Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([C:31]([OH:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3([C:31]([OH:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[CH:12][CH:11]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C3(C(=O)O)CCCC3)cc2)cc1
Temperature: 150 °C

Procedure:
A mixture of (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (300 mg, 1.113 mmol), 1-(4-chlorophenyl)cyclopentanecarboxylic acid (300 mg, 1.335 mmol), Na2CO3 (472 mg, 4.45 mmol), and dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (7.88 mg, 0.011 mmol) in 1,4-dioxane (6 mL) and H2O (1.2 mL) was heated under microwave irradiation at 150° C. for 10 min. The mixture was concentrated. The residue was purified by HPLC to give the title compound. LCMS m/z=378.3 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:7][N:6]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[C:5]2=[O:22])[CH2:3][CH2:2]1.B(Cl)(Cl)Cl>C(OCC)(=O)C>[CH:1]1([N:4]2[C:8]3([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)[CH2:7][N:6]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:5]2=[O:22])[CH2:2][CH2:3]1
Reactant: COc1ccc(N2CC3(CCCCC3)N(C3CC3)C2=O)cc1
Agent: ClB(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1N(c2ccc(O)cc2)CC2(CCCCC2)N1C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
150 mg (0.5 mmol) of 1-Cyclopropyl-3-(4-methoxy-phenyl)-1,3-diaza-spiro[4.5]decan-2-one, product of example 158, was treated with 1.5 ml (1.5 mmol) of boron trichloride (1.0M solution in Heptane). The reaction mixture was stirred at RT for 20 h. The reaction mixture was then taken up in Ethyl acetate and washed with 1N HCl and water. The raw product was purified by chromatography with DCM/Ethyl acetate 9:1 to 4:1 giving 30 mg of a light brown solid. MS (ESI): 287.0 (MH+).)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([N:19]=[C:20]=[S:21])(=O)C1C=CC=CC=1>CC(C)=O>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:20]([NH2:19])=[S:21])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: NC(=S)Nc1ccc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
A solution of 5-aminoindole (8 g, 60.6 mmol) in acetone (150 mL) was reacted with benzoylisothiocyanate (9.88 g, 60. mmol) at RT for about 4 h. The resulting solid was filtered and treated with 2 N NaOH in THF (120 mL). The mixture was refluxed for about 6 h and allowed to warm to RT. The solvent was evaporated off under vacuum. The residue was diluted with water (20 mL) and neutralized to pH 7 with 1 N HCl. The resulting solid was filtered and dried under vacuum to afford 5-indolylthiourea (55-2). 5-Indolyl thiourea (0.01 mol) and ethyl bromopyruvate (0.011 mol) were dissolved in 3 mL ethanol and held at reflux for 2 h. The reaction was cooled, the crystalline ethyl 2-(1H-indol-5-ylamino)thiazole-4-carboxylate (55-3) was collected by filtration and washed with ethanol. Refluxing the mixture of ethyl esters with the NaOH-ethanol solution gave 2-(1H-indol-5-ylamino)thiazole-4-carboxylic acid (55-4) which was used directly in next steps. To a mixture of the crude acid (2.5 mmol), EDCI (2.9 mmol), HOBt (2.6 mmol) and NMM (5.3 mmol) in CH2Cl2 (30 mL) was added HNCH3OCH3HCl salt (2.6 mmol) and stirring continued at RT for overnight. The reaction mixture was diluted with CH2Cl2 (20 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 2-(1H-indol-5-ylamino)-N-methoxy-N-methylthiazole-4-carboxamide (55-5) (45.6% yield for overall 5 steps). At −78° C., to a solution of 5-bromo-1,2,3-trimethoxybenzene (1.235 g, 5.0 mmol) in 30 mL THF was charged n-BuLi in hexane (2.5 N, 2.4 mL, 6 mmol) under Ar2 protection and stirred for 10 min Weinreb amide (1 mmol) in 10 mL THF was added to lithium reagent and allowed to stir at RT for 2 h. