Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:12][CH:11]([C:13]#[N:14])[CH2:10]2)[C:7]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:6]=2[N:5]=1)[CH3:3].Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:6]2[N:5]=[C:4]([C@@H:2]([NH:1][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:3])[N:8]([CH:9]3[CH2:12][CH:11]([C:13]#[N:14])[CH2:10]3)[C:7]=2[CH:15]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CC(C#N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CC(C#N)C1
Yield: 32.1 %

Procedure:
3-[2-((S)-1-Aminoethyl)-6-fluorobenzoimidazol-1-yl]cyclobutanecarbonitrile (0.075 g, 0.29 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.070 g, 0.29 mmol) and DIPEA (0.26 mL, 1.45 mmol) in 2-propanol (5 mL) was stirred at 90° C. in a sealed microwave tube for 16 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH, then the product eluted with 2M NH3/MeOH then concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 100% DCM—10% methanol in DCM to give 399 as a solid (0.035 g, 32%). LCMS (Method K): RT 2.76 min [M+H]+ 376.0. 1H NMR (MeOD-d4) δ: 8.33 (1H, br s), 8.05 (1H, br s), 7.53-7.61 (2H, m), 6.97-7.04 (1H, m), 6.02 (1H, br s), 5.76-5.87 (1H, m), 3.38-3.49 (2H, m), 3.21-3.30 (2H, m), 2.76-2.88 (1H, m), 2.37-2.47 (1H, m), 1.76 (3H, d, J=6.1 Hz)
Reaction SMILES: [C:1](/[N:9]=[C:10](\SC)/[NH:11][C@H:12]([CH:28]([CH3:30])[CH3:29])[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:14])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][NH2:34]>C1COCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:13](=[O:14])[C@H:12]([NH:11][C:10]3[NH:34][N:33]=[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:9]=3)[CH:28]([CH3:30])[CH3:29])[CH2:16][CH2:17]2)=[CH:22][CH:23]=1
Reactant: CS/C(=N\C(=O)c1ccccc1)N[C@@H](C(=O)N1CCC(c2ccc(Cl)cc2)CC1)C(C)C
Reactant: NN
Solvent: C1CCOC1
Product: CC(C)[C@@H](Nc1nc(-c2ccccc2)n[nH]1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
(R,Z)-Methyl N′-benzoyl-N-(1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamimidothioate (47 mg, 0.1 mmol) was dissolved in THF (0.5 mL) and treated with anhydrous hydrazine (10 μL, 0.3 mmol). The reaction was stirred at rt. overnight. After this time, the THF was removed in vacuo and the resulting residue was dissolved in methanol and then purified by preparative HPLC to give (R)-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-ylamino)butan-1-one (20 mg, 45%). MS found: 438 (M+H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:21])[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:22]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])([CH3:24])[CH3:23]>>[CH:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:21])[C:14](=[N:28][C:27]3[CH:29]=[CH:30][CH:31]=[C:25]([CH:22]([CH3:24])[CH3:23])[CH:26]=3)[C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)c1cccc(N)c1
Reactant: O=C(C(=O)N1CCN(C2CCCCC2)CC1)c1cccs1
Product: CC(C)c1cccc(N=C(C(=O)N2CCN(C3CCCCC3)CC2)c2cccs2)c1

Procedure:
Intermediate 12 was generated from 1-(4-cyclohexyl-piperazin-1-yl)-2-thiophen-2-yl-ethane-1,2-dione and 3-isopropylaniline using general method L.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>COCCOC>[C:2]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1ccccc1
Yield: 97.5 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (100 mg, 0.26 mmol) in DME (5 ml)/2M Na2CO3 (450 μL, 0.90 mmol) was treated with phenylboronic acid (47 mg, 0.39 mmol) and Pd[PPh3]4 (30 mg, 0.026 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (98 mg, 98%). LC-MS m/e 387.16 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[I:12]N1C(=O)CCC1=O.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[C:9]([I:12])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(F)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(I)cc1C#N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 4-fluoro-2-methoxybenzonitrile (3.00 g, 20 mmol) and N-iodosuccinimide (NIS) (4.7 g, 21 mmol) under nitrogen was added TFA (35 mL) and the reaction was stirred at room temperature for 20 hours. The volatiles were removed in vacuo and the residue was taken up in 1:1 ethyl acetate:ether and was washed with aqueous sodium bicarbonate and then brine containing enough sodium sulfite to remove the iodine color. The aqueous layers were back extracted with more 1:1 ethyl acetate:ether and the combined organic layers were dried over sodium sulfate and evaporated. The residue was treated with ether/hexanes to afford clean iodo title product as a white solid. 1H-NMR (500 MHz, CDCl3) δ ppm 3.930 (s, 3H), 6.730 (d, J=9.4 Hz, 1H), 7.900 (d, J=6.8 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([C:6]1(O)[C:15]2[CH:14]=[N:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[CH2:5].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:19][N:2]([CH3:1])[CH2:3][C:4]([C:6]1[C:15]2[CH:14]=[N:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]=1)=[CH2:5]
Reactant: C=C(CN(C)C)C1(O)CCCc2cc(OC)ncc21
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(CN(C)C)C1=CCCc2cc(OC)ncc21

