Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH3:11])[C@@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4].C(N(CC)CC)C.[C:19]([Si:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:23]([CH:9]([OH:10])[C@H:7]1[O:8][C@@H:2]([O:1][CH3:11])[C@H:3]([OH:4])[C@@H:5]1[OH:6])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a mixture of methyl β-D-ribofuranoside (Sigma Chemical Co., 460 mg, 2.8 mmol) and anhydrous methylene chloride (20 ml) were added triethylamine (0.468 ml, 3.36 mmol), t-butyldiphenylchlorosilane (0.9 ml, 3.46 mmol), and DMAP (13.7 mg, 0.112 mmol) successively at room temperature. The reaction mixture was stirred for 18 h at room temperature under nitrogen. The reaction mixture was washed with water (20 ml), saturated ammonium chloride (20 ml), and brine (20 ml), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was separated by silica gel column chromatography (CHCl3 --MeOH, 50:1) to yield 1-O-methyl 5-(t-butyldiphenylsilyl)-β-D-ribofuranoside [Rf =0.48 (CHCl3 --MeOH, 10:1), 618 mg, 54.8%] as a thick syrup. 1H NMR (DMSO-d6) d 0.96 (s, 9H, t-Bu), 3.22 (s, 3H, --OCH3), 3.61 (dd, J=11.0 and 5.3 Hz, 1H), 3.74 (d, J=4.4 Hz, 1H), 3.81 (dd, J=11.0 and 2.7 Hz, 1H), 3.90 (m, 1H), 4.00 (m, 1H), 4.68 (s, 1H, H-1'), 4.84 (br s, 1H, exchangeable with D2O, OH), 5.05 (br s, 1H, exchangeable with D2O, OH), 7.45 and 7.67 (m, 10H, Ph2). Anal. Calcd for C22H30O5Si: C, 65.64; H, 7.51; Found: C, 65.73; H, 7.55.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]O)=[CH:8][C:7](=[O:27])[CH2:6][CH2:5]1.C(Cl)(Cl)(Cl)[Cl:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Cl:29][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C@@H:11]1[CH2:10][C:9]2[C@H:4]([CH2:5][CH2:6][C:7](=[O:27])[CH:8]=2)[C@@H:3]2[C@@H:12]1[C@H:13]1[C@@:17]([CH2:19][C@@H:2]2[F:1])([CH3:18])[C:16](=[O:20])[CH2:15][CH2:14]1
Reactant: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[C@]12C[C@H](F)[C@H]3[C@@H]([C@H](CCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O

Procedure:
A solution of 78.7 g of 11β-fluoro-7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione (Example 12e) in 1.41 of carbon tetrachloride and 475 ml of acetonitrile is stirred with 71 g of triphenylphosphine for 8.5 hours at room temperature. Then, it is extracted with water, aqueous sodium bicarbonate and common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. 48.0 g of 7α-(5-chloropentyl)-11β-fluoro-estr-4-ene-3,17-dione is obtained as crystals with a melting point of 51-53° C. [α]D22 =+78.5° (c=0.5% in chloroform).
Reaction SMILES: [CH2:1]([N:4]([CH2:42][CH2:43][CH3:44])[C:5]([C:7]1[CH:8]=[C:9]([CH:39]=[CH:40][CH:41]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[CH:38]=CC=C[CH:34]=1)[CH2:14][NH:15][C@H:16]([C:18]([NH:20][C@H:21]([C:25]([NH:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH3:17])=[O:11])=[O:6])[CH2:2][CH3:3].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(OCC)(=O)C.CO>[CH2:42]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:39]=[CH:40][CH:41]=1)[C:10]([NH:12][C@@H:13]([CH2:32][CH:33]([CH3:38])[CH3:34])[CH2:14][NH:15][C@H:16]([C:18]([NH:20][C@H:21]([C:25]([NH:27][CH2:28][CH:29]([CH3:30])[CH3:31])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[CH3:17])=[O:11])=[O:6])[CH2:43][CH3:44]
Reactant: CCCN(CCC)C(=O)c1cccc(C(=O)N[C@H](CN[C@@H](C)C(=O)N[C@H](C(=O)NCC(C)C)C(C)C)Cc2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(CCC)C(=O)c1cccc(C(=O)N[C@H](CN[C@@H](C)C(=O)N[C@H](C(=O)NCC(C)C)C(C)C)CC(C)C)c1
Reaction time: 72 h
Yield: 32.1 %

