Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]2[CH2:10][NH:9][CH2:8]2)=[C:4]([F:13])[CH:3]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1>C(#N)C>[Cl:14][C:15]1[N:20]=[C:19]([N:9]2[CH2:10][CH:7]([O:6][C:5]3[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][C:4]=3[F:13])[CH2:8]2)[N:18]=[CH:17][N:16]=1
Reactant: Fc1cc(Cl)ccc1OC1CNC1
Reactant: Clc1ncnc(Cl)n1
Solvent: CC#N
Product: Fc1cc(Cl)ccc1OC1CN(c2ncnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
To a solution of 3-(4-chloro-2-fluorophenoxy) azetidine (3.6 g, 18.0 mmol) in acetonitrile (60 mL, 3 mL/mmol) was added TEA (7.2 mL, 50.0 mmol) and 2, 4-dichloro-1, 3, 5-triazine (3.0 g, 20.0 mmol) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×50 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-4-(3-(4-chloro-2-fluorophenoxy)azetidin-1-yl)-1,3,5-triazine (0.800 g, 20%) as a solid. Observed mass (M+1): 315.0
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][SH:8].[H-].[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([CH2:30]Cl)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C=O)C.O>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][C:22]2[C:25]([CH2:30][S:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Reactant: SCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSCc3ccccn3)c2CC1
Reaction time: 2 h
Yield: 39.3 %

Procedure:
Evaporate a solution of 2-pyridine methanethiol (2.5 mL, 10% in EtOH) in vacuo to obtain neat 2-pyridine methanethiol (250 mg). Immediately dissolve 2-pyridine methanethiol (230 mg, 1.84 mmol) in anhydrous DMF (5 mL) under an atmosphere of nitrogen. Add sodium hydride (100 mg, 2.5 mmol, 60% dispersion in mineral oil) and stir for 10 min. Add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (550 mg, 1.67 mmol) in anhydrous DMF (1 mL) and stir under nitrogen for 2 h. Quench reaction by slow addition of water (10 mL), dilute up to 150 mL with water and extract with DCM (3×50 mL). Wash the combined organic extracts with brine, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (9:1 to 1:1 gradient over 60 min, 40 mL/min) to obtain 3-tert-butoxycarbonyl-7-chloro-6-(pyridin-2-ylmethylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (275 mg, 40%) as a light yellow syrup.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:7](O)[C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=23)[S:5][CH:6]=1.[CH3:28][O:29][C:30]([O:34][Si](C)(C)C)=[C:31]([CH3:33])[CH3:32]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH:7]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH3:20])[C:12]=23)[C:31]([CH3:33])([CH3:32])[C:30]([O:29][CH3:28])=[O:34])[S:5][CH:6]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)[nH]c(C(O)c3nc(Cl)cs3)c2n(C)c1=O
Reactant: COC(O[Si](C)(C)C)=C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(c1nc(Cl)cs1)c1[nH]c(-c2ccccc2)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Boron trifluoride THF complex (0.028 mL, 0.255 mmol) was added to a solution of 7-((4-chlorothiazol-2-yl) (hydroxy)methyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (114 mg, 0.283 mmol) and commercially available ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (0.143 mL, 0.707 mmol) in THF (5 mL). The mixture was stirred at room temperature for 5 minutes. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM (2×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-80% EtOAc/hexane afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1)[C:6](O)=[O:7].O.[NH2:19][NH2:20]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1)[C:6]([NH:19][NH2:20])=[O:7]
Reactant: NN
Reactant: COc1cc(C(=O)O)ccc1-n1cnc(C)c1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzoic acid (5 g) in THF (60 mL) was added N,N′-carbonyldiimidazole (6.98 g) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was cooled to −10° C., hydrazine monohydrate (10.44 mL) was added, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, and water was added. The precipitated solid was collected by filtration to give the title compound (0.70 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:30][C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)[N:3]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(Nc2ncnc(Cl)n2)cc(OC)c1OC
Reactant: C=CC(=O)Nc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Nc2ncnc(Nc3cc(OC)c(OC)c(OC)c3)n2)c1
Temperature: 100 °C

