Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][CH:6]1[CH2:11][C:10]([N:18]([CH3:20])[CH3:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:8][C:7]1=[O:21].[CH:25]1[CH:26]=[CH:27][C:28]2[NH:33][CH:32]=[C:31]([CH2:34][CH2:35]O)[C:29]=2[CH:30]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][CH:6]1[C:7]2([C:32]3[NH:33][C:28]4[C:29]([C:31]=3[CH2:34][CH2:35][O:21]2)=[CH:30][CH:25]=[CH:26][CH:27]=4)[CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([N:18]([CH3:19])[CH3:20])[CH2:11]1
Reactant: OCCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)C(Cc2cccc(F)c2)C1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC2(OCCc3c2[nH]c2ccccc32)C(Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(±)-2-(3-fluorobenzyl)-4-dimethylamino-4-phenylcyclohexanone (325 mg, 1 mmol) together with tryptophol (161 mg, 1 mmol) was dissolved in dichloromethane (30 ml) and mixed with trifluoromethane sulphonic acid trimethylsilyl ester (0.22 ml, 1.14 mmol). The batch was stirred at RT for 2.5 h. A precipitate began to separate out after some time (approx. 1 h). For work up the reaction mixture was mixed with 2N NaOH (20 ml) and stirred for 20 min. During this the precipitate went into solution. The organic phase was separated and the aqueous phase extracted with dichloromethane (4×20 ml). The combined organic phases were dried with MgSO4. The solvent was then concentrated by evaporation in a vacuum. One of the possible diastereoisomers was isolated from the residue obtained (352 mg) by means of chromatographic purification [silica gel 60 G (10 g); ethyl acetate 150 ml].
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@H:3]1[C:9](Cl)=[O:10].[F:13][C:14]1[C:19]([F:20])=[C:18]([CH3:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[CH2:24][OH:25].N1C=CC=CC=1>O1CCCC1>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@H:3]1[C:9]([O:25][CH2:24][C:15]1[C:16]([F:23])=[C:17]([F:22])[C:18]([CH3:21])=[C:19]([F:20])[C:14]=1[F:13])=[O:10]
Reactant: Cc1c(F)c(F)c(CO)c(F)c1F
Reactant: CC(C)=C[C@@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)=C[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
2.06 Grams of (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid chloride was added to a mixture of 1.78 g of (2,3,5,6-tetrafluoro-4-methylphenyl)methanol, 0.87 g of pyridine and 20 ml of tetrahydrofuran under ice-cooling. The resulting mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into about 100 ml of ice water and extracted twice with 100 ml of ethyl acetate. The combined ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to obtain 2.75 g (yield: 87%) of (2,3,5,6-tetrafluoro-4-methylphenyl)methyl (1R)-trans-2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([C:15]([NH:18]S(C(C)(C)C)=O)([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[ClH:25].O1CCOCC1>C(Cl)Cl>[ClH:25].[ClH:25].[NH2:18][C:15]([C:12]1[N:13]=[N:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[N:8][CH:7]=2)=[CH:10][CH:11]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(NS(=O)C(C)(C)C)c1ccc(-c2ccc(CO)nc2)nn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(N)c1ccc(-c2ccc(CO)nc2)nn1
Reaction time: 0.75 h

