Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:41]2[CH:42]=[CH:43][C:38]([Cl:37])=[CH:39][CH:40]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: Clc1ccc(I)cc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 1-chloro-4-iodobenzene according to the general procedure C. Obtained as a yellow solid (779 mg).
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:13]([CH3:12])[CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: CNCCN1CCOCC1
Reactant: Fc1ccc2nnc(Cl)n2c1
Agent: N
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: CN(CCN1CCOCC1)c1nnc2ccc(F)cn12
Temperature: 170 °C
Yield: 72 %

Procedure:
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and Intermediate 45b (1.26 g, 8.77 mmol) in NMP (2 mL) was heated in the microwave at 170° C. for 2 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as an orange oil (350 mg, 71%). 1H NMR (400 MHz, CDCl3): 2.41-2.52 (4H, m), 2.58 (2H, t, J 5.6), 3.03 (3H, s), 3.27 (2H, t, J 6.0), 3.62 (4H, t, J 5.2), 7.04-7.08 (1H, m), 7.58-7.65 (1H, m), 8.39 (1H, t, J 2.4).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[C:4]([CH3:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH3:12])[N:5]=[C:4]([CH3:13])[C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(C)nc2cccc(C)c2c1Cl
Reactant: COc1ccc(CN)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(C)c2c1NCc1ccc(OC)cc1
Yield: 78.8 %

Procedure:
A solution of ethyl 4-chloro-2,5-dimethylquinoline-3-carboxylate (Example 12b, 0.518 g, 1.96 mmol) and (4-methoxyphenyl)methanamine (1.15 mL, 8.86 mmol) in toluene (10 mL) and DMF (5 mL) were stirred at 115° C. under nitrogen for 12 hrs. The solvent was removed under vacuum, and the residue was purified by chromatography on silica gel (0% to 50% EtOAc in hexanes) to give the title compound as an oil (563 mg, 79%). 1H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J=7.6 Hz, 3H), 2.45 (s, 3H), 2.78 (s, 3H), 3.73 (s, 3H), 4.2-4.3 (m, 4H), 6.27 (t, J=6.0 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.19 (m, 3H), 7.48 (m, 1H), 7.58 (d, J=8.4 Hz, 1H). MS 365 (MH+).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:61])[N:10]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH2:47][C:48]3[N:49]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH:50]=[CH:51][N:52]=3)[CH2:33][C:34]3[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:36]=[CH:37][N:38]=3)=[O:31])=[CH:26][CH:25]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH2:47][C:48]2[N:49]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:59])([CH3:58])[CH3:60])[CH:50]=[CH:51][N:52]=2)[CH2:33][C:34]2[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:44])[CH3:46])[CH:36]=[CH:37][N:38]=2)=[O:31])=[CH:28][CH:29]=1)[C:9](=[O:61])[O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCCCN(Cc1ccc(C(=O)N(Cc2nccn2COCC[Si](C)(C)C)Cc2nccn2COCC[Si](C)(C)C)cc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccnc1CN(Cc1nccn1COCC[Si](C)(C)C)C(=O)c1ccc(CN(CCCCN)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To the compound 6 (225 mg), a solution of 25% trifluoroacetic acid in dichloromethane (6 mL) was added. The reaction mixture was stirred at room temperature for one hour. The reaction mixture was concentrated and the residue was added by 1N sodium hydroxide and then extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol:28% ammonia water=80:10:1) to obtain the title compound (92 mg) having the following physical properties.
Reaction SMILES: [OH:1][N:2]1[C:6]([I:7])=[CH:5][CH:4]=[N:3]1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>>[I:7][C:6]1[N:2]([O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[CH:4][CH:5]=1
Reactant: On1nccc1I
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1nccc1I)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-5-iodopyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (64%, oil).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:8]=2)[NH:3]1.[CH:27]([NH2:30])([CH3:29])[CH3:28].CCOC(C)=O>C(Cl)Cl>[CH:27]([NH:30][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH:11]=[C:10]3[C:12]([F:15])([F:14])[F:13])=[CH:18][CH:19]=1)(=[O:25])=[O:24])([CH3:29])[CH3:28]
Reactant: CC(C)N
Reactant: O=c1cc(C(F)(F)F)c2cc(Cc3ccc(S(=O)(=O)Cl)cc3)ccc2[nH]1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc(Cc2ccc3[nH]c(=O)cc(C(F)(F)F)c3c2)cc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
A stirred solution of 4-(2-oxo4-trifluoromethyl-1,2-dihydroquinolin-6-ylmethyl)-benzenesulfonyl chloride (Preparation 1, 17 mg, 42 μmol) in anhydrous CH2Cl2 (0.5 mL) was treated dropwise with an excess of i-PrNH2 (145 μL, 1680 μmol). After stirring at 20° C. for 10 min, the reaction mixture was submitted to column chromatography (EtOAc) to furnish the title compound (8 mg, 45%): δH (CD3OD)=1.00 (d, 6H), 3.35 (sept, 1H), 4.20 (s, 2H), 7.00 (s, 1H), 7.15–7.20 (m, 3H), 7.50 (dd, 1H), 7.60 (d, 1H), 7.80 (d, 2H); m/z (ES+)=466.1 [M+H+MeCN]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([C:20](O)=[O:21])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1.CN(C(ON1N=[N:40][C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=NC=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[N:39]1[CH:38]=[CH:37][CH:36]=[C:35]([NH:40][C:20]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[N:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:24])([F:23])[F:1])[CH:5]=2)[CH:19]=[CH:18]3)=[O:21])[CH:34]=1
Reactant: O=C(O)c1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Reaction time: 18 h
Yield: 40.7 %

