Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[C:21]([CH3:23])[CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[SH:38]>CO>[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38][CH:17]([C:18]1[S:19][CH:20]=[C:21]([CH3:23])[CH:22]=1)[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)/C(=C/c1cc(C)cs1)NC(=O)OCc1ccccc1
Reactant: Nc1ccccc1S
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Sc1ccccc1N)c1cc(C)cs1

Procedure:
The title compound was prepared according to the method of Example 94b, employing methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(4-methyl-2-thienyl)acrylate (95b) (3.38 g, 10.2 mmol), triethylamine (0.722 g, 7.14 mmol), and 2-aminothiophenol (6.43 g, 51.4 mmol) in anhydrous methanol (41 mL). The crude product was crystallized from 4:1 (v/v) petroleum ether/ether affording the title compound (2.74 g, 59%) as a pale yellow solid. 1H NMR (300 MHz, d6-DMSO) δ2.04 (s, 3H), 3.38 (s, 3H), 4.56 (t, 1H, J=8.3 Hz), 4.85 (d, 1H, J=7.9 Hz), 5.09 (m, 2H), 5.42 (bs, 2H), 6.36 (t, 1H, J=7.5 Hz), 6.56 (s, 1H), 6.65 (d, 1H, J=7.9 Hz), 6.94-7.02 (m, 3H), 7.30-7.42 (m, 5H), 8.21 (d, 1H, J=9.3 Hz). MS APCI, m/z=457 (M+1). LC/MS: 2.64 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:38]=[CH:37][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34](O)=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:68]1([CH2:73][C@H:74]([C:76]([OH:78])=[O:77])[NH2:75])[CH2:72][CH2:71][CH2:70][CH2:69]1.[BH4-].[Na+]>CN(C=O)C.CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:75][C@@H:74]([C:76]([OH:78])=[O:77])[CH2:73][CH:68]3[CH2:69][CH2:70][CH2:71][CH2:72]3)=[O:35])=[O:31])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: N[C@H](CC1CCCC1)C(=O)O
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@H](CC1CCCC1)C(=O)O
Reaction time: 1.5 h
Yield: 0 %

