Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:23]1([NH:29][C:30](=[O:31])[N:3]([CH2:4][C:5]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:6]=2[CH2:7][N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:9]3=[O:14])[CH3:2])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O)C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and cyclohexyl isocyanate (0.28 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and extracted with H2O (40 mL), then with 1N HCl (40 mL). The organic layer was washed with brine (40 mL) and concentrated on rota-vap. The resulting oil was purified on silica gel column to give 3-cyclohexyl-1-[2-(2,6-dioxo-piperidin-3-yl) 1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea (0.54 g, 71%): mp 219-221° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 30/70 (CH3CN/H2O): tR=4.61 (99%); 1H NMR (DMSO-d6): δ 1.02-1.30 (m, 5H), 1.54-1.76 (m, 5H), 2.00-2.05 (m, 1H), 2.29-2.36 (m, 1H), 2.58-2.64 (m, 1H), 2.76 (s, 3H), 2.87-3.01 (m, 1H), 3.36-3.42 (m, 1H), 4.28 (d, J=17.3 Hz, 1H), 4.36 (d, J=17.5 Hz, 1H), 4.53 (s, 2H), 5.12-5.19 (dd, J=4.9, 13.1 Hz, 1H), 6.07 (d, J=7.7 Hz, 1H), 7.38 (d, J=7.4 Hz, 1H), 7.50 (t, J=7.4 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H), 11.03 (s, 1H). 13C NMR (DMSO-d6) δ: 22.69, 25.10, 25.35, 31.14, 33.22, 34.00, 46.12, 48.21, 49.34, 51.45, 121.59, 128.30, 130.08, 131.87, 134.41, 139.99, 157.09, 168.02, 170.99, 172.84. Anal Calcd for C22H28N4O4+0.1H2O: C, 63.78; H, 6.86; N, 13.52. Found: C, 63.41; H, 6.93; N, 13.33.
Reaction SMILES: [C:1]12[CH2:9][CH:5]([C:6]1(C)C)[CH:4]([OH:10])[CH:3](C1(C3CC4CC(C4(C)C)=C3C)CC3CC(C3(C)C)=C1C)[C:2]=2[CH3:31].BrCBr.[CH2:35]([Mg]Cl)[CH2:36][CH2:37]C>C(OCC)C>[CH:36]([C:4]1([OH:10])[CH2:5][CH2:9][C@:1]2([CH3:6])[C@@H:2]([CH2:31]2)[CH2:3]1)([CH3:37])[CH3:35]
Reactant: CC1=C2CC(CC1C1(C3C(C)=C4CC(C3O)C4(C)C)CC3CC(=C1C)C3(C)C)C2(C)C
Reactant: CCCC[Mg]Cl
Solvent: BrCBr
Solvent: CCOCC
Product: CC(C)C1(O)CC[C@@]2(C)C[C@H]2C1
Reaction time: 16 h
Yield: 85 %

Procedure:
Prepared as described in Example 10 from Terpinen-4-ol (2 g, 13 mmol) and dibromomethane (9.15 g, 52 mmol) in diethyl ether by dropwise addition of tent-butyl magnesium chloride 2M in diethyl ether (26 ml, 52 mmol) at 10°-20° C. Work-up after 16 h at 25° C. and bulb-to-bulb distillation gave 2.1 g (85%) of a colorless oil. Odour: Agrestic. 1H-NMR (CDCl3): δ 0.3 (dd, 1H), 0.43 (dd, 1H), 0.6 (dddd, 1H), 0.89 (d, 3H), 0.91 (d, 3H), 1.03 (s, 3H), 1.1-1.2 (m, 2H), 1.2-1.3 (m, 1H), 1.5-1.7 (2 m, 2H), 1.75-1.9 (2H), 2.2 (m, 2H) ppm. 13C-NMR: δ 14.4 (s), 16.2 (q), 16.4 (q), 17.7 (d), 19.9 (t), 27.2 (q), 28.1 (t), 31.6 (t), 31.9 (d), 35.7 (t), 72.8 (s). syn-configuration confirmed by COSY, HSQC, HMBC, NOESY in CDCl3. MS (EI): m/z (%) 168 [M]+, 3), 150 ([M-18]+, 8), 125 (32), 107 (65), 86 (38), 71 (80), 43 (100). IR (film): 3419 (br), 2936 (m), 2863 (m), 1458 (m), 1379 (w), 1302 (w), 1225 (w), 1133 (m), 1049 (w), 992 (s), 957 (w), 906 (w), 863 (w).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Reaction time: 0.45 h

