Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22](=[O:24])[CH3:23])[CH2:16]1>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22](=[O:24])[CH3:23])[CH2:16]1
Reactant: COCOc1ccc(C2CCCC(NC(C)=O)C2)c(OCOC)c1
Solvent: CO
Product: CC(=O)NC1CCCC(c2ccc(O)cc2O)C1
Yield: 33.8 %

Procedure:
(±)-N-{3-[2,4-bis(methoxymethoxy)phenyl]cyclohexyl}acetamide (20 mg), methanol (2 ml) and acidic ion exchange resin (300 mg) were heated under reflux for 3 hr. The reaction mixture was filtered and the resin was washed with methanol. The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to furnish the title compound as a solid (5 mg, 34%). δH (CD3OD) 1.10-2.00 (11H, m), 2.90 (0.3H, tt), 3.08 (0.7H, tt), 3.70-3.80 (0.3H, m), 4.16 (0.7H, m), 6.20-6.26 (2H, m), 6.84-6.90 (1H, m); m/z (ES+) 250 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[S:24](Cl)(Cl)=[O:25].[CH:28]([Mg]Cl)([CH3:30])[CH3:29].CCOCC>C(Cl)(Cl)Cl.CCCCCC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([S:24]([CH:28]([CH3:30])[CH3:29])=[O:25])=[C:3]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CC(C)[Mg]Cl
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(S(=O)C(C)C)c2cc(OCc3ccccc3)ccc2n1C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
A slurry of ethyl 1-methyl-5-(phenylmethoxy)-1H-indole-2-carboxylate (10.0 g, 32 mmol; Monge Vega A, et al., An. Ouim. 1976;72:267) in 30 mL of chloroform is treated dropwise with thionyl chloride (9.5 mL, 15.5 g, 130 mmol). After stirring for 20 minutes, 90 mL of hexane is added, and stirring is continued for 30 minutes. The crude indole sulfinyl chloride intermediate is filtered, washed with hexane, and dissolved in 200 mL of tetrahydrofuran. The solution is cooled to -78° C. and treated dropwise with a 2.0M solution of isopropylmagnesium chloride in ether (16.4 mL, 32.8 mmol). After stirring for 15 minutes, the reaction mixture is quenched by the dropwise addition of 20 mL of 2.0N HCl. The reaction mixture is warmed to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers are washed with brine, dried (anhydrous magnesium sulfate), and evaporated. The residue is triturated with ether to give a solid which is recrystallized from aqueous methanol to yield 6.8 g (53%) of product; mp 142°-145° C.
Reaction SMILES: Br[CH:2]=[CH:3][CH3:4].[Mg].[CH3:6][C:7]1[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=1[CH:15]=[O:16].[NH4+].[Cl-]>O1CCCC1>[CH3:6][C:7]1[CH2:12][CH2:11][CH2:10][C:9]([CH3:13])([CH3:14])[C:8]=1[CH:15]([OH:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC1=C(C=O)C(C)(C)CCC1
Reactant: CC=CBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC=CC(O)C1=C(C)CCCC1(C)C
Reaction time: 2 h

Procedure:
In an atmosphere of nitrogen, a solution of 280 g. of 1-bromopropene in 430 ml. of tetrahydrofuran was added dropwise at 63°-65° into a suspension of 53.3 g. of magnesium turnings in 660 ml. of tetrahydrofuran. During the addition the reflux condenser fitting the reaction vessel was cooled to -40° to -50° in order to prevent escaping of the vapours of unreacted 1 -bromopropene. The mixture was stirred for an additional 21/2 hours at 60°-62° after which it was cooled to 0°. A solution of 278 g. of β-cyclocitral in 350 ml. of tetrahydrofuran was then added dropwise between 0° and 7°. The mixture was allowed to stand overnight then it was poured onto a mixture of ice and saturated aqueous NH4Cl solution. The organic layer was removed and the aqueous phase extracted with petroleum-ether (b.p. 30°-50°). The combined extracts were washed as usual, dried and then evaporated under vacuum. The residue gave 350 g. of crude 2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene which was used without further purification.
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][O:29][CH3:30]>CN(C=O)C>[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:27][CH2:28][O:29][CH3:30])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Cl)c2cc1S(=O)(=O)C(C)(C)C
Yield: 46.7 %

