Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]([Cl:14])=[CH:13][C:4]=2[N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:14][C:12]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:5]2[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[N:3][C:4]=2[CH:13]=1
Reactant: CN1CCNCC1
Reactant: CC(C)n1c(Cl)nc2cc(Cl)c([N+](=O)[O-])cc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)n1c(N2CCN(C)CC2)nc2cc(Cl)c([N+](=O)[O-])cc21
Yield: 84.7 %

Procedure:
2,5-Dichloro-1-isopropyl-6-nitrobenzimidazole (4.6 g) was suspended in toluene (31 ml) and to the suspension was added dropwise N-methylpiperazine (8.4 g) and then the mixture was refluxed for 30 minutes. To the reaction solution was added ethyl acetate and the mixture was washed with water and then extracted with 2N hydrochloric acid. The water layer was separated and made basic with an aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure to give 5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)-6-nitrobenzimidazole (4.8 g). A part of the obtained product was recrystallized from acetonitrile, which showed the physical properties consistent with those in Preparation 8.
Reaction SMILES: C([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])=[CH:15][CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29][N:30]([CH3:32])C)#N.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1.ClCCl.CO>CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:32]([NH:33][C:34]4[S:35][CH:36]=[N:37][N:38]=4)=[N:30][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])=[CH:18][CH:17]=1)=[O:20])=[O:23])[CH3:26]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)cc1
Reactant: Nc1nncs1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)N=S(C)(=O)c1ccc(COc2cc3ncnc(Nc4nncs4)c3cc2OC)cc1
Yield: 40 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{4-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (85 mg, 0.19 mmol) with 2-amino-1,3,4-thiadiazole (23 mg, 0.22 mmol) and chromatographic purification (silica gel, dichloromethane/methanol: 0→30% methanol) gives the desired product in 40% yield (38 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([C:10]1[CH:19]=[CH:18][C:13]2[NH:14][C:15](=[O:17])[S:16][C:12]=2[CH:11]=1)(=[O:9])[CH3:8].[CH3:20][O:21][CH2:22]Cl.CCOC(C)=O>CN(C)C=O>[C:7]([C:10]1[CH:19]=[CH:18][C:13]2[N:14]([CH2:20][O:21][CH3:22])[C:15](=[O:17])[S:16][C:12]=2[CH:11]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)c1ccc2[nH]c(=O)sc2c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCn1c(=O)sc2cc(C(C)=O)ccc21
Yield: 75.4 %

Procedure:
Add cesium carbonate (1.5 Eq; 310.5 mmoles; 101.1 g) to a solution of 6-acetyl-3H-1,3-benzothiazol-2-one (40.0 g, 207 mmoles) in dimethylformamide (690 mL). Add chloromethyl methyl ether (1.3 Eq, 269 mmoles, 20.4 mL) dropwise and stir at room temperature for 18 hr. Transfer to a separatory funnel, add EtOAc (1 L), wash with water (2×200 mL), and then brine (200 mL). Back extract with DCM (300 mL). Dry the combined organic layers over Na2SO4, filter and concentrate. Slurry the concentrate in 200 ml hexanes/EtOAc (75:25), and filter to give 6-acetyl-3-(methoxymethyl)-3H-1,3-benzothiazol-2-one as a white solid (37.0 g, 156 mmoles, 75% yield). LCMS (low) rt=1.68 min., M+1=238.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([Si:15]([CH3:27])([CH3:26])[O:16][C@@H:17]1[CH2:24][CH2:23][CH2:22][C@H:21]([OH:25])[CH2:20][CH2:19][CH2:18]1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[C:11]([Si:15]([CH3:27])([CH3:26])[O:16][CH:17]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20][CH2:19][CH2:18]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@@H](O)CCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1CCCC(=O)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101 %