Procedure:
To a slurry of (4-chloro-[1,3,5]triazin-2-yl)-(3,4,5-trimethoxy-phenyl)amine (54.9 mg, 0.185 mmol) in IpOH (2.5 ml) was added DIEA (0.048 mL, 0.277 mmol) and N-(3-aminophenyl)acrylamide (33 mg, 0.203 mmol). The mix was heated at 100° C. for 18 h. The solution was cooled to RT and a precipitate formed. The precipitate was filtered off and dried under reduced pressure to give N-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-ylamino]-phenyl)-acrylamide: MS m/z=423[M+H]+. Calc'd for C2H22N6O4: 422.17.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].[NH2:23][CH2:24][CH:25]([OH:32])[CH2:26][N:27]1[CH:31]=[CH:30][N:29]=[N:28]1>>[OH:32][CH:25]([CH2:26][N:27]1[CH:31]=[CH:30][N:29]=[N:28]1)[CH2:24][NH:23][C:19]([C:15]1[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[NH:17][C:16]=1[CH3:18])=[O:21]
Reactant: NCC(O)Cn1ccnn1
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NCC(O)Cn1ccnn1

Procedure:
5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (126.6 mg, 0.4 mmol) was condensed with 1-amino-3(1,2,3)triazole-1-yl-propan-2-ol (85 mg, 0.48 mmol) to precipitate 5-[5-Chloro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-[1,2,3]triazol-1-yl-propyl)-amide (48 mg, 27%). 1H NMR (DMSO-d6) δ2.42, 2.44 (2×s, 6H, 2×CH3), 3.27 (m, 2H), 3.99 (m, 1H), 4.28 (dd, J=7.8, 14 Hz,1H), 4.51 (dd, J=3.2, 14 Hz,1H), 5.39 (d, J=6.0 Hz, 1H, OH), 6.85 (d, J=8.4 Hz, 1H), 7.12 (dd, J=2.0, 8.2 Hz, 1H), 7.70 (m, 2H), 7.74 (s, 1H), 7.97 (d, J=2.0 Hz, 1H), 8.07 (s, 1H), 10.99 (s, 1H, CONH), 13.65 (s, 1H, NH). LC-MS (m/z) 439.4 (M−1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](OC(CC(C)C)CCN(CC3C=CC=CC=3)C)=[CH:7][CH:8]=[CH:9][C:2]1=2.[C:27]([O:31][C:32](=[O:46])[N:33]([CH2:35][CH2:36][CH:37]([OH:45])[CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:34])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:46])[N:33]([CH2:35][CH2:36][CH:37]([O:45][C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH:9]=[CH:8][CH:7]=1)[CH2:38][CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)[CH3:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: CN(CCC(O)CC1CCCCC1)C(=O)OC(C)(C)C
Reactant: CC(C)CC(CCN(C)Cc1ccccc1)Oc1cccc2sccc12
Product: CN(CCC(CC1CCCCC1)Oc1cccc2sccc12)C(=O)OC(C)(C)C

Procedure:
Using a method similar to that for [3-(Benzo[b]thiophen-4-yloxy)-5-methyl-hexyl]-benzyl-methyl-amine, (4-cyclohexyl-3-hydroxy-butyl)-methyl-carbamic acid tert-butyl ester affords the title compound: mass spectrum (ion spray) m/z=418 (M+1); 1H NMR (CDCl3) δ 7.49-7.47 (d, 1H), 7.43-7.41 (d, 1H), 7.31-7.30 (d, 1H), 7.24 (t, 1H), 6.72 (d, 1H), 4.59-4.52 (m, 1H), 3.34-3.27 (m, 2H), 2.80 (s, 3H), 1.98-0.92 (m, 24).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[O:18][CH2:19][CH2:20]Br>C1(C)C=CC=CC=1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:20][CH2:19][O:18][C:17]2[CH:22]=[CH:23][C:24]([N+:25]([O-:27])=[O:26])=[C:15]([OH:14])[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCCN2CCC(Cc3ccccc3)CC2)cc1O
Yield: 93110 %

