Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9][CH3:10])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].[I:15]CI.[N+]([O-])(OCCC(C)C)=O.[N+]([O-])(OCCCCC)=O>C(#N)C>[C:7]([C:6]1[C:2]([I:15])=[C:3]([C:11]([O:13][CH3:14])=[O:12])[S:4][C:5]=1[S:9][CH3:10])#[N:8]
Reactant: ICI
Reactant: COC(=O)c1sc(SC)c(C#N)c1N
Agent: CC(C)CCO[N+](=O)[O-]
Agent: CCCCCO[N+](=O)[O-]
Solvent: CC#N
Product: COC(=O)c1sc(SC)c(C#N)c1I
Temperature: 38 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a suspension of methyl 3-amino-4-cyano-5-(methylthio)thiophene-2-carboxylate (4.0 g, 17.5 mmol) in acetonitrile (20 mL) was added diiodomethane (4.94 mL, 61.3 mmol). The reaction mixture was heated at 38° C. Isoamyl nitrate (5.13 g, 43.8 mmol) was added dropwise over five minutes. After the addition of amyl nitrate, the reaction mixture was allowed to cool to room temperature and stirred for two hours. The reaction mixture was cooled in an ice bath and hexanes (20 mL) were added. The resultant precipitate was filtered and washed with a solution of 90% hexanes in acetonitrile (10 mL), 75% hexanes in diethyl ether (10 mL) and 100% hexanes (20 mL) to give methyl 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate (3.4 g, 57%) as a light orange solid. 1H NMR (400 MHz, CDCl3) δ: 3.91 (s, 3H), 2.70 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13]Cl)=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH3:12])[CH2:9][CH2:10][OH:11].[SH:15][C:16]1[NH:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1>CC(O)C>[NH:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[S:15][CH2:13][C:3]1[C:2]([Cl:1])=[C:7]([N:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][N:4]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CN(CCO)c1ccnc(CCl)c1Cl
Solvent: CC(C)O
Product: CN(CCO)c1ccnc(CSc2nc3ccccc3[nH]2)c1Cl
Temperature: 4 °C

Procedure:
A solution of 2-[(3-chloro-2-chloromethyl-pyridin-4-yl)-methyl-amino]-ethanol isolated in step a) (10.2 g) and 2-mercapto-benzimidazole (5.8 g, 39 mmol) in 2-propanol (250 ml) is boiled under reflux for 2 h. After cooling to 4° C. the precipitate is filtered, washed with 2-propanol and dried in vacuo. The residue is dissolved in water, adjusted to pH 8 with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is crystallized from ethyl acetate to give the title compound as an off-white solid, 7.9 g (58%). M.p. 132-5° C.
Reaction SMILES: C([O:4][CH2:5][C@@:6]1([C:25]#[CH:26])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@H:7]1OS(C)(=O)=O)(=O)C.C1CN2C(=NCCC2)C1.CO>CC#N>[C:25]([C@:6]1([CH2:5][OH:4])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH:8]=[CH:7]1)#[CH:26]
Reactant: C#C[C@]1(COC(C)=O)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Agent: C1CN=C2CCCN2C1
Solvent: CC#N
Solvent: CO
Product: C#C[C@@]1(CO)C=C[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Reaction time: 12 h

Procedure:
A mixture of 13 (105 mg, 0.272 mmol) and DBN (101 μL, 0.815 mmol) in CH3CN (10 mL) was refluxed for 11 h. After being quenched with AcOH, the reaction mixture was partitioned between CHCl3/saturated aqueous NaHCO3 (60 mL×3/20 mL). The product, obtained after purification by silica gel column chromatography (hexane/EtOAc=1/1) of the organic layer, was dissolved in saturated NH3 in MeOH (30 mL), and kept at room temperature for 12 h. Evaporation of the solvent followed by preparative TLC (hexane/EtOAc=1/1) purification gave TKD-4-114 (49.6 mg, 74%) as a solid: mp 207-209° C.; UV (MeOH) λmax 264 nm (ε10800), λmin 235 nm (ε4800); 1H NMR (CDCl3) δ1.83 (3H, s, Me), 2.63 (1H, s, ethynyl), 3.47 (1H, br, OH), 3.88 (1H, d, Jgem=12.5 Hz, H-5′a), 3.96 (1H, d, Jgem=12.5 Hz, H-5′b), 5.91 (1H, dd, J1′,2′=1.1 Hz and J2′,3′=5.9 Hz, H-2′), 6.30 (1H, dd, J1′,3′=2.0 Hz and J2′,3′=5.9 Hz, H-3′), 7.16-7.17 (1H, m, H-1′), 7.44 (1H, d, J6,Me=1.1 Hz, H-6), 9.06 (1H, br, NH); FAB-MS m/z 249 (M++H). Anal. Calcd for C12H12N2O4.