Procedure:
To a solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.05 g, 0.092 mmol) and N-methyl morpholine (0.037 g, 0.37 mmol) in DMF (2 ml), under an atmosphere of nitrogen, was added TBTU (0.039 g, 0.12 mmol). After 1.5 h, 3-cyclopentyl-D-alanine (0.022 g, 0.139 mmol) was added. The reaction was allowed to stir for 1 h after which water (1 ml) was added. After 10 minutes, MeOH (2 ml) and NaBH4 (0.035 g, 0.925 mmol) were added. Full conversion to the corresponding alcohol was achieved within 5 minutes. The reaction was quenched by the addition of 0.1M NH4OAc buffer (2 ml) and the product was isolated by preparative HPLC of the mixture (eluent 0-50% CH3CN in 0.1M NH4OAc buffer). Freeze drying of pure fractions afforded the desired compound (0.031 g, 49%) as a colourless solid. m/z: 680.7 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 0.97-1.10 (m, 2H), 1.38-1.81 (m, 9H), 2.84-2.94 (m, 2H), 3.77 (d, 2H), 4.11-4.16 (m, 1H), 4.25-4.28 (m, 1H), 4.51 (s, 2H), 4.69-4.75 (m, 1H), 5.03-5.06 (m, 1H), 6.97-7.37 (m, 12H), 8.02-8.06 (m, 1H), 8.22 (t, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[CH3:11])=[CH:6][C:5]=1[N+:14]([O-])=O>CO.CCO.[Ni]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:13])[CH3:11])=[CH:6][C:5]=1[NH2:14]
Reactant: COC(=O)c1ccc(C(C)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: CCO
Product: COC(=O)c1ccc(C(C)(F)F)cc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
A solution of 4-(1,1-difluoro-ethyl)-2-nitro-benzoic acid methyl ester (1.61 g, 6.57 mmol) in MeOH (40 mL) was treated with Nickel-raney in EtOH (400 mL) and the mixture was stirred at r.t. for 5 h under H2 (0.1 bar). The mixture was then filtered and concentrated in vacuo to give 2-amino-4-(1,1-difluoro-ethyl)-benzoic acid methyl ester (1.30 g, 6.05 mmol, 92%) as a yellow oil. ESI-MS: m/z 216 [M+H]+, rt 6.30 min.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[C:17](=O)[C:18]([NH2:20])=O)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[CH3:7][C:8]1[NH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]=1[CH2:17][CH2:18][NH2:20]
Reactant: Cc1[nH]c2ccccc2c1C(=O)C(N)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1[nH]c2ccccc2c1CCN
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of LiAlH4 (17 g, 445 mmol) in dry THF(1000 mL) is cooled to 0° C. and 2-methylindole-3-glyoxylamide (30 g, 148 mmol) is added in portions over 30 min. The mixture is stirred at room temperature for 30 min. and then maintained at reflux for 3 h. The reaction is cooled to 0° C. and treated with H2O (17 ml), 15% NaOH (aq., 17ml) and H2O (51 ml). The mixture is treated with MgSO4, filtered and the filtrate evaporated to give 2-methyltryptamine which is dissolved in MeOH. Methyl 4-formylcinnamate (16.9 g, 88.8 mmol) is added to the solution, followed by NaBH3CN (8.4 g) and AcOH (1 equiv.). After 1 h the reaction is diluted with NaHCO3 (aq.) and extracted with EtOAc. The organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by chromatography to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester. The ester is dissolved in MeOH, 1.0 M HCl/dioxane (1–1.5 eqiv.) is added followed by Et2O. The resulting precipitate is filtered and the solid washed with Et2O and dried thoroughly to give 3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-(2E)-2-propenoic acid methyl ester hydrochloride. 1.0 M NaOH (aq., 85 mL) is added to an ice cold solution of the methyl ester hydrochloride (14.9 g, 38.6 mmol) and HONH2 (50% aq. solution, 24.0 mL, ca. 391.2 mmol). After 6 h, the ice cold solution is diluted with H2O and NH4Cl (aq., 0.86 M, 100 mL). The resulting precipitate is filtered, washed with H2O and dried to afford N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide (m/z 350 [MH+]).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:23][CH3:24])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:20]([F:22])[F:21])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:26]([O:28][CH3:29])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:29][O:28][C:26](=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:23][CH3:24])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH:20]([F:22])[F:21])[CH:11]=3)=[CH:4][CH:3]=1
Reactant: CCn1c(-c2ccc(N)cc2)c(C#N)c2ccc(OC(F)F)cc21
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1c(-c2ccc(NC(=O)OC)cc2)c(C#N)c2ccc(OC(F)F)cc21
Reaction time: 8 h