Procedure:
(290 mg, 0.84 mmol) in 6 mL of dry THF is added to L-alanyl-N1-isobutyl-L-valinamide (EXAMPLE 1, 205 mg, 0.84 mmol) under nitrogen. To this is added 0.12 mL of acetic acid and sodium triacetoxyborohydride (300 mg, 1.41 mmol), and the mixture is stirred for 3 days. Methanol (1 mL) is added. And the mixture is stirred for 3 more hours. It is diluted with 150 mL of ethyl acetate and 5 mL of methanol, and the organic phase is washed successively with 15 mL of 1 N NaHCO3, water, and brine. The solution is dried with Na2SO4, concentrated, and chromatographed over silica gel. Elution with 4% methanol in dichloromethane, followed by 8% methanol in dichloromethane, afforded the title compound as a white solid (154 mg, 0.27 mmol, 32%). 1H NMR (CDCl3) δ 7.88 (m, 1H), 7.78 (m, 2H), 7.44 (m, 2H), 7.00 (d, J=8 Hz, 1H), 6.69 (br t, J=6 Hz, 1H), 4.14 (dd, J=7, 9 Hz, 1H), 4.04 (m, 1H), 3.46 (m, 2H), 3.16-3.04 (m, 5H), 2.87 (m, 1H), 2.64 (dd, J=4, 13 Hz, 1H), 2.03 (m, 1H), 1.75-1.63 (m, 5H), 1.53 (m, 2H), 1.39 (m, 1H), 1.30 (d, J=7 Hz, 3H), 1.0-0.83 (m, 21H), 0.74 (br t, J=7 Hz, 3H). HRMS (ESI) calcd for C32H55N5O4+H1 574.4332, found 574.4332.
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]2[O:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:13]=2[C:26]=1[CH3:27])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[C].[Pd]>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:14]2[C:13]3[C:26]([CH3:27])=[C:9]([NH2:8])[C:10]([CH3:29])=[C:11]([CH3:28])[C:12]=3[O:16][CH2:15]2)=[CH:18][CH:19]=1)([CH3:25])[CH3:24]
Reactant: Cc1c(C)c2c(c(C)c1NCc1ccccc1)C(c1ccc(C(C)C)cc1)CO2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)CO2
Yield: 74 %

Procedure:
A mixture of N-benzyl-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 24 (900 mg, 2.33 mmol), 10%-palladium carbon (50% hydrous, 90 mg) and ammonium formate (294 mg, 4.66 mmol) in ethanol (10 mL) was heated under reflux for 2 hours. The solid material was removed and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was crystallized from ethyl acetate-hexane to obtain 510 mg (yield 74%) of the title compound. Melting point: 171-173° C.
Reaction SMILES: NC1C=C(F)C(F)=CC=1C(NCC(NCC1CCNCC1)=O)=O.C(OC(NC1C=CC(OC(F)(F)F)=CC=1C(NCC(NCC1CCNCC1)=O)=O)=O)(C)(C)C.N1CCCCC1.C(OC([NH:70][C:71]1[CH:90]=[CH:89][C:88]([C:91]([F:94])([F:93])[F:92])=[CH:87][C:72]=1[C:73]([NH:75][CH2:76][C:77]([NH:79][CH2:80][CH:81]1[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]1)=[O:78])=[O:74])=O)(C)(C)C>>[NH2:70][C:71]1[CH:90]=[CH:89][C:88]([C:91]([F:94])([F:92])[F:93])=[CH:87][C:72]=1[C:73]([NH:75][CH2:76][C:77]([NH:79][CH2:80][CH:81]1[CH2:82][CH2:83][NH:84][CH2:85][CH2:86]1)=[O:78])=[O:74]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Solvent: C1CCNCC1
Product: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)NCC1CCNCC1

Procedure:
4-[{(N-(2-Amino-4,5-difluorobenzoyl)glycyl)amino}methyl]piperidine, 4-[{N-(2-(tert-Butoxycarbonylamino)-5-trifluoromethoxybenzoyl)glycyl}aminomethyl]piperidine, 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl)amino}methyl]piperidine, and 4-[{(N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl)amino}methyl]piperidine were also prepared pursuant to the above method using the corresponding reactant, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(N)CCCCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Br)cc2)cc1
Solvent: NC1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Br)cc2)cc1
Yield: 70 %

