Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:32][N:33]1[CH2:38][CH2:37][O:36][C:35]2[CH:39]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:41]=[CH:42][C:34]1=2>COCCOC.O.[Pd].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.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>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:40]2[CH:41]=[CH:42][C:34]3[N:33]([CH3:32])[CH2:38][CH2:37][O:36][C:35]=3[CH:39]=2)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CN1CCOc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)OCCN2C
Yield: 69.5 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.138 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.075 g (68%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]([F:55])([F:54])[C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>C(#N)C>[F:55][C:43]([F:42])([F:54])[C:44]1[CH:45]=[CH:46][C:47]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(C(F)(F)F)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 27.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0310 g, 0.0672 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 4-trifluoromethylbenzenesulfonyl chloride (0.0477 mL, 0.195 mmol) to obtain 4-(4-trifluoromethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0122 g, yield 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:37])[F:38])[CH:30]=2)=[CH:40][CH:41]=1
Reactant: Cn1c(=O)n(CCC(=O)OC(C)(C)C)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)n(CCC(=O)O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
tert-Butyl 3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoate (0.23 g, 0.383 mmol, Example 397) was dissolved in DCM (4 mL) and TFA (0.57 mL, 7.66 mmol) was added. The reaction was stirred at room temperature for 1 h; then the solvent was removed under reduced pressure to leave a golden oil (0.21 g). The oil was purified using a 12 g silica gel column eluted with 5% methanol/DCM to give 34744-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)propanoic acid (0.13 g, 63% yield) as an white solid. LCMS retention time=3.903 min and 99% purity, LCMS MH+=539. 1H NMR (CDCl3) δ 7.14-7.47 (m, 8H), 5.41 (s, 2H), 4.35 (t, 2H, J=8 HZ), 3.44 (s, 3H), 2.77 (t, 2H, J=8 HZ).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].O>CN(C)C=O>[F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]=[CH:14][N:15]([CH3:17])[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccc([N+](=O)[O-])cc1F
Reaction time: 1.5 h
Yield: 85 %

Procedure:
5 g of 2-fluoro-4-nitroaniline were dissolved in 35 ml of dry dimethylformamide, admixed at room temperature with 19.90 g of dimethylformamide dimethyl acetal and stirred for 90 min. For workup, 250 ml of water were added to the reaction mixture, and the precipitate was filtered off with suction, washed with water and dried. N′-(2-Fluoro-4-nitrophenyl)-N,N-dimethylformamidine was obtained in a yield of 85%. Molecular weight 211.07 (C9H10FN3O2); retention time Rt=0.49 min. [B]; MS (ESI):
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=2)[N:3]=1.[F:25][C:26]1([F:41])[O:30][C:29]2[CH:31]=[CH:32][C:33]([C:35]3([C:38](Cl)=[O:39])[CH2:37][CH2:36]3)=[CH:34][C:28]=2[O:27]1>N1C=CC=CC=1.C(Cl)Cl>[C:21]([O:20][C:18]([C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:1][C:38]([C:35]3([C:33]4[CH:32]=[CH:31][C:29]5[O:30][C:26]([F:41])([F:25])[O:27][C:28]=5[CH:34]=4)[CH2:37][CH2:36]3)=[O:39])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH:17]=[CH:16][CH:15]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: COC(=O)c1ccc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Reaction time: 7 h
Yield: 67.9 %

Procedure:
A solution of methyl 6-amino-2-(3-(tert-butoxycarbonyl)phenyl)nicotinate (400 mg, 1.2 mmol) and 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (630 mg, 2.4 mmol) in pyridine (12 mL) was stirred at room temperature for 3 days and then at 90° C. for 7 hours. Additional 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (320 mg, 1.2 mmol) was added and the reaction was heated at 90° C. for 12 hours until the amine was completely consumed. The reaction mixture was concentrated and the residue was purified by column chromatography (0-40% ethyl acetate—hexanes). The material obtained was dissolved in CH2Cl2 and was washed with 1N HCl (×3) and saturated aq. NaHCO3 (×3), dried (MgSO4) and concentrated to yield methyl 2-(3-(tert-butoxycarbonyl)phenyl)-6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)nicotinate as a cream colored solid (450 mg, 67%). ESI-MS m/z calc. 552.2, found 553.3 (M+1)+. Retention time 2.49 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.24 (d, J=8.7 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.95-7.91 (m, 2H), 7.64 (d, J=7.9 Hz, 1H), 7.57-7.51 (m, 2H), 7.39 (d, J=8.3 Hz, 1H), 7.34 (dd, J=1.6, 8.3 Hz, 1H), 3.63 (s, 3H), 1.54 (m, 11H), 1.22-1.19 (m, 2H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[F:13][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[C:17]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[CH:18]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([F:14])[CH3:12]
Reactant: CC1(C)OB(c2ccc(F)c(-c3cccnc3)c2)OC1(C)C
Reactant: CC(F)(F)c1ccn2c(Br)cnc2n1
Product: CC(F)(F)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3)cnc2n1

Procedure:
3-Bromo-7-(1,1-difluoroethyl)imidazo[1,2-α]pyrimidine (113 mg, 0.43 mmol) was coupled with 3-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]pyridine as described in Example 1 to give 7-(1,1-difluoroethyl)-3-[4-fluoro-3-(pyridin-3-yl)phenyl]imidazo[1,2-α]pyrimidine as a white powder: δH (360 MHz, DMSO) 2.11 (3H, t, J 7), 7.36 (1H, d, J 7), 7.55-7.64 (2H, m), 7.83-7.87 (1H, m), 7.99-8.01 (1H, m), 8.11-8.13 (1H, m), 8.21 (1H, s), 8.66 (1H, dd, J 5 and 1), 8.91 (1H, s), 9.27 (1H, d, J 7).
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[N:7]=[CH:6][N:5]([C:8]2[C:9]([CH3:19])=[CH:10][C:11]([CH3:18])=[C:12]([S:14](Cl)(=O)=O)[CH:13]=2)[N:4]=1.Cl>C(O)(=O)C.[Fe]>[S:14]([C:12]1[CH:13]=[C:8]([N:5]2[CH:6]=[N:7][C:3]([CH:2]([F:20])[F:1])=[N:4]2)[C:9]([CH3:19])=[CH:10][C:11]=1[CH3:18])[S:14][C:12]1[CH:13]=[C:8]([N:5]2[CH:6]=[N:7][C:3]([CH:2]([F:20])[F:1])=[N:4]2)[C:9]([CH3:19])=[CH:10][C:11]=1[CH3:18]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1cnc(C(F)F)n1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(C)c(-n2cnc(C(F)F)n2)cc1SSc1cc(-n2cnc(C(F)F)n2)c(C)cc1C
Temperature: 120 °C

Procedure:
A quantity of 5.4 g of 5-[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]-2,4-dimethylbenzenesulphonyl chloride is dissolved in 25 ml of glacial acetic acid, and 4.6 ml of hydrochloric acid (32% strength) are added. The mixture is heated at 120° C. (reflux). Then 2.53 g of iron powder in portions are added. Following complete reaction, the major part of glacial acetic acid is distilled off, and water and dichloromethane are added. Following phase separation and concentration of the organic phase on a rotary evaporator, and after chromatographic purification (CH2Cl2), 1.9 g (49.5% of theory) of a white solid are obtained.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][OH:31])=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH:30]=[O:31])=[CH:27][CH:26]=1
Reactant: COc1ccc(CCO)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CC=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (3.2 g, 7.29 mmol, 1.1 equiv) is added in one portion to a mixture of 4-methoxyphenethyl alcohol (1.0 g, 6.63 mmol) and NaHCO3 (1.1 g, 13.2 mmol, 2.0 equiv) in CH2Cl2, under an argon atmosphere. The resulting mixture is stirred for 1 h at RT and directly loaded on a silica gel (60 g) column. Flash chromatography purification (CH2Cl2/Et2O, 95/5), affords the title compound as a colorless oil: ES-MS: 148.9 [M−H]−; single peak at tR=6.12 min (System 1); Rf=0.74 (CH2Cl2/Et2O, 95/5).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH3:22])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[O:10])=[C:4]([F:23])[CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=3)=[CH:3][C:4]=2[F:23])[O:21][CH3:22])=[CH:14][CH:15]=1)#[N:20]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Br)cc1F
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccc(C(OC)C(=O)NCc3ccc(C#N)cc3)c(F)c2)c1

Procedure:
In analogy to example 57.1, (RS)-2-(4-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 41.2) was reacted with 3-methoxyphenylboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(3-fluoro-3′-methoxy-biphenyl-4-yl)-2-methoxy-acetamide. Light yellow gum.