Procedure:
A solution of 2-(4-aminophenyl)-6-difluoromethoxy-1-ethyl-1H-indole-3-carbonitrile (200 mg, 0.611 mmol) and methyl chloroformate (95 μL, 1.23 mmol) in ethyl acetate (2 mL) is treated with 2 M aqueous potassium carbonate solution (0.370 mL, 0.74 mmol), and the resulting mixture is stirred vigorously overnight. Saturated brine solution (1 mL) is added, and the mixture is stirred for 10 minutes. The organic layer is removed, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting solid is triturated with 1/1 ether-hexane, collected by filtration and dried under vacuum to afford the title product as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C1(C([O:28][C:29]([C:31]2[N:32]3[CH:35]([CH2:36][CH2:37][C:38]=2[S:39][C:40]2[S:41][CH:42]=[N:43][N:44]=2)[C@@H:34]([NH:45][C:46](=[O:76])/[C:47](/[C:69]2[N:70]=[C:71]([NH2:75])[S:72][C:73]=2[Cl:74])=[N:48]\[O:49]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:33]3=[O:77])=[O:30])C2C=CC=CC=2)C=CC=CC=1>ClCCl>[NH2:75][C:71]1[S:72][C:73]([Cl:74])=[C:69](/[C:47](=[N:48]/[OH:49])/[C:46]([NH:45][C@H:34]2[C:33](=[O:77])[N:32]3[CH:35]2[CH2:36][CH2:37][C:38]([S:39][C:40]2[S:41][CH:42]=[N:43][N:44]=2)=[C:31]3[C:29]([OH:30])=[O:28])=[O:76])[N:70]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(Sc4nncs4)CCC23)c(Cl)s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(/C(=N/O)C(=O)N[C@H]2C(=O)N3C(C(=O)O)=C(Sc4nncs4)CCC23)c(Cl)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A solution of trifluoroacetic acid (5 mL), triethylsilane (3 mL) and dichloromethane (8 mL) was cooled to 0° C. and (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino]acetamido]-3-[1,3,4-thiadiazol-2-ylthio]-8-oxo-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylate diphenylmethyl ester (1.5 g) was added in portions. The reaction mixture was stirred at 0° C. for 3 hours, was allowed to warm up to room temp. and was evaporated to dryness. The residue was treated with diethyl ether (50 mL), and the solid that formed was filtered and dried to give the crude product. The crude product was purified on HP 20 initially with water elution until the pH was neutral, and thereafter with acetonitrile:water 80:20 to give the title compound (0.63 g.)
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].[Cl:32][CH2:33][C:34]1[N:39]=[C:38]([C:40](O)=[O:41])[CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[Cl:32][CH2:33][C:34]1[N:39]=[C:38]([C:40]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)=[O:41])[CH:37]=[CH:36][CH:35]=1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=C(O)c1cccc(CCl)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.8 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide (100 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (3 mL), 6-(chloromethyl)picolinic acid (50 mg, 0.29 mmol, 1.25 equiv), EDC.HCl (67 mg, 0.35 mmol, 1.50 equiv), and 4-dimethylaminopyridine (43 mg, 0.35 mmol, 1.51 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The mixture was concentrated under vacuum to give 170 mg (75%) of product as a
Reaction SMILES: C(S([C:16]1[CH:32]=CC=C[C:17]=1[O:18][C:19]1C=C[CH:22]=[CH:21][C:20]=1S([O-])(=O)=O)(=O)=O)CCCCCCCCCCC.[Na+].[OH2:34]>>[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:34])[CH:16]=[CH2:32]
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccccc1Oc1ccccc1S(=O)(=O)[O-]
Reactant: O
Agent: [Na+]
Product: C=CC(=O)OCCCC

Procedure:
Emulsifier solution 1: 45% strength by weight solution of sodium (dodecylsulfonylphenoxy)benzenesulfonate (Dowfax® 2 A1 from Dow Chemicals) in water
Reaction SMILES: [F:1][C:2]1[C:19]2[C:18](F)([F:20])[C:17]3[C:16](F)([F:22])[C:15]4[C:10](=[C:11]([F:27])[C:12]([F:26])=[C:13]([F:25])[C:14]=4[F:24])[C:9](F)([F:28])[C:8]=3[C:7](F)([F:30])[C:6]=2[C:5]([F:32])=[C:4]([F:33])[C:3]=1[F:34].FC1C2C(F)(F)C3C(=C(F)C4C(C=3F)=C(F)C(F)=C(F)C=4F)C(F)(F)C=2C(F)=C(F)C=1F>>[F:20][C:18]1[C:17]2[C:8]([C:7]([F:30])=[C:6]3[C:19]=1[C:2]([F:1])=[C:3]([F:34])[C:4]([F:33])=[C:5]3[F:32])=[C:9]([F:28])[C:10]1[C:15](=[C:14]([F:24])[C:13]([F:25])=[C:12]([F:26])[C:11]=1[F:27])[C:16]=2[F:22]
Reactant: Fc1c(F)c(F)c2c(c1F)C(F)(F)C1=C(C2(F)F)C(F)(F)c2c(F)c(F)c(F)c(F)c2C1(F)F
Agent: Fc1c(F)c(F)c2c(c1F)C(F)(F)c1c(c(F)c3c(F)c(F)c(F)c(F)c3c1F)C2(F)F
Product: Fc1c(F)c(F)c2c(F)c3c(F)c4c(F)c(F)c(F)c(F)c4c(F)c3c(F)c2c1F

