Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[CH:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[C:23]1([C:20]2[S:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:15]=[CH:14][C:5]4[CH:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=4[CH:3]=3)[N:19]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: COC(=O)CC1COc2cc(O)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC1COc2cc(OCc3csc(-c4ccccc4)n3)ccc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
Methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (200 mg, 0.961 mmol) and 4-(chloromethyl)-2-phenyl-1,3-thiazole (240 mg, 1.14 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (160 mg, 1.16 mmol) was added, and the mixture was stirred at 60-70° C. for 3 hr. Water was added to the reaction mixture, and the mixture was neutralized with 2 M hydrochloric acid. The precipitated crystals were recrystallized from ethyl acetate-diisopropyl ether to give the title compound (270 mg, yield 74%) as colorless prism crystals.
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH2:33][CH2:34][NH:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].CO.[Li+].[OH-].Cl>C1COCC1>[CH:39]([O:38][C:36]([NH:35][CH2:34][CH2:33][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:42])=[O:2])=[O:37])([CH3:41])[CH3:40]
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(N4CCOCC4)cc3)oc2C)cc1CCNC(=O)OC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(N3CCOCC3)cc2)nc1CCOc1ccc(CCC(=O)O)c(CCNC(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
This ester intermediate was dissolved in THF (0.6 mL) and MeOH (0.4 mL) and treated with aqueous 2M LiOH (1.0 mL, 2.0 mmol). The mixture was stirred for 16 h at ambient temperature, neutralized with HCl (1.0 mL, 2.0 M), and concentrated. The residue was extracted with EtOAc (3×5 mL). The combined organic layers were dried (Na2SO4), concentrated, and purified using silica gel chromatography column (hexanes/EtOAc/HOAc, 5/5/0.02) to afford the title compound (10 mg, 18%). MS (ES+) m/z 566.2 (M+H)+.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.F[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[F-].[Cs+]>CN(C=O)C.O.CCOC(C)=O>[CH2:1]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: O=Cc1ccc(F)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(N2CCc3c([nH]c4ccccc34)C2)cc1
Temperature: 65 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (250 mg, 1.460 mmol) in dry DMF (10 mL) were added 4-fluorobenzaldehyde (181 mg, 1.460 mmol) and CsF (266 mg, 1.752 mmol) and the reaction mixture was stirred at 65° C. for 5 hours. After completion, the reaction mixture was diluted with water (25 mL) and EtOAc (25 mL). The organic layer was separated and the aqueous layer was washed twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulphate and concentrated under vacuum to provide the crude compound. It was then purified by column chromatography using silica gel to obtain 4-(1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)benzaldehyde (125 mg). 1H NMR (CDCl3+DMSO-D6, 200 MHz) ppm: 9.93 (1H, bs), 9.74 (1H, s), 7.99 (1H, s), 7.76 (2H, d, J=8.8 Hz), 7.44 (1H, m), 7.32 (1H, m), 7.13-6.97 (3H, m), 4.61 (2H, s), 3.86 (2H, t, J=5.6 Hz), 2.93 (2H, m); m/e=277 (M+1).
Reaction SMILES: [O:1]1[C:5]([NH:6][C:7](=[O:14])OCC(Cl)(Cl)Cl)=[CH:4][CH:3]=[N:2]1.[C:15]1([C:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:1]1[C:5]([NH:6][C:7]([N:29]2[CH2:30][CH2:31][N:26]([C:23]3[S:24][CH:25]=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:22]=3)[CH2:27][CH2:28]2)=[O:14])=[CH:4][CH:3]=[N:2]1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccno1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccno1)N1CCN(c2nc(-c3ccccc3)cs2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl isoxazol-5-ylcarbamate (200 mg, 0.771 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (189 mg, 0.771 mmol), diisopropylethylamine (0.134 ml, 0.771 mmol) and dimethylsulfoxide (7 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (98.8 mg, 36.1%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](N(CC)CC)[CH3:26]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:11](=[O:23])[C:10]=1[C:25]#[CH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=c1c(I)c(OCc2ccccc2)ccn1Cc1cccc(F)c1
Solvent: CC#N