Procedure:
The 11β-alkyl compounds are produced by reacting 7-aza-6-methoxy-1-tetralone with a solution containing butyl lithium and 2-bromo-3-dimethylaminopropene to yield N,N-di-methyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine. The hydroxyl substituent is removed with a phosphorous oxyhalide, such as phosphorous oxychloride in pyridine or in concentrated sulfuric acid, to yield the N,N-dimethyl-N-(2-[5,6-dihydro-3-substituted-isoquinol-8-yl]alk-2-en-1-yl)amine. For example, N,N-dimethyl-N-(2-[5,6,7,8-tetrahydro-8-hydroxy-3-methoxyisoquinol-8-yl]-prop-2-en-1-yl)amine is contacted with phosphorous oxychloride in pyridine to obtain N,N-dimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine. Quaternarization of the amines with an alkyl halide, e.g. methyl iodide, yields the quaternary salts, which are subsequently reacted with silver oxide and then with 2-(lower alkyl)cyclopentane-1,3-dione to yield the appropriate 5,6-dihydro-3-substituted-8-[3-(2-methyl-1,3-dioxocyclopent-2-yl)alk-1-en-2-yl]isoquinoline. In that manner, the aforementioned N,N-dimethyl-N-(2-[5,6-dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine is treated with methyl iodide to afford the corresponding trimethyl ammonium iodide. Subsequent treatment with silver oxide and 2-(lower alkyl)cyclopentane-1,3-dione produces 5,6-dihydro-3-methoxy-8-[3-(2-methyl-1,3-dioxocyclopent-2-yl)-prop-1-en-2-yl]isoquinoline. Cyclization of the diketones is effected conveniently with sulfuric acid to afford the corresponding dl-2-aza-3-substituted-11β-methylestra-1,3,5(10),8(14),9(11),15-hexaen17-ones. Representative thereof is the formation of dl-2-aza-3-methoxy-11α-methylestra-1,3,5-(10), 8(14), 9(11), 15-hexaen-17-one upon contacting the aforementioned isoquinoline derivative with sulfuric acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][CH:10]=2)[O:3]1.CC[N:22]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:22])=[O:17])=[CH:11][CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(CC(N)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a solution of (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (500 mg) and HOBt ammonium salt (435 mg) in DMF (5 mL) was added EDCI hydrochloride (539 mg), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (420 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:32].[Cl:33]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3]([F:32])=[CH:4][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:26])([CH3:27])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:28])(=[O:29])[CH2:8]2)=[CH:30][C:31]=1[Cl:33]
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4ccc(N)c(F)c4)CS(=O)(=O)C[C@@H]32)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(Cl)c4)CS(=O)(=O)C[C@@H]32)c1