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 55 (51.7% yield). 1H NMR (300 MHz, CDCl3) δ 8.29 (br, 1H), 7.68 (d, 1H), 7.46 (s, 2H), 7.39 (s, 1H), 7.36 (s, 1H), 7.28-7.26 (m, 1H), 7.15-7.12 (m, 1H), 6.55 (m, 1H), 3.93 (s, 3H), 3.89 (s, 6H). MS (ESI) m/z 432.1 (M+Na)+, 408.0 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[N-:29]=[N+:30]=[N-:31].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[NH:31][N:30]=[N:29][N:28]=3)[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2nc(CCCCCC#N)oc2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CCCCCc3nnn[nH]3)oc2-c2ccc(OC)cc2)cc1
Temperature: 105 °C
Reaction time: 60 h
Yield: 44.9 %

Procedure:
The procedure is as in Example 1. A mixture of 3.4 g of 6-[4,5-Bis(4-methoxyphenyl)-2-oxazolyl]hexanenitrile, 1.45 g of sodium azide and 1.76 g of ammonium chloride in 70 cm3 of dimethylformamide is heated to 105° C. for 60 hours. After the addition of sodium azide and ammonium chloride (in the same quantities as before), the mixture is brought again to 105° C. for 60 hours. At room temperature, the mixture is diluted with 210 cm3 of water, acidified with 2N hydrochloric acid and extracted with ethyl acetate (3 times 50 cm3), and the reaction product is purified as described in Example 1. The solid isolated is recrystallised in 60 cm3 of ethyl acetate, and 1.7 g (44.8%) of 5-{5-[4,5-bis(4-methoxyphenyl)-2-oxazolyl]pentyl}tetrazole, a white solid, melting point 150° C. are obtained.
Reaction SMILES: [Li]C(C)(C)C.CCCCC.Br[C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:19]=2)[N:14]([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:13]=1.[C:35](=[O:37])=[O:36]>C1COCC1>[C:31]([Si:28]([CH3:30])([CH3:29])[N:14]1[C:15]2=[N:16][CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:19]=[C:20]2[C:12]([C:35]([OH:37])=[O:36])=[CH:13]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: O=C=O
Reactant: CC(C)(C)[Si](C)(C)n1cc(Br)c2cc(-c3cccc(F)c3)cnc21
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)n1cc(C(=O)O)c2cc(-c3cccc(F)c3)cnc21
Yield: 76 %

Procedure:
1.7 M solution of t-BuLi in pentane (24.8 mL, 42.2 mmol) was added dropwise over a period of 25 min to a stirred and cooled (−78° C.) solution of 9 (8.20 g, 20.3 mmol) in THF (93 in L) at such a rate that the temperature did not exceed −65° C. After the addition, the mixture was stirred for 1 h at −78° C. Dry gaseous CO2 was introduced to the flask over a period of 10 min (exothermic reaction, external dry ice bath). When the exothermic reaction subsided, cooling bath was removed, and the mixture was allowed to reach 0° C. The mixture was then separated between brine-AcOEt. The aqueous layer was extracted with AcOEt (2×). Combined organic solutions were dried dried (MgSO4), concentrated and purified by SGC with CH2Cl2:AcOEt as eluent in gradient (up to 12% AcOEt) to afford 10 (5.74 g, 76%) as tan solid. 1H NMR (400 MHz, CDCl3) δ 0.71 (s, 6H), 0.99 (s, 9H), 7.05-7.12 (m, 1H), 7.37-7.42 (m, 1H), 7.43-7.50 (m, 2H), 8.11 (s, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.61 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[O:31]=[C:32]1[C@@H:41]2[N:37]([CH2:38][CH2:39][CH2:40]2)[CH2:36][C:35]2[CH:42]=[C:43](/[CH:46]=[CH:47]/[C:48](O)=[O:49])[CH:44]=[N:45][C:34]=2[NH:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>CO>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13])[C:48](=[O:49])/[CH:47]=[CH:46]/[C:43]1[CH:44]=[N:45][C:34]2[NH:33][C:32](=[O:31])[C@@H:41]3[N:37]([CH2:38][CH2:39][CH2:40]3)[CH2:36][C:35]=2[CH:42]=1
