Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:10](C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)[C@@H](C=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 527 mg (2.22 mmol) of 1-isopropyl-3-methyl-bicyclo[3.2.1]-1β,3,8-triaza-spiro[4.5]dodecan-2-one in DCE (15 mL) was added 611 mg (2.22 mmol) of (3R,4S)-3-formyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester in DCE (10 mL) and stirred for 2 hours at room temperature. Sodium triacetoxyborohydride (706 mg, 3.33 mmol) was then added and the reaction mixture stirred overnight at room temperature. The reaction mixture was diluted with DCM, the organic layer washed with sodium bicarbonate, and then dried over sodium sulfate. The organic layer was concentrated and purified by flash silica gel chromatography eluting with methanol:DCM (0-10%) to give 612 mg (56%) of (3S,4S)-3-[1-isopropyl-3-methyl-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-spiro[4.5]dodec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([O:12]C)=[O:11])=[CH:5][CH:4]=1.O.[OH-].[Li+:22]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]([O-:12])=[O:11])=[CH:7][CH:8]=1.[Li+:22]
Reactant: COC(=O)C(c1ccc(OC)cc1)N1CCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C(=O)[O-])N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Methyl 2-(4-methoxyphenyl)-2-(piperidin-1-yl)acetate (400 mg, 1.52 mmol) was dissolved in THF/water (12 ml/4 ml). Lithium hydroxide hydrate (127 mg, 3.04 mmol) was added and the solution was stirred at room temperature for 8 hours. Then a second portion of lithium hydroxide hydrate (63.7 mg, 1.52 mmol) was added and the mixture was stirred at 40° C. for 16 hours, then at 50° C. for 7 hours. The solvents were evaporated, the residue was taken up with Et2O and the insoluble were filtered off. The clear solution was evaporated to obtain lithium 2-(4-methoxyphenyl)-2-(piperidin-1-yl)acetate (384 mg, 99% yield) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5]O.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[F-:40].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.C(#N)C.C(OCC)(=O)C.CCCCCC>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][F:40]
Reactant: O=[N+]([O-])c1cc(I)cc(CO)c1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(I)cc(CF)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-iodo-5-nitrobenzyl alcohol (7.2 g, 25.8 mmol) described in Step B, in CH2Cl2 (325 mL) was cooled to 0° C. and treated with iPr2NEt (6.57 mL, 37.7 mmol) and methane sulfonyl chloride (2.19 mL, 28.2 mmol). After stirring for 1.5 hours at 0° C, the reaction was poured into a separatory funnel containing aqueous 5% citric acid. The layers were separated and the aqueous layer was extracted with CH2Cl2. The organic layers were combined and dried (MgSO4), filtered and concentrated to give an orange oil. This material was dissolved in acetonitrile (325 mL), cooled to 0° C. and treated with tetrabutylammonium fluoride (47 mL, 1 M in THF, 47 mmol) via an addition funnel over about 10 minutes giving a dark blue-green mixture. This was stirred overnight as the reaction warmed to room temperature. TLC analysis (1:1 hexane:ethyl acetate) showed the desired product (Rf =0.56). The reaction was diluted with H2O, concentrated and then extracted with ethyl acetate. The ethyl acetate was dried (MgSO4), filtered and concentrated to give a dark brown oil. This material was dissolved in methanol, treated with 7 g of silica gel, concentrated to a free flowing powder and purified by flash chromatography (hexane then 10:1 hexane:ethyl acetate) to give 3-iodo-5-nitrobenzyl fluoride as a tan solid: mp 50.5-51.5° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][N:7](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:6][C:5]=2[N:4]=1.[ClH:34]>CO.O1CCOCC1>[ClH:34].[F:33][C:2]([F:1])([F:32])[C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[N:4]=1
