Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[Cl:7][C:8]1[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[NH2:14].BrCC(C)=C>C1COCC1>[Cl:7][C:8]1[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[NH:14][CH2:1][C:2]([CH3:5])=[CH2:3]
Reactant: CC(C)(C)[O-]
Reactant: Nc1cc(Cl)nnc1Cl
Agent: C=C(C)CBr
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CNc1cc(Cl)nnc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
Potassium tert-butoxide (157.5 g) was charged portionwise to a stirred solution of 3,6-dichloro-pyridazin-4-ylamine (210 g) in THF (3.36 L). After 15 minutes, 3-bromo-2-methylpropene (141.8 mL) was added dropwise over a period of 30 minutes, maintaining the temperature <25° C. The solution was allowed to stir at room temperature for 16 h, after which time the reaction was concentrated and the residue partitioned between DCM (6 L) and water (6 L). The aqueous phase was extracted with DCM (2×5 L). The combined organic phases were washed (brine, 5 L), dried with magnesium sulfate, filtered and concentrated. Chromatography (Silica gel, eluting with 70:30 Heptane:-EtOAc) gave the title compound (211.7 g). 1H NMR (270 MHz, CDCl3): 6.49 (1H, s), 5.48 (1H, br s), 5.00 (1H, s), 4.91 (1H, s), 3.81 (2H, d, J ═6 Hz), 1.80 (3H, s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH:23](B(O)O)[CH2:22][CH2:21][CH2:20]2)[C:12]1=[O:27].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.O>[C:1]([C:3]1[CH:4]=[C:5]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][C:12](=[O:27])[C:13]23[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(F)cc(-c2ccc3c(c2)C2(CCCC2)C(=O)N3)c1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol), and tetrakis (triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the subtitled compound (0.35 g, 44%) as white needles. mp: 235-237° C.; 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.1 (s, 1H), 8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8-7.7 (m, 2H), 7.6 (dd, 1H, J=1.8, 6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS (EI) M+ @ m/z 306.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:22]([CH2:24][C:25]([O:27][CH2:28][CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:26])#[N:23].C([O-])(=O)C.[NH4+]>O.C(O)(=O)C>[C:22]([C:24](=[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:25]([O:27][CH2:28][CH2:29][O:30][C:31](=[O:33])[CH3:32])=[O:26])#[N:23]
Reactant: CC(=O)OCCOC(=O)CC#N
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)OCCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Yield: 60 %

Procedure:
A three-neck round bottom flask fitted with a mechanical stirrer, a thermometer and a Dean-Stark trap fitted with a reflux condenser was charged with 200 ml. of toluene, 182 g. (1 mole) of benzophenone, 205 g. (1.2 moles) of 2-acetoxyethyl 2-cyanoacetate, 40 ml. of glacial acetic acid, 16 g. of ammonium acetate. The contents were heated to reflux (110° C.) for 24 hours while the theoretical amount of water by-product was removed by azeotropic distillation. Upon removal of the solvent, as well as unreacted starting material by vacuum distillation, a yield of 200 g. (60%) of the desired product was obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:16])=[CH:18][CH:19]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(N)CO
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1ccc(C(C)(C)C)cc1
Yield: 105.5 %