Reaction SMILES: [BH4-].[Na+].[H][H].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[CH:15]([CH2:41][N+:42]([O-])=O)[CH2:16][C:17]1[N:21]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=[N:19][N:18]=1>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:42][CH2:41][CH:15]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][C:6]=1[CH3:5])[NH2:12])[CH2:16][C:17]1[N:21]([C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:20]=[N:19][N:18]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1)C[N+](=O)[O-]
Reactant: [H][H]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(N)cc1C(CN)Cc1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
Adapting a literature known protocol (Osby and Ganem, Tetrahedron Lett., 1985, 26(52), 6413-6416), a mixture of nickel(II) dichloride hexahydrate (NiCl2 6H2O) (1.19 g, 5.0 mmol) in methanol (MeOH) (80 mL) is sonicated to effect complete dissolution. Solid sodium borohydride (NaBH4) (567 mg, 15.0 mmol) is added in small portions upon a black precipitate (Ni2B) is generated immediately and hydrogen gas is generated (exotherm!). After about 30 min, a solution of 5-[2-(2-methyl-5-nitro-phenyl)-3-nitro-propyl]-1-trityl-tetrazole (20b) (5.35 g, 10.0 mmol) in MeOH (20 mL) is added followed by portion-wise addition of more NaBH4 (1.13 g, 30.0 mmol) at room temperature. The reaction is monitored by TLC and/or LCMS to completion. The reaction mixture is filtered over Celite® 545 and the filter residue is washed with additional MeOH. The combined filtrates are evaporated to dryness under reduced pressure using a rotary evaporator. The crude material (20c) is used directly in the next step without further isolation and purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.[C:8]([CH2:11][N:12]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][N:18]([CH2:24][C:25]([OH:27])=[O:26])[CH2:17][CH2:16][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:14][CH2:13]1)([OH:10])=[O:9].[OH-].[K+]>O1CCOCC1.O>[OH:5][CH:3]([C:2]([F:7])([F:6])[F:1])[CH2:4][N:21]1[CH2:22][CH2:23][N:12]([CH2:11][C:8]([OH:10])=[O:9])[CH2:13][CH2:14][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:16][CH2:17][N:18]([CH2:24][C:25]([OH:27])=[O:26])[CH2:19][CH2:20]1
Reactant: FC(F)(F)C1CO1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)C(F)(F)F)CCN(CC(=O)O)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
12.94 g (115.44 mmol) of (1,1,1-trifluoro-2,3-epoxypropane) and 10 g (28.86 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane are dissolved in a mixture of 50 ml of dioxane/80 ml of water, and the pH is brought to 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 70° C. with exclusion of pressure. It is evaporated to dryness, the residue is taken up with 300 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 1 with 5N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and precipitated potassium chloride is filtered out. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then put on a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent=gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 10.81 g (68% of theory) of a strongly hygroscopic, vitreous solid is obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1.