Reactant: FC(F)(F)c1ccc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: FC(F)(F)c1ccc2c(n1)CNCC2

Procedure:
A solution of the product (94 mg, 0.20 mmol) from Step A above in 0.5 mL of methanol and 2.0 mL of 4.0M hydrogen chloride in 1,4-dioxane was kept at room temperature for 18 h. The reaction mixture was concentrated under a stream of nitrogen, and the residue was triturated with ether. The resultant precipitate was collected and dried in vacuo to afford the title compound as a pale yellow powder. LC/MS 203.1 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>>[OH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:20][CH:21]=1
Reactant: OCc1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: COC(=O)COc1ccc(CO)cc1
Yield: 47.4 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 8.00 g (64.5 mmol) of 4-hydroxybenzyl alcohol was alkylated with 11.84 g (77.4 mmol) of methyl bromoacetate to afford 6.00 g (48%) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[H-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3=[N:28][CH:29]=[N:30][C:31](Cl)=[C:26]3[CH:25]=[N:24]2)=[CH:19][CH:18]=1>C1COCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:31]2[N:30]=[CH:29][N:28]=[C:27]3[N:23]([C:20]4[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][CH:21]=4)[N:24]=[CH:25][C:26]=23)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ncnc2c1cnn2-c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(Br)cc2)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A mixture of 4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (727 mg, 3.88 mmol), and sodium hydride (465 mg, 19.4 mmol) in THF (12 mL) was stirred for 30 min at 60° C. 1-(4-Bromo-phenyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidine was added to the mixture at room temperature and stirred for 1.0 hr at RT. The reaction was quenched with water and the product extracted in ethyl acetate. The organic layer was concentrated in vacuo to provide Compound A220 as a white solid (1.3 g, 81%). 1H NMR (CDCl3, 400 MHz) δ 1.19 (d, 6H), 1.73–1.85 (m, 2H), 1.98–2.08 (m, 2H), 3.26–3.34 (m, 2H), 3.78–3.87 (m, 2H), 4.88 (h, 1H), 5.54 (h, 1H), 7.57 (d, 2H), 8.07 (d, 2H), 8.13 (s, 1H), 8.55 (s, 1H). Exact mass calculated for C20H22BrN5O3 460.3, found 462.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]=[CH:7][C:8]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:4]=2[CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]=[CH:7][C:8]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=3[N:10]([C:19](=[O:21])[CH3:20])[CH2:11][C:4]=2[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc2c(c1)C=Cc1ccc(Br)cc1CN2
Solvent: Cc1ccccc1
Product: CC(=O)N1Cc2cc(Br)ccc2C=Cc2cc(Cl)ccc21
Yield: 71.7 %

Procedure:
To a mixture of 8-Bromo-2-chloro-5,6-dihydro-dibenzo[b,f]azocine (0.8 g, 2.5 mmole) in toluene (10 mL) was added acetic anhydride (1.2 mL, 12.5 mmole) and N,N-dimethylaminopyridine (1.51 g, 12.5 mmole). The reaction mixture was refluxed for 2 hours, concentrated and purified by flash chromatography over silica gel eluting with 30% ethyl acetate/hexane to give 1-(8-Bromo-2-chloro-6H-dibenzo[b,f]azocin-5-yl)-ethanone (0.65 g, 72%). 1HNMR (CDCl3) δ7.32 (d, 1H, J=1.76 Hz), 7.23 (dd, 1H, J=7.70, 1.76 Hz), 7.19 (m, 2H), 7.06 (d, 1H, J=8.80 Hz), 6.91 (d, 1H, J=8.36 Hz), 6.68 (d, 1H, J=13.16 Hz), 6.47 (d, 1H, J=12.76 Hz), 5.42 (d, 1H, J=14.96 Hz), 4.08 (d, 1H, J=15.36 Hz), 1.68 (s, 3H). HPLC Rt=4.05 min. m/z=362 (M+H+).