Procedure:
30.95 g (347 mmol) of 2-amino-2-methyl-1-propanol was weighed into a 500 mL Erlenmeyer flask fitted with a stir bar and septum. Added 200 mL CH2Cl2. Established and maintained nitrogen atmosphere. Stirred the solution in an ice/water bath. Added 34 mL (174 mmol) of 4-tert-butylbenzoyl chloride dropwise over 30 min. A white precipitate formed. Stirred at room temperature overnight. Removed the solids by filtration and washed with CH2Cl2. Removed the solvent from the filtrate on rotavap and dried at 60°/4 torr to obtain 45.79 g of the title compound as a light yellow resin. MS (ESI) 248 (M−H)−.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][C@@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[C:25]([Si:22]([CH3:24])([CH3:23])[O:21][C@@H:19]([CH3:20])[CH2:18][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([OH:8])[CH:17]=2)[CH:13]=[N:14]1)([CH3:27])([CH3:28])[CH3:26]
Reactant: C[C@@H](Cn1ncc2ccc(OCc3ccccc3)cc21)O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H](Cn1ncc2ccc(O)cc21)O[Si](C)(C)C(C)(C)C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A mixture of the product from Step A (5.44 g, 13.7 mmol) and palladium-on-carbon (10%, 0.50 g) in methanol (200 mL) was stirred under an atmosphere of hydrogen for 18 h, filtered and evaporated to give an off-white solid (3.80 g, 90%): mp 171-172° C.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10](=[O:42])[NH:11][C@H:12]([C:27]([NH:29][CH2:30][CH:31]([OH:41])[CH2:32][NH:33]C(OC(C)(C)C)=O)=[O:28])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19]CC1C=CC=CC=1)=[O:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[CH2:2]([N:16]([CH2:15][CH2:14][CH2:13][C@H:12]([NH:11][C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:42])[C:27]([NH:29][CH2:30][CH:31]([OH:41])[CH2:32][NH2:33])=[O:28])[C:17](=[O:18])[OH:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCC(O)CNC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(O)CNC(=O)[C@H](CCCN(Cc1ccccc1)C(=O)O)NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
6.8 ml of a 4N solution of hydrogen chloride in dioxane are added to a solution of 0.263 g (0.46 mmol) of the compound from Example 258A in 1 ml of dioxane at 0° C. After 2 h at RT, the reaction solution is concentrated in vacuo and coevaporated with dichloromethane several times. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]([NH:33][NH2:34])=[O:32])[CH2:26][CH2:25]1>>[O:24]1[CH2:25][CH2:26][N:27]([CH2:30][C:31]([NH:33]/[N:34]=[C:21](/[C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[N:20][CH:19]=2)\[CH3:22])=[O:32])[CH2:28][CH2:29]1
Reactant: NNC(=O)CN1CCOCC1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: C/C(=N\NC(=O)CN1CCOCC1)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and 2-morpholinoaceto-hydrazide. The title compound was obtained as light yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.45 (d, 1H), 8.90 (d, 1H), 8.36 (d, 1H), 8.01 (m, 2H), 7.83 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 3.65 (d, 4H), 3.26 (s, 2H), 2.57 (d, 4H), 2.41 (s, 3H). LCMS (method B): [MH]+=446.2, tR=1.37 min.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].[CH3:12][C:13]([NH:25][C@@H:26]1[CH2:30][C@H:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:40])[F:39])[CH:32]=2)[N:28]([C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)[C:27]1=[O:50])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=1)[CH3:14]>ClCCl>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[CH3:14][C:13]([NH:25][C@@H:26]1[CH2:30][C@H:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]([F:41])([F:39])[F:40])[CH:32]=2)[N:28]([C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)[C:27]1=[O:50])([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[N:16]=1)[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CC(C)(N[C@@H]1C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C#N)cc2)C1=O)c1cccc(C(F)(F)F)n1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
Tosylate Salt formation: Add p-toluenesulonic acid monohydrate (28.2 mg, 0.146 mmol) to a solution of 4-[(3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-2-oxo-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-1-yl]-benzonitrile (80 mg, 0.146 mmol) in dichloromethane. Evaporate to give a quantitative mass balance of 4-[(3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-2-oxo-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-1-yl]-benzonitrile tosylate as a foam. LC-MS ESI m/z: 548.6 (M+H)+, 571.6 (M+Na)+, Tr=2.34 min., method 2.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([F:8])[CH:7]=1.I[CH3:11]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([O:9][CH3:11])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=c1[nH]cc(F)cc1Br
Reactant: CI
Solvent: Cc1ccccc1
Product: COc1ncc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
3-Bromo-5-fluoropyridin-2(1H)-one (10.0 g, 52.1 mmol) and Ag2CO3 (10.0 g, 36.5 mmol) were combined in toluene (100 mL) and iodomethane (3.89 mL, 62.5 mmol) was added drop-wise. The reaction was stirred at ambient temperature overnight, filtered through Celite and the solids were washed with toluene. The filtrate was concentrated and the residue was purified on a silica gel column (5-25% EtOAc/hexanes) to afford 3-bromo-5-fluoro-2-methoxypyridine (4.70 g, 43.8%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:29])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.Br[C:31]1[CH:32]=[N:33][C:34]([CH3:37])=[N:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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]>[NH2:1][C:2]1[C:3]([F:29])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:31]4[CH:32]=[N:33][C:34]([CH3:37])=[N:35][CH:36]=4)[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Cc1ncc(Br)cn1
Reactant: CC1(C)OB(c2cnc3[nH]cc(C(=O)c4c(F)ccc(N)c4F)c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ncc(-c2cnc3[nH]cc(C(=O)c4c(F)ccc(N)c4F)c3c2)cn1
Temperature: 100 °C

Procedure:
In a reaction vial, (3-amino-2,6-difluoro-phenyl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone is combined with (48, 0.850 g, 2.129 mmol), 5-bromo-2-methyl-pyrimidine (49, 0.737 g, 4.26 mmol), potassium carbonate (0.589 g, 4.26 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.174 g, 0.213 mmol) in 14.20 mL of dioxane and 7.10 mL of water (7.10 mL). The reaction is heated at 100° C. overnight. Upon cooling, the reaction mixture is partitioned between water/brine and ethyl acetate/tetrahydrofuran and then filtered through Celite. The organic layer is separated and concentrated under vacuum. The resulting residue is purified by silica gel column chromatography eluting with 0-10% methanol in dichloromethane to provide the desired compound as a tan solid (50, ˜220 mg).
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:34]1[N:38]([CH3:39])[N:37]=[CH:36][CH:35]=1.NN>O1CCCC1.CO>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[O:6][C:2]([Cl:1])=[C:3]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][CH:35]=2)[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)oc1Cl
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)oc1Cl
Yield: 66.7 %