Procedure:
To a mixture of 2-(3-(trifluoromethoxy)phenyl)quinoline-8-carboxylic acid (1 gram, 3.3 mmol) and HATU (1.71 g, 4.5 mmol) in DMF (30 mL) was added 3-aminopyridine (423 mg, 4.5 mmol) followed by DIPEA (1.03 mL, 6 mmol). The mixture was stirred 18 hours, water (150 mL) was added and the resulting precipitate was collected by filtration. The crude material was purified by chromatography (silica gel, gradient 0 to 100% Ethyl acetate in Pentane), the desired fraction was concentrated and the product recrystallized from methanol to obtain the product as a white solid (550 mg, 45% yield).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[OH:6][CH2:7][CH2:8][O:9][C:10](=[O:13])C=C.O1CC[CH2:16][CH2:15]1>CCOCC>[CH:2]12[CH2:1][CH:5]([CH:15]=[CH:16]1)[CH2:4][CH:3]2[C:10]([O:9][CH2:8][CH2:7][OH:6])=[O:13]
Reactant: C=CC(=O)OCCO
Reactant: C1=CCC=C1
Reactant: C1CCOC1
Solvent: CCOCC
Product: O=C(OCCO)C1CC2C=CC1C2

Procedure:
Cyclopentadiene of Formula VI and 2-hydroxyethylacrylate of the following Formula VII are dissolved at the same rate in ether or tetrahydrofuran and reacted at a temperature of about −30 to 60° C. for 24 hours. Thereafter, the solvent is removed by use of a rotary evaporator and the residue is distilled in vacuo to give 2-hydroxyethyl 5-norbornene-2-carboxylate of the following Formula VIII, which occurs in an endo- and exo-mixture.
Reaction SMILES: [H-].[Na+].[CH:3]([OH:21])=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.[CH3:31]N(C)C=O>>[C:23]1([CH2:22][O:21][CH2:3][C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH2:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCCCCCC=CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C=C(CCCCCCCCCCCCCCCC)COCc1ccccc1
Reaction time: 15 h