Reaction SMILES: C(N)CN.[OH-].[Na+].[C-]#N.[Na+].C=O.O.[CH2:13]([N:24]([CH2:29][C:30]([O-:32])=[O:31])[CH2:25][C:26]([O-:28])=[O:27])[CH2:14][N:15]([CH2:20][C:21]([O-:23])=[O:22])[CH2:16][C:17]([O-:19])=[O:18].[Na+].[Na+].[Na+].[Na+]>>[CH2:14]([N:15]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][C:17]([OH:19])=[O:18])[CH2:13][N:24]([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][C:26]([OH:28])=[O:27]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Agent: C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: NCCN
Solvent: O
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 70 °C

Procedure:
1-mol of ethylenediamine (60.0-g) is mixed with 0.16-mol sodium hydroxide (12.8-g of 50% NaOH) and raised to 70° C. 1.95-mol of sodium cyanide (318.4-g of 30% aq sln) and 1.99-mol of formaldehyde (119.2-g of 50% aq sln) are added at a constant rate over 2-hrs, quickly allowing the mixture to heat to boiling temperatures. At the start of the addition and throughout the reaction, steam is used to distill off the ammonia. Another 1.95-mol of sodium cyanide (318.4-g of 30% aq sln) and 1.99-mol of formaldehyde (119.2-g of 50% aq sln) are added at a constant rate over 4-hrs to complete the reaction. Upon completion of the addition, the reaction is boiled for 2-hrs to remove any excess ammonia. 222.2-mol of water (151.3-g) are added back to the reaction and the reaction is cooled to room temperature. The resulting product contains 39.24-wt % Na4EDTA and 0.4-wt % Na3NTA, as determined by HPLC analysis.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([NH:12][NH:13]C(OC(C)(C)C)=O)=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[S:1]1[C:5]2[CH:6]=[C:7]([C:10]([NH:12][NH2:13])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc2ncsc2c1
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)c1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A mixture of tert-butyl 2-(benzothiazol-6-ylcarbonyl)hydrazinecarboxylate (5.28 g, 18.0 mmol) and trifluoroacetic acid (20 mL) was stirred at room temperature for 1 hr. Trifluoroacetic acid was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (5.18 g, yield 94%) as colorless crystals.
Reaction SMILES: C(OC([NH:8][CH:9]([CH3:21])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[N:12]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>CC(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[CH3:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([CH2:10][CH:9]([NH2:8])[CH3:21])[N:12]=1
Reactant: Cc1nn(CC(C)NC(=O)OC(C)(C)C)c2ccccc12
Agent: O=C(O)/C=C/C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1nn(CC(C)N)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
A mixture of (RS)-1-[2-(tert-butoxycarbonylamino)propyl]-3-methylindazole (1.2 g, 4.3 mmol), dichloromethane (15 mL) and trifluoroacetic acid (5 mL) was stirred for 1 h. The mixture was partitioned between aqueous sodium hydroxide solution (2 N, 30 mL) and dichloromethane (3×30 mL). The combined organic extracts were washed with brine (2×), dried (magnesium sulfate) and concentrated in vacuo to give an orange oil. 2-Propanol (5 mL) was added, the mixture was heated to boiling, then fumaric acid (0.5 g, 4.3 mmol) was added. The mixture was cooled to room temperature and filtered. The filter cake was dried in vacuo to give the title compound (0.89 g, 68%) as a pale brown solid: mp 145-147° C.; IR νmax (Nujol/cm−1) 1618, 1510, 1458, 1377, 973, 742 and 652; NMR δH (400 MHz, DMSO-d6) 1.09 (3H, d, J 6.5 Hz), 2.49 (3H, s), 3.56 (1H, m), 4.39 (2H, m), 6.47, (2H, s), 7.09-7.15 (1H, m), 7.36-7.41 (1H, m), 7.62 (1H, d, J 8 Hz) and 7.72 (1H, d, J 8 Hz).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:21]3[CH2:20][N:19]([C:22]4[N:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][N:23]=4)[CH2:18][CH2:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:61][O:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][O:64]1>C(Cl)Cl>[O:64]1[CH2:65][CH2:66][CH2:67][CH2:68][CH:63]1[O:62][NH:61][C:28]([C:25]1[CH:24]=[N:23][C:22]([N:19]2[CH2:18][CH2:17][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[C:21]=3[CH2:20]2)=[N:27][CH:26]=1)=[O:29]
