Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:19](Cl)=[O:20])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25].C(N(CC)CC)C>ClCCl.O>[Cl:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:19]([C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1)=[O:20]
Reactant: CSc1ncc2cc(C(=O)Cl)n(-c3ccc(F)cc3)c2n1
Reactant: Nc1ccccc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ncc2cc(C(=O)Nc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(4-fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonyl chloride, 25, (0.57 g, 1.77 mmol) in dichloromethane (10 mL) is added 2-chloroaniline (0.28 mL, 2.66 mmol) and triethylamine (0.74 mL, 5.3 mmol). The mixture is allowed to stir at ambient temperature for 16 hours. The reaction was diluted with H2O and extracted three times with EtOAc. The combined organic phases are rinsed with brine, dried (MgSO4), filtered and concentrated in vacuo wherein the crude residue is purified over silica (5% to 40% EtOAc/hexanes) to afford 365 mg the desired product: 1H NMR (300 MHz, CDCl3) δ 9.00 (s, 1H), 8.42 (d, J=8.2 Hz, 1H), 8.32 (br s, NH), 7.55-7.50 (m, 2H), 7.42 (d, J=8.2 Hz, 1H), 7.36-7.20 (m, 3H), 7.12 (t, J=8.7 Hz, 1H), 2.49 (s, 3H); ESI+ MS: m/z (rel intensity) 413.0 (100, M++H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:18][C:19]([C:21]1[O:22][C:23]([CH2:26]Cl)=[CH:24][CH:25]=1)=[O:20]>>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:26][C:23]3[O:22][C:21]([C:19]([OH:20])=[O:18])=[CH:25][CH:24]=3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)c1ccc(CCl)o1
Product: O=C(O)c1ccc(COc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)o1

Procedure:
5-(4′-Nitro-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid was prepared using general procedure A from 4-hydroxy-4′-nitrobiphenyl (available from TCI America, Portland, Oreg.) and 5-chloromethylfuran-2-carboxylic acid methyl ester (available from Aldrich, Milwaukee, Wis., or from Maybridge plc, Tintagel, UK). Yield: 40 mg. Mass spectrum (ES) MH+=340.
Reaction SMILES: [Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[H][H]>C(O)(=O)C.[Pt]>[Br:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH3:13])[NH:7]2
Reactant: [H][H]
Reactant: Cc1ccc2c(Br)c(F)ccc2n1
Agent: [Pt]
Solvent: CC(=O)O
Product: CC1CCc2c(ccc(F)c2Br)N1