Procedure:
2-Methyl-propane-2-sulfinic acid{1-[6-(6-hydroxymethyl-pyridin-3-yl)-pyridazin-3-yl]-1-methyl-ethyl}-amide (4 mg, 0.011 mmol) was dissolved in CH2Cl2 (0.25 mL) and 4M HCl in dioxane (2 mL, 8 mmol) was added. After 45 minutes, the solvent was removed under a stream of N2 to give {5-[6-(1-amino-1-methyl-ethyl)-pyridazin-3-yl]-pyridin-2-yl}-methanol dihydrochloride as a crude light brown solid residue. This was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][N:15]3[CH:19]=[N:18][C:17]([C:20](OC)=[O:21])=[N:16]3)[CH:11]=[N:10][C:9]=2[O:24][CH3:25])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][N:15]3[CH:19]=[N:18][C:17]([CH2:20][OH:21])=[N:16]3)[CH:11]=[N:10][C:9]=2[O:24][CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ncn(Cc2cnc(OC)c(-c3cccc(Cl)c3)n2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ncc(Cn2cnc(CO)n2)nc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
To a solution of methyl 1-((6-(3-chlorophenyl)-5-methoxypyrazin-2-yl)methyl)-1H-1,2,4-triazole-3-carboxylate (Example 127, 77.00 mg, 0.21 mmol), in THF (1 mL) was added lithium borohydride (4.66 mg, 0.21 mmol). The mixture was stirred at room temperature for 3 hr. The mixture was diluted with water and extracted into DCM. The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification (FCC, SiO2, 0-5% DCM/MeOH) afforded the title compound (50 mg; 70%). 1H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 8.21 (s, 1H), 8.02 (td, J=1.1, 2.1 Hz, 1H), 8.00-7.92 (m, 1H), 7.45-7.38 (m, 2H), 5.53 (s, 2H), 4.59 (s, 2H), 4.06 (s, 3H). [M+H]=332.15.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:18][NH:19][CH3:20]>C1COCC1>[CH3:18][N:19]([CH3:20])[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(CCl)N1CCCc2ccc([N+](=O)[O-])cc21
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-chloro-1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanone (1 g, 3.9 mmol) was dissolved in 10 ml of dry THF and 7.8 ml of a 1M solution of dimethylamine in THF (7.8 mmol) were added. This reaction mixture was stirred at ambient temperature for 24 h. The solvent was removed under reduced pressure and the residue was crystallized from diethyl ether to give the expected compound 2-(dimethylamino)-1-(7-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanone in the form of a brown solid (Mp 130-132° C.).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][CH2:21]Cl.O>CN(C)C=O>[CH3:19][O:20][CH2:21][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1]
Reactant: COCCl
Reactant: Oc1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-trifluoromethoxyphenol (10.00 g) was dissolved in N,N-dimethylformamide (50 mL), and potassium carbonate (15.52 g) and chloromethyl methyl ether (4.70 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and then the mixture was extracted with n-hexane. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (12.21 g) as a colorless oily substance.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:34]=[CH:35][CH:36]=1)[CH:23]=[C:24]1[C:29](=[O:30])[O:28][C:27]([CH3:32])([CH3:31])[O:26][C:25]1=[O:33])([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH:37]1([Mg]Br)[CH2:39][CH2:38]1.Cl.O>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]([CH:23]([CH:37]2[CH2:39][CH2:38]2)[CH:24]2[C:25](=[O:33])[O:26][C:27]([CH3:31])([CH3:32])[O:28][C:29]2=[O:30])[CH:34]=[CH:35][CH:36]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC1(C)OC(=O)C(=Cc2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C(=O)O1
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC(=O)C(C(c2cccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)C2CC2)C(=O)O1
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
Under an argon atmosphere, to a solution of 5-(3-(((tert-butyldiphenylsilyl)oxy)methyl)benzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6.39 g) in THF (85 mL) was added dropwise a 0.70 M solution of cyclopropylmagnesium bromide in THF (54.7 mL) at 0° C. over 15 min, and the mixture was stirred at 0° C. for 5.5 hr. 0.50N Hydrochloric acid (300 mL) was added dropwise at 0° C., and water was further added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.05 g) as a colorless oil.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:21]([F:22])=[CH:20][C:16]([C:17]([OH:19])=O)=[C:15]([F:23])[C:14]=3[Cl:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:25]1([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:28][CH2:27][CH2:26]1>>[C:1]12([CH2:11][O:12][C:13]3[C:21]([F:22])=[CH:20][C:16]([C:17]([NH:32][S:29]([N:25]4[CH2:28][CH2:27][CH2:26]4)(=[O:31])=[O:30])=[O:19])=[C:15]([F:23])[C:14]=3[Cl:24])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)c1cc(F)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1F
Reactant: NS(=O)(=O)N1CCC1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(F)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1F