Reactant: O=C(O)c1cnc(N2CCc3c(n(CCN4CCOCC4)c4ccccc34)C2)nc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOC1CCCCO1)c1cnc(N2CCc3c(n(CCN4CCOCC4)c4ccccc34)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
To a solution of 2-[9-(2-morpholin-4-ylethyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxylic acid (160 mg, 0.39 mmol) in DCM (20 mL) were added EDCI (170 mg, 0.88 mmol), HOBT (90 mg, 0.66 mmol), DIEA (152 mg, 1.17 mmol) and NH2OTHP (47 mg, 0.4 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained was purified by column chromatography using EtOAc in hexanes (50%) to obtain N-(tetrahydro-2H-pyran-2-yloxy)-2-[9-(2-morpholin-4-ylethyl)-1,3,4,9-tetrahydro-2H-b-carbolin-2-yl]pyrimidine-5-carboxamide (46 mg, 23% yield). 1H NMR (200 MHz, CDCl3) ppm: 8.75 (s, 2H), 7.50 (d, 1H, J=7.0 Hz), 7.30 (m, 1H), 7.16 (m, 2H), 5.13 (s, 2H), 5.04 (s, 1H), 4.24 (m, 4H), 4.00 (m, 1H), 3.69 (m, 4H), 2.91 (m, 2H), 2.70 (m, 2H), 2.49 (m, 4H), 1.85 (m, 2H), 1.47 (m, 5H); m/e=506 (M+1).
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([O:40]CC)=[O:39])=[CH:36][N:35]=[C:34]2[CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]([F:54])([F:53])[F:52])=[CH:29][CH:28]=1.[OH-].[Li+].C1COCC1>O.CO>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:37]([C:38]([OH:40])=[O:39])=[CH:36][N:35]=[C:34]2[CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]([F:53])([F:52])[F:54])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cnc(CCc2ccccc2C(F)(F)F)n1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(CCc2ccccc2C(F)(F)F)n1-c1ccc(F)cc1

Procedure:
1-(4-Fluorophenyl)-2-(2-(trifluoromethyl)phenethyl)-1H-imidazole-5-carboxylic acid (48) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 1-(4-fluorophenyl)-2-(2-(trifluoromethyl)phenethyl)-1H-imidazole-5-carboxylate (47), lithium hydroxide, THF, methanol, and water.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:29]([C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:34]3[CH:35]=[N:36][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=Cc1ccc(B(O)O)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 66.1 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.5 g, 1.12 mmol) and (6-formylpyridin-3-yl)boronic acid (0.39 g, 1.68 mmol) in dioxane/water mixture (15 mL+3 mL), Na2CO3 (0.42 g, 4.09 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.130 g, 0.112 mmol) was added the mixture was purged again for 10 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.35 g, 66% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[B:16]([O-])([O-:18])[O-:17].Cl>C1COCC1.CCOCC>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([B:16]([OH:18])[OH:17])[CH:7]=1
Reactant: [O-]B([O-])[O-]
Reactant: COc1ccc(Cl)cc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1B(O)O
Reaction time: 8 h

Procedure:
A solution of 2-bromo-4-chloroanisole (5.0 g, 22.6 mmol) in dry THF (60 ml) under nitrogen was cooled to −70° C. and n-butyl lithium (12.4 ml of a 2.0 M solution in hexanes, 24.8 mmol) was added. After 10 min. at −70° C. trlbutyl borate (8.5 ml, 31.4 mmol) was added and the temperature was allowed to rise to room temperature overnight. Aqueous hydrochloric acid (40 ml, 2 M) was added and the product was extracted with 2×60 ml ether. The ethereal phase was extracted with aqueous sodium hydroxide (2×40 ml, 1 M). Acidification with concentrated HCl during ice-cooling gave a precipitate that was dissolved in ether. Drying over magnesium sulfate and evaporation of the solvent gave the title compound. Yield 1.93 g, 46%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]#[N:12])[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=O.[Li+].[BH4-]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:10]=[C:9]([C:11]#[N:12])[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)c(C#N)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cc(CO)ccc1-c1ccccc1
