Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:13]=[O:14].O.C(Cl)Cl>C1(C)C=CC=CC=1.[Sn](Cl)(Cl)(Cl)Cl.C(N(CCCC)CCCC)CCC>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:13]=[O:14])=[C:8]([OH:12])[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=O
Reactant: Oc1cccc(C2CCCC2)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: O=Cc1ccc(C2CCCC2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
2.90 g of 3-cyclopentylphenol was dissolved in 14.5 mL of toluene, to which 0.21 mL of tin tetrachloride and 1.7 mL of tri-n-butylamine were added at room temperature in a stream of nitrogen, and then this mixture was stirred for 30 minutes at room temperature followed by addition thereto of 1.18 g of paraformaldehyde, and this mixture was stirred for 1.5 hours at 80° C. Then, the reaction mixture was cooled to room temperature and poured into water, to which methylene chloride was added, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=10:1] to yield 0.77 g of 4-cyclopentyl-2-hydroxybenzaldehyde as yellow oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[N:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23]2[N:31]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[CH:24]=2)=[CH:11]1.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.Cl>CC#N>[CH3:22][O:21][C:15]1[N:14]=[C:13]2[C:12]([C:23]3[N:31]([S:32]([C:35]4[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=4)(=[O:33])=[O:34])[C:26]4=[N:27][CH:28]=[CH:29][CH:30]=[C:25]4[CH:24]=3)=[CH:11][N:10]([CH2:9][CH2:8][N:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)[C:18]2=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCI
Reactant: CN1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(nc1OC)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCN1CCN(C)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 20.2 %