Reactant: CNCc1sc2ccccc2c1C
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN1CCC[C@@H]1C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Solvent: CO
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN2CCC[C@@H]2C(=O)N3)sc2ccccc12
Yield: 57 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (R)-(E)-3-(10-oxo-2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-benzo[f]azulen-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (96 mg, 57%) was prepared as a tan powder: [α]25D −154.3° (c 1.01, methanol); 1H NMR (300 MHz, DMSO-d6) δ 12.47 (br s, 1H), 11.29 (br s, 1H), 8.84 (s, 1H), 8.33 (s 1H), 7.89-7.86 (m, 1H), 7.75-7.72 (m, 1H), 7.65-7.60 (m, 1H), 7.42-7.31 (m, 3H), 5.13-4.90 (m, 2H), 4.48-4.25 (m, 2H), 3.59-3.47 (m, 5H), 3.17-2.95 (m, 3H), 2.42 (s, 3H), 2.10-1.89 (m, 2H); MS (ESI) m/e 447 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@@:8]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][Si](C(C)(C)C)(C)C)=[CH:17][CH:16]=1)([CH3:12])[C@H:9]([OH:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O.C([O-])(O)=O.[Na+]>C(#N)C>[C:1]([O:5][C:6](=[O:29])[NH:7][C@@:8]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:12])[C@H:9]([OH:11])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](O)[C@@](C)(CCc1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H](O)[C@@](C)(CCc1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of ((1R,2R)-1-{2-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-ethyl}-2-hydroxy-1-methyl-propyl)-carbamic acid tert-butyl ester (19 mg, 0.045 mMol) in acetonitril (2 ml) is added HF (0.2 ml, 40% solution), and the reaction is stirred at RT for 3.5 hours. The reaction mixture is then poured onto a biphasic mixture of AcOEt and NaHCO3 (saturated aqueous solution). The aqueous phase is extracted with AcOEt (3 times). The combined organic layers are dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 30% AcOEt in heptane gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[O:4][C:5]([CH3:11])([CH2:9][CH3:10])[C:6]([OH:8])=O.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[CH2:34]([O:36][C:37](=[O:45])[CH2:38][C:39]1[N:40]=[C:41]([NH2:44])[S:42][CH:43]=1)[CH3:35].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:34]([O:36][C:37](=[O:45])[CH2:38][C:39]1[N:40]=[C:41]([NH:44][C:6](=[O:8])[C:5]([O:4][C:3]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:2]=2[F:1])([CH3:11])[CH2:9][CH3:10])[S:42][CH:43]=1)[CH3:35]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CCC(C)(Oc1ccc(F)cc1F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)Cc1csc(NC(=O)C(C)(CC)Oc2ccc(F)cc2F)n1
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