Procedure:
A solution of 4.5 g (58 mmol) of dimethyl sulphoxide in 25 mL dichloromethane was added dropwise to a stirred solution of 3.7 g (29 mmol) of oxalyl chloride in 50 mL of dichloromethane at −78° C. The solution was stirred for 30 minutes at −78° C. and then 5.0 g (19.3 mmol) of cis-5-(tert-butyl-dimethyl-silanyloxy)-cyclooctanol (57) in 30 mL of dichloromethane was added dropwise keeping the temperature at −78° C. After stirring for 30 minutes, 9.8 g (97 mmol) of triethylamine was added dropwise and the temperature allowed to warm to −30° C. Further 50 mL of dichloromethane were added and the solution stirred for 1 h at −30° C. With stirring 300 mL of a saturated ammonium chloride solution were added portionwise and then the organic layer was separated. After washing with further ammonium chloride solution, the organic phase was dried over magnesium sulfate, filtered and evaporated to give 5.0 g of the desired product as a yellow oil which was used without purification. Rt=1.96 min (Method C). Detected mass: 257.3 (M+H+).
Reaction SMILES: C1(=O)N(C2CCCNC2)C(=O)C2=CC=CC=C12.CN(C)C(Cl)=O.[CH3:24][N:25]([CH3:45])[C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH:30]([N:34]2C(=O)C3=CC=CC=C3C2=O)[CH2:29]1)=[O:27].O.NN>>[CH3:24][N:25]([CH3:45])[C:26]([N:28]1[CH2:33][CH2:32][CH2:31][CH:30]([NH2:34])[CH2:29]1)=[O:27]
Reactant: CN(C)C(=O)N1CCCC(N2C(=O)c3ccccc3C2=O)C1
Agent: CN(C)C(=O)Cl
Agent: NN
Agent: O=C1c2ccccc2C(=O)N1C1CCCNC1
Solvent: O
Product: CN(C)C(=O)N1CCCC(N)C1

Procedure:
In addition, reacting 3-phthalimidopiperidine with N,N-dimethylcarbamoyl chloride and treating the resulting 1-(N,N-dimethylcarbamoyl)-3-phthalimidopiperidine with hydrazine hydrate gives 1-(N,N-dimethylcarbamoyl)-3-aminopiperidine. Reacting this piperidine compound with 9-acetoxyxanthene by the procedure of Example 1 gives N-[1-(N,N-dimethylcarbamoyl)-3-piperidinyl]-9-xanthenylamine.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([OH:5])=[O:4].[Cl:12][C:13]1([Cl:19])[CH2:15][CH:14]1[C:16]([NH2:18])=[O:17]>C1(C)C=CC=CC=1>[Cl:12][C:13]1([Cl:19])[CH2:15][CH:14]1[C:16]([NH:18]/[C:2](=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])/[C:3]([OH:5])=[O:4])=[O:17]
Reactant: NC(=O)C1CC1(Cl)Cl
Reactant: CCCCCCC(=O)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCC/C=C(\NC(=O)C1CC1(Cl)Cl)C(=O)O
Yield: 6 %

Procedure:
A mixture of 1.19 g (7.5 mmoles) of 2-ketooctanoic acid, 0.77 g (5.0 mmoles) of 2,2-dichlorocyclopropanecarboxamide, and 5 ml toluene were reacted using the same procedure as in the previous example. The crude product (537 mg) was purified by conversion to the methyl ester (BF3 /CH3OH), prepartive TLC (silica gel G, 4:1 hexane-EtOAc) and saponification of the pure Z-methyl ester (0.3M LiOH/CH3OH) to give 88 mg of Z-2-(2,2-dichlorocyclopropanecarboxamido)-2-octenoic acid as a partially crystalline gum. NMR spectrum (DMSO-d6): 9.68δ (s, 1H, NH), 6.50δ (t, 1H, ##STR74## 2.83δ (t, 1H, 1.97δ (d, ##STR75## 0.87δ (t, 3H, CH3).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2ccccc12
Reaction time: 6 h
Yield: 94 %

Procedure:
A mixture of 52.35 g (368.1 mmol) of 1-methylnaphthalene, 68.79 g (368.5 mmol) of N-bromosuccinimide (NBS), 0.45 g (1.86 mmol) of benzoyl peroxide (BPO) and 250 ml of carbon tetrachloride was stirred for 6 hours while heating and refluxing. The deposit was removed by filtration, and the filtrate was concentrated to obtain 84.64 g (purity: 90.4%, yield: 94%) of an oily crude product of 1-(bromomethyl)naphthalene.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:21]=[CH:22][C:23]4[C:27]([C:28]([OH:30])=O)=[C:26]([CH3:31])[S:25][C:24]=4[CH:32]=3)[CH:11]=2)=[O:9])[CH2:4]1.[CH2:33]([CH2:35][NH2:36])[OH:34].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:34][CH2:33][CH2:35][NH:36][C:28]([C:27]1[C:23]2[CH:22]=[CH:21][C:20]([O:19][C:16]3[CH:15]=[CH:14][N:13]=[C:12]4[CH:11]=[C:10]([C:8]([N:5]5[CH2:6][CH2:7][C@@H:3]([O:2][CH3:1])[CH2:4]5)=[O:9])[S:18][C:17]=34)=[CH:32][C:24]=2[S:25][C:26]=1[CH3:31])=[O:30]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)sc5c4)c3s2)C1
Reactant: NCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NCCO)c(C)sc5c4)c3s2)C1
Yield: 28.1 %

