Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:3]1.CCN(CC)CC.[CH3:25][S:26](Cl)(=[O:28])=[O:27].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:25][S:26]([O:1][CH:2]1[CH2:5][C:4]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:3]1)(=[O:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)C2
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(OS(C)(=O)=O)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
tert-butyl 2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (392 mg, 1.62 mmol, 1.0 equiv) was dissolved in DCM (6.0 mL). The solution was cooled to 0° C. with an external ice-bath. Et3N (237 μL, 1.706 mmol, 1.05 equiv)) and DMAP (2.0 mg, 1 mol %) were added. Methanesulfonyl chloride (132 μL, 1.706 mmol, 1.05 equiv) was then added dropwise by a syringe. The solution was stirred at 0° C. for 2.0 hrs, was then allowed to warm to room temperature and stirred at room temperature for 18 hrs. Et3N (23 μL, 0.1 equiv) and methanesulfonyl chloride (13 μL, 0.1 equiv) were added and the mixture was stirred for another 6 h. A saturated solution of NH4Cl (20 mL) was added and stirred at room temperature for 10 min. The layers were separated. The aqueous phase was extracted with DCM (3×30 mL). The combined organic phase were washed with HCl (1N, 20 mL) and water (20 mL) and were dried over anhydrous Na2SO4, concentrated in vacuo to afford 482 mg (yield 93%) of tert-butyl 2-(methylsulfonyloxy)-7-azaspiro[3.5]nonane-7-carboxylate as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][NH:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=1>>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([N:5]2[CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4]2)=[CH:21][CH:22]=1
Reactant: Clc1ccc(I)cn1
Reactant: C[C@H]1CCNC[C@H]1NC(=O)OC(C)(C)C
Product: C[C@@H]1CCN(c2ccc(Cl)nc2)C[C@H]1NC(=O)OC(C)(C)C
Yield: 24.4 %

Procedure:
The trans product from Example 39C (0.146 g, 0.68 mmol) and 2-chloro-5-iodopyridine (0.21 g, 0.88 mmol; Aldrich) were processed according to the procedure in Example 1A to provide the title compound (0.054 g, 24%). MS (CI/NH3) m/z 326/328 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.[CH3:33]C#N.C(=O)=O.[Li]C>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[CH:17]=[N:16][CH:15]=3)([OH:13])[CH3:33])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=1
Reactant: CC#N
Reactant: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=C=O
Agent: [Li]C
Solvent: C1CCOC1
Product: COc1nc2ccc(C(C)(O)c3cncn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (400 mg, 0.87 mmol, Intermediate 12: step b) was added THF (20 mL) and the solution was cooled to −43° C. (CH3CN—CO2). MeLi (1.6 M in Et2O, 0.63 mL, 1.01 mmol) was then introduced. After 30 minutes, the reaction mixture was quenched with saturated aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (4×30 mL) and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (30% CH3CN-DCM increasing to 3% MeOH-DCM) provided the title compound as a white amorphous solid. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=1.9 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 7.49 (dd, J=8.6, 2.2 Hz, 3H), 7.40 (d, J=8.1 Hz, 2H), 7.34 (s, 1H), 7.17 (d, J=0.8 Hz, 1H), 4.35 (s, 2H), 4.07 (s, 3H), 3.25 (s, 3H), 3.0 (br. s, 1H), 1.99 (s, 3H); MS (ESI): mass calcd. for C24H21ClF3N3O2, 475.1, m/z found 475.9 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1-methyl-1H-imidazol-5-yl)ethanol was purified by chiral SFC: (Stationary phase: CHIRALCEL OD-H, 5 μm, 250×20 mm), Mobile phase: 70% CO2, 30% MeOH), to give 2 enantiomers. The first eluting enantiomer was Example 9b and the second eluting enantiomer was Example 9c.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:33])=[C:29](F)[CH:30]=3)[C:25](=[O:34])[N:24]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:23]2=[O:43])=[CH:18][CH:17]=1>>[F:33][C:28]1[CH:27]=[CH:26][C:31]([N:22]2[C:19]3[C:20](=[CH:21][C:16]([F:15])=[C:17]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:18]=3)[C:25](=[O:34])[N:24]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:23]2=[O:43])=[CH:30][CH:29]=1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2ccc(F)cc2)CC1
Yield: 96.8 %