Procedure:
To a solution of 20 g of 5-bromo-6-fluoroquinaldine in 150 ml of glacial acetic acid was added 2.0 g of platinum on charcoal. The mixture was hydrogenated on a Paar apparatus at a temperature of about 20° C. until the theoretical amount of hydrogen was taken up. The mixture was then filtered through celite to provide a solution of 5-bromo-6-fluoro-1,2,3,4-tetrahydroquinaldine. Evaporation of the solvent provides the desired intermediate. This intermediate could be used directly in Part C below without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.S(=O)(=O)(O)O.[N+:17]([O-])(O)=O>>[NH2:17][C:9]1[CH:10]=[C:2]([F:1])[CH:3]=[C:4]2[C:8]=1[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: O=S(=O)(O)O
Product: Nc1cc(F)cc2c1NC(=O)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
5-Fluoro-1,3-dihydro-indol-2-one (5.0 g, 33 mmol) was added with 98% sulfuric acid (17.6 ml) and 65%-68% nitric acid (2.1 ml) in an ice-water bath with salt at −5° C. Upon the completion of the addition, the mixture was stirred for 1 hour at room temperature and added with ice-water until precipitate was formed. The solid was filtered and washed with water (50 ml×3) and recrystallized from acetic acid and water to give 7-amino-5-fluoro-1,3-dihydro-indol-2-one (4.0 g, 62.5%) as an orange solid.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[F:6][C:7]([F:19])([F:18])[C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.Cl.C(N(CC)CCCl)C>CN(C=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH3:5][O:4][N:3]([CH3:2])[C:15](=[O:16])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:19])([F:18])[F:6])[CH:9]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CNOC
Agent: CCN(CC)CCCl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cc1cccc(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (1.577 g, 16.2 mmol) in DMF (25 mL) and CH2Cl2 (25 mL) at 0° C. was added triethylamine (2.25 mL). After stirring for 5 minutes, 3-trifluoromethylphenyl acetic acid (3.0 g, 14.7 mmol), HOBT (3.177 g, 23.5 mmol), and DEC (2-diethylaminoethyl chloride hydrochloride, 3.10 g, 16.2 mmol) were added. The reaction mixture was stirred at room temperature for 18 h and was concentrated in vacuo. The residue was diluted with EtOAc and the organic solution was washed consecutively with 1N NaOH (2 times), water, and brine. The organic solution was dried (MgSO4), filtered and concentrated in vacuo. Medium pressure chromatography (20% EtOAc in hexanes to 50% EtOAc in hexanes) provided N-methoxy-N-methyl-2-(3-trifluoromethyl-phenyl)-acetamide.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C1C=C(C=CC=1)CNC(C1C=CN=C(C2C=C(N3CCCCC3)C=CC=2NC(=O)C2C=CC=C(C(N(CCC(NCCOC)=O)C)=O)C=2)C=1)=O.[C:99]([N:102]1[CH2:107][CH2:106][NH:105][CH2:104][CH2:103]1)(=[O:101])[CH3:100]>>[C:99]([N:102]1[CH2:107][CH2:106][N:105]([C:34]([C:33]2[CH:32]=[C:31]([CH:39]=[CH:38][CH:37]=2)[C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:1])([F:44])[F:43])[CH:4]=2)=[O:9])=[O:30])=[O:35])[CH2:104][CH2:103]1)(=[O:101])[CH3:100]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: COCCNC(=O)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CC(=O)N1CCN(C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid 4.1e using the procedure described for the preparation of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N3-(3-(2-methoxyethylamino)-3-oxopropyl)-N3-methylisophthalamide 4.2. N-Acetylpiperazine was used as the amine component in this coupling. 1H-NMR (400 MHz, DMSO-d6, ppm): δ 12.48 (s, 1H), 9.57 (m, 1H), 8.93 (d, J=5.2 Hz, 1H), 8.39 (d, J=11.2 Hz, 2H), 7.99˜7.46 (m, 11H), 4.63 (d, J=6.0 Hz, 2H), 3.55˜3.42 (m, 12H), 2.21 (s, 3H), 1.79 (s, 4H), 1.62 (s, 2H). MS (ES, m/z): 713 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[C:5]([CH3:17])=[C:4]([CH3:18])[N:3]=1.[O:19]1[CH2:24][CH2:23]OCC1>>[CH3:18][C:4]1[C:5]([CH3:17])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([O:19][C:24]2[CH:23]=[CH:6][CH:5]=[CH:4][CH:18]=2)[N:3]=1
Reactant: C1COCCO1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCO)c1C
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCO)c1C
Reaction time: 8 h

Procedure:
4-[(2-Chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butan-1-ol (20.00 g, 93.07 mmol) and additional dioxane (˜30 mL) were added. The reaction mixture was heated at reflux for 3 hours and then allowed to stand at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and then extracted with ethyl acetate (300 mL). The extract was washed with water (2×100 mL) then with brine, dried over magnesium sulfate, filtered and then concentrated under reduced pressure to provide an oil. The oil was purified by flash chromatography (600 mL of silica gel, eluting initially with 2000 mL 1:3 ethyl acetate:hexanes, then with 2000 mL 1:1 ethyl acetate:hexanes and finally with 1000 mL 3:1 ethyl acetate: hexanes) to provide 13.46 g of 4-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]butan-1-ol as a yellow solid.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:3]=1.P(Cl)(Cl)([Cl:20])=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1cccc(-c2nc(C)cc(O)n2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCc1cccc(-c2nc(C)cc(Cl)n2)n1
Yield: 93.9 %