Procedure:
compounds (8) and/or (9) are/is reacted with a reducing agent so as to obtain compound (10). That is, as shown in scheme 6, 1,2,3,4,5,5,6,6,7,8,9,10,11,11,12,12-hexadecafluoro-5,6,11,12-tetrahydronaphthacene (8) is reacted with a reducing agent so that it is partially defluoridated so as to obtain dodecafluoronaphthacene (10). Also, s shown in scheme 7, 1,2,3,4,5,5,6,7,8,9,10,11,12,12-tetradecafluoro-5,12-dihydronaphthacene (9) is reacted with a reducing agent so that it is partially defluoridated so as to obtain dodecafluoronaphthacene (10).
Reaction SMILES: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)S([O-])(=O)=O.[C:18]1([CH3:39])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S+:24]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:38])[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]1=2.[OH-].[Na+].[F:42][C:43]([F:59])([F:58])[C:44]1[CH:45]=[C:46]([S:54]([OH:57])(=[O:56])=[O:55])[CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1>CO.O>[F:53][C:50]([F:51])([F:52])[C:48]1[CH:47]=[C:46]([S:54]([O-:57])(=[O:56])=[O:55])[CH:45]=[C:44]([C:43]([F:59])([F:42])[F:58])[CH:49]=1.[C:18]1([CH3:39])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S+:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31](=[O:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:37]1=2
Reactant: O=S(=O)(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cc1ccccc1-[s+]1c2ccccc2c(=O)c2ccccc21
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(=O)([O-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 114.5 %

Procedure:
This compound was synthesized using 1.5 g of 10-tolyl-9-oxothioxanthenium nonafluorobutanesulfonate (Z-1) obtained in Synthesis Example 1. 10-Tolyl-9-oxothioxanthenium nonafluorobutanesulfonate (1.5 g) was dissolved in a methanol/water (=1/1) solution, and the resulting solution was passed through an ion exchange resin (Amberlite IRA402C1 in which the anion is replaced by OH with use of aqueous NaOH). After adding 1 g of 3,5-bistrifluoromethylbenzenesulfonic acid thereto, the solution was extracted with chloroform to obtain 1.7 g of 10-tolyl-9-oxothioxanthenium 3,5-bistrifluoromethylbenzene-sulfonate (Z-2) as a compound changed in the counter salt.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:22]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:25]4[CH2:26][CH2:27][N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:24]4)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)CC1
Yield: 90.5 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.28 g, 0.97 mmol) and tert-butyl piperazine-1-carboxylate (0.182 g, 0.97 mmol) according to the example 1, which was given tert-butyl 4-(2-(4-(adamantan-1-yl)phenoxy)acetyl)piperazine-1-carboxylate as a white solid (0.399 g, 90.0% yield).
Reaction SMILES: [C:1]1(=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd]>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCCC=C1CCCCC1
Agent: [Pd]
Product: OCCCCCCC1CCCCC1
Yield: 95.9 %