Procedure:
To a solution of 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (202 mg, 0.36 mmol) in tetrahydrofuran (1.8 ml) and methanol (1.8 ml) at 25° C. was added hydrazine (0.08 ml, 2.54 mmol) dropwise. After 12 h the solution was concentrated, dry loaded onto silica and purified by column chromatography (2% MeOH in DCM (1% NH4OH)). The free base was transferred to the HCl salt by addition of excess 2M HCl in diethyl ether (2 ml) to the residue in DCM (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide (120 mg, 0.24 mmol, 66% yield) as a yellow solid: LCMS (ES) m/z=427, 429 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.87 (d, J=9.09 Hz, 1H) 8.11 (br. s., 3H) 7.66-7.73 (m, 2H) 7.57 (t, J=7.45 Hz, 2H) 7.53 (d, J=1.52 Hz, 1H) 7.44 (d, J=6.82 Hz, 1H) 6.50 (d, J=1.52 Hz, 1H) 4.43-4.51 (m, 1H) 3.86 (s, 3H) 2.99-3.17 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:42])[CH2:9][N:10]([CH2:33][C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[C:36]([F:41])[CH:35]=2)[C:11]([C:13]2[CH:14]=[N:15][N:16]([C@H:22]3[CH2:27][CH2:26][C@H:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]3)[C:17]=2[C:18]([F:21])([F:20])[F:19])=[O:12])=[C:6]([Cl:43])[CH:5]=[CH:4][N:3]=1.[N-:44]=[N+:45]=[N-:46].[Na+]>CN(C=O)C>[N:44]([C:2]1[C:7]([C:8](=[O:42])[CH2:9][N:10]([CH2:33][C:34]2[CH:35]=[C:36]([F:41])[CH:37]=[C:38]([F:40])[CH:39]=2)[C:11]([C:13]2[CH:14]=[N:15][N:16]([C@H:22]3[CH2:23][CH2:24][C@H:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:26][CH2:27]3)[C:17]=2[C:18]([F:20])([F:21])[F:19])=[O:12])=[C:6]([Cl:43])[CH:5]=[CH:4][N:3]=1)=[N+:45]=[N-:46]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)ccnc3Cl)Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)ccnc3N=[N+]=[N-])Cc3cc(F)cc(F)c3)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ethyl trans-4-(4-((2-(2,4-dichloropyridin-3-yl)-2-oxoethyl)(3,5-difluorobenzyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)cyclohexanecarboxylate (100 mg, 0.15 mmol) in DMF (5 mL) was added NaN3 (50 mg, 0.7 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 30% EtOAc/hexane as eluent) to provide compound 21-1 (60 mg, 59%) as a brown oil.
Reaction SMILES: [Si:1]([O:8][C:9]1([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][C:20]=2[N+:29]([O-])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[Pt].C(OCC)(=O)C>[Si:1]([O:8][C:9]1([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][C:20]=2[NH2:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1(CCCNc2c([N+](=O)[O-])cnc3ccccc23)CCCCC1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1(CCCNc2c(N)cnc3ccccc23)CCCCC1
Reaction time: 2 h

