Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1)(=[O:41])=[O:40].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:45]3[CH:46]=[CH:47][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:43][CH:44]=3)=[CH:21][CH:22]=2)[CH2:29][CH2:28][CH2:27]1)([CH3:35])([CH3:34])[CH3:36]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(S(C)(=O)=O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1

Procedure:
A mixture of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.097 mmol), [4-(methyl sulfonyl)phenyl]boronic acid (39 mg, 0.20 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7 mg, 0.1 mmol), and 2M Na2CO3 aq. (0.097 mL, 0.20 mmol) in DMF (1.5 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water (×3), brine, dried over Na2SO4, and then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:1×2) to afford the mixture of the desired product and tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl)cyclobutyl}carbamate (51 mg) as a yellow solid. LCMS: 634 [M+H].
Reaction SMILES: Br[C:2]1[C:3]2[NH:7][C:6]([C:8](C3C(C)=CC(C)=CC=3C)=[C:9]3[N:35]=[C:12]([C:13](Br)=[C:14]4[NH:33][C:17](=[C:18](C5C(C)=CC(C)=CC=5C)[C:19]5[CH:20]=[CH:21][C:22]=1[N:23]=5)[CH:16]=[CH:15]4)[CH:11]=[CH:10]3)=[CH:5][CH:4]=2.C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:3]12[CH:2]=[C:22]3[N:23]=[C:19]([CH:20]=[CH:21]3)[CH:18]=[C:17]3[NH:33][C:14]([CH:15]=[CH:16]3)=[CH:13][C:12]3=[N:35][C:9]([CH:10]=[CH:11]3)=[CH:8][C:6]([NH:7]1)=[CH:5][CH:4]=2
Reactant: Cc1cc(C)c(-c2c3nc(c(Br)c4ccc([nH]4)c(-c4c(C)cc(C)cc4C)c4nc(c(Br)c5ccc2[nH]5)C=C4)C=C3)c(C)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
The general procedure was used to couple 5,15-dibromo-10,20-di(2′,4′,6′-trimethylphenyl)porphyrin (0.035 g, 0.05 mmol) with (+)-dihydrocholesterol (0.1556 g, 0.4 mmol), using Pd2(dba)3 (0.0046 g, 0.005 mmol) and DPEphos (0.0107 g, 0.02 mmol) in the presence of Cs2CO3 (0.0652 g, 0.2 mmol). The reaction was conducted in toluene (5 mL) at 100° C. for 20 h. The title compound was isolated by flash column chromatography (silica gel, ethyl acetate:hexanes (v/v)=1:10) as purple solids (0.052 g, 80%). 1H NMR (300 MHz, CDCl3): δ 9.42 (d, J=4.8 Hz, 4H), 8.67 (d, J=4.8 Hz, 4H), 7.32 (s, 4H), 5.02 (m, 2H), 2.31-0.55 (m, 92H), 2.67 (s, 6H) 1.90 (s, 12H), −2.43 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 139.4, 138.1, 137.6, 135.5, 127.8, 117.6, 91.7, 56.4, 56.2, 54.3, 45.0, 42.5, 40.0, 39.5, 37.1, 36.1, 35.8, 35.4, 32.0, 29.4, 28.7, 28.2, 28.0, 24.2, 23.8, 22.8, 22.6, 21.7, 18.6, 12.6, 12.1. UV-vis (CHCl3, λmax, nm): 418, 519, 557, 601, 659. HRMS-MALDI ([M+H]+): calcd for C92H127N4O2, 1319.9954; found: 1320.0008 with an isotope distribution pattern that is the same as calculated one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[NH:12][CH:11]3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36].[H-].[Li+].[Cl:43][CH2:44][CH2:45][CH2:46]Br.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[N:12]([CH2:46][CH2:45][CH2:44][Cl:43])[CH:11]3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36]
Reactant: ClCCCBr
Reactant: Cc1ccc(F)cc1C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(F)cc1C1CC(=O)N(CCCCl)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 8 h
Yield: 24.2 %