Procedure:
To 1.4 g of washed sodium hydride in 100 ml of dry N,N-dimethylformamide is added a solution of 10 g of 1-octadecenol in 100 ml of dimethylformamide followed by 5.8 g of benzyl bromide. This mixture is stirred for 15 hours, then water added and the mixture extracted with ether. The ether extract is dried, evaporated and purified by chromatography, to give 9.0 g of the desired compound.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:12][C:13](=[O:15])[CH:14]=2)=[O:11])=[CH:5][CH:4]=1)#C.NC1C=CC=CC=1[OH:23].CC(C)=O.C(OC(=O)C)(=O)C>C([O-])(=O)C.[Ni+2].C([O-])(=O)C.C(N(CC)CC)C>[OH:23][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:12][C:13](=[O:15])[CH:14]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: C#Cc1ccc(C2=CC(=O)NC2=O)cc1
Reactant: Nc1ccccc1O
Agent: [Ni+2]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: O=C1C=C(c2ccc(O)cc2)C(=O)N1

Procedure:
4-hydroxyphenyl maleimide was prepared by the same procedure as for 4-ethynylphenyl maleimide with the following starting materials aminophenol (54.5 g, 0.50 mole) maleic anhydride (49.0 g, 0.50 mole), acetone (500 ml), triethylamine (11 ml), nickel (II) acetate (0.5 g, 43 mmol), and acetic anhydride (63.8 g, 0.625 mol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]([N:22]2[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH2:24][CH2:23]2)=[O:21])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:30]1COCC1.C[Mg]Br.O.O.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C@H:13]2[CH2:19][C:20]([N:22]2[CH2:28][CH2:27][CH2:26][C:25]([OH:29])([CH3:30])[CH2:24][CH2:23]2)=[O:21])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCCN(C(=O)C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(O)CCCN(C(=O)C[C@@H]2C(=O)NC=CN2S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(2-(1-(3,4-dichlorophenylsulfonyl)-3-oxo-1,2,3,4-tetrahydropyrazin-2-yl)acetyl)azepan-4-one (4) (0.0250 g, 0.054 mmol) in THF (8.00 ml, 0.054 mmol) under N2 was added methylmagnesium bromide (1.4M solution in THF/Toluene (75:25), 2.70 ml, 3.78 mmol) in thee times, and stirred overnight. The reaction mixture was cooled in ice-water bath and sodium sulfate dodecahydrate (10.0 g) was added slowly followed by AcOEt (20 ml). After stirring at r.t. for 1 h, the mixture was filtered and the solid was washed with AcOEt. The filtrate was concentrated under reduced pressure and the crude product was chomatographed on silica (CH2Cl2→CH2Cl2/MeOH=20/1) to yield the product. MS 476 (M+H).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=3)[C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[CH3:41][N:42]([CH3:48])[CH:43]1[CH2:47][CH2:46][NH:45][CH2:44]1>C(Cl)Cl.CN(C=O)C>[CH3:41][N:42]([CH:43]1[CH2:47][CH2:46][N:45]([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][N:11]3[C:10]4[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=4[N:8]=[C:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:21][CH:20]=2)[CH2:44]1)[CH3:48]
Reactant: CN(C)C1CCNC1
Reactant: O=C(O)c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc(Cn3c(-c4ccccc4)nc4ccccc43)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The 4-(2-phenyl-benzoimidazol-1-ylmethyl)-benzoic acid (0.2 mmol) obtained in step 2 is dissolved in DCM (5 mL) and oxalylchloride (0.2 mL, 0.4 mmol, 2 M solution in DCM) and DMF (2 drops) are added. The solution is stirred for 2 hours at room temperature then concentrated in vacuo. The residue is dissolved in THF, treated with diisopropylethylamine (DIEA) (0.09 mL, 0.5 mmol) and 3-(dimethylamino)pyrrolidine (0.22 mmol, 22 uL), stirred at room temperature overnight then concentrated. This residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL) and purified by reverse-phase semi-preparative HPLC1 to the title product as a white powder (13 mg), identified by HPLC2 and MS [425.2 m/e (M+H)].
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:12][CH:11]=1>O1CCCC1>[Br:1][C:19]1[C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[N:17]([Si:27]([CH:31]([CH3:33])[CH3:32])([CH:34]([CH3:36])[CH3:35])[CH:28]([CH3:29])[CH3:30])[CH:18]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c(-c2ccncc2)c1-c1ccc(F)cc1
Reaction time: 6 h
Yield: 42.6 %