To a solution of 2-(2,4-Difluoro-phenoxy)-2-methyl-butyric acid (0.2 g, 0.87 mmol) in DCM (5 ml) added N-Methyl morpholine (0.6 ml, 5.2 mmol) and HOBt (0.2 g, 1.3 mmol) at 0° C. After stirring at this temperature for 5 min. added (2-Amino-thiazol-4-yl)-acetic acid ethyl ester (0.17 g, 0.92 mmol) and followed by EDCI (0.217 g, 1.3 mmol). The resulting solution was stirred for 12 h. then quenched with sat NH4Cl solution (15 ml). The aqueous phase was extracted with CH2Cl2 (3×50 ml). The organic phase were successively washed with 2% HCl (50 ml), brine (50 ml) and dried over Na2SO4. After evaporation, the residue was purified by flash chromatography to give {2-[2-(2,4-Difluoro-phenoxy)-2-methyl-butyrylamino]-thiazol-4-yl}-acetic acid ethyl ester (0.2 g, 59%). 1H NMR (400 MHz, CDCl3): 1.03 (t, J=7.2 Hz, 3H), 1.28 (t, J=7.6 Hz, 3H), 1.43 (s, 3H), 1.83-1.89 (m, 1H), 2.04-2.1 (m, 1H), 3.73 (s, 2H), 4.2 (q, J=6.8 Hz, 2H), 6.8-6.93 (m, 3H), 7.0-7.04 (m, 1H); MS (EI) m/z: 399 (M+1).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]1[CH2:17][O:16][S:13](=[O:15])(=[O:14])[CH2:12][CH2:11]1.CC(C)=O>O1CCCC1.CCO>[CH2:1]([NH:9][CH2:17][CH2:10][CH2:11][CH2:12][S:13]([OH:16])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S1(=O)CCCCO1
Reactant: CCCCCCCCN
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCCCCCCCNCCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31 %

Procedure:
To a solution of octylamine (2.20 g, 17.0 mmol) in tetrahydrofuran (11 mL) was added 1,4-butane sultone (2.30 g, 16.2 mmol). The solution was heated to reflux for 5 hours. The reaction was cooled to room temperature. The product formed a gel. A few drops of EtOH were added to dissolve the product. The solution was poured in a large excess of acetone (25 mL). After 5 minutes, a white solid precipitated. The solid was collected by filtration and dried in vacuo. The product was dissolved in EtOH and Dowex 50×8 resin (pre-washed, 6 g) was added to the solution. The suspension was stirred for 15 minutes and the resin was filtered. The filtrate was evaporated under educed pressure and the product was dried in vacuo. Yield: 31%. 1H NMR (DMSO, 500 MHz) δ ppm 8.24 (s (broad), 1H), 2.85 (m, 4H), 2.45 (m, 2H), 1.64 (m, 4H), 1.61 (m, 2H), 1.25 (m, 10H), (m, 2H), 0.85 (t, 3H, J=6.8 Hz). 13C (DMSO, 125 MHz) δ ppm 51.22, 47.54, 47.38, 31.82, 29.14, 26.59, 26.13, 25.51, 22.95, 22.75, 14.64. ES-MS 266 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:28][CH2:29]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: Cc1ccccc1N1CCNCC1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccccc2C)CC1
Yield: 95 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 95%). 1H NMR (300 MHz, CDCl3): δ 2.32-2.56 (m, 6H), 2.88-3.00 (m, 4H), 3.77 (s, 3H), 4.08-4.13 (m, 4H), 7.02-7.04 (m, 3H), 7.19-7.39 (m, 3H), 7.51-7.65 (m, 2H).
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=[O:16].O>C(O)(=O)C>[CH:11]1[C:12]2[S:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6](=[O:16])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc2c(c1)Sc1ccccc1S2
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=S1c2ccccc2Sc2ccccc21
Reaction time: 5 h

Procedure:
In 300 ml of acetic acid was refluxed 20 g of thianthrene and 36 ml of diluted nitric acid was gradually added dropwise thereto. After reacting for 5 hours, the reaction solution was poured into 1.2 liters of water to deposit crystals. The crystals were collected by filtration and recrystallized from acetonitrile to obtain 12 g of thianthrene-S-oxide. 1H-NMR (400 MHz, CDCl3): σ 7.42 (t, 2H), 7.56 (t, 2H), 7.63 (d, 2H), 7.93 (d, 2H).