Product: C#Cc1c(OCc2ccccc2)ccn(Cc2cccc(F)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Degassed a solution of 4-(benzyloxy)-1-(3-fluorobenzyl)-3-iodopyridin-2(1H)-one (2.01 g, 4.62 mmol) in anhydrous acetonitrile (25 mL) under argon atmosphere. Triethylamine (1.11 g, 11 mmol) was added and quickly degassed. The reaction mixture was chilled in an ice bath for 15 minutes before adding bistriphenylphosphine-palladium chloride (0.34 g, 0.48 mmol) and cuprous iodide (0.2 g). The reaction was stirred at room temperature for 30 minutes before heating at 60° C. under an atmosphere of argon for 2 hours. The reaction mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure. The dark brown residue was diluted with CH2Cl2 (100 mL) and washed with water. The organic extracts were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The dark brown residue was purified by flash chromatography using 30% ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (1.34 g, 72%) as a light yellow solid. 1H-NMR (CD3OD, 400 MHz) δ 7.74 (d, 1H, J=7.6 Hz), 7.47 (d, 2H, J=7.6 Hz), 7.35 (m, 4H), 7.09 (m, 3H), 6.46 (d, 1H, J=7.6 Hz), 5.26 (s, 2H), 5.13 (s, 2H), 0.18 (s, 9H); ES-HRMS m/z 406.1638 (M+H calculated for C24H25NO2FSi requires 406.1610). Step 3. Preparation of 4-(benzyloxy)-3-ethynyl-1-(3-fluorobenzyl)pyridin-2(1H)-one
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O)(=O)C.B(F)(F)F.CCOCC>O>[C:6]1([C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:1][CH2:2][C:3]([OH:5])=[O:4])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 64574.2 %

Procedure:
A mixture of distilled mercaptoacetic acid (20.87 g, 0.23 mmol), triphenylmethanol (60.0 g, 0.23 mol) and glacial acetic acid (200 ml) was heated to 70° C. Boron trifluoride etherate (32 ml, 0.25 mol) was added and the resulting brown mixture was stirred for 45 minutes at room temperature. The reaction mixture was then poured into water (500 ml), depositing a buff, granular solid which was filtered off, washed well with water then ether, and dried to give compound (V) (49.67 g, 67%). A further crop (12.27 g, 16%) was recovered from the ether washings, purified by recrystallization from benzene/hexanes. Both crops were homogeneous by TLC, mp 158.5°-160°.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH:37]1[CH2:41][N:40]([CH2:42][CH3:43])[N:39]([CH2:44][CH3:45])[CH2:38]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:44]([N:39]1[CH2:38][CH:37]([NH:36][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])=[CH:20][CH:19]=2)[CH2:41][N:40]1[CH2:42][CH3:43])[CH3:45]
Reactant: CCN1CC(N)CN1CC
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(NC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)CN1CC
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a solution of 4- geranyloxybenzoic acid (1.10 g) in chloroform (20 ml), triethylamine (1.11 ml) and a solution of diphenylphosphinic chloride (0.95 g) in chloroform (5 ml) were successively added. After the reaction solution was stirred for 30 minutes, 4-amino-1,2-diethylpyrazolidine (0.57 g) was added and then the mixture was stirred at room temperature for one night. The reaction solution was washed with aqueous solution of sodium hydrogencarbonate, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) and then recrystallized from n-hexane, thereby yielding 1.39 g (87%) of the aimed compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.I.O>O1CCOCC1>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:25][C:24]3[CH:26]=[CH:27][C:21]([C:20]([F:19])([F:28])[F:29])=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: I
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cc1
Temperature: 130 °C
Yield: 91 %

Procedure:
6-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (0.6 g, 2.3 mmol) was dissolved in anhydrous dioxane (2 mL) and 4-(trifluoromethyl)aniline was added (0.43 mL, 3.45 mmol), followed by HI/H2O (0.2 ml, 47%). The mixture was heated at 130° C. in a sealed tube for 10 min in a microwave (Smith creator model, Personal Chemistry). The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the desired compound as a yellow solid (800 mg, 91%) which was used as such for the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](Br)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([N:35]2[C:43]3[C:38](=[CH:39][C:40](B4OC(C)(C)C(C)(C)O4)=[CH:41][CH:42]=3)[CH2:37][CH2:36]2)=[O:34])[CH:29]=[CH:30][CH:31]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.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>[NH2:1][C:2]1[C:3]2[C:10]([C:40]3[CH:39]=[C:38]4[C:43](=[CH:42][CH:41]=3)[N:35]([C:33](=[O:34])[CH2:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=3)[CH2:36][CH2:37]4)=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c3c(N)ncnc32)CC1