Procedure:
6-(tert-Butylsulfonyl)-4-chloroquinolin-7-ol (0.81 g, 2.70 mmol), K2CO3 (1.143 g, 8.11 mmol), and 1-bromo-2-methoxyethane (0.508 ml, 5.40 mmol) in DMF (8.50 ml) were heated at 70° C. The reaction mixture cooled and partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc twice and the combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The residue was purified via Biotage (SNAP Cartridge KP Sil 25 g, 10-50% EtOAc/Hexane) to yield 6-(tert-butylsulfonyl)-4-chloro-7-(2-methoxyethoxy)quinoline (0.461 g, 1.262 mmol, 46.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.93 (d, J=4.55 Hz, 1H), 8.66 (s, 1H), 7.73-7.79 (m, 2H), 4.40 (dd, J=3.54, 5.31 Hz, 2H), 3.76 (dd, J=3.66, 5.18 Hz, 2H), 3.34 (s, 3H), 1.33 (s, 9H), MS: m/z: 358.1 [M+H]+.
Reaction SMILES: N#N.[CH2:3]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:6]=1[NH2:7])[CH3:4].[CH2:14](Br)[C:15]#[CH:16].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:3]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:6]=1[NH:7][CH2:16][C:15]#[CH:14])[CH3:4]
Reactant: C#CCBr
Reactant: CCc1cccc(CC)c1N
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#CCNc1c(CC)cccc1CC

Procedure:
A reactor equipped with a thermometer, stirrer, N2 inlet and outlet tubes and reflux condenser fitted with a drying tube is charged with 74.5 g (0.5 mole) of 2,6-diethylaniline, 71.4 g (0.6 mole) of propargyl bromide, 41.4 g (0.3 mole) of anhydrous potassium carbonate, and 125 ml of absolute ethanol. The mixture is refluxed for 18 hours under slight positive N2 pressure. The reaction mixture is cooled and additional potassium carbonate is added until the solution is weakly basic. It is then transferred to a separatory funnel. The supernatant organic layer which develops is isolated and dried over anhydrous potassium carbonate. The liquid is then separated by filtration and the solvent stripped in vacuo. The residue remaining is vacuum distilled. The clear liquid product (17.6 g) is approximately 90% pure 2,6-diethyl-N-propargylaniline as indicated by vapor phase chromatography. It has a boiling point of 86°-88° C at 0.6-0.7 mm Hg pressure. The impurities are 2,6-diethylaniline and 2,6-diethyl-N,N-dipropargylaniline.
Reaction SMILES: C[C:2]1([C:8](O)=O)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C([N:13]([CH2:16]C)CC)C.P(N=[N+]=[N-])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=[O:19].[OH-].[Na+]>C1(C)C=CC=CC=1>[N:13]([C:2]1([CH3:8])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1)=[C:16]=[O:19]
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC1(C(=O)O)CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC1(N=C=O)CCOCC1
Temperature: 85 °C
Yield: 42.1 %

Procedure:
A stirred solution of 4-methyltetrahydro-2H-pyran-4-carboxylic acid (D9) (1.26 g, 8.74 mmol) in Toluene (50 mL) at room temperature under argon was treated with triethylamine (1.58 mL, 11.36 mmol) and diphenyl azidophosphate (1.88 mL, 8.74 mmol) and heated to 85° C. for 2 hr. The mixture was allowed to cool to room temperature, then treated with 1 M NaOH solution (40 mL) and extracted with Et2O (3×). The combined extract was dried (Na2SO4), filtered and concentrated under vacuum to give the title compound (D10) (520 mg, 34%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1
Reactant: COC(=O)CCl
Reactant: Cc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)CNc1cccc(C)c1
Yield: 130.5 %

