Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=[O:4].N([C@H]1[C@H](O)CCCN(C(OC(C)(C)C)=O)C1)=[N+]=[N-].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[O:44][CH2:45][O:46][CH3:47])=[O:35])=[CH:30][CH:29]=1>>[OH:4][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[O:44][CH2:45][O:46][CH3:47])=[O:35])=[CH:30][CH:29]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COCOc1ccc(OC)cc1C(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](O)[C@H](N=[N+]=[N-])C1
Product: COCOc1ccc(OC)cc1C(=O)c1ccc(CO)cc1

Procedure:
Compound (W) used in Examples (U8) and (U9) was obtained from tert-butyl (3R,4R)-3-azido-4-(benzyloxy)-hexahydro-1H-azepine-1-carboxylate (see Example (S) by debenzylation with trifluoroacetic acid to tert-butyl (3R, 4R)-3-azido-4-hydroxy-azepane-1-carboxylate and O-alkylation of this compound with (4-bromomethyl-phenyl)-(5-methoxy-2-methoxymethoxy-phenyl)-methanone. The latter compound was obtained by the bromination of (4-hydroxymethyl-phenyl)-(5-methoxy-2-methoxymethoxy-phenyl)-methanone (M8).
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][NH:17][CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:34]([C:37]1[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40])=[C:35]=[O:36]>C1(C)C=CC=CC=1>[C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][N:17]([C:35]([NH:34][C:37]3[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=3[C:39]([O:41][CH3:42])=[O:40])=[O:36])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: C[C@@H](NCC1CNCCC1c1ccccc1)c1cccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1NC(=O)N1CCC(c2ccccc2)C(CN[C@H](C)c2cccc3ccccc23)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
To a solution of 158 mg of (1R)-1-(1-naphthyl)-N-[(4-phenylpiperidin-3-yl)methyl]ethaneamine and 0.100 mL of triethylamine in 3.0 mL of toluene was added 83 mg of methyl 2-isocyanatobenzoate at room temperature. It was stirred at 90° C. overnight, and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 27.3 mg of methyl 2-({[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}amino)benzoate as a colorless foamy substance.
Reaction SMILES: O.[OH-].[Li+].O.C([O:7][C:8]([C:10]1[CH:11]=[N:12][N:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]4[CH2:29][CH2:28][CH2:27][CH2:26][C:20]=4[CH:21]=3)[N:16]=2)[CH:14]=1)=[O:9])C>C1COCC1>[O:25]=[C:23]1[C:22]2[C:17](=[CH:18][C:19]3[CH2:29][CH2:28][CH2:27][CH2:26][C:20]=3[CH:21]=2)[N:16]=[C:15]([N:13]2[CH:14]=[C:10]([C:8]([OH:9])=[O:7])[CH:11]=[N:12]2)[NH:24]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)CCCC4)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)CCCC4)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
Lithium hydroxide monohydrate (25.5 mg, 0.608 mmol) and water (0.45 mL) were added to 1-(4-oxo-3,4,6,7,8,9-hexahydro-benzo[g]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (87.5 mg, 0.259 mmol) in THF (0.55 mL). The reaction mixture was stirred at room temperature for 18 h and was then concentrated. The residue was redissolved in water (5 mL) and this solution was brought to pH 1 with 1M aqueous HCl. The resulting precipitate was collected and dried to yield the titled compound (76.6 mg, 95% yield). MS (ESI/Cl): mass calcd. for C16H14N4O3, 310.1; m/z found, 311.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 13.00 (s, 1H), 12.61 (s, 1H), 8.91 (s, 1H), 8.24 (s, 1H), 7.83 (s, 1H), 7.40 (s, 1H), 2.89 (br d, J=4.7 Hz, 4H), 1.84-1.72 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:16]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:15]3[C:10](=[N:11][CH:12]=[C:13](I)[CH:14]=3)[O:9][C:5]2=[CH:6][C:7]=1[F:8].C[Si](C)(C)[C:25]#[C:26][C:27]1([CH3:31])[CH2:30][O:29][CH2:28]1.CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:16]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:25]#[C:26][C:27]4([CH3:31])[CH2:30][O:29][CH2:28]4)[CH:14]=3)[O:9][C:5]2=[CH:6][C:7]=1[F:8]
Reactant: NC1=NC2(CO1)c1cc(Br)c(F)cc1Oc1ncc(I)cc12
Reactant: CC1(C#C[Si](C)(C)C)COC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C#Cc2cnc3c(c2)C2(COC(N)=N2)c2cc(Br)c(F)cc2O3)COC1
Reaction time: 4 h
Yield: 42.2 %