Procedure:
Using General Method 4, the reaction of N-methylpiperazine (0.14 mL, 1.23 mmol), triethylamine (0.17 mL, 1.23 mmol), and 1-(4-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B-1, 0.163 g, 0.41 mmol) provided 0.19 g of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][NH:24][S:23]2(=[O:29])=[O:28])[CH2:17][CH2:16]1.[H-].[Na+].[CH:32](I)([CH3:34])[CH3:33]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][CH:18]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][N:24]([CH:32]([CH3:34])[CH3:33])[S:23]2(=[O:28])=[O:29])[CH2:19][CH2:20]1
Reactant: COc1cc2ncnc(N3CCC(CN4CCCNS4(=O)=O)CC3)c2cc1OC
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCC(CN4CCCN(C(C)C)S4(=O)=O)CC3)c2cc1OC
Reaction time: 0.75 h

Procedure:
A stirred solution of 1-(6,7-dimethoxyquinazolin-4-yl)-4-[(1,1-dioxotetrahydro-1,2,6-thiadiazin-2-yl)methyl]piperidine 1/2 CH3CH2OCOCH3 (0.7 g) (prepared as in Example 9) in dimethylformamide (4.0 cm3) was treated at room temperature with sodium hydride (100 mg. of a 50% dispersion in oil) and the mixture was stirred for 45 minutes. Isopropyl iodide (255 mg) was then added and the resulting mixture was stirred for 6 hours. The solvent was removed in vacuo and the residue was taken into chloroform (50 cm3) and water (25 cm3). The aqueous phase was extracted with chloroform (2×20 cm3) and the dried (MgSO4) extracts were evaporated to yield an oil which was chromatographed on silica (Merck 60.9385) eluting with chloroform to give a gum. Crystallisation from ethyl acetate afforded 1-(6,7-dimethoxyquinazolin-4-yl)-4-([1,1-dioxo-6-isopropyltetrahydro-1,2,6-thiadiazin-2-yl]methyl)piperidine, m.p. 158°-161° (460 mg).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:3]=[C:4]([C:9]3[N:10]([CH2:18][CH3:19])[C:11]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=4[N:17]=3)[C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3ccc(OCc4ccccc4)cc3)cnc2N)nc2cnccc21
Temperature: 200 °C
Yield: 23.4 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), 4-benzyloxy-phenylboronic acid (0.046 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes. The reaction mixture was concentrated in vacuo and the residue purified by HPLC to give 0.0099 g of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]([N:10]=[C:11]=[O:12])[CH2:7][CH2:8][CH2:9][C:2]1=2.[C:13]([NH2:16])(=[O:15])[CH3:14]>>[C:13]([NH:16][C:11]([NH:10][CH:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH2:9][CH2:8][CH2:7]1)=[O:12])(=[O:15])[CH3:14]
Reactant: O=C=NC1CCCc2sccc21
Reactant: CC(N)=O
Product: CC(=O)NC(=O)NC1CCCc2sccc21

Procedure:
A 2.94 g sample of benzoyl isocyanate in 5 ml of CH2Cl2 is added to 3.04 g of 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine in 50 ml of CH2Cl2 under N2 atmosphere. After stirring overnight at room temperature, the reaction mixture is evaporated to dryness in vacuo. The residue is then stirred in 100 ml of Et2O and filtered to afford 1-benzoyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, m.p. 189° C. to 194° C. Substitution of trichloroacetyl isocyanate for benzoyl isocyanate affords 1-trichloroacetyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea. Use of 4,5,6,7-tetrahydrobenzo[b]thien-4-ylisocyanate and acetamide in the above manner affords 1-acetyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[O:24][CH3:25].Cl>ClCCCl>[Cl:23][C:22]1[C:17]([Cl:16])=[C:18]([O:24][CH3:25])[CH:19]=[CH:20][C:21]=1[C:4]([C:3]1[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=1[F:11])=[O:5]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2c(F)cccc2F)c(Cl)c1Cl
Reaction time: 1 h