Procedure:
4-Bromoanisole (13 ml, 0.1038 mol) in THF (13.5 ml) is added to a mixture of magnesium (2.24 g, 92.2 mmol) in dry THF (20 ml). When the magnesium is consumed the reagent mixture (XIII) is cooled in a ice/water bath and a mixture of 1-benzyl-4-piperidone (XII, 15 ml, 80.9 mmol) in THF (35 ml) is added dropwise over 21 minutes. The bath is then removed and the mixture stirred for 27 minutes, then poured into saturated aqueous sodium bicarbonate. The mixture is extracted several times with ether and the combined organic extracts are dried over magnesium sulfate, concentrated and the resulting material chromatographed on silica gel eluting with methanol/dichloromethane (4/96) containing ammonium hydroxide (0.4%). Impure fractions are combined and rechromatographed as above to give 1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol (XIV), NMR (CDCl3) 1.74, 2.14, 2.46, 2.78, 3.58, 3.80, 6.88, 7.31 and 7.44 δ.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.[CH3:19][C:20]1([CH3:27])[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:19][C:20]1([CH3:27])[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=2)[CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nc(C(F)(F)F)nc12
Reactant: CC1(C)CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CCC(Nc2nc(C(F)(F)F)nc3c([N+](=O)[O-])cccc23)CC1
Yield: 45.2 %

Procedure:
A suspension of 4-chloro-8-nitro-2-(trifluoromethyl)quinazoline (200 mg, 0.72 mmol), 4,4-dimethylcyclohexanamine (109 mg, 0.86 mmol), K2CO3 (398 mg, 2.89 mmol) in CH3CN (2 mL) was heated at reflux for 8 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.91-8.89 (d, J=7.2 Hz, 1H), 8.69-8.66 (d, J=7.8 Hz, 1H), 8.39-8.37 (d, J=7.8 Hz, 1H), 7.84-7.79 (t, J=8.1 Hz, 1H), 4.12 (m, 1H), 1.76-1.64 (m, 4H), 1.46-1.28 (m, 4H), 0.98 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(#N)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(OC)cc1C=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-hydroxy-5-methoxybenzaldehyde (21.75 g, 143 mmol) in 240 mL acetonitrile were successively added Cs2CO3 (55.9 g, 1.2 eq.) and ethyl bromoacetate (16.6 mL, 1.05 eq.) and the mixture vigorously stirred at ambient temperature for 2 h. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents left 34.36 g of the title product, sufficiently pure to be used for the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(CC(=O)C)(=O)C>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=3[C:6]=2[CH:7]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2)cc1
Solvent: CC(=O)CC(C)=O
Product: Cc1ccc2oc3ccc(C)cc3c2c1