Procedure:
Add K2CO3 (1.1 equiv., 13.2 mg, 0.095 mmol) to bisazaindole iodide 18 (52 mg, 0.0862 mmol) in CH3CN (6.0 mL) at 60° C., then add 1-methylpiperazine (1.10 equiv., 9.515 mg, 10.55 μL, 0.095 mmol). After stirring for 2 h at 60° C., add extra K2CO3 (13.2 mg) and 1-methylpiperazine (21 μL) and continue stirring at 60° C. for 30 h. The reaction mixture is then concentrated to give a residue, which is treated with 2N HCl and washed with CH2Cl2. The aqueous phase is then treated with 2N NaOH until pH>10 and extracted with CH2Cl2, dried (MgSO4) and concentrated under vacuum, to give 21 (10 mg, 20.2%) as an ivory-colored solid: 1H NMR (CDCl3) δ 8.35 (dd, 1H, J=4.4, 1.1 Hz), 7.72 (dd, 1H, J=4.4, 1.1 Hz), 7.67 (d, 2H, J=8.4 Hz), 7.60 (s, 1H), 7.15 (m, 2H), 7.03 (d, 2H, J=8.4 Hz), 6.98 (s, 1H), 5.28 (s, 3H), 4.26 (t, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 2.86 (t, 2H), 2.55 (m broad, 8H), 2.30 (s, 3H). TLC (MeOH at 10%/CH2Cl2, 0.25% of NH3) Rf=0.35, m/z obs.=575 (M+1).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][C:38]([O:40]C)=[O:39])=[CH:31][CH:30]=2)[CH:22]=1)(=O)C.[OH-].[Li+].OS([O-])(=O)=O.[Na+]>CO.C1COCC1.O>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([C@H:6]2[C@H:5]([OH:4])[C@@H:10]([OH:11])[C@H:9]([OH:15])[C@@H:8]([S:19][CH3:20])[O:7]2)=[CH:22][C:23]=1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:33][CH:34]=1
Reactant: COC(=O)CCCc1ccc(Cc2cc([C@@H]3O[C@H](SC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C)cc1
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(CCCC(=O)O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
(2S,3S,4R,5S,6R)-2-(3-(4-(4-methoxy-4-oxobutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (9, 1.65 g, 2.81 mmol) was dissolved in a MeOH/THF/H2O solution (25 mL, 2:1:2 vol. ratio). Lithium hydroxide (674 mg, 28.1 mmol) was added and the reaction stirred at room temperature for 1 hour. The reaction was acidified to pH=1-2 with saturated aqueous NaHSO4. The acidic aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was rotovapped down once from hexanes to provide the product as white transferable solid (1.27 g, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (s, 1 H), 6.96-7.16 (m, 7H), 5.16 (d, J=5.8 Hz, 1 H), 5.06 (d, J=4.3 Hz, 1 H), 4.82 (d, J=5.6 Hz, 1 H), 4.32 (d, J=9.6 Hz, 1H), 4.04 (d, J=9.1 Hz, 1 H), 3.90 (s, 2 H), 2.53 (t, J=7.3 Hz, 2 H), 2.19 (t, J=7.3 Hz, 2 H), 2.17 (s, 3H), 2.03 (s, 3 H), 1.76 (quin, J=7.6 Hz, 2 H). MS (ES+) [M+NH4]+=464.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].N>CO.C(Cl)Cl.CN(C=O)C>[CH3:29][O:28][CH:25]1[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:5]3([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)=[CH:12][CH:13]=2)[CH2:27][CH2:26]1
Reactant: COC1CCN(CCCCl)CC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC1CCN(CCCOc2ccc(C3(CN(C)C)CCOCC3)cc2)CC1
Yield: 49.9 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 1-(3-chloro-propyl)-4-methoxy-piperidine (410 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM:MeOH:NH3) to give the title compound as a yellow oil (415 mg, 50%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.34 (s, 3H), 3.22 (m, 1H), 2.83-2.71 (m, 2H), 2.51 (t, 2H), 2.40 (s, 2H), 2.23-1.81 (m, 10H), 1.97 (s, 6H), 1.67-1.53 (m, 2H).
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.O=[C:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.[Cl-].[Na+].O>[C:28]([CH2:27][C:23]1([N:21]2[CH:22]=[C:18]([C:17]3[C:12]4[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:19]=[N:20]2)[CH2:24][N:25]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH2:26]1)#[N:29]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into the solution of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (2.6 g, 6.3 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (1.3 g, 6.3 mmol) in THF (30 mL) were added N,N-diisopropylethylamine (4.4 mL, 25 mmol) and sodium triacetoxyborohydride (2.2 g, 10 mmol). The mixture was stirred at room temperature overnight. After adding 20 mL of brine, the solution was extracted with EtOAc. The extract was dried over anhydrous Na2SO4 and concentrated. The residue was purified by combiflash column eluting with 30-80% EtOAc in hexanes to give the desired product, tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate. Yield: 3.2 g (86%); LC-MS: [M+H]+=593.3.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH:17]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]2)=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:22])([CH3:19])[CH3:18]>>[CH:17]([O:20][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[S:28]([C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][CH:40]([NH:1][CH2:2][CH:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:22])([CH3:19])[CH3:18]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 14, 1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid isopropyl ester, according to the procedure of Example 1 as an off-white solid; mp 52-58° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.10-1.20 (m, 6). 1.20-1.35 (m, 2H), 1.50-2.00 (m, 6H), 2.91 (s, 3H), 2.50-3.00 (m, 7H) 3.70-3.90 (m, 2H), 4.00 (m, 1H), 4.40-4.50 (m, 1H), 4.85-5.00 (m, 1H), 6.77 (d, 1H), 6.98 (d, 1H), 7.03 (d, 2H), 7.18 (d, 1H), 7.57 (d, 2H); MS (ES) m/z: 625.1 (MH+); HRMS Calcd. for C28H40N4O8S2 (MH+): 625.2360. Found: 625.2366.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[I-:24].[Na+]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([I:24])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(F)cc1
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(I)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
The obtained 4-fluorophenylpropan-1-ol (4.83 g, 31.3 mmol) was dissolved in dichloromethane (50 ml), and triethylamine (6.55 ml, 47.0 mmol) and methanesulfonyl chloride (2.91 ml, 37.6 mmol) were added thereto in the ice bath followed by stirring under a nitrogen atmosphere for 30 minutes. The reaction mixture was diluted with dichloromethane (50 ml), and washed with 10% hydrochloric acid and subsequently with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was dissolved in acetone (100 ml), and then sodium iodide (9.39 g, 62.6 mmol) was added thereto followed by stirring under a nitrogen atmosphere for 2 hours at 50° C. The reaction mixture was diluted with ethyl acetate (250 ml), and washed with 10% aqueous sodium thiosulfate solution and subsequently with a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was evaporated in vacua, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=5 :1-2:1) to afford 4-fluorophenyl-1-iodopropane (7.12 g, 86% yield) as a yellow oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH3:23])[CH:14]=3)=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(OP([CH2:32][C:33]#[N:34])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH2:22][CH3:23])[CH:14]=3)=[CH:32][C:33]#[N:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOc1cc(C(=O)c2ccc3c(c2)OCCO3)ccc1OC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(C(=CC#N)c2ccc3c(c2)OCCO3)ccc1OC