Procedure:
To a solution of 24.6 g of 2,6-difluoro benzoylchloride in 100 ml of 1,2-dichloroethane, 18.5 g of AlCl3 is added in portions over a 30 minute period. A solution of 22.5 g of 2,3-dichloroanisole in 100 ml of 1,2-dichloroethane is added thereto. The mixture is stirred for one hour and poured over 100 ml concentrated HCl and ice. The organic layer is separated and the aqueous layer extracted with CHCl3. The organic extract is washed with water, dried (Na2SO4) and evaporated to give an oil which crystallizes from hexane to yield solid 2,3-dichloro-4-methoxy-2',6'-difluorobenzophenone which upon recrystallization from ether has an mp 94°-96° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].C(N(CC)CC)C.Cl.Cl[CH2:25][C:26]1[C:27]([NH2:33])=[N:28][C:29]([CH3:32])=[N:30][CH:31]=1>CN(C)C=O>[CH3:32][C:29]1[N:28]=[C:27]([NH2:33])[C:26]([CH2:25][N:13]2[CH2:12][CH2:11][N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14]2)=[CH:31][N:30]=1
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Reactant: Cc1ncc(CCl)c(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(CN2CCN(c3ccccc3[N+](=O)[O-])CC2)c(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
A solution of 1.25 g (0.0060 mol) of 1-(2-nitro-phenyl)-piperazine and 2.1 ml (0.015 mol) of triethylamine in 20 ml of dimethylformamide was treated with 0.97 g (0.0050 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride and the mixture was stirred at room temperature under argon for 3 hours. The mixture was completely freed from the solvents and the residue was triturated in 20 ml of water. The resulting crystals were filtered off under suction, dried and chromatographed over silica gel with dichloromethane/methanol 19:1 as the eluent. 1.25 g (76%) of 2-methyl-5- [4-(2-nitro-phenyl )-piperazin-1-ylmethyl]-pyrimidin-4-ylamine were obtained as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.Cl[CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(Br)cc1

Procedure:
4-Bromophenol (0.870 g, 5.00 mmol), 2-chloro-N,N-diethylethanamine hydrochloride (0.90 mg, 5.24 mmol) and Cs2CO3 (8 g, 25 mmol) were combined in DMF (20 mL) and the mixture was heated at reflux over night. H2O (20 mL) was added and the mixture was extracted with EtOAc, then washed with 2N NaOH and brine. The organic layers were combined, dried over Na2SO and concentrated to a brown oil which was then purified by flash chromatography (eluent: 20% EtOAc in hexanes).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][N:19]3[C:23](=[O:24])[CH2:22][O:21][C:20]3=[O:25])[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:26][NH2:27]>O1CCCC1>[CH2:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][NH:19][C:20](=[O:25])[O:21][CH2:22][C:23]([NH:27][CH3:26])=[O:24])[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cccc(N2CCC(CCN3C(=O)COC3=O)CC2)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCC1CCN(c2cccc(CC(C)C)n2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.5). Starting with 0.72 g (2.08 mmol) of 3-{2-[1-(6-isobutyl-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione, obtained in step 13.4, and 5.20 ml (10.40 mmol) of a solution (2M) of methylamine in tetrahydrofuran, and after chromatography on silica gel, eluting with a 95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous ammonia, followed by crystallization from diisopropyl ether, 0.540 g of pure product is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:4]=1.Cl[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:28]=[N:29][CH:30]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:24][C:25]2[CH:26]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:28]=[N:29][CH:30]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: COc1cccc(N(Cc2cncc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
4-(m-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]=O>>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1/[CH:19]=[C:6]1/[C:7](=[O:11])[C:8]2[C:4]([CH2:5]/1)=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2
Reactant: O=Cc1ccncc1Br
Reactant: Cc1ccc2c(c1)CCC2=O
Product: Cc1ccc2c(c1)C/C(=C\c1ccncc1Br)C2=O

Procedure:
The title compound 90 is prepared according to the procedure reported in Example 34.1 with 5-methyl-1-indanone (0.73 g, 5 mmol) and 3-bromo-4-pyridinecarboxaldehyde (0.93 g, 5 mmol) as reactants. White solid. (Yield 1.24 g, 79%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1(=[O:17])[NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[C:1]([CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)c1ccccc1
Product: O=C1NCCCCC1C(=O)c1ccccc1
Yield: 95 %

Procedure:
The title compound is prepared in a yield of 95% from benzoyl chloride and caprolactam as in Example 1. The purity of the product is 98%.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:5]=1[C:6]([O:8]C)=[O:7].[OH-].[Li+]>O1CCOCC1.O>[F:15][CH:2]([F:1])[O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1c(F)cccc1OC(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(F)cccc1OC(F)F
Reaction time: 15 h
Yield: 60.9 %