Procedure:
Prepared analogous to Example 25 from 4-(4'-bromo-4-biphenylyl)-4-oxo-butyric acid. Yield: 70% of theory; m.p. 127° C. Melting point of the cyclohexylamine salt: 193° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-thiazol-2-yl-benzylamino-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and 4-chlorobenzenesulfonyl chloride following the method described in Example 3, Step B with a reaction time of 96 h. MS 584 (M+1).
Reaction SMILES: S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1N=C(C(O)=O)C(CCCOC3C=CC(N4CCN(C)CC4)=CC=3)=CC=1)CC2)=O.[S:49]1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[N:51]=[C:50]1[NH:58][C:59]([C:61]1[CH:62]=[CH:63][CH:64]=[C:65]2[C:70]=1[CH2:69][N:68]([C:71]1[N:76]=[C:75]([C:77]([O:79]C(C)(C)C)=[O:78])[C:74]([CH2:84][CH2:85][CH2:86][O:87][C:88]3[CH:93]=[CH:92][C:91]([NH:94][CH:95]4[CH2:100][CH2:99][N:98]([CH3:101])[CH2:97][CH2:96]4)=[CH:90][CH:89]=3)=[CH:73][CH:72]=1)[CH2:67][CH2:66]2)=[O:60]>>[S:49]1[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][C:52]=2[N:51]=[C:50]1[NH:58][C:59]([C:61]1[CH:62]=[CH:63][CH:64]=[C:65]2[C:70]=1[CH2:69][N:68]([C:71]1[N:76]=[C:75]([C:77]([OH:79])=[O:78])[C:74]([CH2:84][CH2:85][CH2:86][O:87][C:88]3[CH:89]=[CH:90][C:91]([NH:94][CH:95]4[CH2:100][CH2:99][N:98]([CH3:101])[CH2:97][CH2:96]4)=[CH:92][CH:93]=3)=[CH:73][CH:72]=1)[CH2:67][CH2:66]2)=[O:60]
Reactant: CN1CCC(Nc2ccc(OCCCc3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)OC(C)(C)C)cc2)CC1
Agent: CN1CCN(c2ccc(OCCCc3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)CC1
Product: CN1CCC(Nc2ccc(OCCCc3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)CC1

Procedure:
The title compound 104 was prepared in a similar manner to the synthesis of compound 94 by substituting compound 94G with compound 104B: 1H NMR (DMSO-d6): δ 12.84 (s, 1H), 9.40 (s, 1H), 8.04 (d, J=7.63 Hz, 1H), 7.79 (d, J=8.24 Hz, 1H), 7.60 (d, J=7.32 Hz, 1H), 7.55 (d, J=8.85 Hz, 1H), 7.34-7.49 (m, 4H), 6.96 (d, J=8.85 Hz, 1H), 6.60-6.79 (m, 1H), 4.92 (s, 2H), 3.81-3.88 (m, 4H), 2.97-3.00 (m, 4H), 2.74-2.80 (m, 4H), 2.10-2.13 (m, 2H), 1.87-1.92 (m, 4H) ESI (+)/MS: 677 (M+H)+.
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CC(O)C.[C]=O.[C:16]([O:19][CH:20]([CH2:27][CH2:28][S:29][CH3:30])[C:21]([O:23][CH:24](C)C)=O)(=[O:18])[CH3:17]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:16]([O:19][CH:20]([CH2:27][CH2:28][S:29][CH3:30])[C:21]([O:23][CH3:24])=[S:8])(=[O:18])[CH3:17]
Reactant: CSCCC(OC(C)=O)C(=O)OC(C)C
Reactant: CSCC=COC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 100 °C
Yield: 10.1 %

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene, (Z: E ratio 43:57), and 2.5 mmoles 2-propanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. Ten mole percent, based on 1-acetoxy-3-methylthiopropene, of a catalyst comprising bis(triphenylphosphine)dichloropalladium, (φ3P )2PdCl2, was added. Toluene was included as an internal standard Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 100° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that 2-acetoxy-4-(methylthio)butanoic acid, 2-propyl ester was produced in a yield of 4.7 percent, and that 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced in a yield of 10.1 percent, based on the 1-acetoxy-3-methylthiopropene reactant charged. Note that each of the products is hydrolyzable to methionine hydroxy analog.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[OH-].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][C:14](=O)[CH2:13][CH2:12]2>O>[CH3:20][O:19][C:18]1[CH:17]=[C:16]2[C:11](=[CH:10][C:9]=1[O:8][CH3:7])[CH2:12][C:13](=[N:4][O:2][CH3:3])[CH2:14][CH2:15]2
Reactant: COc1cc2c(cc1OC)CC(=O)CC2
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C1CCc2cc(OC)c(OC)cc2C1
Yield: 89.1 %

