Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Si:4]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13][C:14]2[C:19](C(O)=O)=[CH:18][N:17]=[C:16]3[NH:23][CH:24]=[CH:25][C:15]=23)[CH2:8]1)([CH3:3])[CH3:2].C([N:34]([CH2:37]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:46])C=CC=CC=1.O>O1CCOCC1>[CH:26]([Si:4]([CH:29]([CH3:31])[CH3:30])([CH:1]([CH3:3])[CH3:2])[O:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([N:13]2[C:14]3=[C:15]4[CH:25]=[CH:24][NH:23][C:16]4=[N:17][CH:18]=[C:19]3[NH:34][C:37]2=[O:46])[CH2:8]1)([CH3:28])[CH3:27]
Reactant: CC(C)[Si](OC[C@@H]1CCC[C@H](Nc2c(C(=O)O)cnc3[nH]ccc23)C1)(C(C)C)C(C)C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[Si](OC[C@@H]1CCC[C@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1)(C(C)C)C(C)C
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a solution of 4-{[cis-3-{[(triisopropylsilyl)oxy]methyl}-cyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (1.06 g) in dioxane (28 ml) was added triethylamine (1.33 ml) and diphenylphosphoryl azide (2.86 ml). After stirring at 120° C. for 4 hours, the reaction mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane:EtOAc=60:40-35:65 to give 1-[cis-3-{[(triisopropylsilyl)oxy]methyl}cyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (970 mg) as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:30][C:31]#[N:32]>CN(C=O)C>[C:17]([C:16]1[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[O:13][C:12]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([O:1][CH2:30][C:31]#[N:32])[CH:11]=[CH:10]2)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: N#CCBr
Reactant: CCCCC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(=O)c1c(-c2ccc3cc(OCC#N)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Method A, Step 5 of Example 1, the title compound was prepared from 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (0.600 g, 1.74 mmol), sodium hydride (0.106 g, 2.65 mmol of a 60% dispersion on mineral oil) and bromoacetonitrile (0.18 mL, 2.6 mmol) in DMF (10 mL). Purification by flash chromatography using 60-80% chloroform in hexane as an eluant afforded a thick yellow oil (0.359 g). 1HNMR (200 MHz, DMSO-d6): δ8.45 (s, 1H), 8.0-8.2 (m, 3H), 7.85-7.95 (m, 1H), 7.7-7.8 (m, 1H), 7.65 (d, 1H, J=2.0 Hz), 7.35-7.5 (m, 1H), 5.35 (s, 2H), 2.75 (t, 2H, J=7.4 Hz), 1.45-1.65 (m, 2H), 1.05-1.25 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[O:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>FC(F)(F)C(O)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([CH:20]3[O:25][CH2:24][CH2:23][NH:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C(=O)C2CNCCO2)CC1
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
Trifluoroacetic acid/dichloromethane (1:1, 10 ml) was added to tert-butyl 2-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)carbonyl]morpholine-4-carboxylate (900 mg, impure) followed by stirring for 30 min. The solvent was removed under reduced pressure then taken up in 1M. NaOH (aq.) (30 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layers were dried (MgSO4), filtered and evaporated to form the title compound (700 mg) as a white foam which was used without further purification.
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)#[N:2].C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB([C:42]2[CH:43]=[CH:44][C:45]3[O:49][C:48](=[O:50])[NH:47][C:46]=3[CH:51]=2)O1>C(#N)C.O>[C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:42]2[CH:43]=[CH:44][C:45]3[O:49][C:48](=[O:50])[NH:47][C:46]=3[CH:51]=2)=[CH:7][CH:6]=1)#[N:2]
Reactant: CC1(C)OB(c2ccc3oc(=O)[nH]c3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(I)cc2)CCOCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc4oc(=O)[nH]c4c3)cc2)CCOCC1
Temperature: 90 °C
Yield: 52.6 %