Temperature: 70 °C

Procedure:
6-Cyano-biphenyl-4-carboxylic acid methyl ester from step 2 (1.4 g, 5.9 mmol) was dissolved in THF (24 ml). LiBH4 in THF (2M, 5.9 ml, 11.8 mmol) was added. The reaction mixture was heated to 70° C. for 3 hours. The reaction mixture was quenched carefully with 3N HCl and then extracted with EtOAc (3×20 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield the desired product. FAB MS: 210 m/z (M+ +H)
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH:11]([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][C:16]=1[C:30]1[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=1>>[F:12][CH:11]([F:13])[C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:18]3[CH:19]=[CH:20][C:15]([F:14])=[C:16]([C:30]4[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:17]=3)=[CH:3][N:4]=[C:5]2[N:10]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: FC(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C(F)F)ccn23)ccc1F
Yield: 49 %

Procedure:
3-Bromo-7-difluoromethylimidazo[1,2-α]pyrimidine (248 mg, 1.00 mmol) was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 5′-(7-difluoromethylimidazo[1,2-α]pyrimidin-3-yl)-2′-fluorobiphenyl-2-carbonitrile (180 mg, 49%) as a yellow powder: δH (400 MHz, CDCl3) 6.66 (1H, t, J 55), 7.29 (1H, d, J 7), 7.44 (1H, t, J 9), 7.54-7.74 (5H, m), 7.87 (1H, dd, J 8 and 1), 8.02 (1H, s), 9.00 (1H, d, J 7); m/z (ES+) 365 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:27]([C:24]4[CH:25]=[CH:26][O:22][CH:23]=4)=[O:28])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1ccoc1
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-furamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 3-furoic acid using method B. NMR; δH CDCl3 8.10,(1H, s), 7.97,(1H, s), 7.78,(2H, d), 7.64,(1H, dd), 7.47,(1H, m), 7.38,(1H, d), 7.33,(2H, d), 7.24,(1H, d), 6.80,(1H, s), 6.36,(1H, t), 3.32,(2H, m), 2.21,(3H, s), 1.06,(1H, m), 0.57,(2H, m), 0.28,(2m). LCMS: retention time 3.38 min, MH+375.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1ccccc1F
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccccc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-fluoroaniline to yield 2-[(2-fluorophenyl)amino]phenylacetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH:15]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH2:16]>CN(C)C=O.C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:19]([O:18][P:17]([O:21][CH2:22][CH3:23])(/[CH:15]=[CH:16]/[C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1)=[O:24])[CH3:20]
Reactant: CCOC(=O)CNc1cccc(Br)c1
Reactant: C=CP(=O)(OCC)OCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1cccc(/C=C/P(=O)(OCC)OCC)c1
Temperature: 95 °C
Reaction time: 20 h
Yield: 60.5 %

Procedure:
A solution of ethyl N-(3-bromophenyl)glycinate (Example B) (4 g, 15.5 mmol), diethyl vinylphosphonate (4.92 g, 30 mmol), and bis(triphenylphosphine) palladium (II) chloride (1 g) in dimethylformamide (15 ml) and triethyamine (5 ml) is immersed in an oil bath (95° C.) and stirred for 20 hours. After cooling the dimethylformamide is removed in vacuo and the oily brown residue is dissolved in a saturated solution of sodium chloride and extracted with chloroform. The chloroform layer is dried over magnesium sulfate, filtered and evaporated to give a residue (3.2 g). Purification is accomplished by silica gel chromatography (ethyl acetate as eluant, a single fluorescent spot on tlc, Rf=0.5 (ethyl acetate)).