Procedure:
To solution of 4-hydroxy-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (2 g) in toluene (20 ml), was added phosphoryl chloride (2 g). The mixture was heated under refluxing for one hour and left to stand to room temperature. Aqueous sodium carbonate solution was added thereto until the reaction solution became about pH 8 to be separated into two layers. Toluene layer was collected and washed with water and dried over anhydrous magnesium sulfate. The toluene layer was concentrated under reduced pressure to obtain 4-chloro-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (2.03 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[CH3:8].[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:17])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[CH3:7][C:5]1[S:6][C:2]([NH:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([CH3:18])=[CH:10][CH:11]=2)=[C:3]([CH3:8])[N:4]=1
Reactant: Cc1ccc(CCN)cc1
Reactant: Cc1nc(C)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(CCNc2sc(C)nc2C)cc1
Temperature: 160 °C
Reaction time: 48 h
Yield: 13.2 %

Procedure:
To a solution of 5-bromo-2,4-dimethyl-1,3thiazole (1.00 g, 5.21 mmol) in DMSO (5 mL) was added 2-(p-tolyl)ethylamine (1.06 g, 7.81 mmol) and potassium carbonate (1.1 g, 7.9 mmol). The reaction mixture was stirred for 6 d at ambient temperature and for 2 d at 160° C. under a nitrogen atmosphere. After cooling to ambient temperature it was diluted with ethyl acetate (20 mL) and washed with aqueous sodium carbonate (saturated, 20 mL) and water (20 mL). Drying over sodium sulfate, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=70:30 to 0:100) afforded the title compound (170 mg, 13%) as a light brown solid. MS m/e: 247.0 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[CH2:12][CH2:11][O:10][C@H:9]([CH2:13][OH:14])[CH2:8]1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:19]([O:14][CH2:13][C@H:9]1[O:10][CH2:11][CH2:12][NH:7][CH2:8]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC[C@@H]1CNCCO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](OC[C@@H]1CNCCO1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
Pyridine (0.207 ml, 2.56 mmol) and DMAP (0.021 g, 0.17 mmol) were added to a solution of (S)-morpholin-2-ylmethanol (A, Tyger Scientific Inc, 0.2 g, 1.71 mmol) in DCM (5.0 ml) followed by tert-butylchlorodiphenylsilane (0.526 ml, 2.05 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by column chromatography (ISCO, eluting with 10% MeOH/DCM) to provide (S)-2-((tert-butyldiphenylsilyloxy)methyl)morpholine B (INTERMEDIATE 48B, 0.26 g, yield: 43%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:5]=1[NH2:6].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:3][C:2]([F:13])([F:12])[F:1])[CH:10]=1
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Reactant: OB(O)c1ccccc1F
Product: Nc1ccc(-c2ccccc2F)cc1OC(F)(F)F
Yield: 57.1 %

Procedure:
The title compound (0.294 g) was prepared from 2-trifluoromethoxy-4-bromo aniline (0.5 g, 1.9 mmol) and 2-fluorophenylboronic acid (0.345 g, 2.5 mmol) as a yellow liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.47 (td, J 1.2, 4.7, 1H), 7.33-7.20 (m, 5H), 6.89 (d, J 8.8, 1H), 5.62 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:12]([C:14]1[N:19]2[N:20]=[CH:21][N:22]=[C:18]2[N:17]=[CH:16][CH:15]=1)[CH3:13]>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([C:14]2[N:19]3[N:20]=[CH:21][N:22]=[C:18]3[N:17]=[CH:16][CH:15]=2)[CH3:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(Br)c1ccnc2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(Oc1ccc(F)cc1)c1ccnc2ncnn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Fluorophenol (1.12 g) was added to a stirred suspension of sodium hydride (0.48 g) in dry 1,2-dimethoxyethane (35 ml). The mixture was stirred at room temperature for 30 minutes, then a solution of 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine (2.27 g, prepared in a similar manner to that described in Example 6 below) in dry 1,2-dimethoxyethane (85 ml) was added dropwise. The mixture was stirred at room temperature for 24 hours. The sodium bromide was removed from the mixture by filtration. The solvent was evaporated from the filtrate and the residue dissolved in dichloromethane and washed with 200 ml of a 5% aqueous solution of sodium hydroxide, followed by water. The organic layer was dried over magnesium sulphate. Evaporation of the solvent afforded a crude product which was purified by column chromatography on silica gel using as eluent a mixture of petroleum ether and ethyl acetate (in the ratio 6:4 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-[1-(4-fluorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]-pyrimidine. Yield 1.03 g, (mp 106°-108° C.).
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[C:29]=1[F:35])=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Br:34][C:30]1[C:29]([F:35])=[C:28]([CH:9]2[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]32[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[NH:19][C:18]3=[O:27])[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.2 %