Procedure:
A mixture of m-toluidine (55.0 g), methyl chloroacetate (85.0 g) and sodium bicarbonate (86.2 g) in acetonitrile (400 ml) was heated at reflux for 2 days under nitrogen. Ethyl acetate (250 ml) was added and the mixture was washed with water (2×250 ml), dried and evaporated to give an oil (120 g), a sample of which (1.4 g) was purified by FCC eluting with System A (3:7) to give the title compound (0.8 g) as a solid, m.p. 40°.
Reaction SMILES: [N:1]#[N:2].C([O:6][C@H:7]1[C@@H:12]([O:13]C(=O)C)[C@H:11]([O:17]C(=O)C)[C@@H:10]([CH2:21][O:22]C(=O)C)[O:9][C@@H:8]1[S:26][CH2:27][CH2:28][C:29]([NH:31][C@H:32]([C:66]([NH:68][C@H:69]([C:103]([OH:105])=[O:104])[CH2:70][CH2:71][CH2:72][CH2:73][NH:74][C:75](=[O:102])[CH2:76][CH2:77][S:78][C@H:79]1[O:96][C@H:95]([CH2:97][O:98]C(=O)C)[C@@H:90]([O:91]C(=O)C)[C@H:85]([O:86]C(=O)C)[C@@H:80]1[O:81]C(=O)C)=[O:67])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:65])[CH2:39][CH2:40][S:41][C@H:42]1[O:59][C@H:58]([CH2:60][O:61]C(=O)C)[C@@H:53]([O:54]C(=O)C)[C@H:48]([O:49]C(=O)C)[C@@H:43]1[O:44]C(=O)C)=[O:30])(=O)C>CO.O.C(N(CC)CC)C>[N:1]#[N:2].[C@H:8]1([S:26][CH2:27][CH2:28][C:29]([NH:31][C@H:32]([C:66]([NH:68][C@H:69]([C:103]([OH:105])=[O:104])[CH2:70][CH2:71][CH2:72][CH2:73][NH:74][C:75](=[O:102])[CH2:76][CH2:77][S:78][C@H:79]2[O:96][C@H:95]([CH2:97][OH:98])[C@@H:90]([OH:91])[C@H:85]([OH:86])[C@@H:80]2[OH:81])=[O:67])[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:65])[CH2:39][CH2:40][S:41][C@H:42]2[O:59][C@H:58]([CH2:60][OH:61])[C@@H:53]([OH:54])[C@H:48]([OH:49])[C@@H:43]2[OH:44])=[O:30])[O:9][C@H:10]([CH2:21][OH:22])[C@@H:11]([OH:17])[C@H:12]([OH:13])[C@@H:7]1[OH:6]
Reactant: CC(=O)OC[C@H]1O[C@H](SCCC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)NC(=O)CCS[C@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)C(=O)O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N#N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CO
Product: O=C(CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)NC(=O)CCS[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)C(=O)O
Yield: 88.7 %

Procedure:
A solution of 4 (2.0 g) in methanol-water-triethylamine 5:4:1 (v/v/v, 20 ml) is kept overnight at room temperature, and evaporated in vacuo to a residue that is put on a column of silica gel and eluted with chloroform-methanol-water 60:40:10 (v/v/v). The desired fractions are combined and evaporated to dryness. A solution of this compound in water (15 ml) is lyophilized to give 5 (1.2 g, 90%): mp 95°-100° C.; [α]D27 +115±0.9° (c 1.1, H2O); NMR (D2O) δ: 5.37 (s, 1H, H-1), 5.34 (s, 2H, H-1), 4.36, 4.19 (q,q, α-CH), 3.24 (m, ε-CH2), 2.95 (m, SCH2), 2.71 (t, 2H), 2.61 (t, 4H) (SCH2CH2), 1.33-1.92 (CCH2CH2CH2C).
Reaction SMILES: C1(COC([NH:11][C@H:12]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=O)C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C@H:12]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)OCC[Si](C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)OCC[Si](C)(C)C

Procedure:
1 g. of 10% palladium on carbon catalyst is added to a solution of [(phenylmethoxy)carbonyl]-L-leucine, 2-(trimethylsilyl)ethyl ester (9.1 g., 24.9 mmole) in ethyl acetate (200 ml.) cooled in an ice-bath under nitrogen. The reaction mixture is subjected to a steady stream of hydrogen gas for 2.5 hours at room temperature, then filtered and concentrated in vacuo to remove volatiles and yield 5.8 g. of L-leucine, 2-(trimethylsilyl)-ethyl ester as a liquid product. TLC (silica gel, 3:1 hexane:ethyl acetate) Rf =0.08.
Reaction SMILES: [I-].[C:2]([CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][N+:7]([CH3:10])([CH3:9])C)(=[O:4])[CH3:3].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])C=NC[CH2:20]2.C(O)C.O>ClCCl>[CH2:11]([CH:5]1[CH2:6][N:7]2[CH2:9][CH2:20][C:19]3[C:24]([CH:10]2[CH2:3][C:2]1=[O:4])=[CH:25][C:26]([O:27][CH3:28])=[C:17]([O:16][CH3:15])[CH:18]=3)[CH:12]([CH3:13])[CH3:14]
Reactant: COc1cc2c(cc1OC)CCN=C2
Reactant: CC(=O)C(CC(C)C)C[N+](C)(C)C
Agent: [I-]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C1CC(=O)C(CC(C)C)CN1CC2
Yield: 37.1 %