⅙H2O: C, 57.37; H, 4.95; N, 11.15. Found: C, 57.36; H, 4.69; N, 10.98.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[CH2:12][C:11](=[O:23])[N:10]([CH3:24])[N:9]=2)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH:44]#[C:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>CC#N.[Cu]I.Cl[Pd]Cl>[C:44]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[CH2:12][C:11](=[O:23])[N:10]([CH3:24])[N:9]=2)=[CH:4][CH:3]=1)#[C:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: C#CCCCCC
Reactant: COc1cc2c(cc1OC)C(c1ccc(I)cc1)=NN(C)C(=O)C2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCCCCC#Cc1ccc(C2=NN(C)C(=O)Cc3cc(OC)c(OC)cc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Stir for 3 hours at room temperature under an inert atmosphere a mixture of 1-(4-iodophenyl)-7,8-dimethoxy-3-methyl-3,5-dihydro-4H-2,3-benzodiazepin-4-one IIIah, 12 mg of CuI, 7 mg of PdCl2, 23 mg of PPh3, 2 ml of TEA, 4 ml of heptyne, in 12 ml of CH3CN. Evaporate to dryness and purify by silica chromatography (AcOEt 1/hexane 1).
Reaction SMILES: [CH2:1]1[C:6]2[S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[Na+].[Na+].Cl[CH2:21][CH2:22][CH2:23][C:24]#[N:25]>C(#N)C.CC1C=CC=CC=1>[CH2:1]1[C:6]2[S:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=2[CH2:4][CH2:3][N:2]1[CH2:21][CH2:22][CH2:23][C:24]#[N:25]
Reactant: c1ccc2c3c(sc2c1)CNCC3
Reactant: N#CCCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: N#CCCCN1CCc2c(sc3ccccc23)C1
Yield: 101.4 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-[1]benzothieno[2,3-c]pyridine (0.02 mol), Na2CO3 (5 g), KI (0.1 g) and 4-chlorobutanenitrile (0.025 mol) in acetonitrile (50 ml) and methylbenzene (150 ml) was stirred and refluxed overnight, then cooled, filtered and the filtrate was evaporated. The residue (oil) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 5.2 g of 3,4-dihydrobenzothieno[2,3-c]-pyridine-2(1H)-butanenitrile (interm. 6).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([CH2:28][OH:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][C@H:9]([C:14]([NH:16][C@H:17]([CH2:28][OH:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC[C@H](C)[C@H](N)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Reaction time: 4 h

Procedure:
To a solution, being ice cool, ed, of N-tert-butoxycarbonyl-(L)-isoleucyl-(L)-tryptophanol (1.0 g) in chloroform (10 ml), trifluoroacetic acid (5%, 0.5 g) was added, followed by stirring at the same temperature for 4 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue. The ethyl acetate layer was washed with water and dried (MgSO4), and the solvent was distilled off to yield (L)-isoleucyl-(L)-tryptophanol as an oily substance. This oily substance was dissolved in chloroform (20 ml), and p-toluenesulfonyl chloride (0.52 g) was added and then triethylamine (1.4 ml) was added at 0° C. After stirring at room temperature for 2 days, the reaction mixture was poured over water and extracted with chloroform. After the chloroform layer was dried (MgSO4), the solvent was distilled off, and the oily residue was recrystallized from ethyl acetate to yield N-(p-toluenesulfonyl)-(L)-isoleucyl-(L)-tryptophanol (0.32 g, 28%).