Procedure:
A mixture of 0.56 g (6.7 mmol) of methoxylamine hydrochloride and 6.5 ml (6.5 mmol) of a 1 M aqueous solution of NaOH was added to 0.689 g (3.34 mmol) of 6,7-dimethoxy-2-tetralone (IV). While under a nitrogen atmosphere the mixture was warmed to ca. 100° for 15 minutes and then kept at 40° using an infrared lamp for 18 hours. Water was added to the mixture which was then extracted with ether. The combined extracts were dried (MgSO4) and the solvent was removed on a rotary evaporator, affording 0.700 g (89.2%) of brown oil: nmr (CDCl3) δ2.3-2.9 (m, 4H), 3.32 (S, 1H), 3.57 (S, 1H), 3.73 (S, 6H), 3.78 (S, 3H), 6.4-6.6 (m, 2H). The compound was used without further purification.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cc(Br)ccc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccc1F

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 5-bromo-2-fluorobenzenesulfonamide (231 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (180 mg, 35%). MS (ISP) 587.2[(M+H)+]; mp 247-249° C.
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=C(OC)C=2)O)=CC=1[N+]([O-])=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28](Br)[CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33].[Mg].[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([N+:48]([O-:50])=[O:49])=[C:44]([CH:47]=1)[CH:45]=[O:46]>>[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([N+:48]([O-:50])=[O:49])=[C:44]([CH:45]([C:28]2[CH:27]=[C:26]([O:25][CH3:24])[C:31]([O:32][CH3:33])=[C:30]([O:34][CH3:35])[CH:29]=2)[OH:46])[CH:47]=1
Reactant: COc1ccc([N+](=O)[O-])c(C=O)c1
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: COc1ccc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Agent: [Mg]
Product: COc1ccc([N+](=O)[O-])c(C(O)c2cc(OC)c(OC)c(OC)c2)c1
Yield: 53.6 %

Procedure:
(5-Methoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol was prepared analogously to (4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol using 3,4,5-trimethoxy-bromobenzene (4.6 g, 18.5 mmol), magnesium turning (0.5 g, 18.5 mmol) and 5-methoxy-2-nitro-benzaldehyde (2.8 g, 15.5 mmol). The crude product was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 9:1) to afford (5-methoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (2.9 g, 53%); 1H NMR (CDCl3) δ 8.08 (d, J=9 Hz, 1H), 7.20 (d, J=2 Hz, 1H), 6.91-6.87 (dd, J=3, 9 Hz, 1H), 6.57 (s, 2H), 6.45 (d, J=4 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.80 (s, 6H), 3.04 (d, J=4 Hz, 1H).
Reaction SMILES: C([S:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])C1C=CC=CC=1.S(Cl)(Cl)(=O)=O>ClCCl.CCCCCCC>[Cl:18][C:15]1[CH:16]=[CH:17][C:9]2[S:8][N:13]=[C:11]([OH:12])[C:10]=2[CH:14]=1
Reactant: NC(=O)c1cc(Cl)ccc1SCc1ccccc1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Solvent: CCCCCCC
Product: Oc1nsc2ccc(Cl)cc12
Reaction time: 1 h
Yield: 117.7 %