Procedure:
By treating 4,4'-dimethyldiphenyl ether under the same reaction conditions as in Example 2 except that acetylacetone was not added, 1.3 g (6.8 m. moles) of 2.8-dimethyldibenzofuran was obtained and 0.36 g (0.9 m. mole) of the dimer also obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][OH:16])=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH2:18][CH2:19][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21].C(N(CC)CC)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C@@H:14]([CH3:17])[CH2:15][OH:16])=[CH:8][C:4]=1[C:5]([NH:18][CH2:19][C:20](=[O:21])[NH:22][CH:23]([CH3:25])[CH3:24])=[O:7]
Reactant: CC(C)NC(=O)CN
Reactant: C[C@@H](CO)COc1ccc(N)c(C(=O)O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)CNC(=O)c1cc(OC[C@@H](C)CO)ccc1N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-amino-5-[(S)-(+)-3-hydroxy-2-methylpropoxy]benzoic acid hydrochloride (200 mg, 0.76 mmol), 2-amino-N-isopropylacetamide*HCl (INTERMEDIATE I.1) (105 mg, 0.70 mmol) and triethylamine (0.23 mL, 1.68 mmol) in DMF (5 mL) was stirred at room temperature for 5 min. EDC (176 mg, 0.92 mmol) and HOBt (124 mg, 0.92 mmol) were added and stirring continued at room temperature for 16 h. The mixture was partitioned between ethyl acetate and sat. NaHCO3 (aq.) and the aqueous extracted with additional ethyl acetate. The combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude 2-amino-5-[(S)-(+)-3-hydroxy-2-methylpropoxy]-N-(isopropylcarbamoylmethyl)benzamide (INTERMEDIATE VIII.1) was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])[CH:5]=[C:6]([F:25])[C:7]=1[O:8][CH2:9][C:10]1[N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:17])[F:16].O1CCCC1.[Li+].[OH-]>O>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:5]=[C:6]([F:25])[C:7]=1[O:8][CH2:9][C:10]1[N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][C:14]=1[C:15]([F:18])([F:16])[F:17]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccccc2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1cc(F)c(OCc2c(C(F)(F)F)ccn2-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-(3,5-difluoro-4-[[1-phenyl-3-(trifluoromethyl)-1H-pyrrol-2-yl]methoxy]phenyl)propanoate (100 mg, 0.22 mmol, 1.00 equiv), tetrahydrofuran (1 mL) and a solution of LiOH (100 mg, 4.18 mmol, 18.93 equiv) in water (1 mL). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was then concentrated under vacuum. The pH value of the solution was adjusted to pH5 with hydrogen chloride (2 mol/L). The resulting solution was extracted with ethyl acetate (3×5 mL) and the organic layers combined. The resulting residue was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/H2O (0.05% CF3COOH)=1:1 increasing to ACN/H2O (0.05% CF3COOH)=9:1 within 10 min; Detector, UV 254 nm to yield 3-(3,5-difluoro-4-[[1-phenyl-3-(trifluoromethyl)-1H-pyrrol-2-yl]methoxy]phenyl)propanoic acid as a white solid (22.5 mg, 23%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:15])[NH2:14])=[N:6]1.[C:20]([CH:22]([C:30]#[N:31])[C:23]([CH3:29])([CH3:28])[C:24](OC)=[O:25])#[N:21].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[NH2:21][C:20]1[C:22]2[C:23]([CH3:29])([CH3:28])[C:24](=[O:25])[NH:31][C:30]=2[N:15]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[F:1])[N:6]=2)[N:14]=1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Reactant: COC(=O)C(C)(C)C(C#N)C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nc(N)c21

Procedure:
300 mg (1.15 mmol) of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide were admixed with 2 ml of tert-butanol, 287 mg (1.38 mmol) of methyl 3,3-dicyano-2,2-dimethylpropanoate dissolved in 2 ml of tert-butanol and 181 mg (1.61 mmol) of potassium tert-butoxide, and the mixture was heated under reflux for 72 h. The mixture was concentrated to dryness and the residue was stirred with water/isopropanol (v/v=3:1). The solid was filtered off and dried under high vacuum. 385 mg (80% of theory) of the target compound were obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([NH:30][C:31]([NH:33][C:34]4[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=4[F:41])=[O:32])=[N:25][CH:26]=[N:27]3)=[CH:22][C:21]=2[O:42][CH3:43])[CH2:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([NH:30][C:31]([NH:33][C:34]4[C:35]([F:41])=[CH:36][CH:37]=[CH:38][C:39]=4[F:40])=[O:32])=[N:25][CH:26]=[N:27]3)=[CH:22][C:21]=2[O:42][CH3:43])[CH2:12][CH2:11]1
Reactant: COc1cc2c(NC(=O)Nc3c(F)cccc3F)ncnc2cc1OCCCN1CCC(CNC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(NC(=O)Nc3c(F)cccc3F)ncnc2cc1OCCCN1CCC(CN)CC1

Procedure:
Using an analogous procedure to that described in Example 21, 1-{7-[3-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)propoxy]-6-methoxyquinazolin-4-yl}-3-(2,6-difluorophenyl)urea was reacted with trifluoroacetic acid to give the title compound; NMR Spectrum: (DMSOd6) 1.0-1.4 (m, 3H), 1.7 (d, 2H), 1.9-2.1 (m, 6H), 2.4 (m, 2H), 2.9 (d, 2H), 3.3 (s, partially obscured by a water signal), 4.0 (s, 3H), 4.24 (t, 3H), 5.0-7.0 (br m, 1H), 7.2-7.4 (m, 4H), 8.05 (s, 1H), 8.68 (s, 1H), 11.75S(s, 1H); Mass Spectrum: M+H+ 501.
Reaction SMILES: [C:1]12([PH:11][C:12]34[CH2:21][CH:16]5[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]5)[CH2:13]3)[CH2:19]4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Li]CCCC.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(OCCCC)CCC.C1(C)C=CC=CC=1>[C:1]12([P:11]([C:12]34[CH2:19][CH:18]5[CH2:20][CH:14]([CH2:15][CH:16]([CH2:17]5)[CH2:21]3)[CH2:13]4)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: C1C2CC3CC1CC(PC14CC5CC(CC(C5)C1)C4)(C2)C3
Reactant: CCCCCCBr
Agent: [Li]CCCC
Solvent: CCCCOCCCC
Solvent: Cc1ccccc1
Product: CCCCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2