Procedure:
(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-(3-ethoxy-4-methoxyphenyl)methanone (0.83 g, 2.64 mmol), cyanomethylphosphonic acid diethyl ester (0.83 ml, 5.28 mmol) in anhydrous THF (20 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 5.28 ml, 5.28 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give a foam, which was lyophilized to give 3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(3-ethoxy-4-methoxy-phenyl)-acrylonitrile as a waxy oil (0.70 g, 78%): 1HNMR (DMSO-d6) 7.09-6.73 (m, 6H, Ar), 6.12 (s, 0.5H, double bond proton of one isomer), 6.07 (s, 0.5H, double bond proton of the other isomer), 4.33-4.25 (m, 4H, CH2CH2 for the two isomers), 4.05-3.97 (m, 2H, CH2CH3), 3.83 (s, 1.5H, OCH3 of one isomer), 3.79 (s, 1.5H, OCH3 of the other isomer), 1.31 (t, J=6 Hz, 3H, CH2CH3); 13C NMR (DMSO-d6) 161.0, 160.8, 151.0, 150.1, 147.8, 147.4, 145.5, 144.7, 143.2, 143.0, 131.3, 130.5, 130.1, 129.2, 122.6, 122.3, 120.0, 118.8, 118.7, 118.0, 117.1, 117.1, 117.0, 113.7, 112.1, 111.5, 111.3, 93.0, 92.9, 64.3, 64.2, 64.0, 64.0, 63.8, 55.5, 55.5, 14.6, 14.6. Anal. Calcd. For C20H19NO4 (+0.45H2O): C, 70.08; H, 5.76; N, 4.09. Found: C, 69.91; H, 5.54; N, 4.13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:18])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1
Reactant: COc1ccc(NC(=O)Oc2ccccc2)c([N+](=O)[O-])c1
Reactant: NC1CCCC1
Solvent: Cc1ccccc1C
Product: COc1ccc(NC(=O)NC2CCCC2)c([N+](=O)[O-])c1
Yield: 91 %

Procedure:
Phenyl 4-methoxy-2-nitrophenylcarbamate (1.1 g) and cyclopentylamine (0.37 g) were dissolved in xylene (10 ml) and the solution was heated under reflux for 2 hrs. After allowing the reaction solution to cool, the crystals formed was filtered, washed with xylene, and dried to give 1-(4-methoxy-2-nitrophenyl)-3-cyclopentylurea (0.97 g, 87%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Yield: 99.8 %

Procedure:
To a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone (29b) (2.00 g, 8.21 mmol) in toluene (40 mL) was added ethyl 2-triphenylphosphoranylideneacetate (4.29 g, 12.31 mmol). The reaction was refluxed overnight then concentrated in vacuo and purified by silica gel chromatography (Hexanes:EtOAc). The desired product eluted at 15% ethyl acetate. Clean fractions were combined and concentrated to give 2.57 g of 62a. LCMS+: 314.18 at 3.75 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24]([OH:26])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:26])[NH:31][CH2:30][CH2:29][O:28][CH3:27])=[CH:12][N:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCN
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Product: COCCNC(=O)c1cnc(CNC(=O)OC(C)(C)C)c2c(OC)cc(OC)cc12

Procedure:
As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with 2-methoxy-ethylamine to give 92 mg of [6,8-dimethoxy-4-(2-methoxy-ethylcarbamoyl)-isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester. H1-NMR (CDCl3): δ, 8.46 (s, 1H), 7.34 (s, 1H), 6.73 (br s, 1H), 6.59 (s, 1H), 6.51 (br s, 1H), 5.03 (d, J=3.9 Hz, 2H), 3.98 (s, 3H), 3.95 (s, 3H), 3.75 (q, J=5.1 Hz, 2H), 3.65 (t, J=5.1 Hz, 2H), 3.43 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:35]=[CH:36][CH:37]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:13])=[N:7]2.[CH3:47][N:48](C=O)C>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.[C-]#N.[Zn+2].[C-]#N>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[C:47]#[N:48])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH3:13])=[N:7]2
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)c(=O)c12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#N)c3)c(=O)c12
Temperature: 120 °C
Yield: 66 %