Procedure:
This material was prepared from the reaction of 6-[(2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 123b (130 mg, 0.278 mmole) with ethanolamine (84 μL, 1.39 mmole), N,N-diisopropylethylamine (0.15 mL, 0.83 mmole), and HBTU (263 mg, 0.694 mmole) in a manner similar to that previously described for example 117 to give a yellow solid (40 mg, 28%). 1H NMR (DMSO-d6, 300 MHz) δ 8.58 (1H, d, J=5.27 Hz), 8.33 (1H, t, J=5.56 Hz), 8.06 (1H, s), 7.96 (1H, d, J=2.26 Hz), 7.86 (1H, d, J=8.85 Hz), 7.32 (1H, dd, J=2.26, 8.85 Hz), 6.75 (1H, d, J=5.46 Hz), 4.76 (1H, br s), 4.13–3.81 (3H, m), 3.67–3.50 (4H, m), 3.43–3.32 (2H, m), 3.27, 3.24 (3H, s), 2.61 (3H, s), 2.18–1.94 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[CH3:11])=[O:5])[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(CCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice/water bath cooled solution of 2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (11.43 g) and (2-bromo-ethyl)-benzene (20.20 mL) in DMF (100 mL) was carefully added NaH (3.88 g, 60% suspension in mineral oil). The mixture was subsequently stirred at room temperature overnight, and cooled with ice/water bath again, another 20.20 mL of (2-brom-ethyl)-benzene and 3.88 of NaH were added to the reaction, which was allowed to stir for another 5 h; then the mixture was quenched by pouring into a mixture of ammonium chloride and ice/water, extracted with EtOAc; EtOAc phase was washed with water twice, saturated NaCl solution (once) and then dried over anhydrous sodium sulfate, filtered, concentrated; the residue was purified with silica column to give the desired title product (3.30 g) with recovered starting pyrrole (6.31 g). The title compound, ESI MS (m/z): 258 (M+H)+.
Reaction SMILES: [CH2:1](O)[CH2:2][CH3:3].[F:5][C:6]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:7]=1[O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11]>S(=O)(=O)(O)O.ClC(Cl)C>[F:5][C:6]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:7]=1[O:8][CH:9]([CH3:13])[C:10]([O:12][CH2:1][CH2:2][CH3:3])=[O:11]
Reactant: CC(Oc1ccc(O)cc1F)C(=O)O
Reactant: CCCO
Agent: O=S(=O)(O)O
Solvent: CC(Cl)Cl
Product: CCCOC(=O)C(C)Oc1ccc(O)cc1F
Reaction time: 6.5 h
Yield: 35.5 %

Procedure:
n-Propanol (35 ml) and concentrated sulfuric acid (6 drops) were added to a solution of crude 2-(2-fluoro-4-hydroxyphenoxy)propionic acid (8.6 g) in dichloroethane (13 ml). The mixture was heated under reflux with stirring for a period of 6.5 hours, cooled, and the solvent was evaporated under reduced pressure. The residue was treated with water and the aqueous mixture was extracted with dichloromethane. The organic phase was washed with a saturated aqueous solution of sodium hydrogen carbonate and then with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to give an oil (5.7 g; 54.8%). The oil was purified by vacuum distillation to give n-propyl 2-(2-fluoro-4-hydroxyphenoxy)propionate (3.7 g; 35.5%); bp 210°-220° C. at 0.1 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[C:5]([CH3:16])[NH:4][N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:3]1[C:2]([CH3:1])=[C:6]([B:7]2[O:11][C:10]([CH3:12])([CH3:13])[C:9]([CH3:15])([CH3:14])[O:8]2)[C:5]([CH3:16])=[N:4]1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Yield: 94.2 %