Procedure:
A suspension of 8.61 g (47.4 mmol) of N-bromosuccinimide in 100 ml of tetrahydrofuran was added to a solution of 18.70 g (47.4 mmol) of 2-(4-fluorophenyl)-3-(pyridin-4-yl)-1-triisopropylsilyl-1H-pyrrole [prepared as described in step 7(ii) above] in 300 ml of tetrahydrofuran at −78° C., after which the resulting mixture was stirred at the same temperature for 6 hours. After removal of the cooling bath, the mixture was then stirred at room temperature for a further 1 hour. At the end of this time, 400 ml of hexane was added to the reaction mixture and the insoluble material was removed by filtration. The resulting filtrate was concentrated by evaporation under reduced pressure and the residue thus obtained was purified by chromatography on a silica gel column using a 2:1 by volume mixture of hexane and ethyl acetate as the eluant to give 9.57 g (yield 43%) of the title compound as pale yellow prismatic crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33]Cl)[CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH:39]=[CH:38][N:37]=[C:36]1[Na].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:35]4[CH:39]=[CH:38][N:37]=[CH:36]4)[CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:17]
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2-c1cccc(OCCCl)c1
Reactant: [Na]c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: N
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2-c1cccc(OCCn2ccnc2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2 g of 5-(3-benzyloxyphenyl)-7-[3-(2-chloroethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine (Ex. 153) and 0.46 g of imidazolyl sodium are heated to 50° C. in 45 ml of DMF and the mixture is stirred for 15 h. The mixture is then cooled to RT and treated with water, extracted 3 times with ethyl acetate and concentrated. After chromatography on silica gel (methylene chloride/methanol containing 5% of about 5N ammonia in methanol), 5-(3-benzyloxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an Rf=0.4 (silica gel, methylene chloride/methanol containing 5% of about 5N ammonia in methanol=9:1) is obtained.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1>[OH-].[Na+]>[C:2](=[O:3])([O:4][CH3:5])[O:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][C:9]=1[CH3:14]
Reactant: COC(=O)Cl
Reactant: Cc1cc(F)ccc1O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Oc1ccc(F)cc1C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
Methyl chloroformate (6.8 ml, 88 mmol) was added over 30 minutes to a solution of 4-fluoro-2-methylphenol (10 g, 79 mmol) in 6% aqueous sodium hydroxide solution at 0° C. The mixture was stirred for 2 hours, then extracted with ethyl acetate (100 ml). The ethyl acetate extract was washed with water (100 ml) and dried (MgSO4) and the solvent removed by evaporation to give 4-fluoro-2-methylphenyl methyl carbonate (11.4 g, 78%) as an oil.
Reaction SMILES: [OH-:1].[Na+].[CH:3]([CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])=[CH:11][CH:10]=1)[C:7]#N)([CH3:5])[CH3:4].C(O)C[OH:24]>>[CH3:4][CH:3]([CH3:5])[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])=[CH:11][CH:10]=1)[C:7]([OH:24])=[O:1]
Reactant: OCCO
Reactant: CC(C)C(C#N)c1ccc(OC(F)(F)C(F)F)cc1
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)C(C(=O)O)c1ccc(OC(F)(F)C(F)F)cc1
Temperature: 135 °C
Yield: 89 %

Procedure:
A stirred mixture of 48.0 g (24.0 g real, 0.60 mol) of 50% sodium hydroxide, 21.78 g (0.0791 mol) of α-isopropyl-p-(1,1,2,2-tetrafluoroethoxy)phenylacetonitrile, and 240 ml of ethylene glycol is heated at 135° C. for 12 hours. After dilution with 600 ml of water the reaction mixture is washed twice with 100 ml of ether. The water layer is acidified with concentrated hydrochloric acid and then extracted twice with 300 ml of ether. The ether solution is washed twice with 500 ml of water, dried with sodium sulfate, filtered, and then evaporated to give 20.74 g (89%) of a brown solid, melting point 92° C. to 97° C. (hexane).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[O:12]1[C:16]2[CH:17]=[CH:18]C=CC=2N=C1>>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:18][CH:17]3[CH2:16][O:12]3)[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccc(O)cc2s1
Reactant: c1ccc2ocnc2c1
Product: Cc1nc2ccc(OCC3CO3)cc2s1