Procedure:
The compound was prepared in a similar manner to step 2 of Example 412 from 4-(adamantan-1-ylmethoxy)-3-chloro-2,5-difluorobenzoic acid and azetidine-1-sulfonamide. LCMS (Method D): RT=7.35 min, m/z: 475.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (dd, J=11.7, 6.6 Hz, 1H), 3.86 (t, J=7.6 Hz, 4H), 3.77 (d, J=1.7 Hz, 2H), 2.08 (p, J=7.6 Hz, 2H), 2.02-1.93 (m, 3H), 1.77-1.59 (m, 12H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]([O:13][C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[C@H:18]([CH2:20][CH3:21])[CH3:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:10][C:9]([O:13][C:14](=[O:15])[NH:16][CH:17]([C:22]([NH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:23])[CH:18]([CH3:19])[CH2:20][CH3:21])([CH3:12])[CH3:11]
Reactant: NCc1cccnc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NCc1cccnc1
Yield: 70.7 %

Procedure:
The title compound is prepared by the procedure of Example 1, using 1.0 g of 3-(aminomethyl)pyridine, 2.33 g of N-(tert-butoxycarbonyl)-L-isoleucine, 6.95 g of BOP, 11.95 g of Hunig's base and 15 ml of methylene chloride to give 2.1 g of the desired product after chromatography.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([OH:7])=O.C([NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(OC(C)(C)C)=O.C(N(CC)C(C)C)(C)C.CCCP(=O)=O>C(Cl)Cl>[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:5](=[O:7])[CH2:4][CH2:3][O:2][CH3:1])[CH2:18][CH2:17]1
Reactant: COCCC(=O)O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCC(=O)N1CCC(N)CC1
Reaction time: 4.5 h
Yield: 36.2 %

Procedure:
3-Methoxypropanoic acid (225 μL, 2.40 mmol) was added to a solution of 4-(N-Boc-amino)-piperidine (400 mg, 2.00 mmol) in methylene chloride (25 mL) at room temperature. N,N-diisopropylethylamine (1.30 mL, 7.49 mmol) and propylphosphonic anhydride (1.78 mL, 50 wt. % in ethyl acetate, 3.00 mmol) was added, and the solution was stirred for 4.5 h. The reaction mixture was concentrated and partitioned between ethyl acetate (5 mL) and water (5 mL). The organic portion was washed with 0.2M HCl (2 mL), sat. Sodium bicarbonate (5 mL) and brine (5 mL). The solution was then dried over sodium sulfate and concentrated to a white solid. This solid was taken up in methylene chloride (6 mL), and trifluoroacetic acid (3 mL) was added at room temperature. After 1 h the solution was concentrated. The resulting solid was dissolved in methylene chloride (2 mL) and 1M sodium hydroxide (1 mL). This mixture was extracted with methylene chloride (4×2 mL) and ethyl acetate (4×2 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give 135 mg of the title compound, 1-(4-aminopiperidin-1-yl)-3-methoxypropan-1-one (36% over two steps). 1H NMR (300 MHz, CD3OD) δ 4.51-4.41 (m, 1H), 4.03-3.93 (m, 1H), 3.64 (d, J=6.3 Hz, 2H), 3.32 (s, 3H), 3.17-3.05 (m, 1H), 2.96-2.83 (m, 1H), 2.75-2.55 (m, 3H), 1.99-1.80 (m, 2H), 1.40-1.14 (m, 2H).
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]1[NH:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][O:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[S:29](Cl)(=[O:31])=[O:30])[CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:1]([O:5][CH2:6][C@H:7]1[N:14]([S:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:28]=2[N:19]=[CH:20][CH:21]=[CH:22]3)(=[O:30])=[O:31])[CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][O:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC[C@@H]1COCc2ccccc2CN1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: c1ccncc1
Product: CC(C)(C)OC[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Reaction time: 16 h
Yield: 45.4 %