Procedure:
To a solution of methyl 2-[(difluoromethyl)oxy]-6-fluorobenzoate (800 mg) in anhydrous dioxane (20 ml) was added a solution of lithium hydroxide (260 mg) in water (10 ml). It was stirred for 15 hours, evaporated, dissolved in water (25 ml) and extracted with ethyl acetate (25 ml) and ether (25 ml). The aqueous phase was acidified with 5M hydrochloric acid and extracted with ethyl acetate (2×25 ml). The combined organic phases were washed with water (10 ml) and saturated brine (10 ml), dried over Na2SO4 and evaporated to give an oil which crystallised (616.3 mg). It was triturated with heptane (ca. 10 ml) and filtered off to give the title compound (456 mg).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:13]3[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:2]1.[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH:32]3[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]3)=[CH:31][C:26]=2[O:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)Cl.CC(O)C>C(Cl)Cl>[O:23]1[C:27]2[CH:28]=[CH:29][C:30]([CH:32]3[CH2:37][CH2:36][CH:35]([N:1]4[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]5[C:13]6[CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=[CH:17][C:12]=6[O:11][N:10]=5)[CH2:2]4)[CH2:34][CH2:33]3)=[CH:31][C:26]=2[O:25][CH2:24]1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3ccc4c(c3)OCO4)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide (100 mg, 0.318 mmol) and 4-benzo[1,3]dioxol-5-yl-cyclohexanone (69 mg, 0.318 mmol) in DCM (10 mL) was added TEA (55 μL, 0.382 mmol) and the resulting solution was stirred at RT for 30 minutes. Sodium triacetoxyborohydride (81 mg, 0.382 mmol) was then added and the reaction was and stirred at RT overnight. The reaction was dissolved into DCM/IPA (3:1) solution and washed with saturated NaHCO3. The organic layers were dried over anhydrous Na2SO4, concentrated in vacuo and purified by column chromatography using EtOAc (A) and 7N NH3 in MeOH (B) (from 100% A to 10% B in A) to give the above products as white solids. The less polar isomer from the silica gel column was tested in vitro as described in Example 107.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH2:15]Br.[OH:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:13])([F:12])[F:14])[CH:7]=[C:6]2[CH2:15][O:25][CH2:26][C:27]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:29][CH2:28]1
Reactant: C[Si](C)(C)CCOCn1nc2c(CBr)cc(C(F)(F)F)cc2c1Br
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3c(Br)n(COCC[Si](C)(C)C)nc23)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Bromo-7-(bromomethyl)-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (140 mg, 0.29 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (75 mg, 0.26 mmol) were combined in dimethylformamide (2 mL) and cooled to 0° C. The reaction was treated with sodium hydride (14 mg, 0.57 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (10%→20% ethyl acetate/hexanes) gave 101 mg (50%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.44 (s, 1H), 7.14-7.18 (m, 5H), 5.26 (s, 2H), 4.68 (s, 2H), 3.69 (m, 2H), 3.44 (s, 2H), 3.38-3.41 (m, 2H), 2.98-3.02 (m, 2H), 2.11-2.14 (m, 2H), 1.72-1.77 (m, 2H), 1.41 (s, 9H), 0.74-0.77 (m, 2H), 0.10 (s, 9H). Mass spec.: 700.11 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[CH2:5][C:6]1[NH:14][C:13]2[C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:10](=[O:24])[N:9]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:8]=2[N:7]=1.[Cl:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([CH3:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH:26]1([CH2:25][N:9]2[C:8]3[N:7]=[C:6]([CH2:5][C:4]4[CH:3]=[C:2]([NH:1][S:40]([C:34]5[C:35]([CH3:39])=[N:36][N:37]([CH3:38])[C:33]=5[Cl:32])(=[O:41])=[O:42])[CH:31]=[CH:30][CH:29]=4)[NH:14][C:13]=3[C:12](=[O:15])[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:10]2=[O:24])[CH2:28][CH2:27]1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: Nc1cccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)c1
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1cccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)c1

Procedure:
Prepared from 8-(3-amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride. Light yellow solid; (ES)+-HRMS m/e calculated for C28H27ClFN7O4S (M+Na)+ 634.1411, found 634.1410.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>>[CH3:43][O:42][C:40](=[O:41])[CH2:39][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH2:9][N:8]([CH2:20][C:21](=[O:22])[NH:23][CH:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH:7]2[CH2:6][C:5]2[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COC(=O)CBr
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COC(=O)COc1cc2c(cc1OC)CCN(CC(=O)NC1CCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with methyl bromoacetate