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (1.2 g, 2.1 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (5 g). The reaction mixture was stirred at room temperature for 20 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a light yellow solid (1.3 g, 98%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)=[C:4]([CH3:23])[C:3]=1[CH3:24].[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)#[N:26].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[N:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]3)=[C:4]([CH3:23])[C:3]=2[CH3:24])=[CH:29][CH:28]=1)#[N:26]
Reactant: Cc1c(Cl)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2ccc(C#N)cc2)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Yield: 94.2 %

Procedure:
Heat a mixture of tert-butyl 1-(6-chloro-4,5-dimethylpyridazin-3-yl)piperidin-4-yl(methyl)carbamate (1.5 g, 4.23 mmol), 4-cyanophenylboronic acid (932 mg, 6.34 mmol), Cs2CO3 (5.51 g, 16.9 mmol) and (SP-4-1)-bis[bis(1,1-dimethylethyl)(4-methoxyphenyl)phosphine-κP]dichloro-palladium (29 mg, 0.042 mmol) in a mixture of 1,4-dioxane (30 mL) and H2O (10 mL) under N2 at 90° C. overnight. Partition the reaction mixture between EtOAc and H2O with dissolved NaHCO3. Separate the layers, and extract the aqueous layer with EtOAc. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 2% 2 M NH3/MeOH in CH2Cl2) to provide the title compound as a yellow solid (1.68 g, 94%). ES/MS m/z 422.2 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=2)=[O:22])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+].[C:43](N1C=CN=C1)([N:45]1[CH:49]=[CH:48][N:47]=[CH:46]1)=[O:44]>CN(C=O)C.C1COCC1.CCOC(C)=O>[N:45]1([C:43]([N:17]2[CH2:18][CH2:19][CH:14]([C:12]3[CH:11]=[CH:10][C:9]([NH:20][C:21]([C:23]4[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=4)=[O:22])=[C:8]([N:5]4[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]4)[CH:13]=3)[CH2:15][CH2:16]2)=[O:44])[CH:49]=[CH:48][N:47]=[CH:46]1
Reactant: CC1CCN(c2cc(C3CCNCC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CCN(c2cc(C3CCN(C(=O)n4ccnc4)CC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a mixture of 4-cyano-1H-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amide bis(trifluoroacetic acid salt) (as prepared in Example 35, 20.0 mg, 0.0320 mmol) and anh Na2CO3 (6.8 mg, 0.065 mmol) in 0.30 mL of DMF was added carbonyldiimidazole (11 mg, 0.068 mmol) in 0.3 mL of THF at RT. The mixture was stirred at RT for 2 h. Treated with 20 mL of EtOAc, the mixture was washed with H2O, brine and dried with Na2SO4. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-5% MeOH/DCM) gave 14 mg (86%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 10.7 (s, 1H), 9.16 (s, 1H), 8.33 (d, 1H, J=8.3 Hz), 7.95 (s, 1H), 7.47 (s, 1H), 7.13 (s, 1H), 7.06 (s, 1H), 7.03 (s, 1H), 6.88 (s, 1H), 4.28 (d, 2H, J=12.9 Hz), 3.16 (d, 2H, J=12.0 Hz), 2.97 (d, 2H, J=11.6 Hz), 2.71-2.84 (m, 3H), 1.99 (d, 2H, J=12.1 Hz), 1.87 (d, 2H, J=12.1 Hz), 1.71-1.83 (m, 2H), 1.65 (s, 1H), 1.54-1.65 (m, 1H), 1.34-1.48 (m, 2H), 1.10 (d, 3H, J=6.5 Hz). Mass spectrum (ESI, m/z): Calcd. for C27H31N7O2, 486.2 (M+H), found 486.0.
Reaction SMILES: C(O[CH:4]([O:13]CC)[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)C.[CH2:16]([Mg]Br)[CH2:17][CH2:18][CH2:19][CH3:20].[NH4+].[Cl-]>C1COCC1>[OH:13][CH:4]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC[Mg]Br
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC(O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 369.2 %