Procedure:
Compound 51 was prepared in the manner of compound 6 substituting compound 50 for compound 8 in part C-5 of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH:5]=[C:6]1[C:10](=[O:11])O[C:8]([CH3:12])=[N:7]1.[CH2:17]([NH2:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:17]([N:19]1[C:10](=[O:11])[C:6](=[CH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[O:2][CH3:1])[N:7]=[C:8]1[CH3:12])[CH3:18]
Reactant: COc1ccccc1C=C1N=C(C)OC1=O
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1C(=O)C(=Cc2ccccc2OC)N=C1C
Temperature: 80 °C

Procedure:
4-(2′-Methoxybenzylidene)-2-methyl-4H-oxazol-5-one (5 g) was dissolved in ethanol (100 ml) and an aqueous ethylamine solution (15 ml) and potassium carbonate (7 g) were added thereto. The mixture was heated at 80° C. for 5 hr. After cooling, the solvent was evaporated under reduced pressure and the precipitated yellow crystals were collected by filtration to give the title compound (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[NH:10][C:11](=O)[C:12]([C:17]1[C:25](OC)=[CH:24][C:23]([CH3:28])=[C:22]2[C:18]=1[CH:19]=[CH:20][N:21]2C(OC(C)(C)C)=O)([CH3:16])[CH2:13][CH:14]=[CH2:15].[OH2:37].[C:38]1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:38][O:37][C:25]1[C:17]([C:12]([C:11]2[NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=3[N:10]=2)([CH2:13][CH:14]=[CH2:15])[CH3:16])=[C:18]2[C:22](=[C:23]([CH3:28])[CH:24]=1)[NH:21][CH:20]=[CH:19]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Reactant: C=CCC(C)(C(=O)Nc1cc(C#N)ccc1N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: C=CCC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12
Temperature: 135 °C

Procedure:
(±)-tert-Butyl 4-(1-((2-amino-5-cyanophenyl)amino)-2-methyl-1-oxopent-4-en-2-yl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 156-E) (0.36 g, 0.737 mmol) was dissolved in toluene (2.76 mL) and dioxane (0.921 mL). p-Toluenesulfonic acid monohydrate (0.042 g, 0.221 mmol) was then added and the mixture heated at 135° C. for 3 hours. At this point another aliquot of p-toluenesulfonic acid monohydrate (0.030 g) was added and the reaction was heated for 1 hour. At this point another aliquot of p-toluenesulfonic acid monohydrate (0.025 g) was added and the reaction was heated for 1.5 hour. The reaction was then cooled to room temperature, concentrated and absorbed onto silica to purify via FCC(0-50% EtOAc:heptanes) to obtain the title compound that was used directly in the next step. MS (ESI+) m/z 371.4 (M+H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:20](=[O:37])[N:19]([C:38]2[CH:39]=[CH:40][C:41]3[O:45][C:44]([CH3:47])([CH3:46])[CH2:43][C:42]=3[CH:48]=2)[N:18]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:3][C:4](=[O:7])[O:5][N:36]=3)=[CH:27][CH:28]=2)[C:20](=[O:37])[N:19]([C:38]2[CH:39]=[CH:40][C:41]3[O:45][C:44]([CH3:47])([CH3:46])[CH2:43][C:42]=3[CH:48]=2)[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nn(-c2ccc3c(c2)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nn(-c2ccc3c(c2)CC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
A mixture of hydroxylammonium chloride (2.1 g), sodium hydrogen carbonate (3.0 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-{[3-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile (1.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.73 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.67 mL) were added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.59 g, 38%) as a colorless solid.