Procedure:
A solution of 6-cyclohexylidene-hexan-1-ol (1.05 g, 5.77 mmol) in MEOH (40 mL) was hydrogenated with Pd—C (0.23 g, 10% w/w) in a Parr apparatus at 50 psi of H2 overnight. The catalyst was removed by filtration, and the filtrate was evaporated under reduced pressure to give 6-cyclohexyl-hexan-1-ol (1.02 g, 96%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.63 (2H, t, J=6.6 Hz), 1.46–1.80 (7H, m), 1.04–1.44 (12H, m), 0.86 (2H, m); 13C NMR (75 MHz, CDCl3) δ 63.33, 37.92, 37.74, 33.72, 33.08, 30.04, 27.10, 27.04, 26.73, 26.05.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12.Br[CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][O:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:12][CH:13]3[CH2:17][CH2:16][CH2:15][O:14]3)[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: BrCC1CCCO1
Reactant: Ic1ccnc2cn[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1ccnc2cn(CC3CCCO3)nc12
Yield: 64 %

Procedure:
7-Iodo-1H-pyrazolo[4,3-b]pyridine (50 mg, 0.204 mmol), 2-(bromomethyl)tetrahydrofuran (33.7 mg, 0.204 mmol) and cesium carbonate (133 mg, 0.408 mmol) in DMF (1.0 mL) were heated in a microwave 80° C. for 15 minutes. The reaction was cooled, poured into water (10 mL) and extract with ethyl acetate (5 mL). The organics were dried over sodium sulfate, filtered and concentrated to provide 7-iodo-2-((tetrahydrofuran-2-yl)methyl)-2H-pyrazolo[4,3-b]pyridine (43 mg) which was used as is without further purification. MS [M+H] found 330.1.
Reaction SMILES: [Cl:1][C:2]1[CH:60]=[CH:59][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][O:27]C5CCCCO5)[CH:19]=4)[CH2:16][N:15]([CH2:34][CH2:35][S:36]([N:39](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)(=[O:38])=[O:37])[C:14]3=[O:58])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][OH:27])[CH:19]=4)[CH2:16][N:15]([CH2:34][CH2:35][S:36]([NH2:39])(=[O:37])=[O:38])[C:14]3=[O:58])=[CH:9][CH:8]=2)=[CH:59][CH:60]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)CCN2C[C@H](c3cccc(OCCOC4CCCCO4)c3)N(c3ccc(Oc4ccc(Cl)cc4)cc3)C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)CCN1C[C@H](c2cccc(OCCO)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.7 %

Procedure:
A solution of 2-((4S)-3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)phenyl)imidazolidin-1-yl)-N,N-bis(4-methoxybenzyl)-ethane-sulfonamide (40 mg, 0.046 mmol) in TFA (1 mL) is stirred at room temperature for 2 h and is then concentrated. The residue is dissolved in MeOH (1 mL) and NaOH (0.09 mmol, 1M aqueous solution) is added. The mixture is stirred at room temperature for 14 h and is treated with water (3 mL) and extracted with EtOAc (3×3 ml). The combined organic layers are concentrated and purified by flash column chromatography (silica gel, 0-100% EtOAc/hexane) to provide the title compound as a white solid (20 mg, 81%). 1H NMR (CDCl3, 400 MHz) δ 7.21-7.28 (m, 5H), 6.81-6.97 (m, 7H), 5.67 (s, 2H), 5.16 (dd, J=9.2, 6.8 Hz, 1H), 3.98-4.08 (m, 2H), 3.92 (m, 3H), 3.75-3.80 (m, 2H), 3.26-3.41 (m, 3H), 2.37 (br s, 1H); HPLC-MS calculated for C25H26ClN3O6S (M+H+) 532.1, found 532.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.Cl.[O:28]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29]1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[O:18][CH:15]1[CH2:16][CH2:17][N:12]([C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]=[CH:8][C:6]3=[N:7][C:2]=2[NH:33][C@H:30]2[CH2:31][CH2:32][O:28][CH2:29]2)[CH2:13][CH2:14]1
Reactant: N[C@H]1CCOC1
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1ccc(OC2CCN(c3nc4ccncc4nc3N[C@H]3CCOC3)CC2)c(F)c1
Temperature: 70 °C
Reaction time: 14 h
Yield: 70.5 %