Procedure:
5.5 g (18 mmol) of di(1-adamantyl)phosphine were placed in 60 ml of di-n-butyl ether, and 20 ml of a 2.5 M solution of n-BuLi (50 mmol) in toluene were added. The mixture was refluxed for 45 min and cooled and 3.0 g (18 mmol) of 1-bromohexane were added dropwise. The mixture was refluxed for 30 min, cooled and washed with saturated ammonium chloride solution (3×), the organic phase was separated off and dried over sodium sulfate and the solvent was distilled off under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH2:13].[CH3:14][C:15]1[N:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[S:18][C:19]=1[C:20](O)=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:20]([C:19]1[S:18][C:17]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[N:16][C:15]=1[CH3:14])=[O:21]
Reactant: Cc1ccc(-c2nc(C)c(C(=O)O)s2)cc1
Reactant: NCCc1c[nH]c2ccc(F)cc12
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: Cc1ccc(-c2nc(C)c(C(=O)NCCc3c[nH]c4ccc(F)cc34)s2)cc1
Yield: 27.2 %

Procedure:
This compound was prepared following Method A starting from 2-(5-fluoro-1H-indol-3-yl)ethanamine (0.030 g; 0.168 mmol), 4-methyl-2-p-tolylthiazole-5-carboxylic acid (0.043 g; 0.185 mmol), HATU (0.070 g; 0.185 mmol) and N,N-diisopropylethylamine (0.78 mL; 0.420 mmol) in DMF (5 mL). Flash chromatography on silica gel eluting with 1 to 5% of ethyl acetate in dichloromethane gave 0.018 g (27%) of N-(2-(5-fluoro-1H-indol-3-yl)ethyl)-4-methyl-2-p-tolylthiazole-5-carboxamide as a solid.
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[CH:30]=[CH:29][C:10]2[N:11]3[CH:28]=[CH:27][CH:26]=[C:12]3[C:13]3([CH2:19][CH2:18][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:16][CH2:15]3)[O:14][C:9]=2[CH:8]=1.CN([CH:34]=[O:35])C>>[Cl:6][C:7]1[CH:30]=[CH:29][C:10]2[N:11]3[C:28]([CH:34]=[O:35])=[CH:27][CH:26]=[C:12]3[C:13]3([CH2:15][CH2:16][N:17]([C:20](=[O:25])[C:21]([F:23])([F:24])[F:22])[CH2:18][CH2:19]3)[O:14][C:9]=2[CH:8]=1
Reactant: CN(C)C=O
Reactant: O=C(N1CCC2(CC1)Oc1cc(Cl)ccc1-n1cccc12)C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2n1-c1ccc(Cl)cc1OC21CCN(C(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
POCl3 (1.33 mL, 14.3 mmol) was added dropwise at 0° C. under N2 to dry DMF (1.1 mL, 14 mmol). The reaction mixture was left for 20 min at this temperature, which led to the formation of a white solid. A solution of 1-(7′-chlorospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)-2,2,2-trifluoro-ethanone (353 mg, 9.535 mmol) in dry DMF (26.5 mL) was added dropwise and the cooling bath was removed. The reaction was allowed to stir at room temperature for 1 h. The mixture was poured over ice and 1M NaOH (25 ml) was added. The pH was adjusted to 7 with 3M HCl and the mixture was extracted with DCM three times. The combined organics were dried, filtered and concentrated. Column chromatography (5-30% AcOEt in hexanes) on the residue gave 7-chloro-1′-(2,2,2-trifluoroacetyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1-carbaldehyde. ESI-MS m/z calc. 398.1, found 399.3 (M+1)+; Retention time: 1.96 minutes (3 min run).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(CCCCCO)OCc1ccccc1
Solvent: ClCCl
Product: O=C(CCCCCOC(=O)c1ccccc1)OCc1ccccc1