Reactant: Cc1cccc(CC(=O)N2CCc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)c1
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: Cc1cccc(CC(=O)N2CCc3cc(-c4cn(C5CCN(C(=O)OC(C)(C)C)CC5)c5ncnc(N)c45)ccc32)c1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
To 1,1-dimethylethyl 4-(4-amino-5-bromo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (200 mg, 0.505 mmol), and 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (228 mg, 0.606 mmol) dissolved in 1,4-Dioxane (4 mL) was added saturated aqueous NaHCO3 (2 mL). The mixture was then bubbled with N2 gas for 10 minutes and then Pd(Ph3P)4 (58.3 mg, 0.050 mmol) was added and then bubbled for 5 additional minutes. Then reaction was then capped and heated at 100° C. overnight. The mixture was allowed to cool then diluted with water (10 mL) then extracted with EtOAc (3×20 ml). The organics were combined, washed with brine, dried over MgSo4, filtered and concentrated to isolate a amber color oil. The oil was then purified on a 25 g Biotage SNAP column conditioned with Hexane and eluting with a gradient of 0 to 10% MeOH in DCM for 30 minutes to afford 1,1-dimethylethyl 4-(4-amino-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-piperidinecarboxylate (230 mg, 80% yield) as a amber color oil. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.13 (s, 1H), 7.45 (s, 1H), 7.32 (s, 1H), 7.20-7.26 (m, 2H), 7.12 (s, 1H), 7.09 (t, J=7.58 Hz, 2H), 4.71-4.83 (m, 1H), 4.20 (t, J=8.46 Hz, 2H), 4.08-4.15 (m, 2H), 3.94 (s, 2H), 3.82 (s, 2H), 3.20 (t, J=8.46 Hz, 2H), 2.95 (br. s., 2H), 2.31 (s, 3H), 1.86-1.97 (m, 4H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[O:10][C:9](=[O:11])[CH:8]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:19])[CH2:6]1)[CH2:2][C:3]#[CH:4].Br[C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.CC(O)=O>CC#N>[CH:20]1([C:5]2([CH2:1][CH2:2][C:3]#[C:4][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=3)[O:10][C:9](=[O:11])[CH:8]([S:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7](=[O:19])[CH2:6]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Oc1cccc(Br)c1
Reactant: C#CCCC1(C2CCCC2)CC(=O)C(Sc2ccccc2)C(=O)O1
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C1CC(CCC#Cc2cccc(O)c2)(C2CCCC2)OC(=O)C1Sc1ccccc1

Procedure:
The title compound was prepared analogously to Example 6 using 6-but-3-ynyl-6-cyclopentyl-3-phenylsulfanyl-dihydro-pyran-2,4-dione (described in Example 16) in place of 6-but-3-ynyl-6-dihydro-pyran-2,4-dione and 3-bromophenol in place of iodobenzene. 1H NMR (CDCl3): δ1.40-1.82 (m, 8H); δ2.14 (t, 1H, J=7.58 Hz); δ2.21-2.33 (m, 2H); δ0.40-2.56 (m, 2H); δ0.92 (dd, J1=17.94 Hz, J2=22.99 Hz, 2H); δ0.06-7.56 (m, 9H). Anal. Calcd. for C26H26O4S.0.2 AcOH. 1 MeCN: C, 69.95; H, 6.16; S, 6.85. Found C, 70.23; H, 6.58; S, 6.09. ESIMS (M+Na+): 457.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26][NH2:27])(=[O:23])=[O:22]>CO.C(O)C.[Pd]>[CH3:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26][NH:27][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1)(=[O:23])=[O:22]
Reactant: CN(C)S(=O)(=O)CCCN
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CN(C)S(=O)(=O)CCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (280 mg) in methanol (10 mL) was added 3-amino-propane-1-sulfonic acid dimethylamide (284 mg) and the reaction stirred at room temperature for 16 h. The solvent was reduced in vacuo and the residue redissolved in ethanol (50 mL). Palladium on carbon (20 mg) was added and the reaction stirred at room temperature under a hydrogen balloon for 48 h. The reaction was then filtered through Celite and the filtrate reduced in vacuo to give 3-[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-amino]-propane-1-sulfonic acid dimethylamide as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:31][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.O>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:24]3[CH2:25][CH2:26][C@@H:27]([NH:31][C@@H:32]4[CH2:36][CH2:35][NH:34][CH2:33]4)[CH2:28][CH2:29]3)[CH:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)CC1