Procedure:
A solution of (3aR,7S,7aS)-7-(4-amino-3-fluoro-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (4.0 g, 8.69 mmol, example 81) and N-chlorosuccinimide (1.276 g, 9.55 mmol) in ACN (130 mL) was heated at reflux for 2 h. The reaction mixture was evaporated and the residue was purified by chromatography (Combi Flash, 120 g silicagel, hexane-EtOAc) to provide the title compound as a colorless solid: TLC (toluene-EtOAc 3:1) Rf=0.42; UPLC RtD=1.887 min; [M+NH4]+=512, 514; 1H NMR (600 MHz, DMSO-d6): δ 7.38 (s, 1H), 7.32 (d, 1H), 7.27 (t, 1H), 7.13 (d, 1H), 6.93 (s, 1H), 6.89 (d, 1H), 5.28 (s, 2H), 4.42 (d, 1H), 4.21 (d, 1H), 4.11 (t, 1H), 3.68 (m, 2H), 3.46 (t, 1H), 3.05 (m, 2H), 2.78 (d, 1H), 2.50 (m, 2H), 1.26 (s, 9H).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[F:16][C:17]1[N:22]=[C:21]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:20]=[CH:19][CH:18]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:29]1[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][O:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[N:22]=2)[CH2:27][CH2:28]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Reactant: Fc1cccc(OCCN2CCNCC2)n1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(F)n2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-[2-(6-fluoro-2-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH:26]=2)[C:21]([OH:23])=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C:64]1[S:65][C:66]([CH3:69])=[CH:67][N:68]=1>CN(C=O)C>[CH2:16]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:36])([CH3:37])[CH3:35])([CH3:32])[CH3:33])[CH:26]=1)[C:21]([NH:63][C:64]1[S:65][C:66]([CH3:69])=[CH:67][N:68]=1)=[O:23])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cnc(N)s1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
DIPEA (7.5 mL) was added to a suspension of 3-{(phenylmethyl)oxy}-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (4.5 g, 0.011 mol), HATU (8.6 g, 0.023 mol) and 2-amino-5-methylthiazole (2.46 g, 0.022 mol) in DMF (70 mL). The resulting mixture was stirred at ambient temperature for 72 hours. The DMF was removed in vacuo. Water (100 mL) was added and the mixture extracted with ethyl acetate (3×50 mL). The extracts were combined and washed with brine (100 mL). The solution was dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound. (1.7 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1.[Br:26]C1C=C(C2N=CN(C)C=2C2SC3N=CN=C(SC)C=3C=2)C=CC=1>>[Br:26][C:22]1[CH:21]=[C:20]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:6]=2[C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: CSc1ncnc2sc(-c3c(-c4cccc(Br)c4)ncn3C)cc12
Product: Cn1cnc(-c2cccc(Br)c2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 17 but using 6-[4-(3-bromophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 58) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7). Pale yellow foam (740 mg, 82%);
Reaction SMILES: C1(C)C=CC=CC=1.FC(F)(F)S(O[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])[CH:22]=2)[CH:17]=[N:16][CH:15]=1)(=O)=O.CC1(C)C(C)(C)OB([C:43]2[CH:58]=[CH:57][C:46]([O:47][CH2:48][CH2:49][O:50][CH:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[CH:45][CH:44]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[O:54]1[CH2:53][CH2:52][CH:51]([O:50][CH2:49][CH2:48][O:47][C:46]2[CH:57]=[CH:58][C:43]([C:17]3[C:18]4[C:23](=[CH:22][C:21]([C:24]([O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[O:25])=[CH:20][CH:19]=4)[CH:14]=[CH:15][N:16]=3)=[CH:44][CH:45]=2)[CH2:56][CH2:55]1
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(OS(=O)(=O)C(F)(F)F)c2c1
Reactant: CC1(C)OB(c2ccc(OCCOC3CCOCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOC(=O)c1ccc2c(-c3ccc(OCCOC4CCOCC4)cc3)nccc2c1
Yield: 51.8 %

Procedure:
Into toluene (10 ml), 2-(trimethylsilyl)ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-6-carboxylate (500 mg, 1.2 mmol) was dissolved, to which 4-{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethoxy}tetrahydro-2H-pyran (630 mg, 1.8 mmol) synthesized in Reference Example 2, 4,5-bis(diphenylphosphino)-9-dimethylxanthene (210 mg, 0.36 mmol), tris(dibenzylideneacetone)palladium (160 mg, 0.17 mmol), and potassium carbonate (500 mg, 3.6 mmol) were added. The resulting mixture was stirred at 100° C. for four hours, to which ethyl acetate was added. The resulting mixture was sequentially washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-50:50, V/V) to give the desired title compound (307 mg, yield 52%).
Reaction SMILES: O=C1C=CC=CC1C[C@@H]1COCN1[C:10](=[O:28])[C@@H:11]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[OH:33]O.O[Li].O>C1COCC1>[C:16]([O:15][C:13]([CH2:12][C@H:11]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[C:10]([OH:28])=[O:33])=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)N1COC[C@H]1CC1C=CC=CC1=O
Reactant: OO
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-[(4R)-2-oxo-4-benzyl-(1,3-oxazolidin-3-yl)](3S)-3-[(4-chlorophenyl)methyl]-4-oxobutanoate (Step 3) (0.3 g, 0.656 mmol) in 10 mL of THF was added 0.1 mL of H2O2 (35%) and 33 mg of LiOH—H2O (0.787 mmol). The reaction was stirred at RT for 3 h and extracted with 30 mL of Et2O. The aqueous solution was acidified with 2N HCl to pH˜2 and extracted with 50 mL of EtOAc. These EtOAc extractions were combined, dried over Na2SO4 and concentrated in vacuo. (2S)-3-[(tert-Butyl)-oxycarbonyl]-2-[(4-chlorophenyl)methyl]-propanoic acid was obtained as light yellow oil (0.15 g) and was used in the next step without further purification. MS (ESI, pos. ion) m/z: 299.0 (M+1). Calc'd for C15H19ClO4: 298.10.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([NH:12][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)=[C:2]([OH:1])[CH:3]=1
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Product: COC(=O)c1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)c(O)c1