Procedure:
Using similar reaction conditions as described in (step i of Intermediate-2), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 4.5 mmol) was reacted with 3-fluoro benzyl bromide (1.02 g, 5.4 mmol) in DMF (10 ml) and potassium carbonate (1.86 g, 13.5 mmol) to afford 1.4 g (94.59% yield) of the pure product.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([C:10]([O:12]CC)=O)=[CH:8][N:7]=[C:6]([S:15][CH3:16])[N:5]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27].Cl>C(OCC)(=O)C.CN(C)C=O>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]1[C:10](=[O:12])[C:9]2[C:4](=[N:5][C:6]([S:15][CH3:16])=[N:7][CH:8]=2)[NH:3][C:26]1=[O:27]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cnc(SC)nc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1ncc2c(=O)n(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.9 %

Procedure:
315 mg of sodium hydride was added to an N,N-dimethylformamide (15 mL) solution of 1.0 g of ethyl 4-amino-2-(methylthio)pyrimidin-5-carboxylate, and stirred at room temperature for 5 minutes. 970 mg of 2,6-dichlorophenylisocyanate was added to the reaction liquid, and stirred at room temperature for 1 hour. Ethyl acetate and aqueous 1 N hydrochloric acid solution were added to the reaction solution, and the organic layer was separated. This was washed with saturated saline water, dried with anhydrous sodium sulfate, and the solvent was evaporated away. The precipitated solid was solidified with methanol, and the solid was taken out through filtration to obtain 1.43 g of the entitled compound as a white solid.
Reaction SMILES: [Se-2:1].[Na+].[Na+].Cl[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=1[C:11]#[N:12].Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C[O-].[Na+]>CN(C=O)C.CO>[NH2:12][C:11]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]=2[Se:1][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCl
Reactant: [Se-2]
Reactant: N#CC1=C(Cl)CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)c1[se]c2c(c1N)CCCC2
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a suspension of sodium selenide (4.7 g, 37.3 mmol, prepared from 3.0 g of selenium as described above) in DMF (37 mL) was added a solution of 2-chlorocyclohex-1-enecarbonitrile (5.24 g, 37.3 mmol) in DMF (18 mL) at rt for 5 min and stirred the mixture at 60° C. for 45 min. The reaction mixture was allowed to rt and added ethyl chloroacetate (3.16 mL, 37.3 mmol) dropwise for 5 min. The reaction mixture was stirred at 60° C. for 3 h. Then, a solution of sodium methoxide (2.0 g, 37.3 mmol) in methanol (37 mL) was added dropwise and stifling was continued for 2 h at the same temperature. The mixture was allowed to rt and poured into ice cold water and stirred for 15 min. The solution was extracted with chloroform (3×200 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (90:10) as eluents to give the product as a yellow color oil of a mixture of ethyl and methyl ester (2.4 g, 25%). 1H NMR (400 MHz, CDCl3): δ 5.54 (2H, s, —NH2), 4.24 (2H, q, J=7.1 Hz, —COOCH2CH3), 2.74-2.75 (2H, m, H-7), 2.27-2.28 (2H, m, H-4), 1.81-1.84 (4H, m, H-5,6), 1.31 (3H, t, J=7.1 Hz, —COOCH2CH3); LC-MS (positive ion mode): m/z 294, 296 (M+Na)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[NH:14][C:13](=O)[C:12]2[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8][C:7]=2[N:6]=1)=[N+:2]=[N-:3].P(Cl)(Cl)([Cl:20])=O>C(Cl)(Cl)Cl>[N:1]([CH2:4][C:5]1[N:14]=[C:13]([Cl:20])[C:12]2[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][CH2:8][C:7]=2[N:6]=1)=[N+:2]=[N-:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(C)CCc2nc(CN=[N+]=[N-])[nH]c(=O)c2C1
Solvent: ClC(Cl)Cl
Product: CC1(C)CCc2nc(CN=[N+]=[N-])nc(Cl)c2C1
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of 2-(azidomethyl)-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4(3H)-one (151 mg, 0.65 mmol) in chloroform (1.2 mL) was treated with phosphorus oxychloride (600 uL) at 60° C. for 1 h 20 min. After cooling to rt, the volatile materials were removed in vacuo, and the resulting residue was dissolved in ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate, and the aqueous phase was back extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 2-(azidomethyl)-4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazoline (136 mg, 0.54 mmol, 83% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 4.47 (s, 2H), 2.94 (t, 2H), 2.55 (s, 2H), 1.68 (t, 2H), 1.05 (s, 6H); MS (EI) for C11H14ClN5: 252 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH:10]=[CH:9][C:8]=1[CH3:22])[CH3:2].Cl.O1CCOCC1>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:10]=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(CCC(=O)OC(C)(C)C)ccc1C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(CCC(=O)O)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To dichloromethane (8.8 ml) were added the compound (1.79 g, 4.40 mmol) obtained in step B and 4N hydrochloric acid-dioxane solution (8.8 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with dichloromethane, washed with water, and dried over sodium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (1.21 g, yield 79%) as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].Cl.[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>>[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH:1][C@@H:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]3[C:8]([OH:10])=[O:9])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Yield: 24.8 %