Procedure:
Racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.40 g, 0.67 mmol) prepared in example 146a was reacted with LiH (0.13 g, 16.70 mmol) and 1-chloro-3-bromo-propane (0.63 g, 4.01 mmol) in N,N-dimethyl-formamide (3 mL), a catalytic amount of KI. After the solution was stirred overnight, the solution was poured into water. The water layer was extracted with ethyl acetate and the combined organic layers were dried, concentrated to obtain the crude product. The crude product was purified by chromatography to give racemic (2′S,3S,4′R)-6-chloro-1′-(3-chloro-propyl)-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a yellow solid (Yield: 0.11 g, 24%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=[O:36].C(OCC)(OCC)OCC.NC1CCOCC1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([CH:1]4[CH2:6][CH2:5][O:36][CH2:3][CH2:2]4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: NC1CCOCC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3)c2ncn1C1CCOCC1
Yield: 57.1 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 4-aminotetrahydropyrane (0.102 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 76.7 mg (0.25 mmol, 57.1% yield) of the title compound.
Reaction SMILES: COC[O:4][C:5]1[CH:43]=[CH:42][C:8]2[CH:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][CH:15]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1.Cl.O>CO>[OH:4][C:5]1[CH:43]=[CH:42][C:8]2[CH:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:10]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCSCCN2CCCCC2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCSCCN1CCCCC1
Temperature: 40 °C
Reaction time: 5 h
Yield: 94.4 %

Procedure:
(3RS,4RS)-7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-4-[9-(2-piperidinoethylthio)nonyl]-2,3-dihydro-4H-benzopyran (174 mg, 0.28 mmol) and methanol solution of 5N--HCl (1 ml) were dissolved in methanol (10 ml) and then stirred for 5 hours at 40° C. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer thus separated was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified with flash column chromatography (dichloromethane:ethanol=9:1) to obtain 139 mg (yield: 93%) of the title compound as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:13][N:12]2[C@H:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@H:15]3[C:10]3[C:11]2=[C:6]([CH:7]=[CH:8][CH:9]=3)[NH:5]1.I[CH3:26]>CCCCCC.CN(C)C=O>[CH3:26][N:5]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C@@H:15]4[CH2:16][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:19][C@@H:14]4[N:12]([C:11]=23)[CH2:13][C:4]1=[O:3]
Reactant: CI
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
Sodium hydride (900 mg of 60% dispersion in oil; 22.5 mmol) was washed with hexane, and suspended in anhydrous dimethylformamide (5 mL). The suspension was added to a stirred solution of ethyl (6bR, 10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (6.02 g, 20 mmol) in anhydrous dimethylformamide (50 mL) under nitrogen. After gas evolution had subsided, the mixture was cooled in ice-water bath and treated with iodomethane (3.55 g., 25 mmol). The mixture was stirred at room temperature for 1 h and then concentrated. The residue was treated with water and extracted with dichloromethane (2×) and the extract was washed with brine, dried over magnesium sulfate and evaporated to dryness to yield 5.48 g (87%) of ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate as a tan solid, m.p. 149-151° C. (dec.). [M+H] calc. 316; found 316. 1H NMR (CDCl3, 300MHz) δ 1.28 (t, J=7.3 Hz, 3H), 1.85 to 1.93 (m,1H), 2.65 to 2.82 (m, 1H),3.08 to 3.25 (m, 1H), 3.25 to 3.40 (m, 1H),3.30-3.50 (m, 1H), 3.34 (s, 3H), 3.42 (d, J=14.3 Hz, 1H), 3.85 to 4.0 (m,1H), 4.02 (d, J=14.3 Hz, 1H, 4.15 (q, J=7.2 Hz, 4H), 6.76 (d, J=8.1 Hz, 1H), 6.83 (t, J=7.3 Hz, 1H), 6.90 (d, J=7.3 Hz, 1H). MS (CI): 316 (M+H+).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:24]C(=O)OC(C)(C)C)[CH2:11][NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)(C(C)(C)C)(C)C.[ClH:32]>CO>[NH2:24][C@@H:10]([CH2:11][NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]3)[CH2:21]1)[CH2:15]2)[CH2:9][OH:8].[ClH:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNCC12CC3CC(CC(C3)C1)C2)CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: N[C@H](CO)CNCC12CC3CC(CC(C3)C1)C2