Procedure:
To a solution of benzyl 6-hydroxyhexanoate (b) (27.37 g) in methylene chloride were added 4-dimethyl amino pyridine (19.5 g) and benzoyl chloride (19.53 g), and the resultant mixture was stirred for 2 hours. The reaction mixture was treated in the conventional manner and was distilled under reduced pressure (1 mmHg, 190°-215° C.) to give the title compound (c).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[NH2:12].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[F:10][C:8]([F:11])([F:9])[C:6]1[CH:7]=[C:2]2[CH:1]=[N:13][NH:12][C:3]2=[CH:4][N:5]=1
Reactant: O=N[O-]
Reactant: Cc1cc(C(F)(F)F)ncc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1cc2cn[nH]c2cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-methyl-6-(trifluoromethyl)pyridin-3-amine [944317-54-8] (1.00 g, 5.68 mmol) in acetic acid (75 mL) was treated with a solution of sodium nitrite (392 mg, 5.68 mmol) in water (1 mL). The reaction mixture was stirred at RT for 15 min and then was allowed to stand at ambient temperature for 48 h. Acetic acid was evaporated under reduced pressure and the residual aqueous solution was partitioned between EtOAc and sat. aq. NaHCO3. The organic solution was washed with water and brine, then dried (Phase separator) and concentrated under vacuum. MS (LC-MS): 188 [M+H]+, tR (HPLC conditions k): 2.49 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[I:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(I)cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(I)cc4)nc23)CC1
Yield: 19.5 %

Procedure:
Beginning with 0.090 gm (0.39 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.157 gm (0.59 mMol) 4-iodobenzoyl chloride, 0.035 gm (19%) of the title compound was recovered as a crystalline solid by the procedure described in Example 4.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:23])=[C:18](B(O)O)[CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:23])=[C:16]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH2:12])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH:15]=1
Reactant: Cc1ccc(F)cc1B(O)O
Reactant: Nc1cc2ccc(Br)cc2cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Yield: 79.4 %

Procedure:
7-Bromoisoquinolin-3-amine (15.0 g, 67.4 mmol), 5-fluoro-2-methylphenylboronic acid (12.4 g, 81.0 mmol), Pd(dppf)Cl2 (2.76 g, 3.38 mmol) and Cs2CO3 (26.4 g, 81.0 mmol) in MeCN/H2O (10:1, 150 mL) was stirred at 120° C. for 6 h under N2. After the reaction mixture was filtered, the filtrate was concentrated and purified by chromatography on silica gel to give the desired product (13.5 g, 79.4%). LCMS (ESI): RT (Min)=0.869, M+H+=252.8, method=A. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.75 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.34-7.30 (m, 1H), 7.11-7.07 (m, 2H), 6.64 (s, 1H), 6.00 (s, 2H), 2.22 (s, 3H).
Reaction SMILES: I[CH2:2][CH2:3][C:4]1([CH3:19])[C:16](=[O:17])[N:7]2[CH2:8][CH:9]=[CH:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[N:6]2[C:5]1=[O:18].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CC(C)=O>[C:20]([S:22][CH2:2][CH2:3][C:4]1([CH3:19])[C:16](=[O:17])[N:7]2[CH2:8][CH:9]=[CH:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[N:6]2[C:5]1=[O:18])(=[O:23])[CH3:21]
Reactant: CC([O-])=S
Reactant: COC(=O)C1C=CCN2C(=O)C(C)(CCI)C(=O)N12
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1C=CCN2C(=O)C(C)(CCSC(C)=O)C(=O)N12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6.43 g (17 mmol) of methyl 2,3,5,8-tetrahydro-2-(2-iodoethyl)-2-methyl-1,3-dioxo-1H-pyrazolo-[1,2-a]pyridazine-5-carboxylate and 1.94 g (17 mmol) of potassium thioacetate in 150 ml of acetone was stirred at room temperature for 5 hours. The solvent was removed by evaporation and the residue was partitioned between dichloromethane and water. The organic phase was separated, dried over magnesium sulfate and evaporated to give methyl 2-(2-acetylthioethyl)-2,3,5,8-tetrahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate as a mixture of diastereomers. Chromatography on silica gel using diethyl ether for the elution gave 3.81 g (69%) of diastereomer A in the form of a colorless oil and 1.26 g (23%) of diastereomer B in the form of a colorless oil.
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:19]C1C=C(Br)C=CC=1N.FC1C=C(Br)C=CC=1N>>[CH3:19][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Reactant: Cc1cc(Br)ccc1N
Agent: Nc1ccc(Br)cc1F
Product: Cc1cc(-c2ccccc2S(N)(=O)=O)ccc1N

Procedure:
This compound was prepared by the method described for 2-fluoro-4-(2-aminosulfonylphenyl)aniline described in EXAMPLE 8 by starting with 2-methyl-4-bromoaniline rather than 2-fluoro-4-bromoaniline.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[F:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: Fc1ccccc1CBr
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccccc2F)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 2-fluorobenzyl bromide