Procedure:
A vial charged with Pd(PPh3)4 (0.73 g, 0.63 mmol), copper(I) iodide (0.48 g, 2.52 mmol), 7-bromo-8-fluoro-3-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (3.0 g, 6.30 mmol), trimethyl((3-methyloxetan-3-yl)ethynyl)silane (1.06 g, 6.30 mmol) and 13 mL DMF was degassed with argon and treated with DIPA (4.49 mL, 31.5 mmol). The resulting slurry was allowed to stir at RT for 18 h at which point an additional portion of copper(I) iodide (0.48 g, 2.52 mmol) was added. After stirring for an additional 4 h the reaction mixture was poured into water (50 mL) and was extracted with EtOAc (3×100 mL). The resulting suspension was filtered through a glass frit and the filtrate was dried over MgSO4 and concentrated in vacuo. Purification of the crude residue by column chromatography [0-50% (9:1 CH2Cl2:MeOH)/CH2Cl2] provided 7-bromo-8-fluoro-3-((3-methyloxetan-3-yl)ethynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (1.18 g, 2.66 mmol).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C1C[CH2:30][N:29]2[C:24](=[N:25][CH2:26][CH2:27][CH2:28]2)CC1.[C:32](O)(=O)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:25]4[CH2:26][C:27](=[CH2:32])[CH:28]([NH:29][CH3:30])[CH2:24]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)O
Solvent: CC#N
Product: C=C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1NC
Yield: 82 %

Procedure:
A solution of 350 mg (1.24 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (II-1), 424 mg (2.48 mmol) of 3-methylamino-4-methylene-1-pyrrolidine dihydrochloride, and 754 mg of DBU in 15 ml of acetonitrile is refluxed for 2 hours. After cooling, the reaction mixture is neutralized with acetic acid. The resulting crystals are collected by filtration, washed with acetonitrile, and dried to give 368 mg (Yield: 82%) of the objective compound (I-5). mp. 239°-243° C.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11](#[N:15])[CH2:12][C:13]#[N:14].[OH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][N:21]2[CH3:26]>>[NH2:14][C:13]1[O:16][C:17]2[C:25]([CH:9]([C:7]3[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:12]=1[C:11]#[N:15])=[CH:24][CH:23]=[C:22]1[N:21]([CH3:26])[CH:20]=[CH:19][C:18]=21
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#CCC#N
Reactant: Cn1ccc2c(O)cccc21
Product: Cn1ccc2c3c(ccc21)C(c1ccc([N+](=O)[O-])s1)C(C#N)=C(N)O3

Procedure:
The title compound was prepared from 5-nitrothiophene-2-carboxaldehyde, malononitrile and 4-hydroxy-1-methyl-indole similar to Example 22, yielded 0.002 g (9%) of a brown solid. 1H-NMR (CDCl3): 7.70 (dd, J=17.0, 3.8 Hz, 1H), 7.12 (m, J=8.2, 4.1, 2.7 Hz, 2H), 6.99 (d, J=4.1 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.56 (d, J=2.7 Hz, 1H), 5.14 (s, 1), 4.88 (brs, 2H), 3.80 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:7]2[NH:8][CH2:9][C@H:4]([O:5][C:6]2=[O:10])[CH2:3]1.CN(C)C=O.C(N(CC)CC)C.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>Cl>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:8]2[CH2:9][C@H:4]3[CH2:3][C:2]([CH3:11])([CH3:1])[C@@H:7]2[C:6](=[O:10])[O:5]3)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CC1(C)C[C@@H]2CN[C@H]1C(=O)O2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)C[C@@H]2CN(S(=O)(=O)c3ccc(OCc4ccccc4)cc3)[C@H]1C(=O)O2
Reaction time: 1 h

Procedure:
A solution of (1R,4R)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXVI, 10 mmol) and dimethylformamide (20 ml) at about 0° C. was treated with triethylamine (10–20 mmol) and 4-benzyloxybenzenesulfonyl chloride (15 mmol). After stirring for about 1 hours, the mixture is warmed to a temperature of about 20° C. to about 25° C. and stirred for about an additional 12 hours. The mixture is diluted with 1M hydrochloric acid, extracted twice with ethyl acetate, and the combined organic layers are dried over sodium sulfate, filtered and concentrated in vacuo to give (1R,4R)-5-(4-benzyloxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one as a colorless syrup.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[H-].[Na+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1>O>[F:6][C:7]1[CH:14]=[C:13]([O:15][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: Fc1ccc(CCl)nc1
Reactant: O=Cc1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccc(F)cn2)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.2 %