Procedure:
A solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-((1-adamantylmethyl)amino)propan-2-ylcarbamate (10 g, 22 mmol) in 1N HCl in CH3OH (30 mL) was stirred for 3 h at rt. After the reaction was complete, the solution was concentrated to give crude (S)-2-amino-3-((1-adamantylmethyl)amino)propan-1-ol as its HCl salt, which was used for the next step without purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:20][CH2:19]2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[O:17])[CH2:23][CH2:22]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)Nc2ccc(OCc3ccccc3)cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)Nc2ccc(O)cc2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
A suspension of N-[4-(benzyloxy)phenyl]-4-(2-tert-butylphenyl)piperazine-1-carboxamide (Example 173, 2.0 g, 4.51 mmol) and palladium hydroxide (20% on carbon, wetted with ca. 50% water, 100 mg) in ethyl acetate (100 mL) was stirred under hydrogen at 60° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=90:10 to 30:70) to provide 4-(2-tert-butylphenyl)-N-(4-hydroxyphenyl)piperazine-1-carboxamide (1.47 g, 92%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([N:5]([CH2:12][C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][S:2]([N:5]([CH2:12][C@@H:13]1[N:18]([C:27]2[N:28]=[CH:29][C:30]([C:33]([OH:42])([C:34]([F:35])([F:36])[F:37])[C:38]([F:40])([F:41])[F:39])=[CH:31][N:32]=2)[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CN(c2ccccc2)S(C)(=O)=O)C1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)[C@@H](CN(c2ccccc2)S(C)(=O)=O)C1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
A 20-mL vial was charged with tert-butyl (3R)-3-(((methylsulfonyl)(phenyl)amino)methyl)-1-piperazinecarboxylate (0.425 g, 1.15 mmol, step 4), 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.411 g, 1.47 mmol, Intermediate D), DIPEA (0.602 mL, 3.45 mmol) and 1,4-dioxane (5 mL). The vial was sealed and the reaction mixture was heated at 100° C. for 20 h. The reaction mixture was allowed to cool to room temperature and partitioned between water (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (2×30 mL). The combined organic phases were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 0 to 50% EtOAc in hexanes) to afford tert-butyl (3R)-3-(((methylsulfonyl)(phenyl)amino)methyl)-4-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-1-piperazinecarboxylate (0.464 g) as a light-brown solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12]([CH3:14])=O)[N:9]=[C:8]([NH2:15])[N:7]=1.SC[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[C:10]([S:12][CH2:14][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:9]=[C:8]([NH2:15])[N:7]=1
Reactant: CS(=O)c1cc(-c2ccco2)nc(N)n1
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(SCCc2ccccn2)cc(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 299 (M+H+, 100), 194 (98), 106 (70).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[CH:5][C:4]=1[OH:12].[CH3:13]C(O)=O>CO.[Pd]>[CH3:1][N:2]1[C:3]2[C:4]([OH:12])=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=[CH:13]1
Reactant: CNc1c(O)cccc1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CO
Product: Cn1cnc2cccc(O)c21

Procedure:
2-Methylamino-3-nitrophenol (1.00 g, 5.98 mmol) in MeOH (100 mL) with HOAc (0.22 mL) was hydrogenated (50 psi) for 2 hours over 10% Pd on carbon (186 mg). The catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was dissolved in formic acid and refluxed for 17 hours under N2 (g). Excess acid was removed in vacuo, and the residue was taken up in 5% MeOH in EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was taken up in 5% MeOH in EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to yield a red-brown solid which was chromatographed on silica (50-100% EtOAc/hexanes). The desired product (GC/MS m/z 148) was obtained as a yellow solid, 0.748 g; 84%.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:22])([CH3:21])[CH2:4][CH2:5][CH2:6][C:7](=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:24].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C.OS(O)(=O)=O.O>[CH2:16]([O:15][C:13](=[O:14])[C:12]([CH3:19])([CH3:18])[CH2:11][CH2:10][CH2:9][CH2:8][C:7](=[O:20])[CH2:6][CH2:5][CH2:4][C:3]([CH3:21])([CH3:22])[C:2]([OH:24])=[O:1])[CH3:17]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCC(C)(C)CO
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCCCC(=O)CCCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 46 h
Yield: 78.8 %

Procedure:
A mixture of 221 (3.26 g, 10.4 mmol) and pyridinium dichromate (14.0 g, 37.2 mmol) in DMF (45 mL) was stirred at room temperature for 46 h. The solution was diluted with 48% H2SO4 (30 mL) and water (300 mL) and extracted with ethyl acetate (5×100 mL). The combined organic layers were washed with saturated aqueous NaCl solution (5×100 mL), dried over anhydrous MgSO4, and concentrated in vacuo to give the crude product (3.19 g) as greenish oil. The crude product was subjected to column chromatography (silica gel; hexanes/ethyl acetate=3:1, 2:1), affording 223 (2.69 g, 79%) as a pale yellow oil. 1H NMR (CDCl3): δ 11.30 (br., 1H), 4.10 (q, 2H, J=7.2), 2.39 (t, 4H, J=7.2), 1.56-1.48 (m, 8H), 1.25-1.15 (m, 2H), 1.24 (t, 3H, J=7.2), 1.20 (s, 6H), 1.15 (s, 6H). 13C NMR (CDCl3): δ 210.9, 184.4, 178.1, 60.4, 43.1, 42.7, 42.2, 40.5, 39.8, 25.3, 25.0, 24.7, 24.3, 19.3, 14.4. HRMS (LSIMS, gly): Calcd for C18H33O5 (MH+): 329.2328. found: 329.2330.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([CH2:27][O:28][CH3:29])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[O:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:8][CH2:7]1)C.[BH4-].[Li+].O>O1CCCC1.CO.CCCCCC.C(OCC)(=O)C>[CH3:29][O:28][CH2:27][C:24]1[N:23]=[CH:22][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][CH2:4][OH:3])[CH2:7][N:8]=2)=[CH:19]3)=[CH:26][CH:25]=1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CCO)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
To a solution of ethyl{2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (500 mg) in tetrahydrofuran (10 mL) and methanol (15 mL) was added lithium tetrahydroborate (80 mg) at room temperature 3 times at 30 min intervals, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio), and further to silica gel column chromatography (methanol:ethyl acetate:hexane=0:0:100 to 10:90:0, volume ratio). The obtained crude product was purified by preparative HPLC to give the title compound (122 mg, yield 26%) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])=[O:6])[CH:2]=[CH2:3].[CH:25](N(C(C)C)CC)(C)C.CI>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH3:25])[CH2:20][C:19]1=[O:24])=[O:6])[CH:2]=[CH2:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCNCC1=O
Solvent: CI
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCN(C)CC1=O
Reaction time: 12 h

