Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH:47]C(=O)OC(C)(C)C)[CH2:42]2)=[C:34]2[S:40][CH:39]=[CH:38][C:35]2=[N:36][CH:37]=1)=[O:30])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[S:20][C:19]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH2:47])[CH2:42]2)=[C:34]2[S:40][CH:39]=[CH:38][C:35]2=[N:36][CH:37]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2ccsc2c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2ccsc2c1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
TFA (2.0 mL) was added to a solution of tert-butyl {(3S)-1-[6-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[3,2-b]pyridin-7-yl]piperidin-3-yl}carbamate (78.5 mg, 0.114 mmol) in DCM (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (28.5 mg, 51%). LCMS calc. for C22H21F2N6OS2 (M+H)+: m/z=487.1. found 487.1. 1H NMR (500 MHz, DMSO-d6) δ 9.56 (s, 1H), 7.95 (d, J=5.5 Hz, 1H), 7.66 (s, 2H), 7.57-7.50 (m, 1H), 7.49 (d, J=5.5 Hz, 1H), 7.28 (t, J=8.8 Hz, 2H), 3.24-3.16 (m, 1H), 3.08-3.01 (m, 1H), 3.01-2.91 (m, 2H), 2.83-2.74 (m, 1H), 1.90-1.67 (m, 3H), 1.24-1.10 (m, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:21])([F:20])[F:22])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1cccc(Cl)n1
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3cccc(Cl)n3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 6-chloro-2-pyridinol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 226.4-227.4° C. 1H NMR (acetone-d6/300 MHz) 7.99 (m, 1H), 7.96 (s, 1H), 7.75 (s, 1H), 7.30 (d, 1H, J=7.7 Hz), 7.16 (d, 1H, J=8.0 Hz), 7.10 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.3 (d, J=7.2 Hz). FABLRMS m/z 404 (M−H). ESHRMS m/z 405.9853 (M+H, Calc'd 405.9861). Anal. Calc'd for C16H8Cl2F3NO4: C, 47.32; H, 1.99; N, 3.45; Cl, 17.46. Found: C, 47.26; H, 1.93; N, 3.35; Cl, 17.19.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][NH:7][C:6]1=[O:10].[H-].[Na+].Cl[CH2:16][C:17]([N:19]([C:22]1[C:23]([Cl:33])=[N:24][N:25]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:26]=1)[CH2:20][CH3:21])=[O:18]>>[Cl:33][C:23]1[C:22]([N:19]([CH2:20][CH3:21])[C:17](=[O:18])[CH2:16][N:7]2[CH2:8][CH2:9][CH:5]([CH2:4][CH2:3][C:2]([F:1])([F:11])[F:12])[C:6]2=[O:10])=[CH:26][N:25]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[N:24]=1
Reactant: CCN(C(=O)CCl)c1cn(-c2cccnc2)nc1Cl
Reactant: O=C1NCCC1CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: CCN(C(=O)CN1CCC(CCC(F)(F)F)C1=O)c1cn(-c2cccnc2)nc1Cl

Procedure:
To 3-(3,3,3-trifluoropropyl)pyrrolidin-2-one in an appropriate reaction vessel may be added NaH (from about 1.0 eq to about 2.0 equivalent) in a solvent, such as THF (at a concentration between about 0.01 M to about 1 M) followed by 2-chloro-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (from about 0.5 eq to about 1.5 eq). The reaction may be stirred at a temperature from about 0° C. to about 25° C. until determined to be complete. After completion of the reaction, the product may be obtained using standard organic chemistry techniques for workup and purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[CH:20]2)([O-:16])=[O:15].C(N(CC)CC)C>C(#N)C>[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[N:21]=[CH:20]2)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)n2ncc3cc([N+](=O)[O-])ccc32)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
In 100 ml of acetonitrile were dissolved 10 g of 4-nitrophenylsulfonyl chloride and 8.8 g of 5-nitroindazole and the solution was cooled to 0° C. Then, 6.8 g of triethylamine was gradually added dropwise to the solution and the mixture was allowed to stand overnight to precipitate crystals. Then, 50 ml of water was added dropwise to the system and the crystals formed were collected by filtration, washed with water and then ethyl acetate, and dried to provide 12.1 g of the desired product having a melting point of from 196° C. to 197° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH2:34]([N:36](CC)[CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][C:42]=1[F:48])C>>[NH2:45][C:44]1[CH:46]=[CH:47][C:41]([O:40][CH2:39][CH2:38][CH2:37][N:36]([CH3:34])[C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]5[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=5[F:31])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)=[C:42]([F:48])[CH:43]=1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CCN(CC)CCCOc1ccc(N)cc1F