Procedure:
To a mixture of compound 14f (crude, 129 mg, 0.5 mmol) in pyridine (4 mL) at rt was added quinoline-8-sulfonyl chloride (142 mg, 0.6 mmol). The reaction mixture was stirred for 16 h and concentrated under reduced pressure. The residue was partitioned between CHCl3 and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC to give compound 14 (100 mg, 44% yield). 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.49 (d, 1H, J=8.0 Hz), 8.17 (d, 1H, J=8.0 Hz), 7.97 (d, 1H, J=8.0 Hz), 7.56 (t, 1H, J=8.0 Hz), 7.47-7.44 (m, 1H), 7.21 (d, 1H, J=8.0 Hz), 7.02-7.00 (m, 1H), 6.94-6.93 (m, 1H), 6.87 (d, 1H, J=8.0 Hz), 5.17 (d, 1H, J=8.0 Hz), 4.98-4.93 (m, 2H), 4.66 (d, 1H, J=8.0 Hz), 4.51 (s, 1H), 4.27 (d, 1H, J=8.0 Hz), 3.78 (d, 1H, J=8.0 Hz), 3.53 (t, 1H, J=7.2 Hz), 3.21-3.18 (m, 1H), 1.00 (s, 9H). MS (ESI) calcd for [C24H28N2O4S+H]+ (m/z): 441.56. found: 441.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.[Cl:28][C:29]1[N:33]([CH3:34])[N:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36].CCN(CC)CC>C(Cl)Cl>[Cl:28][C:29]1[N:33]([CH3:34])[N:32]=[CH:31][C:30]=1[C:35]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)=[O:36]
Reactant: Cn1ncc(C(=O)Cl)c1Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5cnn(C)c5Cl)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a mixture of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.41 mmol) and 5-chloro-1-methyl-1H-pyrazole-4-carbonyl chloride (0.073 g, 0.41 mmol) in CH2Cl2 (50 mL), was added Et3N (0.086 mL, 0.62 mmol) and the reaction stirred under nitrogen at room temperature for 1 hour. The residue was concentrated and purified by flash chromatography on silica gel, eluting with 70% CH2Cl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% (92:7:1 CHCl3/MeOH/concentrated NH4OH), to afford the title compound as a white solid (0.159 g, 76%). 1H NMR (500 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.12 (d, J=9.0 Hz, 2H), 7.77 (s, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.69 (d, J=2.3 Hz, 1H), 6.47 (d, J=2.3 Hz, 1H), 3.88 (s, 3H), 3.80-3.87 (m, 6H), 3.63-3.80 (m, 4H), 3.38-3.44 (m, 4H). APCI MS m/z 509 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[NH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(O)(=O)C>C(O)C>[C:25]([O:24][C:23]([NH:22][CH2:21][CH2:20][NH:19]/[C:11](/[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])=[CH:12]\[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1OC
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\NCCNC(=O)OC(C)(C)C)c1ccc(OC)cc1OC

Procedure:
A solution of ethyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate (41.91 g, 166 mmol), tert-butyl 2-aminoethylcarbamate (54.7 g, 342 mmol), and acetic acid (16.14 g, 269 mmol) in ethanol (180 mL) was heated at reflux for 5.3 h. After removal of most of the solvent by rotary evaporation, the resulting oil was partitioned between EtOAc (ca. 300 mL) and 10% (w/v) aq. ammonium chloride. The EtOAc layer was separated and then washed with water, 10% (w/v) aq. ammonium chloride (3 mL), and brine (10 mL). The EtOAc layer was washed with sat. aq. sodium bicarbonate, brine (6 mL) was added, and the emulsion was allowed to settle. The EtOAc layer was finally washed with brine and dried over sodium sulfate. Evaporation of the EtOAc layer's volatile components afforded a viscous, amber taffy (62.3 g, 95%). This crude product was used without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH2:2][CH2:3][CH3:4].[NH2:17][C:18]1[CH:34]=[CH:33][CH:32]=[CH:31][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:21]>>[CH2:1]([O:5][C:6]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([NH:17][C:18]1[CH:34]=[CH:33][CH:32]=[CH:31][C:19]=1[C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[O:21])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(OC)ccc1C(=O)O
Reactant: COc1ccc(NC(=O)c2ccccc2N)cc1
Product: CCCCOc1cc(OC)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(OC)cc1
Yield: 25.2 %