Procedure:
(S)-tert-Butyl 4-(1-cyano-2-(4-iodophenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 15, step (i), 300 mg), potassium acetate (177 mg) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (Example 33, step (i), 157 mg) in a mixture of acetonitrile (25 mL) and water (10 mL) under a nitrogen atmosphere, was treated with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (12 mg) and the mixture stirred and heated 90° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with water. The products were extracted into ethyl acetate (2×100 mL) and the combined extracts dried over magnesium sulphate and concentrated to dryness. The residue was purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled compound (160 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([CH:16]=[CH2:17])[O:13][N:12]=2)=[CH:3]1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)C.ClCCl>[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[N:15]=[C:14]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[O:13][N:12]=2)=[CH:3]1
Reactant: C1CCNCC1
Reactant: C=Cc1nc(-c2cn(C)c3ccccc23)no1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCO
Product: Cn1cc(-c2noc(CCN3CCCCC3)n2)c2ccccc21
Reaction time: 0.17 h

Procedure:
2[3-(1-Methylindol-3-yl)-1,2,4-oxadiazol-5-yl] ethene (0.4 g) was partially dissolved in ethanol. piperidine (2 ml) was added to the mixture and this was stirred for 10 minutes. Ethanol was evaporated under reduced pressure and excess piperidine was removed by heating under high vacuum. The residual oil crystallised upon refrigeration. The crude oil was converted to the monooxalate salt by treatment with 1 equivalent of oxalic acid in dichloromethane which afforded a white amorphous powder. This was recrystallised from ethanol yielding the title compound m.p. 186°-188° C. Found: C, 59.85; H, 6.10; N, 13.95; C18H22N4O.(COOH)2 requires C, 59.99; H, 6.04; N, 13.99%; δH (360 MHz, D2O) 1.48-2.06 (8 H, m, CH2 pip: NCH2CH2 ×2+NCH2CH2CH2), 3.00-3.08 (2 H, m, NCH2) 3.50 (2 H, t, J=9 Hz, CH2CH2N, 3.58-3.70 (4 H, m, CH2CH2N+NCH2CH2 pip, overlapping), 3.87 (3 H, s, NCH3), 7.36 (dt, 1 H, J=7.2, 1.1 Hz, H-5 or H-6), 7.42 (1 H, d, J=7.2, 1.1 Hz, H-5 or H-6) 7.58 (1 H, d, J=8.2 Hz, H-7), 7.89 (s, 1 H, H-2), 8.00 (1 H, d, J=7.5 Hz, H-4); m/z (CI+) 311 (M+ +1, 100%), 226 (30), 157 (70), 98 (90).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][S-:15].[Na+].Cl>CO>[CH3:14][S:15][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CSc1ccc([N+](=O)[O-])cc1C(=O)O
Reaction time: 24 h

Procedure:
Combine 2-fluoro-5-nitrobenzoic acid (prepared by the method of Tetrahedron, 23, 4041-4045 (1967)) (3.7 g, 20 mmol) and sodium thiomethoxide (2.8 g, 40 mmol) in methanol (60 mL). Heat to reflux. After 24 hours, cool the reaction mixture, adjust the pH to about 2 using aqueous 1 M hydrochloric acid solution. Extract the reaction mixture with ethyl acetate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 2-methylthio-5-nitrobenzoic acid: Rf=0.5 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].Br.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:24]=2[Cl:23])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1csc(Nc2ccc(OC)c(OC)c2)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(OC)c(OC)c2)n1

Procedure:
A mixture of 2.18 g (7.1 mmol) 2-(3,4-Dimethoxy-phenylamino)-thiazole-4-carboxylic acid ethyl ester; hydrobromide, 2.24 g (10.7 mmol) 2,4-Dichlorobenzoyl chloride and 2.96 ml (21.4 mmol) NEt3 in 30 ml DCM was stirred at room temperature for 24 h. After evaporation of the volatiles the residue was taken up in MeOH and purified with flash column chromatography on silica eluting with a gradient of heptane/ethyl acetate to yield after evaporation of the product fractions 0.75 g (22%) of the title compound. MS (m/e): 481.1 (MH+, 100%)
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.CCCCCC>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 93 %