Procedure:
From a mixture of 4-benzylpiperidine (820 mg, 4.68 mmol), 2-(3-hydroxy-4-nitrophenoxy)ethyl bromide (556 g, 2.26 mmol) and KI (180 mg) in toluene (25 mL) was obtained 750 g (97%) of 4-benzyl-1-(2-(3-hydroxy-4-nitrophenoxy)ethyl)piperidine as a yellow powder, mp. 136-7° C. 1H NMR (CDCl3): 1.28-1.40 (m, 2H), 1.50-1.68 (m, 1H), 2.02-2.10 (m, 2H), 2.545 (d, 2H, J=7), 2.792 (t, 2H, J=6), 2.93-2.97 (m, 2H), 4.151 (t, 2H, J=6), 6.50-6.53 (m, 2H), 7.13-7.31 (m, 5H), 8.027 (d, 1H, J=10).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@@H:16]([CH3:26])[C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[OH:18].[CH:27]([C:30]1[CH:31]=[C:32]([C:40]2[CH:45]=[C:44]([CH3:46])[C:43]([O:47][CH2:48][C:49](=O)[CH3:50])=[C:42]([CH3:52])[CH:41]=2)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37])([CH3:29])[CH3:28].C(O)(=O)C>O1CCCC1>[OH:18][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C@@H:16]([NH:15][CH:49]([CH3:50])[CH2:48][O:47][C:43]1[C:42]([CH3:52])=[CH:41][C:40]([C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:30]([CH:27]([CH3:28])[CH3:29])[CH:31]=2)=[CH:45][C:44]=1[CH3:46])[CH3:26]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: COC(=O)c1ccc(-c2cc(C)c(OCC(C)=O)c(C)c2)cc1C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cc(C)c(OCC(C)N[C@@H](C)[C@H](O)c3ccc(O)cc3)c(C)c2)cc1C(C)C
Temperature: 25 °C
Yield: 30.5 %

Procedure:
Sodium triacetoxyborohydride (0.23 g) was added to a mixture of 4-((1R,2S)-2-amino-1-hydroxypropyl)phenol (0.082 g), methyl 3-isopropyl-3′,5′-dimethyl-4′-(2-oxo-propoxy)biphenyl-4-carboxylate (0.17 g) and acetic acid (0.03 mL) in tetra hydrofuran (2.5 mL) at room temperature with stirring, and the mixture was stirred at 50° C. for 4 hrs. After being cooled to room temperature, the reaction mixture was partitioned between a saturated aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride/methanol=9/1) followed by aminopropyl silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to afford methyl 4′-{(2RS)-2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)1-methylethylamino]propoxy}-3-isopropyl-3′,5′-dimethylbiphenyl-4-carboxylate (0.074 g).
Reaction SMILES: CS([C:5]1[N:17]=[C:8]2[N:9]=[C:10]([CH2:15][CH3:16])[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=1)(=O)=O.[F:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][OH:26])=[CH:21][CH:20]=1>>[CH2:15]([C:10]1[CH:11]=[C:12]([CH2:13][CH3:14])[N:7]2[N:6]=[C:5]([O:26][CH2:25][CH2:24][O:23][C:22]3[CH:27]=[CH:28][C:19]([F:18])=[CH:20][CH:21]=3)[N:17]=[C:8]2[N:9]=1)[CH3:16]
Reactant: CCc1cc(CC)n2nc(S(C)(=O)=O)nc2n1
Reactant: OCCOc1ccc(F)cc1
Product: CCc1cc(CC)n2nc(OCCOc3ccc(F)cc3)nc2n1
Yield: 70 %