Procedure:
(2-Acetyl-4-methyl-pentyl)-trimethyl-ammonium iodide (800 mg, 2.55 mmol, 1.00 equiv) was added to a solution of 6,7-dimethoxy-3,4-dihydroisoquinoline (100 mg, 2.62 mmol, 1.00 equiv) and ethanol (10 mL). The resulting solution was heated at reflux for about 5 hours, and then water (20 mL) was added. Following standard extractive workup with dichloromethane (3×50 mL), the crude residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (1:4)) to afford the title compound as a white solid (300 mg, yield=36%). 1H NMR (300 MHz, CDCl3), δ 6.63 (s, 1H), 6.55 (s, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 3.55 (s, 1H), 3.22-3.28 (m, 1H), 2.94-3.14 (m, 4H), 2.31-2.65 (m, 4H), 1.73-1.81 (t, 1H, J=11.4), 1.33-1.39 (m, 1H), 0.996-1.067 (t, 1H, J=10.5), 0.79-0.85 (m, 6H) LC-MS: m/z=318 (MH)+.
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][O:6]1)=[O:4].[SH:10][C@H:11]1[NH:14][C:13](=[O:15])[C@H:12]1[NH:16][C:17](=[O:26])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:19]([CH2:18][C:17]([NH:16][C@H:12]1[C@@H:11]([S:10][CH2:2][C:3]([CH:5]2[CH2:9][CH2:8][CH2:7][O:6]2)=[O:4])[NH:14][C:13]1=[O:15])=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CCl)C1CCCO1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N[C@@H]1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N[C@@H]1SCC(=O)C1CCCO1
Yield: 59 %

Procedure:
(RS)-2-Chloroacetyltetrahydrofuran (2.46g, 16.5mmol), (3R,4R)-4-mercapto-3-phenoxyacetamidoazetidin-2-one (4.157g, 16.5mmol) and potassium carbonate (2.227g 16.5mmol) in DMF (10ml) were stirred for 2h, diluted with ethyl acetate, washed twice with water and with brine, dried concentrated and flash chromatographed eluting with 40,30,20,10 and 0% hexane in ethyl acetate to give the title compound as a foam (3.547g, 59%); vmax (CH2Cl2) 3405, 1785, 1693, 1520, 1496 and 1240cm-1 ; δ(CDCl3, 250MHz) 1.9-2.3 (4H, m), 3.42 and 3.62, 3.46 and 3.56 (together 2H, 2 ABq, J15.8Hz, 15.4Hz), 3.85-4.0 (2H, m), 4.4-4.5 (1H, m), 4.58 (2H, s), 5.01, 5.04 (together 1H, 2d, J4.7Hz), 5.59 (1H, dd, J 8.8, 4.5Hz) 6.62, 6.68 (together 1H, 2s), 6.9-7.4 (5H, m) and 7.45, 7.47 (together 1H, 2d, J8.8Hz). [Mass spectrum: M+ (364)].
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[S:19](Cl)(=[O:21])=[O:20].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[S:19]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])(=[O:20])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: OCC(F)(F)C(F)F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(OCC(F)(F)C(F)F)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.2 %