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (2 mL, 16.4 mmol), 1-tert-butoxycarbonyl piperazine (3.35 g, 18 mmol) and potassium carbonate (2.76 g, 20 mmol) in 7 mL of DMSO was stirred and heated at 100° C. for 2 h. Water (40 mL) and hexane (30 mL) were added and the bright yellow precipitate was collected, washed with water and hexane, and dried in vacuo to afford 4.9 g of 4-(3-methyl-4-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester, m.p. 145-146° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH2:13][OH:14])=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18](SC)=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.O[O:24][S:25]([O-:27])=O.[K+].CO.O1CCC[CH2:32]1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH2:13][OH:14])[NH:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:25]([CH3:32])(=[O:27])=[O:24])=[CH:17][CH:16]=2)=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Reactant: CSc1ccc(-c2nc(CO)[nH]c2-c2ccc(F)cc2)cc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2[nH]c(CO)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 2-hydroxymethyl-imidazole from step 4 (150 mg, 0.4 mmol), OXONE®(450 mg, excess), water (2 ml), methanol (5 ml) and tetrahydrofuran (3 ml) was stirred at 25° C. for 2 hours. The reaction mixture was diluted with water (20 ml) and extracted with methylene chloride. After removal of solvent, the crude material was recrystallized from toluene to give 80 mg (70%) of 4-(4-fluorophenyl)-2-hydroxymethyl-5-(4-methylsulfonylphenyl)-1H-imidazole: m.p. 115-117° C. Anal. Calc'd. for C17H15N2O3FS. H2O: C, 56.03; 4.70; N, 7.69; S, 8.80. Found: C, 56.02; H, 4.64; N, 7.45; S, 8.90.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13](OC)=[O:14])=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:2]1
Reactant: COC(=O)CCCc1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 107 %

Procedure:
A tetrahydrofuran solution (500 ml) of methyl 4-(3-indolyl)-butyrate (103 g) was added dropwise to a suspension of lithium aluminium hydride (25 g) in tetrahydrofuran (1000 ml) at 40° C. followed by stirring for 1 h at room temperature. Usual work-up gave 4-(3-indolyl)-1-butanol (96 g) as an oil. Arylation with 1-fluoro-4-iodobenzene according to the method described in EXAMPLE 5 yielded 4-[1-[4-fluorophenyl)-3-indolyl]-1-butanol which was converted to the title compound 9a by the method described in EXAMPLE 2 using spiro[1 H-2-benzopyran-4(3H),4'-piperidine]. The maleate salt crystallized from acetone by addition of maleic acid. Yield: 1.5 g, mp: 189-90° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:16][S-:17].[Na+]>C1COCC1.CCOCC>[CH3:16][S:17][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc2nc(SC)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of ethyl 2-bromobenzo[d]thiazole-6-carboxylate (4.8 g, 16.8 mmol) from Step 1 of Example 2 in THF (100 mL) was added sodium thiomethoxide (1.74 g, 25.2 mmol) slowly at 0° C. The reaction mixture was stirred at rt overnight. The mixture was diluted with Et2O (200 mL) and washed with saturated aq NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give ethyl 2-(methylthio)benzo[d]thiazole-6-carboxylate as a white solid (4.18 g, 98%). 1H NMR (300 MHz, CDCl3) δ 8.48 (d, J=1.5 Hz, 1H), 8.11 (dd, J=1.6, 8.6 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 2.82 (s, 3H), 1.42 (t, J=7.1 Hz, 3H) LCMS (ESI) m/z 254 (M+H)+.
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH2:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>ClC1C=CC=CC=1>[F:22][C:15]1[C:14]2[CH2:13][CH2:12][N:5]([C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH:4]=[CH:3][C:19]=2[C:18]([O:20][CH3:21])=[CH:17][CH:16]=1
Reactant: COc1ccc(F)c(CCN(CC(OC)OC)C(=O)C(F)(F)F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Clc1ccccc1
Solvent: O
Product: COc1ccc(F)c2c1C=CN(C(=O)C(F)(F)F)CC2
Yield: 73 %

