 g of MNNG by reaction with 45 ml of 40% aqueous KOH topped with 150 ml. of Et2O and cool in an ice bath. Add an Et2O solution (40 ml.) of the product of Step 3 (8.2 g, 24.8 mmoles) in small volumes, stir the solution in the ice bath for 15 min, then heat to reflux for 30 min. Remove the solvent in vacuo. Purify the resulting mixture by flash chromatography on silica gel using CH2Cl2 as eluent. Yield: 7.0 g (IR: 2100 cm-1, 1630 cm-1).
Reaction SMILES: O.O.O.O.O.O.O.O.O.O.B([O-])([O-])[O-].[Na+].[Na+].[Na+].[C:18]([O:29][CH3:30])(=[O:28])[C:19]1[CH:27]=[C:25]([OH:26])[C:23]([OH:24])=[C:21]([OH:22])[CH:20]=1.S(OC)(O[CH3:35])(=O)=O.[OH-].[Na+]>O>[OH:26][C:25]1[CH:27]=[C:19]([CH:20]=[C:21]([O:22][CH3:35])[C:23]=1[OH:24])[C:18]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc(O)c(O)c(OC)c1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a stirred mixture of sodium borate decahydrate (borax, 80 g) in H2O (1 L) was added methyl gallate (3, 15.0 g, 82 mmol) at rt. After stirring for 1 h, dimethyl sulfate (30 ml, 317 mmol) and NaOH (50 ml, 6.5 M) were added dropwise simultaneously via separate addition funnels over the course of 1 h. After stirring an additional 12 h, the methylation was terminated with H2SO4, (65 ml, conc.) and stirring continued an additional h. The product was removed by extraction with DCM (5×500 ml, each time stirring the solution for 20 min). The combined DCM extracts were washed with brine (300 ml), dried, concentrated in vacuo, and the residue crystallized from methanol-benzene to afford methyl ether 4 (13.7 g, 85%) as a light tan solid, mp 110–111° C., (lit. mp 110–111° C., Pettit and Singh, 1987); 1H-NMR (300 MHz): 3.89 (3H, s, —OCH3), 3.94 (3H, s, —OCH3), 5.40 (2H, bs, —OH), 5.80 (2H, bs, —OH), 7.22 (1H, d, J=1.8 Hz, ArH), 7.35 (1H, d, J=1.8 Hz, ArH).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[C:20]4[CH2:28][CH2:27][NH:26][CH2:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[N:2]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[CH:12]=[C:13]([NH:18][C:19]3[C:20]4[CH2:28][CH2:27][N:26]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:25][C:21]=4[N:22]=[CH:23][N:24]=3)[CH:14]=[CH:15][C:16]=2[CH3:17])[N:2]=1
Reactant: Cc1ccc(Nc2ncnc3c2CCNC3)cc1-c1cc2ccccc2cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(Nc2ncnc3c2CCN(S(C)(=O)=O)C3)cc1-c1cc2ccccc2cn1
Reaction time: 8 h

Procedure:
To a solution of N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (20 mg, 0.055 mmol) in DCM (0.4 ml) is added DIEA (21 mg, 0.121 mmol) and methylsulfonyl chloride (6.2 mg, 0.055 mmol) subsequently. The reaction mixture is stirred overnight. After concentrated by rotary evaporation, the residue is subject to HPLC to afford N-(3-(isoquinolin-3-yl)-4-methylphenyl)-7-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine as a white solid. LC-MS m/z: 446.2 (M+1); 1H NMR 400 MHz (CDCl3) δ9.32 (s, 1H), 8.53 (s, 1H), 8.01 (d, 1H, J=8.0 Hz), 7.85 (d, 1H, J=8.0 Hz), 7.77 (s, 1H), 7.72 (t, 2H, J=6.6 Hz), 7.64-7.60 (m, 2H), 7.31 (d, 1H, J=8.4 Hz), 6.47 (s, 1H), 4.35 (s, 2H), 3.64 (t, 2H, J=6.0 Hz), 2.89 (s, 3H), 2.68 (t, 2H, J=5.6 Hz), 2.39 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:27]=1[CH2:28]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:28][C:27]3[C:26]([F:25])=[CH:33][C:32]([F:34])=[CH:31][C:30]=3[F:35])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: Fc1cc(F)c(CCl)c(F)c1
Product: Fc1cc(F)c(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c(F)c1
Yield: 34.5 %

Procedure:
The title compound (0.027 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2,4,6-trifluorobenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C20H17ClF3N3, 391.11; found, m/z 392.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.30-7.26 (m, 4H), 6.80-6.78 (br m, 2H), 5.25 (s, 2H), 2.94-2.92 (m, 4H), 2.82-2.80 (m, 2H), 2.66-2.62 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[C:17]1([N:23]2[C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.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>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:28]([C:27]4[N:23]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:24]=[CH:25][CH:26]=4)=[O:29])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: O=C(O)c1ccnn1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccnn4-c4ccccc4)CC3C2)n1
Yield: 72.6 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0 mg, 0.28 mmol), 2-phenyl-2H-pyrazole-3-carboxylic acid (56.9 mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (106.6 mg, 0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (79.0 mg, 74%). MS (ESI) mass calcd. for C22H24N6O, 388.47; m/z found 389.2 [M+H]+. 1H NMR (CDCl3): 7.67 (d, J=1.7, 1H), 7.50 (d, J=7.4, 2H), 7.37 (t, J=7.8, 2H), 7.29-7.23 (m, 1H), 6.56 (d, J=1.7, 1H), 6.30 (s, 1H), 3.86-3.71 (m, 2H), 3.70-3.51 (m, 2H), 3.43-3.22 (m, 3H), 3.05-2.77 (m, 3H), 2.29 (s, 6H).
Reaction SMILES: [CH:1](=[C:8]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.Cl>CO>[CH2:1]([CH:8]1[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2ccccc2)C(=O)N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1NC(=O)C(Cc2ccccc2)C(=O)N1

Procedure:
To a suspension of 5-benzylidenebarbituric acid (4 g) in 200 ml of methanol are added portionwise 1.4 g of sodium borohydride. After 10 minutes from the end of the addition, 100 ml of water are added and the mixture is acidified with 1 N hydrochloric acid to pH=2. The solvent is evaporated off and the aqueous phase is extracted with ethyl acetate. The pooled extracts are dried over sodium sulfate and concentrated to dryness. 3.6 g of the product crystallize, m.p. 207-209° C.