Product: CN(CCCOc1ccc(N)cc1F)c1nccc(-c2c(-c3cccc(NC(=O)c4c(F)cccc4F)c3)nn3ccccc23)n1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo-[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 4-{[3-(diethylamino)-propyl]oxy}-3-fluoroaniline in a manner analogous to Example 27, Step D. HRMS calcd for C37H34F3N7O2: 665.2726; found: 666.2804 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:48]=[C:49]3[CH:55]=[CH:54][NH:53][C:50]3=[N:51][CH:52]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH:53]1[C:50]2=[N:51][CH:52]=[C:47]([C:2]3[C:10]4[C:9]([NH:11][C@H:12]([C:14]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:18](=[O:26])[C:17]6=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]6[N:15]=5)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=3)[CH:48]=[C:49]2[CH:55]=[CH:54]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cnc5[nH]ccc5c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 48 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (103 mg, 0.17 mmol) was treated with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (103 mg, 0.42 mmol), sodium carbonate (51 mg, 0.48 mmol), 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (43 mg, 0.05 mmol) in 1,2-dimethoxyethane (4 ml) and water (1 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 55 mg (48% yield, 96% purity) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([CH2:7][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Product: CN1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 100 °C

Procedure:
A mixture of 3-nitrobenzyl chloride (1 g) and N-methylpiperazine (3 ml) was stirred and heated to 100° C. for 4 hours. The mixture was cooled to ambient temperature and partitioned between methylene chloride and water. The organic phase was evaporated to give 3-(4-methylpiperazin-1-ylmethyl)nitrobenzene (1.05 g); NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 2.31-2.38 (m, 8H), 3.57 (s, 2H), 7.6 (t, 1H), 7.54 (d, 1H), 8.07-8.13 (m, 2H).
Reaction SMILES: Cl.[CH2:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:20][C:21]1[C:26]([OH:27])=[C:25]([F:28])[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH3:35])[C:22]=1[C:36]#[N:37]>C(OCC)(=O)C>[F:28][C:25]1[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH3:35])[C:22]([C:36]#[N:37])=[C:21]2[C:26]=1[O:27][C:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=[N:20]2
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)c(F)c2oc(-c3cccnc3)nc2c1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Nicotinyl chloride hydrochloride (192 mg, 1.08 mmol) and triethylamine (301 μl, 2.16 mmol) were added to a dichloromethane (9 ml) solution of 4-amino-6-fluoro-5-hydroxy-2-methylbiphenyl-3-carbonitrile (I-41) (218 mg, 0.900 mmol), followed by stirring at room temperature for 2 hours. Ethyl acetate (100 ml) was added to the reaction liquid, followed by washing with water (50 ml) and saturated brine (50 ml).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH2:9](N(C(C)C)C(C)C)[CH3:10].[OH:18][C:19]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:20]=1[CH:21]=O>C(O)C>[OH:18][C:19]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:20]=1[CH:21]1[NH:2][CH:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][S:5]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=Cc1cc(O)ccc1O
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CSC(c2cc(O)ccc2O)N1

Procedure:
To a round bottom flask, equipped with magnetic stirrer, containing 9.25 g (50 mM) ethyl ester of L-cysteine hydrochloride in 75 mL of absolute ethanol was added 8.4 mL (48 mM) ethyldiisopropylamine. A clear solution was obtained after stirring for several minutes with a magnetic stirrer under nitrogen. To this solution was added 6.65 g (49 mM) 2,5-dihydroxybenzaldehyde in 50 mL absolute ethanol, and the reaction mixture was stirred for another 4 hrs. Evaporation to dryness produced a viscous oil, which was dissolved in 20 mL absolute ethanol and loaded on a silica gel column. Elution with ethylacetate/hexane (at molar ratios from 2:8 to 3.5:6.5) produced 5.9 g of the desired product. 1H NMR (DMSO-d6; 1:1 diastereoisomeric mixture at C2) δ; 1.21-1.25 m 3H; 2.95-3.02 m and 3.19-3.22 m, 2H; (3.5 m, 3.76 m 3.90 m and 4.25 m, 2H); 4.15 m, 2H; (5.56 d, J=11.9 Hz and 5.75 d, J=9.9 Hz, 1H); (6.45-6.48 dd, J=2.9 Hz, 8.7 Hz, 6.52-6.55 dd, J=2.9 Hz, 8.7 Hz, 6.57 d, J=8.8 Hz, 6.61 d, J=8.8 Hz 2H); 6.76 dd, J=2.8 Hz, 9.2 Hz, 1H; 8.64 s and 8.75 s, 1H; 9.01 s and 9.19 s 1H.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[C:3]21[CH2:17][CH2:16]2.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[C:3]21[CH2:17][CH2:16]2
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1(CC1)N(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CCN(C)C12CC2

Procedure:
The title compound is prepared from a mixture of 2′,8′-dimethyl-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrido[4,3-b]indole], 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: N#N.Br[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([F:14])=[CH:6][CH:5]=1.C([Li])CCC.[B:20](OCC)([O:24]CC)[O:21]CC>CCCCCC.O1CCCC1>[F:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([B:20]([OH:24])[OH:21])=[CH:5][CH:6]=1
Reactant: Fc1ccc(Br)c2ccccc12
Reactant: CCOB(OCC)OCC
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(F)c2ccccc12
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a 250 mL three-necked round-bottomed flask equipped with septum and N2 (nitrogen) inlet were added 4.62 g (20.53 mmol) 4-bromo-1-fluoronaphthalene and 100 mL dry tetrahydrofuran. The solution was cooled to −70° C., and 15.4 mL (24.64 mmol) of a 1.6 M solution of butyl lithium in hexane was added dropwise over 5 min. The reaction was stirred at −70° C. for 10 min, then 4.2 mL (3.59 g, 24.64 mmol) triethyl borate was added, and the reaction stirred at −70° C. for 20 min and warmed to room temperature. After stirring overnight at room temperature, the reaction was quenched with saturated aqueous ammonium chloride solution, acidified with 1 N hydrochloric acid, and extracted into ethyl acetate (twice). The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was triturated with hexane to give an off-white powder, 1.97 g (51%), as a mixture of monoaryl and diaryl boronic acids. 1H-NMR (δ, CDCl3): 7.2-7.4 (m, 1H), 7.5-7.7 (m, 3H), 8.0-8.5 (m, 1H), 8.5 and 9.2 (m, 1H); APCl (−) (%): 189 (parent-1, 60).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][CH2:11][Cl:12].CO>C1COCC1>[Cl:12][CH2:11][CH2:10][CH2:9][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: ClCCCn1ccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
Anhydrous THF (25 mL) was cooled in an ice bath. After NaH (1.40 g, 35 mmol, 60%) was added to the THF in one portion, the mixture was stirred at rt for 30 min and cooled in an ice bath. Then a solution of 1H-imidazole (2.00 g, 30 mmol) in anhydrous THF (6 mL) was added dropwise. The reaction mixture was then warmed to rt and stirred at rt for 1.5 h. To the mixture was added 1-bromo-3-chloropropane (4.60 g, 30 mmol) dropwise, and stirred at rt overnight. To the resulting mixture was added MeOH (5 mL) in one portion. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=30:1) to give the title compound as pale yellow oil (3.10 g, 73%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][O:1][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:10][CH:9]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13]1
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCOCc3ccccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 24(t)] with 2-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[3-(pyridin-2-ylmethoxy)-propyl]-phenyl]-piperidine-1-carboxylate as a colourless, amorphous solid, which was used in the following step without further purification and characterization.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12].[Br:14][C:15]1[NH:16][CH:17]=[C:18]([CH3:20])[N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.ClCCl>[Br:14][C:15]1[N:16]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=2[N+:11]([O-:13])=[O:12])[CH:17]=[C:18]([CH3:20])[N:19]=1
Reactant: Cc1c[nH]c(Br)n1
Reactant: COc1cc(F)cc(F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(F)cc(-n2cc(C)nc2Br)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
A mixture of 1,5-difluoro-3-methoxy-2-nitrobenzene (9 g, 47.6 mmol), 2-bromo-4-methylimidazole (7.7 g, 47.6 mmol) and potassium carbonate (14.5 g, 104.7 mmol) in 240 mL DMF was stirred at room temperature overnight. The majority of solvent was removed by rotavap and the residue was diluted with ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with water, brined, dried over magnesium sulfate. Condensation and purification using 5-10% ethyl acetate in dichloromethane as eluent provided 4.8 g (31% yield) of 2-bromo-1-(5-fluoro-3-methoxy-2-nitrophenyl)-4-methyl-1H-imidazole as a yellow solid. 1H NMR (400 MHz, DMSO) δ ppm 7.60 (dd, 1H), 7.38 (dd, 1H), 7.21 (s, 1H), 3.98 (s, 3H), 2.09 (s, 3H). EIMS 330.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])=[C:6](Cl)[N:5]2[N:17]=[C:18]([CH3:20])[N:19]=[C:4]2[N:3]=1.O.C1COCC1.[NH4+].[Cl-]>C(O)C.[Zn]>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])=[CH:6][N:5]2[N:17]=[C:18]([CH3:20])[N:19]=[C:4]2[N:3]=1
Reactant: Cc1nc2nc(Cl)c(-c3ccc(F)cc3F)c(Cl)n2n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc2nc(Cl)c(-c3ccc(F)cc3F)cn2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