Procedure:
The title compound was prepared according to the experimentals described for Example 14 above from 2-methanesulfonyl-5,7-diethyl-[1,2,4]triazolo[1,5-a]pyrimidine and 2-(4-fluorophenoxy)ethan-1-ol in 70% yield. EM (calc.): 330.1; MS (ESI) m/e: 331.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:15](S(Cl)(=O)=O)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1>CCCCCC.O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:15]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCCN1
Reactant: COc1cccc(S(=O)(=O)S(=O)(=O)Cl)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)N2CCCC2=O)c1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
15.75 cm3 of a 1.6M solution of M-butyllithium in hexane is added to 2.22 g of 2-pyrrolidinone in solution in 80 cm3 of tetrahydrofuran and cooled to -25° C., the temperature being maintained between -25° C. and -20° C. After agitation for 30 minutes at -25° C., a solution of 5.40 g of 3-methoxybenzenesulphonyl sulphonyl chloride [J. Chem. Soc. P.T.2., 579 (1982)] in 40 cm3 of tetrahydrofuran is poured drop by drop into the mixture, operating between -25° C. and -20° C. After agitation for 30 minutes at -25° C., the whole is allowed to return to ambient temperature. The solvent is evaporated under reduced pressure; the residue is taken up in water, filtered and crystallized from isopropanol. 3.5 g of expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:25](#N)C.[H-].[Na+]>IC>[Cl:1][C:2]1[N:24]=[C:5]2[C:6]([N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:25])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CC#N
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(Cc1ccccc1N(C)S(C)(=O)=O)c1cccn2nc(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
185 a) To a solution of N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (250.0 mg, 0.6834 mmol) in acetonitrile (1 mL, 20 mmol) at room temperature was added sodium hydride, 60% disp. in mineral oil (33.0 mg, 0.825 mmol) followed by iodomethane (46.80 uL, 0.7517 mmol). The mixture was stirred at room temperature for 2 hours then additional iodomethane (10 uL) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to a tan resin. The recovered material was purified via chromatography using an ISCO automated purification apparatus (silica gel column 24 g 20%→80% ethyl acetate:hexane solvent gradient). N-(2-{[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-methyl-amino}-methyl]-phenyl)-N-methyl-methanesulfonamide was isolated as tan foam (0.207 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.6 Hz, 1H), 7.35-7.27 (m, 4H), 6.89-6.84 (m, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.54-5.40 (br m, 1H), 5.06-4.90 (br m, 1H), 3.32 (s, 3H), 3.24 (s, 3H), 3.01 (s, 3H). MS=380, 382 (MH)+. 185 b) N-Methyl-N-{2-[(methyl-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-amino)-methyl]-phenyl}-methanesulfonamide was prepared from N-(2-{[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-methyl-amino]-methyl}-phenyl)-N-methyl-methanesulfonamide (75.0 mg, 0.197 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (42.0 mg, 0.220 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (18.0 mg, 0.0329 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.023 g, 21%). 7.94 (d, J=6.6 Hz, 1H), 7.56-7.51 (m, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.35-7.28 (m, 3H), 6.88 (d, J=8.1 Hz, 2H), 6.70 (t, J=7.3 Hz, 1H), 6.57-6.50 (m, 2H), 5.35-5.23 (m, 1H), 5.12-5.00 (m, 1H), 3.23 (s, 3H), 3.15-3.10 (m, 4H), 3.07 (s, 3H), 2.99 (s, 3H), 2.63-2.58 (m, 4H), 2.36 (s, 3H). MS=535 (MH)+.
Reaction SMILES: [CH2:1]([N:3]([CH:11]([C:19]1[NH:20][C:21](=[O:37])[C:22]([OH:36])=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:26])[N:24]=1)[CH2:12][CH2:13][C@H:14]([O:17][CH3:18])[CH2:15][OH:16])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(C#N)(C)=O.C(Cl)Cl.O>[CH3:38][S:39]([O:37][C:21]1[C:22]([O:36][S:39]([CH3:38])(=[O:41])=[O:40])=[C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:26])[N:24]=[C:19]([CH:11]([N:3]([C:4]([O:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:10])[CH2:1][CH3:2])[CH2:12][CH2:13][C@H:14]([O:17][CH3:18])[CH2:15][O:16][S:39]([CH3:38])(=[O:41])=[O:40])[N:20]=1)(=[O:41])=[O:40]
Reactant: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](CO)OC)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Agent: CC(=O)C#N
Solvent: ClCCl
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)C(CC[C@@H](COS(C)(=O)=O)OC)c1nc(OS(C)(=O)=O)c(OS(C)(=O)=O)c(C(=O)NCc2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl ethyl[(4S)-1-(4-{[(4-fluorobenzyl)amino]carbonyl}-5-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)-5-hydroxy-4-methoxypentyl]carbamate (30 g, 57.4 mmol) in AcCN (500 mL) at 0° C. was added TEA (48 mL, 344 mmol) followed by a dropwise addition of a solution of MsCl (22.37 mL, 287 mmol) in DCM (15 mL). The resulting mixture was stirred at 0° C. for 30 minutes, then diluted with H2O (˜100 mL) and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was used in the next step without further purification. LC-MS: 757.5 (M+1).
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH3:34])=[O:32])=[CH:26][CH:25]=1>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>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:31]([NH:33][CH3:34])=[O:32])=[CH:28][CH:29]=2)=[CH:7][CH:6]=1
Reactant: CNC(=O)Nc1ccc(Br)cc1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CNC(=O)Nc1ccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)cc1
Temperature: 100 °C
Yield: 24.9 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.149 g, Example 33), N-(4-bromophenyl)-N′-methyl urea (0.225 g) 2M aqueous sodium carbonate (1.0 ml) and tetrakis(triphenylphosphine)palladium (0) (0.028 g) in ethanol (3 ml). The reaction mixture was heated in a sealed vial at 100° C. for 2 hours. After cooling, the solution was concentrated under reduced pressure. The residue was purified by chromatography over silica eluting with tetrahydrofuran:hexane (1:1). The residue was further purified by chromatography over silica gel eluting dichloromethane:ethanol (9:1). The residue was then further purified by reverse-phase HPLC eluting a gradient of 25-100% acetonitrile in 0.1 w/v aqueous ammonium acetate solution. The HPLC fractions were concentrated under reduced pressure, the residue dissolved in ethanol, filtered and concentrated under reduced pressure to give the title compound as a solid (0.050 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[C:19]([CH2:20][CH2:21]O)=[CH:18][N:17]=[CH:16]2)=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:21][CH2:20][C:19]1[N:15]([CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:16]=[N:17][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1cncn1Cc1ccccc1-c1ccc(F)cc1
Solvent: ClCCl
Product: Fc1ccc(-c2ccccc2Cn2cncc2CCCl)cc1