Procedure:
A 5-mL reaction vial equipped with a magnetic stirrer was charged with compound 138 (200 mg, 0.300 mmol), tetrakis(triphenylphosphine)palladium (34.0 mg, 0.029 mmol), zinc cyanide (70 mg, 0.60 mmol) and anhydrous DMF (1 mL). The vial was purged with nitrogen, heated to 120° C. for 3.5 h then cooled to ambient temperature and poured into a saturated aqueous sodium bicarbonate solution (25 mL). The resulting suspension was extracted with methylene chloride (3×20 mL), and the organic extracts were combined, dried over sodium sulfate and filtered. Concentration of the filtrate followed by purification by column chromatography gave a 66% yield of compound 141 as a white solid. 1H NMR (CDCl3) δ (ppm) 8.30 (d, 1H, J=6.9 Hz), 7.58-8.02 (m, 7H), 7.30 (d, 1H, J=7.0 Hz), 5.60 (s, 2H), 5.07 (bs, 1H), 3.65 (m, 2H), 2.84 (s, 3H), 1.58 (d, 3H, J=6.7 Hz), 0.96 (m, 2H), 0.02 (s, 9H).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([O:28]C)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8](=[O:31])[C@H:7]2[CH2:32][CH3:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.O>[OH-].[Li+].CO>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([OH:28])=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8](=[O:31])[C@H:7]2[CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)OC)c4c3OCC4)nc2N1C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Yield: 97.7 %

Procedure:
Methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylate 1p (5 g, 11 mmol) was dissolved in 180 mL mixture solution of 1 mol/L lithium hydroxide solution and methanol (V/V=1:1). The resulting mixture was heated to reflux for 3 hours with stirring. The reaction solution was added with 50 mL of water, concentrated under reduced pressure and extracted with ethyl acetate (50 mL×3). 1 M hydrochloric acid was added dropwise to adjust the aqueous phase pH to 2 resulting in the formation of precipitate. The precipitate was filtered, and dried to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (4.70 g, yield: 97.0%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11]CC)=[O:10])=[N:4][NH:3]1.[Li+].[OH-].O>C1COCC1>[O:1]=[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([OH:11])=[O:10])=[N:4][NH:3]1
Reactant: CCOC(=O)C(C)c1ccc(=O)[nH]n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(=O)[nH]n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
To a solution of Ethyl (3-oxo-2,3,-dihydropyridazin-6-yl)-propionate (3.00 mmol, 589 mg) in THF was added LiOH (2M, aqueous) (7.50 mL). The solution was stirred at rt. for 15 minutes, additional water (25 mL) was added and the THF removed in vacuo. The pH of the aqueous phase was adjusted to 3.0 by addition of HCl (2M, aqueous) and the solid material filtered off and washed with water (2×3 mL). The solid was dried in vacuo to yield the desired product (461 mg, 91.4%) as a colorless powder. 1H NMR (CDCl3): δ 11.62 (s br, 1H, NH), 7.18 (d, J=9.7 Hz, 1H, arom.), 7.88 (d, J=9.7 Hz, 1H, arom.), 4.11 (q, J=7.1 Hz, 2H, CH2), 2.90 (t, J=7.0 Hz, 2H, CH2), 2.64 (t, J=7.0 Hz, 2H, CH2), 1.25 (t, J=7.1 Hz, 3H, CH3). FAB+ MS: 169.0611 (M+H+, calc. for C9H12N2O3+H+ 169.0613).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:29]([NH:31][C@H:32]([C:42]([NH:44][C@H:45]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:46][O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:43])[CH2:33][CH2:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:30])[CH2:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:18])[CH2:8][CH2:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:5])[CH3:3].[H][H]>[Pd].CO>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:17]([NH:19][C@H:20]([C:29]([NH:31][C@H:32]([C:42]([NH:44][C@H:45]([C:52]([O:54][C:55]([CH3:56])([CH3:58])[CH3:57])=[O:53])[CH2:46][O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:43])[CH2:33][CH2:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:30])[CH2:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:18])[CH2:8][CH2:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:5])[CH3:3]
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 97.6 %

Procedure:
6.61 g. (6.85 mmoles) of Z-27-31-OtBu are dissolved in 150 ml. of methanol with gentle heating. The solution is cooled to room temperature; 1 g. of palladium-on-carbon is added to it, and gaseous hydrogen is bubbled into the mixture for 0.5 hours. The catalyst is removed by filtration, the filtrate is evaporated to dryness, the solid residue is triturated with n-hexane; and the mixture is filtered. 5.55 g. (97.6 %) of H-27-31-OtBu are obtained. M.p.: 138°-142° C, Rf2 = 0.15.