Reaction SMILES: IC1C=CC=CC=1S([O-])(=O)=O.[Na+].OOS([O-])=O.[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].[Si:26]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]([OH:40])[CH3:39])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(OCC)(=O)C>[Si:26]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:40])[CH3:39])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(O)CCCCO[Si](C)(C)C(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1I
Agent: O=S([O-])OO
Solvent: CCOC(C)=O
Product: CC(=O)CCCCO[Si](C)(C)C(C)(C)C
Temperature: 70 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
6.1 mg (0.02 mmol) sodium 2-iodobenzenesulfonate prepared by Preparation Example 4, 0.49 g (0.8 mmol) of powdered Oxone (registered trademark), 0.5 g (3.5 mmol) of anhydrous sodium sulfate and 232 mg (1 mmol) of 6-(tert-butyldimethylsilyloxy)hexan-2-ol were added to 5 ml of ethyl acetate, and the mixture was heated at 70° C. while being stirred under a nitrogen for seven hours. The later treatment was carried out in the same way as in Example 1, and then 6-(tert-butyldimethylsilyloxy)hexan-2-one was obtained. The yield of the obtained 6-(tert-butyldimethylsilyloxy)hexan-2-one was determined and the result is shown in Table 2. (Yield 90%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]=2[Cl:14])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=[N:33]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH2:28][CH:29]([N:32]2[CH:36]=[C:35]([C:2]3[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]4[O:10][C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[C:13]=4[Cl:14])[CH:3]=3)[CH:34]=[N:33]2)[CH2:30][CH2:31]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ncc(Br)cc1-c1oc2ccccc2c1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4oc5ccccc5c4Cl)c3)cn2)CC1
Temperature: 105 °C

Procedure:
To a solution of 5-Bromo-3-(3-chlorobenzofuran-2-yl)-pyridin-2-ylamine (57.9 mg, 0.179 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (69.5 mg, 0.184 mmol) in 1,4-dioxane (2.5 mL, 32 mmol) in a microwave reactor tube were added PS-PPh3-Pd (0.10 mmol/g loading; 100 mg, 0.0100 mmol; Argonaut) and a solution of Cs2CO3 (117 mg, 0.358 mmol) in H2O (0.75 mL, 42 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 105° C. for 30 min. More 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (21 mg, 0.056 mmol) was added, the tube was evacuated and refilled with nitrogen again (3×) and heated in the microwave reactor to 105° C. for 45 min. The resin was filtered off and washed with DCM. The combined filtrate and washings were diluted with DCM to ≈50 mL, washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel [10 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM]. Fractions containing product were combined and dried in vacuo. One obtained the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=8.30 (d, J=2.4 Hz, 1H), 8.09 (d, J=2.4 Hz, 1), 7.74 (s, 1H), 7.65 (dd, J=7.2, 1.2 Hz, 1H), 7.63 (s, 1H), 7.52 (dd, J=7.0, 1.4 Hz, 1H), 7.41 (ddd, J=1.6, 7.2, 7.2 Hz, 1H), 7.38 (ddd, J=1.4, 7.0, 7.0 Hz, 1H), 5.27 (brs, 2H), 4.37-4.17 (m, 3H), 2.91 (brt, J=11.2 Hz, 2H), 2.18 (brdd, J=2.2, 12.8 Hz, 2H), 1.97 (dq, J=12.4, 4.0 Hz, 2H), 1.48 (s, 9H). MS(ES+): m/z=494.15/496.08 (100/48) [MH+]. HPLC: tR=3.23 min (nonpolar—5 min, ZQ3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:37]4[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][OH:31])[CH2:35][CH2:36]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OCCN1CCNCC1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCN(CCO)CC1

Procedure:
In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and 4-(2-hydroxy-ethyl) piperazine was converted to 32.3 mg of the title compound (free base) and mass spectrum (electrospray, m/e): M+H 539.1, 42.2 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electrospray, m/e): M+H 539.1.
Reaction SMILES: [OH:1][CH:2]1[CH:9]2[CH:5](OC(C)(C)[O:8]2)[O:4][CH:3]1[CH:12]1[CH:16]([OH:17])[CH2:15][CH2:14][NH:13]1.[OH-].[Na+]>O.[Pt]>[CH2:15]1[C@H:16]([OH:17])[C@H:12]2[N:13]([CH2:5][C@H:9]([OH:8])[C@@H:2]([OH:1])[C@@H:3]2[OH:4])[CH2:14]1
Reactant: CC1(C)OC2OC(C3NCCC3O)C(O)C2O1
Agent: [Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O[C@H]1[C@H](O)[C@@H](O)CN2CC[C@H](O)[C@H]12

Procedure:
A solution of [3aR-[3aα,5α(2R*,3S*),6α,6aα]]-2-(Tetrahydro-6-hydroxy-2,2-dimethylfuro[2,3-d]-1,3-dioxol-5-yl)-3-pyrrolidinol (V) (0.5g, 2.0 mmol) in trifluor (9:1) (25 mL) was stirred, under nitrogen, at ambient temperature for 20h. The purple solution was then concentrated in vacuo (40° C.) leaving a thick syrup which was dissolved in deionized water (25 mL). This solution was basified to a pH of about 9.0 by the addition of lN aqueous sodium hydroxide (5.5 mL) and hydrogenated at 3.4 atmospheres over 5% Pt on carbon (0.3 g) on a Parr apparatus for l6h. The mixture was filtered through a celite pad and the collected catalyst washed with water (2×20 mL). The combined filtrate was adsorbed on a column of Dowex 50 W-X8 (H+) ion exchange resin (l0mL) (prewashed with 200 mL of water) and eluted first with deionized water (200 mL) and then with lN ammonium hydroxide solution (twenty ×20 mL fractions were collected). (+)-Castanospermine (VI), 0.23 g (61%) was obtained from fractions 1-15. An analytical sample was obtained as colorless prisms by recrystallization from 90% ethanol: mp 210°-212° C. dec. [lit. 212°-215° -C dec]; [α]D25 =81.4° (c 1.0, H2O) [lit. [α]o2α=+79.7° (C 0.93, H2O 1H NMR (D2O) δ4.42 (ddd, 1, J=7.0, 4.5, 2.lHz, H-1), 3.62 (ddd, 1, J=l0.6, 9.4, 5.1 Hz, H-6), 3.60 (dd, 1, J=9.8, J=l0.8, 5.lHz, H-5), 3.08 (ddd, 1, J=9.0, 8.8, 8.8Hz, H-3), 2.34 (dddd, 1, J=l3.9, 9.0, 7.0, 2.2 Hz, H-2), 2.22 (ddd, 1, J=9.3, 9.0, 8.8Hz, H-3'), 2.06 (dd, 1, J=10.8, 10.6 Hz, HM 5'), 2.02 (dd, 1, J=9.8, 4.5Hz, H-8a), l.7l(dddd, 1, J=l3.9,9.3, 8.8, 2.1 Hz, H-2'); 13C NMR (D2O) δ35.6, 54.5, 58.3, 71.9, 72.5, 73.0, 74.3, 81.9; mass spectrum, m/z(rel intensity) 190 (MH+, 50), 172 (MH+ -H2O, 100).
Reaction SMILES: ClC1C=CC([C:6]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][C:18]([OH:20])=[O:19])=[CH:14][C:13]([F:21])=[CH:12][CH:11]=3)=[O:7])=CC=1.Br[C:25]1[CH:26]=[C:27]([Cl:31])[CH:28]=[CH:29][CH:30]=1>>[Cl:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH2:17][C:18]([OH:20])=[O:19])=[CH:14][C:13]([F:21])=[CH:12][CH:11]=2)=[O:7]
Reactant: Clc1cccc(Br)c1
Reactant: O=C(O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2ccc(F)cc12
Product: O=C(O)Cc1c(C(=O)c2cccc(Cl)c2)[nH]c2ccc(F)cc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 7 from 5-fluoro-2-[(N-methoxy-N-methylamino)carbonyl]indole (Example 21, step 1) and 3-bromochlorobenzene.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([S:13][C:9]2[C:8]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:26])=[O:5])[CH:15]=1
Reactant: CC(C)(C)OC(=O)c1cccc(Sc2cccnc2)c1-c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cccc(Sc2cccnc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
To a 0° C. solution in dichloromethane (1 mL) of 3-pyridylthio-2-phenylbenzoic acid tert-butyl ester (245 mg, 0.67 mmol), prepared as in Example 241 A, and triethylsilane (390 mg, 3.4 mmol) was added trifluoroacetic acid (1.53 g, 13.4 mmol) and the reaction mixture was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was concentrated and azeotroped with toluene (3×) to give 3-pyridylthio-2-phenylbenzoic acid (209 mg) as a translucent film which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.N#N.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[C:49]([Si:51]([CH3:54])([CH3:53])[CH3:52])#[CH:50].C(NC(C)C)(C)C>CCOC(C)=O.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu](I)I.C(Cl)Cl>[Si:14]([O:13][C@H:10]([CH2:11][OH:12])[C@@H:9]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:50]#[C:49][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:3]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Br)c1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: N#Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C#C[Si](C)(C)C)c1)[C@@H](CO)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tert-Butyl (2S,3S)-1-(3-bromophenyl)-3-(tert-butyldimethylsilyloxy)-4-hydroxybutan-2-ylcarbamate (2.09 g, 4.40 mmol) was concentrated under reduced pressure from DCM in a 50-mL RBF. The flask was filled with N2 (g), then PdCl2(PhCN)2 (0.101 g, 0.264 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.153 g, 0.529 mmol), and copper iodide (33.6 mg, 0.176 mmol) were added. The flask was evacuated and refilled with N2 (g). This process was repeated 3×, then a rubber septum was attached. Ar (g)-degassed dioxane (10 mL,) was added, and the flask was sonicated for 5 min to dissolve the starting materials. Ethynyltrimethylsilane (0.915 ml, 6.61 mmol) and diisopropylamine (0.942 ml, 6.61 mmol) were added in sequence, and the resulting black solution was stirred at RT for 4 h. The reaction mixture was diluted with EtOAc and filtered through a pad of celite. The filtrate was evaporated, and the crude product was purified by chromatography on a 120-g Redi-Sep silica gel column, eluting with 5-40% ethyl acetate/hexanes to give tert-butyl (2S,3S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-1-(3-(2-(trimethylsilyl)ethynyl)phenyl)butan-2-ylcarbamate as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH:27]1([O:32][C:33](=[O:47])[C@@H:34]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][CH2:36][CH2:37]Br)[CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])[O-]>C(#N)C.