Procedure:
A mixture of N-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]-3-nitroquinolin-4-amine (1.40 g, 3.16 mmol) and 5% platinum on carbon (0.14 g) in ethyl acetate (15 mL) was hydrogenated at 30 psi (2.1×105 Pa) for 2 h on a Parr apparatus. The reaction mixture was filtered through CELITE filter agent, which was rinsed with ethyl acetate afterwards, and the filtrate was concentrated to give N4-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]quinoline-3,4-diamine as an orange colored gum. The gum was dissolved in dichloromethane (15 mL) and the solution was cooled to 0° C. Ethoxyacetyl chloride (0.350 mL, 3.48 mmol) was added dropwise over 2 min. The reaction was allowed to stir at 0° C. for 1 h, then was concentrated in vacuo to yield N-(4-{[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]amino}quinolin-3-yl)-2-ethoxyacetamide hydrochloride as a yellow solid. The yellow solid was dissolved in ethanol (12 mL) and 2 M NaOH (2.4 mL, 4.8 mmol) was added. The reaction was heated at 60° C. for 1 h. The reaction was cooled to rt and the solvent was removed in vacuo. The residue was partitioned between dichloromethane (50 mL) and water (30 mL), and 1 M HCl was added to the mixture until the pH=7-8. The aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford 1-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline as a brown oil (1.57 g, 96%) that contained some dichloromethane.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH:5]([C:7]([OH:9])=[O:8])[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:28](O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[CH2:28]([O:8][C:7]([CH:5]1[CH:4]([C:10]([OH:12])=[O:11])[CH2:3][C:2](=[O:1])[O:6]1)=[O:9])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OCc1ccccc1
Reactant: O=C1CC(C(=O)O)C(C(=O)O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)=O
Product: O=C1CC(C(=O)O)C(C(=O)OCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
5.3 g of (2RS,3SR)-5-oxotetrahydrofuran-2,3-dicarboxylic acid was dissolved in 90 ml of acetone, and 6.6 g of N,N'-dicyclohexylcarbodiimide was added thereto, followed by stirring at room temperature for 2.5 hours. 3.3 ml of benzyl alcohol was added to the reaction solution, followed by stirring at the same temperature for 2 days. Insoluble matters were filtered off, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→chloroform/methanol=50/1) to obtain 6.55 g of the above-identified compound as a yellow solid.
Reaction SMILES: [C:1]([N:4]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][C:27]3[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([NH2:38])[C:28]=3[C:29](=[O:31])[CH:30]=2)=[CH:21][C:20]=1[F:39])[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])(=[O:3])[CH3:2].I[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:1]([N:4]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][C:27]3[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([NH:38][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[C:28]=3[C:29](=[O:31])[CH:30]=2)=[CH:21][C:20]=1[F:39])[CH2:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13])(=[O:3])[CH3:2]
Reactant: CCCCCCI
Reactant: CC(=O)N(CCCN1C(=O)c2ccccc2C1=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(CCCN4C(=O)c5ccccc5C4=O)C(C)=O)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
450 mg of Compound 28 was dissolved in 15 ml of dimethylformamide, 0.62 ml of 1-iodohexane and 34 mg of sodium hydride (60% oil dispersion) were added under ice-cooling and the mixture was stirred at room temperature for 2 hours. An aqueous solution of ammonium chloride was added, the reaction solution was concentrated under reduced pressure and the residue was extracted once with chloroform. The chloroform layer was washed with an aqueous saturated solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=1:1-1:3) to give 184 mg (35%) of Compound 31.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C(OCC)(=O)C>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:21])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=2[CH3:20])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccccc1)C(C)(C)O2
Yield: 92 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 92%. Melting point: 156-158° C. (Ethyl acetate)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH2:22][CH3:23])[CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:24](Br)CC>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH2:22][CH2:23][CH3:24])[CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CCCBr
Reactant: CCn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Product: CCCn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Yield: 75 %

Procedure:
This compound was prepared in the manner described above for intermediate 5b by replacing ethylbromide with n-propylbromide (13.1 g, 11 mmol) to afford 4.33 g (75%) of the title compound as a oil: MS EI m/e 324 (M+)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:15][CH:14]3[NH:16][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:24][C:25]([F:39])([F:38])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[O:27]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH:11]3[N:16]([CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:26](=[O:27])[C:25]([F:24])([F:38])[F:39])[CH:14]([CH2:13][CH2:12]3)[CH2:15]2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)OCCCCNC(=O)C(F)(F)F
Reactant: Clc1ccc(N2CC3CCC(C2)N3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCCCCN1C2CCC1CN(c1ccc(Cl)cc1)C2)C(F)(F)F
Yield: 39 %

Procedure:
3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1] octane hydrochloride salt (1.5 g, 5.79 mmol), triethylamine (1.77 mL, 12.73 mmol) and methanesulfonic acid 4-(2,2,2-trifluoro-acetylamino)-butyl ester (2.29 g, 8.68 mmol) were combined in tetrahydrofuran (25 mL). The resulting white heterogeneous reaction was heated at reflux for 24 hours. The mixture was cooled diluted with saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (200 mL), dried with magnesium sulfate and concentrated to a light brown oil. Silica gel flash chromatography using 5% methanol/ chloroform as eluent yielded N-{4-[3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butyl}-2,2,2-trifluoro-acetamide (0.88 9, 39%) as an off-white solid which had the following properties: Mp. 83-85° C., 1H NMR CDCl3 δ: 7.77 (brd s, 1H), 7.16 (d, J=9.1 Hz, 2H), 6.68 (d, J=9.1 Hz, 2H), 3.44-3.35 (m, 4H), 3.29 (d, J=9.6 Hz, 2H), 3.02 (d, J=9.6 Hz, 2H), 2.51 (t, J=6.2 Hz, 2H), 2.10-1.90 (m, 2H), 1.83-1.76 (m, 2H), 1.73-1.57 (m, 6H).