Procedure:
2-Benzylsulphanyl-5-chlorobenzamide (523 mg, 1.89 mmol) was dissolved in dichloromethane (20 mL) and sulphuryl chloride (0.183 mL, 3.29 mmol) added dropwise. The resultant white suspension was stirred for a further 1 h, diluted with heptane (15 mL), filtered, washed with heptane and dried under suction to afford the title compound as a white solid (413 mg, >100%).
Reaction SMILES: [Cl-].[CH:2]1([CH2:8][NH2+:9][CH2:10][CH2:11]Cl)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[N:9]([CH2:8][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:10][CH2:11][S:26]1
Reactant: COc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: ClCC[NH2+]CC1CCCCC1
Agent: [Cl-]
Product: COc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclohexylmethyl bromide according to Method B2a to give N-cyclohexylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclohexylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methoxy4-nitrophenyl isothiocyanate to give 2-(2-methoxy-4-nitrophenylimino)-3-(cyclohexylmethyl)-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH2:27]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][C:31]=1[Cl:38])[CH3:28]>O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:35][CH2:34][C:33]1[CH:36]=[CH:37][C:30]([O:29][CH2:27][CH3:28])=[C:31]([Cl:38])[CH:32]=1
Reactant: CCOc1ccc(CN)cc1Cl
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: C1COCCO1
Product: CCOc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1Cl
Yield: 68.9 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (150 mg, 0.35 mmol) with 4-ethoxy-3-chloro-benzylamine (94.7 mg, 0.51 mmol) in anhydrous 1,4-dioxane (10 mL). Purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (100:0 to 77:23 gradient) to obtain 7-chloro-6-(3-chloro-4-ethoxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (111.3 mg, 68%). MS (ES+) m/z: 483 (M+Na)+.
Reaction SMILES: N1C[C@H](O)C[C@H]1C(O)=O.[CH3:10][O:11][C:12]([C@@H:14]1[C@H:18]([OH:19])[CH2:17][CH2:16][NH:15]1)=[O:13].[Cl:20][C:21]1[C:28]([CH3:29])=[C:27]([N:30]=[C:31]=[O:32])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>C(Cl)Cl>[CH3:10][O:11][C:12]([C@@H:14]1[C@H:18]([OH:19])[CH2:17][CH2:16][N:15]1[C:31](=[O:32])[NH:30][C:27]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:20])[C:28]=1[CH3:29])=[O:13]
Reactant: COC(=O)[C@H]1NCC[C@H]1O
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Agent: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@H](O)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of hydroxyproline compound 1F (493 mg, 3.40 mmol) in CH2Cl2 (15 mL) was added 4 Å molecular sieves (˜3.0 g), followed by isocyanate 23E (725 mg, 3.22 mmol), and the resulting mixture was stirred at rt overnight, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 0.5% MeOH in EtOAc/hexane, 1:1) to afford the title compound (736 mg) as an off-white solid. HPLC column: YMC S-5 C18 (4.6×50 mm), 0% to 100% B, 4 min gradient, 1 min hold (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA), flow rate at 4 mL/min, UV detection at 220 nm, 1.57 min retention time (100%); MS (ES) m/z 338 [M+H]+.
Reaction SMILES: [OH-].[Na+:2].[Br:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][S:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]([O:22]CC)=[O:21])[C:7]2=[CH:8][CH:9]=1.O>CCO>[Br:3][C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][S:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]([O-:22])=[O:21])[C:7]2=[CH:8][CH:9]=1.[Na+:2]
Reactant: CCOC(=O)CN1C(=O)C2(CCSCC2)c2cc(Br)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])CN1C(=O)C2(CCSCC2)c2cc(Br)ccc21
Temperature: 60 °C
Reaction time: 14 h

Procedure:
5 M Sodium hydroxide solution (0.748 mL, 3.74 mmol) was added to a solution of ethyl (5-bromo-2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-thiopyran]-1(2H)-yl)acetate from Step D (479 mg, 1.25 mmol) in EtOH(2 mL) and the mixture was heated to 60° C. After 14 h, H2O (5 mL) was added to the reaction and the resulting precipitate was collected by filtration to give the desired product. MS: m/z=357 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:17][C:6]=12>S(=O)(=O)(O)O>[N+:1]([C:14]1[CH:13]=[CH:12][C:11]2[C:7]3[C:6](=[N:5][CH:10]=[CH:9][CH:8]=3)[CH2:17][C:16]=2[CH:15]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)Cc1ncccc1-2
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2c(c1)Cc1ncccc1-2
Reaction time: 1 h

Procedure:
A ca. 10° C.-cold mixture of nitric acid (65%, 1.1 mL) and sulfuric acid (96%, 1.6 mL) is added dropwise to a solution of 9H-indeno[2,1-b]pyridine (2.44 g) in sulfuric acid (96%, 3 mL) chilled in an ice bath. The solution is stirred in the cooling bath for 1 h and poured then onto crushed ice. The precipitate formed is separated by filtration and the filtrate is neutralized using 4 M aqueous NaOH solution. The precipitate formed is separated by filtration and combined with the precipitate separated before. The precipitate is triturated with acetone and dried to give the title compound as a solid. Yield: 2.64 g (85% of theory); LC (method 1): tR=2.93 min; Mass spectrum (ESI+): m/z=213 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=1.[CH3:13]CN(CC)CC.CI.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[CH:6]=1
Reactant: CCN(CC)CC
Reactant: Brc1cnn(C2CCNCC2)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1CCC(n2cc(Br)cn2)CC1
Reaction time: 0.08 h
Yield: 63.1 %

Procedure:
To a solution of 4-(4-bromo-pyrazol-1-yl)-piperidine (375 mg, 1.63 mmol) in DMF (3.26 mL) was added NEt3 (230 μL, 1.63 mmol) and stirred for 5 minutes. Methyliodide (MeI) (1.63 mL, 1M MeI in DMF, freshly made) was added and the reaction was stirred overnight at room temperature. Water was added and the solution was extracted with EtOAc (4×10 mL). The organic solution was washed with brine, dried with Na2SO4, concentrated, and dried in vacuo to afford 4-(4-bromo-pyrazol-1-yl)-1-methyl-piperidine (251 mg, 63% yield).