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:37][CH2:36][CH2:35][C@@H:34]([C:33]([O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:47])[NH:39][C:40]([O:42][C:43]([CH3:45])([CH3:46])[CH3:44])=[O:41])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCBr)C(=O)OC1CCCC1
Reactant: Oc1ccc(Br)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCOc1ccc(Br)cc1)C(=O)OC1CCCC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 4-bromophenol (261 mg, 1.510 mmol) in acetonitrile (2 ml) under nitrogen, was added BEMP (397 μl, 1.373 mmol). The mixture was stirred at 50° C. for 30 minutes before being cooled to room temperature and (S)-5-bromo-2-tert-butoxycarbonylamino-pentanoic acid cyclopentyl ester (500 mg, 1.373 mmol) added as a solution in acetonitrile (2 ml). The reaction was heated at 50° C. for a further 1 hour and then the mixture was analysed by LCMS. The reaction was poured onto 2M Na2CO3 (100 ml) and extracted with EtOAc (2×100 ml). The combined organic layers were washed with 2M Na2CO3 (3×100 ml) and brine (100 ml), dried over magnesium sulphate, filtered and concentrated in vacuo to afford a colourless oil. MP-carbonate (1.0 g) was added to a solution of the crude product in dichloromethane (3.4 ml) and the solution was left overnight at room temperature. LCMS indicated complete removal of 4-bromophenol and so the reaction was filtered to remove the MP-carbonate and the resin was washed with DCM (2×50 ml). The filtrate was concentrated to afford the crude product which was purified by column chromatography eluting with 5% EtOAc in iso-hexane. Yield of title compound=435 mg, 0.953 mmol, 69.4% yield. m/z 456 and 458 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.ClCCl.C(=O)([O-])[O-].[K+].[K+].[CH2:35]([S:38](Cl)(=[O:40])=[O:39])[CH2:36][CH3:37]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[O:20][S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: CCCS(=O)(=O)Cl
Reactant: CCn1ncc(C(=O)c2cc(C)c3c(c2C)C(C)CCS3(=O)=O)c1O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Oc1c(C(=O)c2cc(C)c3c(c2C)C(C)CCS3(=O)=O)cnn1CC
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A 30-ml eggplant type flask was charged with 0.25 g (0.69 mmol) of 4,5,8-trimethyl-6-(1-ethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide, 5 ml of dichloromethane, 5 ml of water and 0.09 g (0.69 mmol, 1 equivalent) of potassium carbonate, and 0.11 g (0.76 mmol, 1.1 equivalents) of n-propanesulfonyl chloride was dropwise added with stirring at room temperature. 5 mg of benzyltriethylammonium chloride (BTEAC) was added, and the mixture was allowed to react at the above temperature for 2 hours and then liquid-separated. An aqueous layer was extracted with dichloromethane. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off to give 0.35 g of a crude product, which was recrystalized from ethanol to give 0.31 g (yield 95%) of 4,5,8-trimethyl-6-(1-ethyl-5-n-propanesulfonyloxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 51).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=O)[C:9]3[C:14]([S:15](=[O:19])(=[O:18])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([OH:3])=[O:2].Cl>C(O)(=O)C.[Zn]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C:9]3[C:14]([S:15](=[O:19])(=[O:18])[C:16]=2[CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C2=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)S(=O)(=O)c1ccccc1C2
Reaction time: 2 h

Procedure:
3-Carboxythioxanthone-10,10-dioxide (prepared as in Reference Preparation 4) (5.0 g), zinc wool (10.0 g) and mercuric acetate (0.2 g) in acetic acid (100 ml) were brought to the boil and concentrated hydrochloric acid (10 ml) was added. Vigorous evolution of hydrogen chloride occurred at first. After 2 hr., further hydrochloric acid (7 ml), was added and the mixture boiled under reflux for further 4 hr. It was then filtered while hot and poured on to ice and water. The precipitated product was filtered off and dried at 80° C. in vacuo, m.p. 229°-248° C. Two recrystallisations from methanol gave the product m.p. 254° C.