[F:13][C:14]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][N:18]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:11][C:9]1[C:10]2[C:2]([C:22]3[C:14]([F:13])=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:17][CH2:16]4)=[CH:3][N:4]([CH3:12])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Cn1cc(Br)c2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc3c(c2F)CCN3C(=O)OC(C)(C)C)c2c(N)ncnc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
A mixture of 5-bromo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (413 mg, 1.817 mmol), 1,1-dimethylethyl 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole-1-carboxylate (660 mg, 1.817 mmol), Pd2(dba)3 (83 mg, 0.091 mmol) and Potassium Phosphate (K3PO4) (771 mg, 3.63 mmol) and (t-Bu)3PHBF4 (52.7 mg, 0.182 mmol) in 1,4-Dioxane (7.5 mL) and Water (2.5 mL) was stirred at 100° C. overnight on a stirrer hot-plate. The reaction mixture was allowed to cool to room temperature, at which point a yellow crystalline precipitate was observed. The organic layer removed, the aqueous was diluted with water (10 mL) and extracted with one portion of ethyl acetate (1×30 mL) and two portions of DCM-MeOH (9:1, x x 30 mL) to solubilize the solids. The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was adsorbed onto silica and purified by flash chromatography (0-100% EtOAc in hexanes→0-10% MeOH in DCM, 40-g silica gel column) to afford 1,1-dimethylethyl 5-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2,3-dihydro-1H-indole-1-carboxylate (441 mg, 63.3% yield) as an off-white solid. LC-MS (ES) m/z=384 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 9H), 3.15 (t, J=8.46 Hz, 2H), 3.75 (s, 3H), 4.03 (t, J=8.59 Hz, 2H), 5.88-6.12 (m, 2H), 7.12-7.22 (m, 1H), 7.25 (s, 1H), 7.44-7.72 (m, 1H), 8.15 (s, 1H).
Reaction SMILES: [H-].[Na+].COC(=O)[CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:14]2[C:10](=[CH:11][N:12]([CH3:17])[N:13]=2)[C:9]=1[C:18]([O:20]C)=O.Cl.[OH-].[Na+]>O1CCCC1.CO>[CH3:17][N:12]1[CH:11]=[C:10]2[C:14]([CH:15]=[CH:16][C:8]3[CH2:7][CH2:6][C:18](=[O:20])[C:9]=32)=[N:13]1
Reactant: COC(=O)CCc1ccc2nn(C)cc2c1C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc2c3c(ccc2n1)CCC3=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
To a suspension of 60% sodium hydride (145 mg, 3.62 mmol) in tetrahydrofuran (10 mL) were added a solution of methyl 5-(3-methoxy-3-oxopropyl)-2-methyl-2H-indazole-4-carboxylate (500 mg, 1.81 mmol) in tetrahydrofuran (10 mL) and methanol (1 drop), and the mixture was heated under reflux for 3 hr. The reaction solution was concentrated to dryness to give yellow-brown crystals. The obtained crystals were gradually added to 12M hydrochloric acid (5 mL) heated to 100° C., and the mixture was stirred for 4 hr. The reaction solution was neutralized with 8M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed 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 (ethyl acetate) to give the title compound (285 mg, yield 85%).