Procedure:
Using the procedure described in Example 102, Part A, 2-butoxy-4-methoxybenzoic acid (0.54 mmol)and 2-amino-N-(4-methoxyphenyl)benzamide (0.54 mmol) yielded 61 mg (25%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([O:18]CC2C=CC=CC=2)=[O:17])[NH:3]1>CO.C(OCC)(=O)C.[Pd]>[CH3:15][O:14][C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2](=[O:1])[NH:3][CH:4]([C:16]([OH:18])=[O:17])[NH:5]2)=[CH:10][CH:9]=1)=[O:13]
Reactant: COC(=O)c1ccc2c(=O)[nH]c(C(=O)OCc3ccccc3)nc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)NC(C(=O)O)NC2=O
Reaction time: 24 h
Yield: 95.9 %

Procedure:
To a solution of 2-benzyl 7-methyl 4-oxo-3,4-dihydroquinazoline-2,7-dicarboxylate (0.70 g, 2.0 mmol) in methanol (7 mL) and ethyl acetate (4 mL) was added 10% palladium on carbon (20 mg). The mixture was purged with H2 gas (3×) and stirred under an atmosphere of H2 for 1 d. The reaction mixture was then filtered through Celite, washed with MeOH and concentrated to afford 7-(methoxycarbonyl)-4-oxo-1,2,3,4-tetrahydroquinazoline-2-carboxylic acid (0.48 g, 90%). LC-MS: (FA) ES+ 251; 1H NMR (400 MHz, DMSO) δ 7.66 (d, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.17 (d, J=8.2 Hz, 1H), 4.65 (s, 1H), 3.82 (s, 3H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(Cl)Cl.[OH-].[Na+]>O>[CH2:8]1[CH2:9][CH2:10][N:5]([C:1]([N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:2])[CH2:6][CH2:7]1
Reactant: C1CCNCC1
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(N1CCCCC1)N1CCCCC1
Reaction time: 0.08 h
Yield: 96 %

Procedure:
Phosgene was passed for 17 minutes, at the rate of 3 grams per minute, through a mixture of 84 grams (1 mole) of piperidine, 500 ml. of methylene chloride and 100 ml. of water. The pH was maintained in the range of 8-11 by the addition of 50% aqueous sodium hydroxide solution during the latter portion of the phosgene passage. An exothermic reaction occurred which caused refluxing of the mixture. After phosgenation was complete, additional base was added until the pH remained constant at 11 for 5 minutes, after which 200 ml. of water was added and the organic layer was removed, washed twice with aqueous hydrochloric acid solution and filtered. Upon vacuum stripping, the desired bis(pentamethylene)urea was obtained in 96% yield. Its structure was confirmed by proton nuclear magnetic resonance spectroscopy.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[O:6])[CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[N:38]=[N:39][C:40](Cl)=[CH:41][CH:42]=1>C(O)C>[Cl:36][C:37]1[N:38]=[N:39][C:40]([N:1]2[CH2:4][CH:3]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([CH:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[CH:10][CH:9]=3)=[O:6])[CH2:2]2)=[CH:41][CH:42]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CNC3)cc2)CC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CN(c4ccc(Cl)nn4)C3)cc2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
In a 50 mL round-bottomed flask was added tert-butyl 4-(4-(azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate (918 mg, 2.55 mmol) and diisopropylethylamine (0.558 ml, 3.19 mmol) in ethanol (10.6 ml). 3,6-dichloropyridazine (317 mg, 2.128 mmol) was added as a solid in a single portion. The reaction was stirred overnight at 45° C.; and the reaction was cooled and concentrated. Dichloromethane and water were added and the layers were separated. The aqueous layer was extracted three times with dichloromethane and the combined organics were dried with magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl.[N-:13]([C:16]#[N:17])[C:14]#[N:15].[Na+]>O>[C:14]([N:13]=[C:16]([NH2:17])[NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)#[N:15]
Reactant: N#C[N-]C#N
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CN=C(N)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.2 %

Procedure:
3-Trifluoromethylaniline (10 g, 62.1 mmol) was dissolved in 6N HCl (10.35 mmol, 62.1 mmol) and 50 ml of water. Sodium dicyanamide (5.53 g, 62.1 mmol) was added and the mixture was stirred for 12 hours at ambient temperature. The mixture was then cooled to 0° C. and stirred for 1 hour resulting in the formation of a precipitate. Filtration provided 12.22 g of the desired product as a white solid.