Procedure:
To a mixture of 3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (2.5 g, 6.64 mmol) in DMF (30 mL) was added (S)-tetrahydrofuran-3-amine hydrochloride (4.10 g, 33.2 mmol) and Et3N (9.25 mL, 66.4 mmol) at room temperature. The reaction mixture was stirred at 70° C. for 14 h then cooled to room temperature and diluted with EtOAc (80 mL), washed with water (30 mL) and brine (2×30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo, then the residue was purified by column chromatography (petroleum ether:EtOAc from 10:1 to 1:1) on silica gel to give the title compound as a yellow solid (2.0 g). ESI-MS m/z [M+H]+ 428.1.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>CS(C)=O.CCOCC>[F:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(F)cc(F)c1
Reactant: COc1ccc(CN)cc1
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc(F)cc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A mixture of 3,5-difluoro-benzonitrile (2.78 g, 20 mmol) and p-methoxybenzyl amine (5.74 ml, 44 mmol) in DMSO (20 ml) was stirred for 8 hr. in an oil bath (100-110° C.). After cooling to room temperature, the mixture was diluted with ether, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA: hexane (from 1:13 to 1:10)) to afford 3.92 g (76%) of a white solid. m.p. 93-94° C.; 1H NMR (200 MHz, CDCl3) δ 3.61 (3H, s), 4.04 (2H, s); 4.16 (1H, br. s), 6.27 (1H, m), 6.42-6.47 (2H, m), 6.69 (2H, d, J=7.2 Hz), 7.06 (2H, d, J=7.2 Hz).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[C:5][CH2:6][Cl:7].[C:8](OCC)(=[O:10])[CH3:9].C(OC(=O)C)(=O)C>C([O-])(=O)C.[Na+]>[C:8]([NH:2][CH2:3][C:4]#[C:5][CH2:6][Cl:7])(=[O:10])[CH3:9]
Reactant: CCOC(C)=O
Reactant: NCC#CCCl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCC#CCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Amino-4-chloro-2-butyne hydrochloride (59.75 g) was dissolved in 10% aqueous sodium acetate-solution (335 ml). Ethyl acetate (500 ml) was added, and acetic anhydride (70 ml) was added dropwise at room temperature. A 25% aqueous sodium acetate solution was added to pH 5 and the solution was stirred for 30 min at room temperature. The ethyl acetate layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulphate, filtered and evaporated in vacuo yielding 1-acetylamino4-chloro-2-butyne as a yellow syrup (58.8 g).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[C:11]([OH:17])=[N:12][CH:13]=[N:14][C:15]=1[OH:16].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[OH:17][C:11]1[C:10]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:15]([OH:16])[N:14]=[CH:13][N:12]=1
Reactant: SCc1ccccc1
Reactant: Oc1ncnc(O)c1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ncnc(O)c1SCc1ccccc1
Temperature: 100 °C
Yield: 47 %

Procedure:
Benzylmercaptan (6 ml, 0.05 mole) was added to a stirred and heated (90°) suspension of 5-bromo-4,6-dihydroxypyrimidine (9.5 g, 0.05 mole) and potassium carbonate (7.5 g, 0.055 mole) in dimethylformamide (25 ml). The reaction mixture was stirred and heated at 95-105° C. under an atmosphere of dry nitrogen for 3.5 hours. The mixture was poured into ice cold water (400 ml) with vigorous stirring and then acidified to pH 1 with hydrochloric acid. After stirring for 0.5 hours the suspension was filtered and the solid which was collected was rinsed several times with n-hexane and diethyl ether. The remaining brown solid was air dried to give 4,6-dihydroxy-5-benzylthiopyrimidine (5.5 g 50%) PMR spectrum: (d6DMSO) 3.96 (S, 2h); 7.2 (bm, 5H); 8.11 (s, 1H); 12.2 (bs, 2H).