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH:4]([NH:13]CC2C=CC=CC=2)[CH2:3]1>C(O)C>[OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH:4]([NH2:13])[CH2:3]1
Reactant: OC1CC(NCc2ccccc2)CCc2ccccc21
Solvent: CCO
Product: NC1CCc2ccccc2C(O)C1
Temperature: 80 °C
Yield: 103 %

Procedure:
8 g of 10% palladized carbon were added to a mixture of 8.2 g of the product of Step B in 250 ml of absolute ethanol and the mixture was heated to 80° C. under a hydrogen atmosphere for 30 minutes. The mixture was filtered and the filter was washed with ethanol. The filtrate was evaporated to dryness under reduced pressure to obtain 5.6 g of a mixture of the two isomers of 5ξ-hydroxy-7-amino-6,7,8,9-tetrahydro [5H] benzocycloheptene in the form of resin which was used as is for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH2:23]O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:23][C@H:19]3[CH2:20][CH2:21][CH2:22][N:18]3[C:16]([O:15][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:17])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: Oc1cccc2[nH]ccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A stirred solution of 4-hydroxyindole (1.33 g, 10.0 mmol), (R)-(+)-1-(t-butoxycarbonyl)-2-pyrrolidinemethanol (4.02 g, 20.0 mmol) and triphenylphosphine (5.3 g, 20.0 mmol) in THF is treated with diethyl azodicarboxylate (3.2 mL, 20 mmol), stirred for 3 h at room temperature and concentrated in vacuo. The resultant residue is treated with EtOAc and filtered through a pad of silica gel. The filtrate is concentrated to give a residue which is purified by chromatography (silica gel, EtOAc:hexanes, 15:80) to afford the title compound as a white solid, 1.08 g, mp 146-147° C.; identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[NH:8]/[CH:9]=[C:10](\[C:16]#[N:17])/[C:11]([O:13]CC)=O)(=[O:3])[CH3:2].C(NC1C=C(C=CC=1OC)N/C=C(/C#N)\C(OCC)=O)(=O)C.C1(C2C=CC=CC=2)C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[C:16]([C:10]1[C:11](=[O:13])[C:18]2[C:7](=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:20]([O:21][CH3:22])[CH:19]=2)[NH:8][CH:9]=1)#[N:17]
Reactant: CCOC(=O)/C(C#N)=C/Nc1ccc(OC)c(NC(C)=O)c1
Agent: CCOC(=O)/C(C#N)=C\Nc1ccc(OC)c(NC(C)=O)c1
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COc1cc2c(=O)c(C#N)c[nH]c2cc1NC(C)=O
Temperature: 256 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
An amount of 1 g (0.003 mol) of a mixture of ethyl (E)-3-[3-(acetylamino)-4-methoxyanilino]-2-cyano-2-propenoate and ethyl (Z)-3-[3-(acetylamino)-4-methoxyanilino]-2-cyano-2-propenoate was added to a stirring solution of biphenyl (16.3 mL, 0.10 mol) and phenyl ether (48.8 mL, 0.30 mol) at 256° C. After stirring for 2 hours at 256° C., the reaction mixture was cooled to room temperature, diluted with diethyl ether (130 mL), filtered, and evaporated to dryness to give a gray solid (0.53 g, 62% yield), mp 305-310° C.; 1H NMR (DMSO-d6) δ 12.80 (s, 1H), 9.58 (s, 1H), 8.62 (s, 1H), 8.58 (m, 1H), 7.52 (s, 1H), 3.97 (s, 3H), 2.20 (s, 3H); HRMS (EI) m/z 257.0793 (M+1).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1)=O.Cl.[NH2:16][C:17]([NH2:19])=[NH:18].C[O-].[Na+]>C(O)CCC>[NH2:18][C:17]1[N:19]=[C:5]([C:7]2[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=2)[CH:4]=[CH:3][N:16]=1
Reactant: N=C(N)N
Reactant: Cc1ncc(C(=O)C=CN(C)C)n1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: Cc1ncc(-c2ccnc(N)n2)n1C
Temperature: 25 °C
Yield: 83.8 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1,2-dimethylimidazole (Method 15; 2.8 g, 14.5 mmol) and guanidine hydrochloride (3.5 g, 36.3 mmol) were suspended in 1-butanol (30 ml). Sodium methoxide (3.1 g, 58 mmol) was added in one portion and the mixture heated under reflux, under an atmosphere of nitrogen, for 18 hours. The reaction mixture was allowed to cool to ambient temperature and was pre-absorbed on to silica gel and purified by column chromatography on silica gel eluting with DCM/2% methanolic ammonia (100:0 increasing in polarity to 95:5) to give the title compound (2.3 g, 84%). NMR 2.16 (s, 3H), 3.93 (s, 3H) 6.52 (s, 2H), 6.80 (d, 1H), 7.47 (s, 1H), 8.17 (d, 1H); m/z 190.