Procedure:
According to the procedure of Example 10, Step 1, the reaction of 486.8 mg (3.4 mmol) of trans-2-amino-1-cyclohexane-carboxylic acid with 1.31 g of 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesufonyl chloride hydrochloride provided 382.7 mg of trans-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylic acid in 25% yield. MS: 455.1 (M+H)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12](Cl)[CH:11]=[C:10]([Cl:15])[N:9]=1.Cl>C1COCC1.[OH-].[Na+]>[Cl:7][C:8]1[CH:13]=[C:12]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:11]=[C:10]([Cl:15])[N:9]=1
Reactant: C1CCNCC1
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Clc1cc(N2CCCCC2)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A mixture of piperidine (0.910 g, 10.7 mmol) in 25 mL of THF and 5 mL of 1N NaOH was stirred for 30 minutes at 0° C., after which time 2,4,6-trichloropyridine (1.63 g, 8.86 mmol) was added. The reaction mixture was then stirred at 30-40° C. for 12-18 hours, after which the reaction mixture was cooled and neutralized with 5% HCl (aq). This product was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography over 100-200 mesh silica gel by elution with 10:90 ethyl acetate: hexanes to afford the product as a pure colorless solid (yield 32%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])=[CH:11][C:10]=2[F:29])[CH:3]=1.[CH3:30][NH2:31].C1COCC1>CCCCO>[F:29][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:28])[CH2:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:19])[CH:13]=[CH:14][C:9]=1[O:8][C:4]1[CH:3]=[C:2]([NH:31][CH3:30])[N:7]=[CH:6][N:5]=1
Reactant: CN
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Cl)ncn2)c(F)c1)Nc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCCCO
Product: CNc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)cc2F)ncn1
Yield: 34 %

Procedure:
A solution of N1-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamide (100 mg, 0.42 mmol, Example 4) in n-BuOH (3 mL) was treated with 2 M methylamine/THF (0.2 mL) and heated in a screw cap vial at 80° C. for 12 h. The mixture was concentrated and the residue purified by preparative HPLC using a gradient of MeOH—H2O containing 0.1% TFA. The fraction containing the product was lyophilized to give the title compound as a pale yellow solid (60 mg, 34%). 1H NMR (DMSO-d6) δ 10.58 (s, 1H), 10.36 (br s, 2H), 8.19 (br s, 1H), 7.76 (d, 1H, J=12.1 Hz), 7.64-7.62 (m, 2H), 7.36-7.27 (m, 2H), 7.15 (dd, 2H, J=8.8, 8.8 Hz), 5.95 (br s, 1H), 3.49 (s, 2H), 2.80 (s, 3H); MS (ESI+) m/z 414.16 (M+H)+.
Reaction SMILES: [CH2:1]=O.[NH:3]1[CH2:6][CH:5]([N:7]2[C:11]([CH2:12][CH3:13])=[C:10]([O:14][C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=3)[C:9]([CH2:23][CH3:24])=[N:8]2)[CH2:4]1>C(O)=O.C(OCC)(=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([Cl:21])[CH:18]=1)[O:14][C:10]1[C:9]([CH2:23][CH3:24])=[N:8][N:7]([CH:5]2[CH2:6][N:3]([CH3:1])[CH2:4]2)[C:11]=1[CH2:12][CH3:13]
Reactant: C=O
Reactant: CCc1nn(C2CNC2)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCc1nn(C2CN(C)C2)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 100 °C
Yield: 72.7 %

Procedure:
Paraformaldehyde (30 mg, 0.330 mmol) was added in one portion to a stirred solution of the pyrazole of Example 51 (120 mg, 0.330 mmol) in formic acid (2 ml) at room temperature. The mixture was heated at 100° C. for 5 hours, cooled to room temperature and concentrated under reduced pressure to leave a colourless oil. The oil was dissolved in ethyl acetate (50 ml) and the resulting solution was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:4:1, by volume) to provide the title compound (85 mg) as a colourless oil.