Procedure:
Prepared by the method of Example 15b), from methyl 3-hydroxy-4-aminobenzoate (12.94 g, 77.0 mmol) and 3-nitrobenzoyl chloride (14.29 g, 77.0 mmol) the subtitle compound was obtained (22.45 g, 92%). The product was used directly in the next step without purification.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH:60]1[CH2:64][CH2:63][CH2:62][CH2:61]1)=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH:60]7[CH2:64][CH2:63][CH2:62][CH2:61]7)[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: O=C(Cl)OC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](NC(=O)OC5CCCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsi-lyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (20 mg) and triethylamine (12 μL) are dissolved in dichloromethane (2 mL), treated with cyclopentyl chloroformate (7.3 μL) and stirred for 12 hours at room temperature. Triethylamine (12 μL) and cyclopentyl chloroformate (7.3 μL) are added and the mixture is stirred for 5 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound, which is directly used in the next step. LC (method 5): tR=1.30 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=2)[CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccc([N+](=O)[O-])cn2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccc([N+](=O)[O-])cn1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (S)-3-(5-nitro-pyridin-2-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester described previously (300 mg, 0.97 mmol) in tetrahydrofuran cooled at 0° C. was added sodium hydride (47 mg, 1.95 mmol) gradually. The mixture was stirred at room temperature for 15 min followed by the addition of methyl iodide (166 mg, 1.17 mmol). The reaction mixture was stirred for 2 h and then extracted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated to give (S)-3-[(5-nitro-pyridin-2-yl)-methyl-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (295 mg, crude) as a yellow solid, which was directly used in the next step without further purification. LCMS calcd for C15H22N4O4 (m/e) 322, obsd 323 (M+H).
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:10])([CH3:9])[C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.[I-:11].[Na+]>CC(=O)CC>[I:11][CH2:2][Si:3]([CH3:10])([CH3:9])[C:4]1[O:5][CH:6]=[CH:7][CH:8]=1
Reactant: [I-]
Reactant: C[Si](C)(CCl)c1ccco1
Agent: [Na+]
Solvent: CCC(C)=O
Product: C[Si](C)(CI)c1ccco1
Temperature: 25 °C

Procedure:
Reflux the distilled chloromethyl(dimethyl)furylsilane (20 g, 114.5 mmol) in butanone (200 mL) containing sodium iodide (17.35 g, 116 mmol) for 4 h. GC/MS shows that the reaction is complete. Cool to room temperature and filter sodium chloride. Evaporate and redissolve in ethyl acetate. Wash with water (3×), then wash with saturated sodium chloride (3'). Dry and evaporate to obtain a yellow liquid. Distill the yellow liquid in a kugelrohr and collect iodomethyl(dimethyl)furylsilane between 90° C.--95° C. as a clear pink oil (26.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([N:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH3:14])[N:8]=[C:9]2O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[C:7]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH3:14])[N:8]=1
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2c(Cl)n1
Temperature: 0 °C

Procedure:
A mixture of 4-[N-(7-chloro-1-hydroxyisoquinolin-3-yl)-N-methylamino]phenol (4.0 g) and phosphorus oxychloride was heated under reflux for approximately 10 minutes at which stage a clear solution had been obtained. The mixture was cooled and poured into ice-water. The precipitated solid was collected and purified by column chromatography over silica gel (eluant dichloromethane/ethyl acetate; 90:10) to give 4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenol (2.57 g) as a yellow crystalline solid mp 124° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[N:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[N:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2cnc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1cnc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.