Procedure:
To an N,N-dimethylformamide (20.0 mL) solution of 2-fluoro-4-hydroxy-benzaldehyde (1.48 g, 10.2 mmol) was added sodium hydride (411 mg, 10.3 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 20 minutes at room temperature. 2-Chloromethyl-5-fluoro-pyridine (1.20 g, 8.56 mmol) described in Manufacturing Example 41-1-2 was then added at room temperature, and stirred for 30 minutes at 80° C. Water was added at room temperature to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: heptane=1:5→1:2) to obtain the title compound (901 mg, 42.2%).
Reaction SMILES: [C:1]1([P:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]([CH3:17])[CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([N:28]=[N+]=[N-])(=[O:27])[O:25][CH3:26]>CCOCC>[CH3:16][N:15]([CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[P:7](=[N:28][C:24](=[O:27])[O:25][CH3:26])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:17]
Reactant: COC(=O)N=[N+]=[N-]
Reactant: CN(C)Cc1ccccc1P(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: COC(=O)N=P(c1ccccc1)(c1ccccc1)c1ccccc1CN(C)C

Procedure:
A 2.0 g portion of 2-(diphenylphosphino)-N,N-dimethylbenzenemethanamine was reacted with 4.0 ml of 1M methyl carbonazidate in ether as described in Example 1, giving 1.32 g of the desired product, mp 95°-97° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:7]=[CH:6][CH:5]=2.Br[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu](I)I>[F:27][C:22]1[CH:21]=[C:20]([N:3]2[C:4]3[C:9](=[C:8]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH:25]=[CH:24][C:23]=1[OH:26]
Reactant: Oc1ccc(Br)cc1F
Reactant: Cc1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc2c(OCc3ccccc3)cccc2n1-c1ccc(O)c(F)c1
Temperature: 190 °C

Procedure:
To a solution of 2-methyl-4-[(phenylmethyl)oxy]-1H-indole {WO9204321} (440 mg, 1.86 mmol) in N-methyl-2-pyrrolidinone (4 mL) was added 4-bromo-2-fluorophenol (0.205 mL, 1.87 mmol), copper iodide (70 mg, 0.37 mmol) and potassium carbonate (641 mg, 4.64 mmol). The reaction mixture was heated in a Biotage Initiator™ Microwave Synthesizer at 190° C. for 6 hours. The mixture was filtered through a pad of Celite which was subsequently washed with ethyl acetate. The ethyl acetate solution was washed with water, dried over magnesium sulfate, filtered and then concentrated in vacuo. The product was purified by MDAP to yield the title compound (D3) (30 mg).
Reaction SMILES: COC1C=C[C:6]([CH2:7][NH:8][C:9]2[N:14]=CN=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:24])=[CH:18][C:17]=3[F:36])[CH:10]=2)=CC=1.NC1C=CC(OC2C=CN=C(N)C=2)=C(F)C=1>C(Cl)Cl>[NH2:14][C:9]1[CH:10]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)=[O:24])=[CH:18][C:17]=2[F:36])[CH:6]=[CH:7][N:8]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Agent: Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Solvent: ClCCl
Product: Nc1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 49.4 %

Procedure:
2-(4-Fluorophenyl)acetyl isocyanate (Compound D of Example 11, 0.362 M, 0.351 mL, 0.127 mmol, 1.3 eq) was added to a solution of 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (0.022 g, 0.100 mmol, 1.0 eq) in CH2Cl2 (2.0 mL) at room temperature. The reaction mixture was stirred for 13 h at room temperature and then concentrated in vacuo. The residue was purified by silica gel flash chromatography (Merck gel 40-63 μM, 230-240 mesh, 1:1 ethyl acetate/hexane) to afford the title compound (0.025 g, 64%) as a solid. 1H NMR (CD3OD) δ 7.62-7.67 (m, 2H), 7.23-7.29 (m, 2H), 7.07-7.12 (m, 2H), 6.95-6.99 (m, 2H), 6.12-6.14 (m, 1H), 5.86-5.87 (m, 1H), 3.61 (s, 2H); MS(ESI+) m/z 399 (M+H)+; HRMS(ESI+) calcd.: 399.1269, found: 399.1269.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].[CH2:17]([N:24]1[CH2:29][C@@H:28]2[C@@H:26]([CH:27]2[NH2:30])[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([N:24]1[CH2:29][C@@H:28]2[C@@H:26]([CH:27]2[NH:30][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NC1[C@H]2CN(Cc3ccccc3)C[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1NC1[C@H]2CN(Cc3ccccc3)C[C@@H]12
Temperature: 130 °C
Reaction time: 18 h