Procedure:
A solution of 4-diethoxymethyl-benzaldehyde (0.300 mL, 1.51 mmol) in THF (3 mL) was cooled to 0° C. Pentylmagnesium bromide (3.0 mL, 2.0 M in THF, 6 mmol) was added dropwise. The reaction was stirred at 0° C. for 1 h and was warmed to room temperature. Aqueous NH4Cl (satd) was added and the aqueous solution was extracted with EtOAc. The organic solution was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was dissolved in 10% aqueous acetone (50 mL) and wet Amberlyst-15 resin (1.5 g) was added. The mixture was stirred for 24 h and the resin was filtered off through Celite. The solution was concentrated in vacuo. Purification via flash chromatography (4:1 hexanes:EtOAc) provided the title compound (1.15 g). 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1tH), 7.86 (d, 2H), 7.51 (d, 2H), 4.77 (m, 1H), 1.89 (m, 1H), 1.74 (m, 2H), 1.48-1.28 (m, 6H), 0.87 (m, 3H).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]([C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([S:27][CH3:28])[N:21]=3)=[C:17]([CH3:19])[N:18]=2)=[O:12])=[N:5][CH:4]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:34].CS(C1N=C(C2SC(N)=NC=2C)C=C(C)N=1)=O>>[CH2:1]([C:3]1[O:7][C:6]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][C:16]([C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([S:27]([CH3:28])=[O:34])[N:21]=3)=[C:17]([CH3:19])[N:18]=2)=[O:12])=[N:5][CH:4]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(SC)n3)s2)o1
Agent: Cc1cc(-c2sc(N)nc2C)nc(S(C)=O)n1
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)=O)n3)s2)o1

Procedure:
This compound is prepared by oxidation of 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[4-methyl-5-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-thiazol-2-yl]-urea with m-CPBA (meta-chloroperoxy-benzoic acid) following the protocol used to prepare 5-(2-Methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-ylamine (intermediate AD).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[N:4]=1.[C:18]([N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)(N1C=CN=C1)=[O:19]>C1COCC1>[Si:11]([O:10][CH2:9][C:5]1[N:4]=[C:3]([CH2:2][NH:1][C:18]([NH:25][CH2:29][C:28]2[CH:2]=[CH:3][CH:8]=[C:26]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[N:27]=2)=[O:19])[CH:8]=[CH:7][CH:6]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CNC(=O)NCc2cccc(CO[Si](C)(C)C(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.4 %

Procedure:
2-Aminomethyl-6-[(tert-butyldimethylsilyloxy)methyl]pyridine (26) (380 mg, 1.50 mmol) and 1,1′-carbonyldiimidazole (150 mg, 0.92 mmol) were suspended in THF (10 mL). The air was evacuated from the reaction system, and then Ar was charged therein. The suspension was stirred for 24 hours at a room temperature. TLC was used to confirm there was no starting material in the mixture. Then, the reaction mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CDCl3:MeOH=50:1) to give N,N′-bis{[6-(tert-butyldimethylsilyloxy)methylpyridin-2-yl]methyl}urea (27) (384 mg, 96%) as yellow crystals.