Procedure:
Dissolve N-(2,2-dimethoxy-ethyl)-2,2,2-trifluoro-N-[2-(2-fluoro-5-methoxy-phenyl)-ethyl]-acetamide (5 g, 14.2 mmol) in chlorobenzene (100 mL). Add polyphosphoric acid (5 g) and P2O5 (2.5 g) and heat at 80° C. for 2 h. Add water to the hot mixture, cool to room temperature and extract with DCM. Dry the organic extracts over Na2SO4 and concentrate in vacuo to obtain the desired intermediate (3.0 g, 73%). MS (ES+) m/z: 290 (M+H)+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]2=[N:8][CH:7]=1)CCC.Br[C:28]1[N:33]=[C:32]([C:34]2[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=2[C:36]#[N:37])[CH:31]=[CH:30][CH:29]=1>>[F:42][C:40]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:6]3[N:10]4[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[N:14][C:9]4=[N:8][CH:7]=3)[N:33]=2)[CH:41]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: N#Cc1ccc(F)cc1-c1cccc(Br)n1
Product: N#Cc1ccc(F)cc1-c1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 14 %

Procedure:
3-Tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2-(6-bromopyridin-2-yl)-4-fluorobenzonitrile as in Example 1 to give 4-fluoro-2-[6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]benzonitrile as a pale pink solid (16 mg, 14%): δH (400 MHz, CDCl3) 7.29-7.32 (1H, m), 7.40 (1H, d, J 7), 7.53 (1H, dd, J 9 and 2), 7.66 (1H, dd, J 8 and 1), 7.88-8.03 (3H, m), 8.59 (1H, s), 10.56 (1H, d, J 7).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[N:14]=[C:13]4[NH:22][CH:23]=[CH:24][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[N:14]=[C:13]4[N:22]([CH2:32][C:33]5[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[CH:34]=5)[CH:23]=[CH:24][C:12]=34)=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Reactant: Fc1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C

Procedure:
A mixture of methyl 4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.943 g, 2.93 mmol) in N,N-Dimethylformamide (DMF) (6.0 mL) was treated with cesium carbonate (1.906 g, 5.85 mmol) and then 4-(bromomethyl)-1,2-difluorobenzene (0.561 mL, 4.39 mmol) and the mixture was heated to 80° C. for 75 minutes. The mixture was cooled to ambient temperature, diluted with ethyl acetate and then washed with water and brine. The water that was used for washing was back extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford a pale yellow residue: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25-7.17 (m, 2 H), 7.14-6.99 (m, 3 H), 6.96 (ddd, J=2.0, 4.1, 6.2 Hz, 1 H), 6.88 (d, J=8.4 Hz, 1 H), 6.44 (d, J=3.7 Hz, 1 H), 5.45 (s, 2 H), 4.30-4.20 (m, 2 H), 3.69 (s, 3 H), 2.84 (t, J=6.4 Hz, 2 H), 2.68 (s, 3 H), 2.14-1.96 (m, 2 H); LC/MS (m/z) ES+=449 (M+1).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]12[CH2:9][C:6]([NH2:10])([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.FC(F)C12CCC(N)(CC1)CC2.[C:24]([N:26]=[C:27](OCC)[C:28]([CH3:37])([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29])#[N:25]>>[C:24]([N:26]=[C:27]([NH:10][C:6]12[CH2:9][C:3]([CH:2]([F:11])[F:1])([CH2:4][CH2:5]1)[CH2:8][CH2:7]2)[C:28]([CH3:37])([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29])#[N:25]
Reactant: NC12CCC(C(F)F)(CC1)C2
Reactant: CCOC(=NC#N)C(C)(C)Oc1ccccc1
Agent: NC12CCC(C(F)F)(CC1)CC2
Product: CC(C)(Oc1ccccc1)C(=NC#N)NC12CCC(C(F)F)(CC1)C2