Procedure:
Potassium carbonate (4.59 g, 33.2 mmol), followed by 1-fluoro-2-nitrobenzene (1.87 g, 13.3 mmol) were added to a solution of (1R,5S)-3-benzyl-3-azabicyclo[3.1.0]hex-6-ylamine (WO 9318001), (2.50 g, 13.3 mmol) in N,N-dimethylformamide (40 ml), and the reaction mixture stirred at 130° C. for 18 hours. The cooled mixture was filtered, and the filtrate concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, the phases separated, and the aqueous layer extracted with ethyl acetate (3×). The combined organic solutions were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (95:5 to 90:10) to afford the title compound as an orange crystalline foam, 3.11 g.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[F-].[K+].Cl>CN(C)C=O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CCCCCCCCI
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.6 %

Procedure:
To dry dimethylformamide (200 mL) were added 2-fluoro-4-hydroxybenzonitrile (13.71 g, 100 mmol), 1-iodooctane (28.82 g, 120 mmol) and potassium fluoride (11.6 g, 200 mmol). This mixture was stirred at room temperature for 16 h, and then at 50° C. for 2 h and then at 90° C. for 2 h. The mixture was then poured into wet-ice (400 g) and 37% HCl (10 mL). The resulting solution was extracted with diethyl ether (3×200 mL). The ether layer was washed with water (2×200 mL) and dried over Na2SO4. After filtration, rotary evaporation gave the crude desired intermediate 2-fluoro-4-n-octyloxybenzonitrile (27.83 g). This liquid intermediate was then added, over a 5-10 min period at 3-13° C. to a flask containing LiAlH(OEt)3 [which had been freshly prepared from LiAlH4 (5.03 g, 0.1326 mol) and ethyl acetate (15.24 g, 0.1730 mol) at 3-8° C. in diethyl ether (130 mL)]. The reaction mixture was stirred at 5° C. for 75 min and 5 N H2SO4 aqueous solution (120 mL) was added dropwise with cooling. After separation, the aqueous layer was extracted with diethyl ether (2×100 mL) and the combination extracts were washed with water (2×100 mL). Standard work-up procedures afforded crude 2-fluoro-4-n-octyloxybenzaldehyde (26.07 g). The crude material was then mixed with N-tert-butylhydroxylamine (8.6 g, 96.4 mmol), molecular sieves (50 g, 4 A) and silica gel (10 g) in chloroform (250 mL). The mixture was stirred at room temperature for 23 h and refluxed for 3 h under argon gas. The mixture was then filtered and rotary evaporated to give a residue which was purified by column chromatography over silica gel eluted with hexanes/ethyl acetate (4:1, v:v). The title compound (12.90 g) was obtained in 39.9% overall yield as a slightly yellowish solid. m.p. 35.6° C. (Rf=0.36 on a silica gel plate using hexanes/EtOAc, 4:1, v:v, as the eluant).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C1COCC1>[O-:24][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc[n+]([O-])c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
To a mixture of 4-(3-pyridyl)toluene (35 g, 0.207 mol) in pyridine (400 ml) and water (400 ml) was added KMnO4 (163 g, 1.03 mol) in portions and refluxed for 12 h. The reaction mixture was filtered through celite and acidified with conc. HCl. The product was washed with water and dried to give 4-(3-pyridyl)benzoic acid (32 g, 76%) as a white solid. To a mixture of 4-(3-pyridyl)benzoic acid (22 g, 0.11 mol) in THF (2.51), mCPBA (152 g, 0.44 mol, 50%) was added and stirred at RT for 12 h. The solid was filtered, and washed with THF to give 4-(1-oxido-3-pyridinyl)benzoic acid (20 g, 86%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH:16]([C:20]([NH:22][C:23]4[CH:24]=[C:25]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=4)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:21])[CH2:17]3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1)#N.C[O-:43].[Na+].Cl.[C:46]([O-])(O)=[O:47].[Na+]>CO>[C:30]([O:29][C:28]([NH:27][CH2:26][C:25]1[CH:24]=[C:23]([NH:22][C:20]([CH:16]2[CH2:17][C:18]3[CH:19]=[C:10]([O:9][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([C:1]([O:47][CH3:46])=[O:43])[CH:8]=4)[CH:11]=[CH:12][C:13]=3[CH2:14][CH2:15]2)=[O:21])[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=1)=[O:34])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(C#N)c4)cc3C2)cc(C(F)(F)F)c1
Reactant: C[O-]
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CNC(=O)OC(C)(C)C)cc(C(F)(F)F)c2)CC3)ccn1
Temperature: 65 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of tert-butyl [3-[({7-[(2-cyanopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalen-2-yl}carbonyl)amino]-5-(trifluoromethyl)benzyl]carbamate (2.00 g, 3.53 mmol) in MeOH (32 mL), was added a 25% solution of sodium methoxide in MeOH (0.402 mL, 1.76 mmol). The reaction mixture was heated at 65° C. for 90 min, then allowed to cool to rt. After the addition of 1N HCl solution (20.0 mL), the reaction mixture was allowed to stir at rt for 3 h. The mixture was basified by the addition of saturated NaHCO3 and the MeOH was evaporated. The mixture was extracted with EtOAc and the organic solutions were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give methyl 4-{[7-({[3-{[(tert-butoxycarbonyl)amino]methyl}-5-(trifluoromethyl)phenyl]-amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}pyridine-2-carboxylate (2.08 g, 98.3%). LCMS: (FA) ES+ 600.3, ES− 598.4.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[F:13][CH:14]([F:18])[C:15](O)=O.Cl.C>[Pd].CO.O>[NH3:1].[F:13][CH:14]([F:18])[C:15]1[NH:10][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=2[N:1]=1
Reactant: COc1cccc([N+](=O)[O-])c1N
Reactant: O=C(O)C(F)F
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cccc2[nH]c(C(F)F)nc12
Product: N
Yield: 170.4 %