Reactant: N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2[C@H]1CC[C@@H](N[C@@H]2CCNC2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone (1.00 g, 2.51 mmol), (3R)-(+)-3-aminopyrrolidine (0.65 g, 7.5 mmol), and acetic acid (0.43 mL, 7.5 mmol) in 1,2-dichloroethane (50 mL) was stirred at ambient temperature under an atmosphere of nitrogen for 45 minutes. Sodium triacetoxyborohydride (0.691 g, 3.26 mmol) was added and the mixture stirred at ambient temperature for 15 hours. Water (50 mL) and sodium bicarbonate (1.35 g, 16.1 mmol) were added and the mixture was stirred for 45 minutes. The reaction mixture was transferred to a separatory funnel and the organic layer was separated. The organic portion was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield an oily brown solid. The compound was purified by flash chromatography on silica gel (1 L 10% MeOH in CH2Cl2, then 1 L 20% MeOH in CH2Cl2, followed by 500 mL 30% MeOH in CH2Cl2) to yield cis-5-(4-phenoxyphenyl)-7-{4-[(3R)tetrahydro-1H-3-pyrrolylamino]cyclohexyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a beige solid (0.285 g, 0.608 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 8.13(1H, s), 7.39-7.49(5H, m), 7.07-7.17(5H, m), 6.09(2H, bs), 4.65 (1H, m), 3.29-3.35 (3H, m), 2.63-2.67(2H, m), 1.94-2.51(8H, m), 1.46-1.80(4H, m); RP-HPLC (Delta Pak C18, 5,μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 12.59 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3[S:32][CH:33]=[CH:34][N:35]=3)=[O:30])[CH2:25][CH2:24]2)[CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CCN(CC)CC.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:19]2[CH2:20][CH:21]([N:23]3[CH2:24][CH2:25][N:26]([C:29]([C:31]4[S:32][CH:33]=[CH:34][N:35]=4)=[O:30])[CH2:27][CH2:28]3)[CH2:22]2)=[O:13])=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(COc2cccc(Cl)c2)cc1
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc(COc2cccc(Cl)c2)cc1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Reaction time: 18 h
Yield: 46.5 %

Procedure:
A mixture of compound 35d (77 mg, 0.29 mmol), compound 5e (108 mg, 0.38 mmol) and HATU (165 mg, 0.44 mmol) in Et3N (1 mL) and DMF (3 mL) was stirred for 18 h, and then poured into water (10 mL). The mixture was then extracted with EtOAc (3×). The combined organic extracts were washed with brine (2×), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography, eluting with 5% MeOH/CH2Cl2, to give compound 453 (67 mg). MS m/z (M+H+) 497.1. 1H NMR (CD3OD): δ 7.95 (d, J=2.0 Hz, 1H), 7.8 (d, J=2.0 Hz, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 7.25 (t, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.90-6.98 (m, 2H), 5.15 (s, 2H), 4.32-4.45 (m, 2H), 4.15-4.25 (m, 2H), 4.00-4.10 (m, 1H), 3.70-3.82 (br. s, 2H), 2.47 (br. s., 4H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH2:11]([O:18][CH2:19][CH:20](O)[CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][CH2:19][CH:20]([O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH2:21][O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(COCc1ccccc1)COCc1ccccc1
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC(COCc1ccccc1)COCc1ccccc1)c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
A suspension of 5-chloro-pyrazine-2-carboxylic acid (prepared as in Example 29, 1.00 g, 6.33 mmol) in methylene chloride (30 mL) was treated with 1,3-dibenzyloxy-2-propanol (2.06 g, 7.57 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.61 g, 6.34 mmol), and triethylamine (1.83 mL, 12.66 mmol). The mixture was stirred at 25° C. overnight. The solution was extracted with methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with water, a saturated aqueous sodium chloride solution, a 1N aqueous hydrochloric acid solution, and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 3/1 hexanes/ethyl acetate) afforded the 5-chloropyrazine-2-carboxylic acid 2-benzyloxy-1-benzyloxymethyl-ethyl ester (1.45 g, 55.7%) as a colorless oil.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([F:36])[CH:3]=1.[BrH:37].N([O-])=O.[Na+]>C(#N)C.O>[Br:37][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([F:36])[CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)cc3F)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)cc3F)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of 6-(N-(4-amino-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (360 mg, 0.7 mmol) in acetonitrile (20 mL) was added hydrobromic acid (5 mL, 40% in water) followed by sodium nitrite (49 mg, 0.77 mmol in 2 mL water) dropwise at 0° C. After stirring for 10 minutes at 0° C., cuprous bromide (115 mg, 0.8 mmol) was added. The mixture was warmed to 80° C. and stirred for 1 hour. The mixture was cooled to room temperature and diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL), dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to afford 6-(N-(4-bromo-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (240 mg, 0.42 mmol, 60% yield) as an off-white solid. LCMS (m/z, ES+)=575, 577 (M+H+).