Procedure:
To a solution of 2-[3-(4′-fluorobiphenyl-2-ylmethyl)-3H-imidazol-4-yl]ethanol (0.341 g, 1.15 mmol) in CH2Cl2 (10 mL) is added, thionyl chloride (0.11 mL, 1.50 mmol) at 0° C. The mixture is then heated to reflux for 3 h before the solvent is removed and the residue dried under reduced pressure to give 5-(2-chloroethyl)-1-(4′-fluorobiphenyl-2-ylmethyl)-1H-imidazole. The residue is taken up in THF (60 mL). TMEDA (0.71 ml, 4.72 mmol) is added, followed by a hexane/THF solution of LDA (2.62 mL, 1.8 M) at −78° C. The resulting mixture is stirred at −78° C. for 5 h. The excess LDA is then quenched by the addition of saturated NH4Cl. The mixture is then diluted with CH2Cl2 and water. The organic layer is separated and washed with water, brine and dried over Na2SO4. After concentration, the residue is purified by flash chromatography (CH2Cl2/MeOH) to give 5-(4′-fluorobiphenyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole. MS (ESI), m/z 279.1 (M+H). Resolution of the (R) and (S) enantiomers of the title compound is achieved by chiral HPLC using ChiralPak AD column and 13% IPA:hexane to give enantiomer A (tr=9.6 min) and enantiomer B (tr=12.6 min). For enantiomer B: 1H NMR (400 MHz, CDCl3) (HCl salt) δ ppm 2.68-2.79 (m, 1H), 2.95-3.06 (m, 2H), 3.13-3.22 (m, 1H), 5.55 (app t, J=7.6 Hz, 1H), 6.96 (dd, J=7.6, 1.5 Hz, 1H), 7.13 (s, 1H), 7.18 (app t, J=8.6 Hz, 2H), 7.27-7.32 (m, 2H), 7.33-7.38 (m, 1H), 7.40-7.49 (m, 2H), 8.01 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:16](=O)[CH2:17][CH3:18]>>[CH2:16]([C:10]1[CH:9]=[CH:8][C:7]2[C:6]3[C:14](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[CH2:13][C:12]=2[C:11]=1[F:15])[CH2:17][CH3:18]
Reactant: CCC=O
Reactant: Fc1cccc2c1Cc1c(F)cccc1-2
Product: CCCc1ccc2c(c1F)Cc1c(F)cccc1-2

Procedure:
The reaction of 1,8-difluorofluorene with propionaldehyde is effected in a similar manner to the procedure described in Example 2. 2-Propyl-1,8-difluorofluorene is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH3:13][Si](C=[N+]=[N-])(C)C.CC(O)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1c(F)cc(Br)cc1F
Yield: 47 %

Procedure:
To a solution of 4-bromo-2,6-difluorobenzoic acid (800 mg, 3.38 mmol) in MeOH (11 mL) at room temperature, trimethylsilyldiazomethane (5.63 mL, 3.38 mmol) was slowly added until yellow solution was turned on. The small amount of AcOH was added until yellow color disappered. All volatile materials were removed in vacuo yielding methyl 4-bromo-2,6-difluorobenzoate (47%). LCMS (m/z): 251.1 (MH+), 0.86 min.