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-(2-oxo-piperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (6.37 g) in dichloromethane (60 ml) were added N,N-diisopropyl-N-ethylamine (3.38 ml) and methyl iodide (1.64 ml) under ice cooling with stirring, and the mixture was allowed to stay in a refrigeration for 12 hours. The mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of ethyl acetate, methanol and isopropylamine (10:1:0.3 v/v/v) to give (2S,4R)-1-allyloxycarbonyl-2-(2-oxo-4-methylpiperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (3.19 g).
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl:9][C:10]1[C:11]([NH:23][C:24]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28](CC3C=CC(OC)=CC=3)[N:27]=2)=[O:25])=[CH:12][C:13]([F:22])=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=1>FC(F)(F)C(O)=O>[Cl:9][C:10]1[C:11]([NH:23][C:24]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][N:27]=2)=[O:25])=[CH:12][C:13]([F:22])=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2nn(Cc3ccc(OC)cc3)c3ccccc23)cc1F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2n[nH]c3ccccc23)cc1F
Yield: 79.8 %

Procedure:
A mixture of anisole (288 μl, 2.66 mmol), trifluoroacetic acid (10 ml), and ethyl (5-chloro-2-fluoro-4-(1-(4-methoxybenzyl)-3-indazolylcarbonylamino)phenyl)acetate (880 mg, 1.77 mmol) was heated under reflux for 15 hours. After cooling, the reaction mixture was distilled under reduced pressure to remove the solvent. Water (50 ml) was added to the residue. The crystals thus precipitated were collected by filtration under reduced pressure and washed with water. The crude crystals thus obtained were recrystallized from chloroform-methanol, whereby ethyl (5-chloro-2-fluoro-4-(3-indazolylcarbonylamino)phenyl)acetate (531 mg, 80%) was obtained as a colorless crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].N[C@@H](C1C[CH2:22][O:21][CH2:20]C1)C(O)=O>>[CH3:1][O:2][C:3]([NH:5][CH:6]([CH:7]1[CH2:9][CH2:22][O:21][CH2:20][CH2:8]1)[C:10]([OH:12])=[O:11])=[O:4]
Reactant: N[C@H](C(=O)O)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Product: COC(=O)NC(C(=O)O)C1CCOCC1

Procedure:
2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid was synthesized similar to N-methoxycarbonyl-L-Valine, using (S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetic acid instead of L-Valine.
Reaction SMILES: O=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])=O)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:8]1([CH2:7][N:6]2[CH2:2][CH2:3][CH:4]([CH2:14][NH:16][CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:5]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NCC(F)(F)F)C1CC(=O)N(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)CNCC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A mixture of 8.50 g (28.3 mole) of 5-oxo-1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinecarboxamide in 100 ml tetrahydrofuran was added dropwise to 3.22 g (84.9 mmole) of lithium aluminum hydride in 50 ml tetrahydrofuran. The reaction was refluxed two hours, then stirred at room temperature overnight. The reaction was cooled in an ice bath and 3.2 ml of water, 3.2 ml of 15% sodium hydroxide, and 9.6 ml of water were added. The precipitated salts were filtered and washed with hot ethanol. The combined filtrates were concentrated under reduced pressure. The residue was taken up in dichloromethane, filtered, and dried over magnesium sulfate. The solvent was removed at reduced pressure to give 7.15 g of 1-(phenylmethyl)-N-(2,2,2-trifluoroethyl)-3-pyrrolidinemethanamine.