2.35 g (7.5 mmol) 5,7-Dichloro-6-(2,4-difluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidine are given in 189 mL ethanol, 135 mL water and 73 mL THF. 1.89 g (35.3 mmol) NH4Cl and 3.1 g (47.7 mmol) zinc powder are added and the mixture is stirred at room temperature for 3 h. The reaction mixture is filtered and the organic solvents are removed. The residue is diluted with water and extracted three times with ethyl acetate. The combined organic layers are washed with brine and dried over Na2SO4. After evaporation of the solvent, the residue is purified by chromatography. 1.2 g (51.6%) of the desired product are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>ClCCl>[CH3:1][C:2]1([CH2:6][O:7][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:5][O:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CO)COC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(COS(C)(=O)=O)COC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
Step A To a solution of 3-methyl-3-oxetanemethanol (Aldrich) (3.5 g, 34 mmol) and triethylamine (10 g, 103 mmol) in dichloromethane (100 mL) at 0° C. was added a dichlormethane solution (20 mL) of methanesulfonyl chloride (Aldrich) (5.08 g, 45 mmol). The reaction mixture was stirred at 0° C. for 2 h. Water was added. Organic layer was separated, the aqueous layer was extracted with dichlormethane. The combined organic layers were washed with diluted aqueous HCl solution, saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated to give methanesulfonic acid 3-methyl-oxetan-3-ylmethyl ester as a yellow oil (6 g, 97%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:7]([CH2:8][CH2:9][CH2:10][OH:11])[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[N:4]=1.C(N(CC)CC)C.ClCCl.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([O:11][CH2:10][CH2:9][CH2:8][N:7]1[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[N:4]=[C:3]1[S:2][CH3:1])(=[O:29])=[O:28]
Reactant: CSc1nc2ccccc2n1CCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1nc2ccccc2n1CCCOS(C)(=O)=O
Reaction time: 1 h

Procedure:
To a stirred mixture of 19 parts of 2-(methylthio)-1H-benzimidazole-1-propanol, 15.2 parts of N,N-diethylethanamine and 195 parts of dichloromethane are added dropwise 11.5 parts of methanesulfonyl chloride. Upon completion, stirring is continued for one hour at reflux. After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated, yielding 3-[2-(methylthio)-1H-benzimidazol-1-yl]propyl methanesulfonate as an oily residue.
Reaction SMILES: C12CC(CC1)C=C2B(O)O.[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:26]2[CH2:27][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:30][CH:31]=2)=[N:16][C:17]=1[CH2:18][NH:19][C@H:20]([CH:23]([CH3:25])[CH3:24])[CH2:21][OH:22]>[Pd]>[N:16]1[CH:17]=[CH:12][CH:13]=[CH:14][C:15]=1[C:26]1[CH2:27][N:28]([C:32]([O-:34])=[O:33])[CH2:29][CH2:30][CH:31]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:27]2)=[N:16][C:17]=1[CH2:18][NH:19][C@H:20]([CH:23]([CH3:25])[CH3:24])[CH2:21][OH:22]
Reactant: CC(C)[C@H](CO)NCc1nc(C2=CCCN(C(=O)OC(C)(C)C)C2)ccc1F
Agent: [Pd]
Agent: OB(O)C1=CC2CCC1C2
Product: CC(C)[C@H](CO)NCc1nc(C2CCCN(C(=O)OC(C)(C)C)C2)ccc1F
Product: O=C([O-])N1CCC=C(c2ccccn2)C1

Procedure:
(R)-tert-butyl 5-fluoro-6-4(1-hydroxy-3-methylbutan-2-yl)amino)methyl)-5′,6′-dihydro-[2,3′-bipyridine]-1′(2′H)-carboxylate was prepared according to Example 199, substituting tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate for bicyclo[2.2.1]hept-2-en-2-ylboronic acid. (R)-tert-butyl 5-fluoro-6-(((1-hydroxy-3-methylbutan-2-yl)amino)methyl)-5′,6′-dihydro-[2,3′-bipyridine]-1′(2′H)-carboxylate was subjected to hydrogenation (H2 atmosphere, Pd/C catalyst) to provide the title compound. MS (ESI+) m/z 396 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][NH:7][N:6]=1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.N1C=CC=CC=1.ClCCl>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][N:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH3:15])[N:6]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CCOC(=O)c1c[nH]nc1OCOC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cn(-c2ccccc2C)nc1OCOC
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
A mixture of ethyl 3-(methoxymethoxy)-1H-pyrazole-4-carboxylate (1.80 g), 2-methylphenylboronic acid (2.45 g), pyridine (1.46 mL), copper(II) acetate (2.45 g) and dichloromethane (50 mL) was stirred at room temperature for 16 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-1:1, v/v) to give ethyl 3-(methoxymethoxy)-1-(2-methylphenyl)-1H-pyrazole-4-carboxylate as a pale-yellow oil (2.39 g, yield 92%).