Procedure:
A mixture of 52.8 parts of 2,2,3,3-tetrafluoro-1-propanol, 117.8 parts of 2-naphthalenesulfonyl chloride, 294 parts of pyridine and 2.0 parts of N,N-dimethyl-4-pyridinamine was stirred for 48 hours at room temperature. The reaction mixture was diluted with water and the whole was left to crystallize. The product was filtered off, washed with water and recrystallized from 2-propanol, yielding 98.2 parts (76.2%) of 2,2,3,3-tetrafluoropropyl 2-naphthalenesulfonate; mp. 89.6° C. (interm. 27).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]#[N:15])=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:16].[Na+].OO.O>CS(C)=O>[C:1]([NH:5][C:6]1[N:11]=[C:10]([S:12][CH3:13])[C:9]([C:14]([NH2:15])=[O:16])=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(NC(C)(C)C)ncc1C#N
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc(NC(C)(C)C)ncc1C(N)=O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
To a stirring solution of 2-(tert-butylamino)-4-(methylthio)pyrimidine-5-carbonitrile (0.6 g, 2.70 mmol) in DMSO (7 mL) was added 6M aqueous sodium hydroxide solution (2.249 mL, 13.49 mmol) and 30% aqueous hydrogen peroxide (1.530 mL, 13.49 mmol) solution at 0° C. Then the mixture was stirred at 50° C. for 15 min. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration of the filtrate under reduced pressure gave the crude product, which was purified by silica gel column chromatography (5% methanol in DCM) to afford 2-(tert-butylamino)-4-(methylthio)pyrimidine-5-carboxamide (0.462 g, 1.922 mmol, 71.2% yield) as a white solid. MS (ESI) m/z 241.0 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].Cl.Cl.[CH:22]12[NH:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][CH2:24][CH2:23]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:27]4[CH2:28][CH:22]5[NH:30][CH2:29][CH:26]4[CH2:25][CH2:24][CH2:23]5)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: C1CC2CNC(C1)CN2
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2nc(N3CC4CCCC3CN4)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
A solution of 1.41 g (5.0 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 1.10 (5.5 mmol) of 6,8-diazabicyclo[3.2.2]nonane, dihydrochloride, 2.26 ml (15 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene, and 30 ml of acetonitrile was heated under reflux for 4 hr. After cooling to room temperature, the precipitated solid was collected to give 0.97 g of the title compound, mp 255°-258° dec.
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:19]2[CH:24]=[CH:23][C:22](C)=[CH:21][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C([O-])(O)=O.[Na+]>C(O)C>[NH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:8]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:9]2
Reactant: Cc1ccc(-c2cc3cc([N+](=O)[O-])ccc3n2C2CCCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)cc(-c1ccccc1)n2C1CCCCC1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a suspension of 1-cyclohexyl-2-(4-methylphenyl)-5-nitro-1H-indole (45 mg; 0.13 mmol) in absolute ethanol (5 ml) was added stannous chloride dihydrate (152 mg; 0.67 mmol) and the mixture was left under stirring at 70° C. for 18 hours. The reaction mixture was cooled to room temperature and then poured into H2O and ice (20 ml), NaHCO3 (saturated solution) was added to pH 8 and the mixture was left under stirring for 20 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][C:3]=1[NH2:4].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([S:9][C:6]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([CH:5]=1)[NH2:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(S)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(SCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-5-mercaptoaniline (0.64 g) and benzyl bromide (0.52 mL) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.61 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=7/3) to give the title compound (0.37 g).
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Cl:11].[F:12][B-:13]([F:16])([F:15])[F:14].[H+].[N:18](OCCC(C)C)=O.C(OCC)C>C(#N)C>[F:12][B-:13]([F:16])([F:15])[F:14].[Cl:11][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[C:9]([Cl:10])[C:2]=1[N+:1]#[N:18]
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Reactant: CC(C)CCON=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CC#N
Solvent: CCOCC
Product: N#Cc1cc(Cl)c([N+]#N)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.5 %

Procedure:
To a solution of 4-amino-3,5-dichlorobenzonitrile (2.00 g, 10.63 mmol) in acetonitrile (12 ml) was added dropwise tetrafluoroboric acid (2.80 ml, 21.27 mmol). After stirring for 10 min, isoamyl nitrite (1.50 ml, 10.63 mmol) was added and the reaction mixture was cooled to 0° C. After a further 10 min, diethyl ether (50 ml) was added and the resulting precipitate was collected by filtration and dried to give the titled compound (1.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:3]=1[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][C:19]=1[C:29]#[N:30])[CH:13]=[CH:12]2)=[O:8].[OH-].[Na+]>CO.O.C(Cl)Cl>[C:29]([C:19]1[CH:20]=[C:21]([CH2:24][C:25]([OH:27])=[O:26])[CH:22]=[CH:23][C:18]=1[N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:7](=[O:8])[NH:6][CH2:5][CH2:4][C:3]3[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:2]=3[Cl:1])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)#[N:30]
Reactant: COC(=O)Cc1ccc(-n2ccc3cc(C(=O)NCCc4ccc(Cl)cc4Cl)ccc32)c(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: N#Cc1cc(CC(=O)O)ccc1-n1ccc2cc(C(=O)NCCc3ccc(Cl)cc3Cl)ccc21
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 2-(4-(5-((2,4-dichlorophenethyl)carbamoyl)-1H-indol-1-yl)-3-cyanophenyl)acetate in methanol (1 mL) at ambient temperature was added aqueous sodium hydroxide (5.0 N, 0.036 mL) and 5 drops of water, and the reaction was stirred for 1 hour. The reaction mixture was taken up in DCM (5 mL) and washed with 2 M HCl (5 mL). The organic layer was dried over MgSO4 and concentrated to give the desired compound as a white solid 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.80 (s, 1H), 7.70 (dd, J=8.5, 2.1 Hz, 1H), 7.65 (d, J=8.6Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.44 (d, J=5.9 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.17-7.25 (m, 3H), 6.82 (d, J=3.0 Hz, 1H), 6.24 (d, J=5.9 NH), 3.81 (s, 2H), 3.74 (q, J=6.6 Hz, 2H), 3.10 (t, J=7.0 Hz, 2H), MS(ESI)=492.3 (M+1).