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH:3](C)C.[C:8]([O:23]C)(=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=O>>[CH3:1][CH:2]([CH3:3])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([OH:23])=[O:22]
Reactant: COC(=O)CCCCCCCCCCC(=O)O
Reactant: CC(C)CC(=O)O
Product: CC(C)CCCCCCCCCCCC(=O)O

Procedure:
13-methyltetradecanoic acid is synthesized electrolytically from isovaleric acid and methyl hydrogen dodecanedioate in methanolic solution, based on Kolbe electrolysis.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[F:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>O1CCCC1.O>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:49]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([F:42])[CH:44]=3)(=[O:51])=[O:50])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (330 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-fluorobenzenesulfonyl chloride (292 mg) under ice-cooling and the mixture was stirred for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 445 mg, 91%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[SH:23][CH2:24][CH2:25][C:26](O)=[O:27]>>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:26](=[O:27])[CH2:25][CH2:24][SH:23])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CCS
Reactant: CC(C)(C)C1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C1CCC(OC(=O)CCS)CC1

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, hot plate, spin bar and thermometer are placed 15.5 grams of 4-t-butylcyclohexanol; 0.5 grams paratoluene sulfonic acid and 15.5 grams of 3-mercapto-propionic acid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1>>[Br:17][C:18]1[CH:19]=[C:20]([CH2:24][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: BrCc1cccc(Br)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cccc(Br)c1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 1-bromo-3-(bromomethyl)benzene: MS (ES) m/z 393 (M+1) and 395 (M+1, isotope).
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:42]=[C:43]([Cl:45])[CH:44]=1)[O:33][C:34]1[NH:38][C:37]([C:39](Cl)=[O:40])=[CH:36][CH:35]=1>>[Cl:29][C:30]1[CH:31]=[C:32]([CH:42]=[C:43]([Cl:45])[CH:44]=1)[O:33][C:34]1[NH:38][C:37]([C:39]([NH:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:40])=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccc(Oc2cc(Cl)cc(Cl)c2)[nH]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccc(Oc4cc(Cl)cc(Cl)c4)[nH]3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 5-(3,5-dichlorophenoxy)-1H-pyrrole-2-carbonyl chloride: ESMS m/e: 634.2 (M+H)+.
Reaction SMILES: Cl.Cl.C[O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:8]=[CH:9][C:10]=1[O:11]C.[BrH:31]>>[BrH:31].[BrH:31].[C:25]1([CH2:24][CH2:23][NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13][C:7]2[CH:6]=[C:5]([OH:4])[C:10]([OH:11])=[CH:9][CH:8]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(CCNCCCCCCNCCc2ccccc2)cc1OC
Agent: Br
Agent: Cl
Product: Oc1ccc(CCNCCCCCCNCCc2ccccc2)cc1O

Procedure:
A solution of the diamine product of step (b) (4.75 g) in 48% aqueous hydrobromic acid (70 ml) was heated under reflux in an atmosphere of nitrogen for 3.5 hours. The solid which formed on cooling was filtered off and crystallised from ethanol, to give the title compound as the dihydrobromide salt, (3.1 g), mp 227°-228°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C1([O:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=2)C=CC=CC=1.Cl>C1COCC1.O>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([CH:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]2=[O:9])=[O:18])=[CH:21][CH:22]=1
Reactant: O=C(Oc1ccccc1)c1ccc(Br)cc1
Reactant: O=C1CCc2sccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 69.8 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL of THF was treated with NaH (60 percent, 1.45 g, 36.3 mmol). After the addition of 4-Bromo-benzoic acid phenyl ester (6.7 g, 24.2 mmol), the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was extracted with ethyl acetate. The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(4-Bromo-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (5.4 g, 16.9 mmol) as yellow solid in 70% yield.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>CC(C)=O>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(COc2ccc3cc[nH]c3c2)cc1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
6-Hydroxyindole (0.90 g, 6.8 mmol) and potassium carbonate (1.04 g, 7.5 mmol), were suspended in 13 mL of acetone. 4-Fluorobenzyl bromide (0.93 mL, 7.5 mmol, prefiltered through basic alumina) was added dropwise via syringe. The reaction mixture was heated at reflux under N2 atmosphere for 24 hours. The reaction mixture was cooled to ambient temperature and partitioned between H2O and methylene chloride. The aqueous phase was extracted twice with methylene chloride. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography on silica gel to give 6-(4-fluorophenylmethoxy)indole (1.4 g, 88%).