Procedure:
2-Amino-3-methoxynitrobenzene (15.10 g, 0.09 mol) was hydrogenated over palladium on carbon in methanol, and the solution was filtered through celite into a methanolic HCl solution. The solvent was removed under vacuum and the resulting hydrochloride salt was combined with difluoroacetic acid (19.2 g, 0.18 mol) and 4 M HCl (100 mL). The mixture was heated under reflux for 3 hrs, diluted with water, decolorized with charcoal, and filtered through celite. Neutralization with aqueous ammonia gave 2-difluoromethyl-4-methoxy-1H-benzimidazole (15.2 g, 84%) as a solid: 1H NMR (CDCl3) (tautomeric mixture) δ 9.95-9.70 (m, exchangeable with D2O, 1H), 7.44 (br d, J=7.9 Hz, 0.4H), 7.31-7.24 (m, 1H), 7.12 (br d, J=8.0 Hz, 0.5H), 6.89 (t, JHF=53.8 Hz, 1H), 6.82-6.74 (m, 1H), 4.03 and 3.98 (2s, 3H).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)[C:2]#[CH:3].I[C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.O.C(Cl)Cl>C(NCC)C.[Cu]I.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>[O:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[O:4][CH2:1][C:2]#[C:3][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1
Reactant: Nc1ccc(I)cn1
Reactant: C#CCOC1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCNCC
Solvent: ClCCl
Product: Nc1ccc(C#CCOC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
2-(2-Propynyloxy)tetrahydro-2H-pyran (360 mg), 5-iodo-2-pyridinylamine (440 mg), CuI (140 mg) and dichlorobis(triphenylphosphine)palladium (60 mg) are dissolved in diethylamine (10 mL). After the mixture is stirred for 1 h at room temperature, water (40 mL) and CH2Cl2 (80 mL) are added. The organic laywer is separated, dried (MgSO4) and concentrated. The resulting residue is purified on a silica gel plate (CH2Cl2/methanol, 9/1) to give 230 mg (50%) of the title compound as an oil which slowly solidifies. MS (ESI+) m/z 233 (M+H)+. 1H NMR (CDCl3) δ8.10, 7.60, 6.65, 5.90, 4.86, 4.48, 3.90, 3.5-3.6, 1.55-1.9.