Procedure:
The titled compound was prepared using the procedure described in Example 85 substituting 4-(difluoromethyl)bicyclo[2.2.1]heptan-1-amine (BA-5) for 4-(difluoromethyl)bicyclo[2.2.2]octan-1-amine (BA-4) and ethyl N-cyano-2-methyl-2-phenoxypropanimidoate (CI-1) for Example 8B. 1H NMR (400 MHz, CDCl3) δ ppm 7.50 (s, 1H), 7.9 (t, J=7.9 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H), 6.94 (d, J=7.6 Hz, 2H), 5.82 (t, J=56.4 Hz, 1H), 2.0 (m, 8H), 1.72 (s, 6H), 1.6-2.0 (m, 2H); LCMS (ESI+) m/z 348.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1>O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: Clc1ccccc1CC1CCC2(CC1)OCCO2
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCC(Cc2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.3 %

Procedure:
A mixture of 4.8 grams (0.018 mole) of 8-(2-chlorophenylmethyl)-1,4-dioxaspiro[4.5]decane in 25 mL of water and 100 mL of acetic acid was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was carefully partitioned between diethyl ether and an aqueous solution saturated with sodium bicarbonate. The combined ether extracts were then washed with an aqueous solution saturated with sodium chloride. The organic layer was then added with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 3.1 grams of 4-(2-chlorophenylmethyl)cyclohexanone, mp 48° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][O:6][B:5](C2C=CC(CCCC(O)=O)=CC=2)[O:4][CH2:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])=[C:36]([C:45]#[N:46])[CH:35]=2)=[O:32])=[C:24]([CH3:47])[CH:23]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1>>[C:45]([C:36]1[CH:35]=[C:34]([NH:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:25]2[CH:26]=[CH:27][C:22]([B:5]3[O:6][CH2:7][C:2]([CH3:20])([CH3:1])[CH2:3][O:4]3)=[CH:23][C:24]=2[CH3:47])[CH:39]=[CH:38][C:37]=1[S:40]([CH2:43][CH3:44])(=[O:42])=[O:41])#[N:46]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2C)cc1C#N
Reactant: CC1(C)COB(c2ccc(CCCC(=O)O)cc2)OC1
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Product: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B3OCC(C)(C)CO3)cc2C)cc1C#N
Yield: 88 %

Procedure:
Using a procedure analogous to that used to prepare 2A, 8B (448 mg, 1.00 mmol) was reacted with 5,5,5′,5′-Tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to afford 8C (425 mg, 88%) as an off-white solid. MS (ESI) m/z 413.1 (M−H)− for free boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:21]([C:23]1[NH:27][C:26]([CH3:28])=[C:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:24]=1[CH3:34])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:21][C:23]4[NH:27][C:26]([CH3:28])=[C:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:24]=4[CH3:34])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)N(C)c3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CCC(=O)O
Yield: 22.5 %

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.34 mmol) was condensed with 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (80 mg, 0.41 mmol) and piperidine (2 drops) in ethanol (3 mL) at 80° C. for 2 hours to give 36 mg (23%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.15 (br s, 1H, NH), 12.07 (br s, 1H, COOH), 9.18 (s, 1H), 8.33 (s, 1H), 7.71 (m, 1H), 7.40 (s, 1H), 7.30-7.39 (m, 2H), 3.32 (s, 3H, CH3), 2.63 (m, 2H, CH), 2.35 (m, 2H, CH2), 2.33 (s, 3H, CH3), 2.13 (s, 3H, CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=1.O[N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:22]1([NH:18][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:9][CH:10]=2)=[O:16])[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=1
Reactant: O=C(O)c1cnc(-c2ccccc2F)nc1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cnc(-c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A mixture of 2-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid (105 mg, 0.48 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (74 mg, 0.54 mmol) and PS-DCC (501 mg, 1.28 mmol/g, 0.64 mmol) in DMF (8 mL) is shaken at room temperature for 15 min. Aniline (29.9 mg, 0.32 mmol) is added. The mixture is shaken at room temperature for 18 hours. PS-trisamine (385 mg, 3.75 mmol/g, 1.44 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with EtOAc. The filtrate is concentrated to afford 2-(2-fluoro-phenyl)-pyrimidine-5-carboxylic acid phenylamide (60 mg, 63%) as a solid. MS: 294 (M+H).