Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:29])[CH:7]([C:15]1[CH:28]=[CH:27][C:18]2[CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[S:21][C:17]=2[CH:16]=1)[C:8]([O:10]C(C)(C)C)=[O:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:25]([O:24][C:22]([C:20]1[S:21][C:17]2[CH:16]=[C:15]([CH:7]([C:8]([OH:10])=[O:9])[C:6]([OH:29])=[O:5])[CH:28]=[CH:27][C:18]=2[CH:19]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cc2ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(C(C(=O)O)C(=O)O)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Di-tert-butyl[2-(ethoxycarbonyl)-1-benzothien-6-yl]malonate (0.873 g, 2.08 mmol) was dissolved in DCM (5 mL) and TFA (5 mL) was added. The solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue partitioned between saturated NaHCO3-EtOAc. The aqueous phase was acidified with 2N HCl and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give the product (white solid). 1H NMR (DMSO-d6) δ 13.10 (br s, 2H), 8.17 (s, 1H), 8.03 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.47 (dd, J=8.4, 1.8 Hz, 1H), 4.83 (s, 1H), 4.33 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[NH:13]1[CH:17]=[C:16]([CH2:18][OH:19])[N:15]=[CH:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:13]1[CH:17]=[C:16]([CH2:18][OH:19])[N:15]=[CH:14]1
Reactant: OCc1c[nH]cn1
Reactant: COc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(CO)c1

Procedure:
A mixture of 1-fluoro-2-methoxy-4-nitro-benzene (1.0 g, 5.8 mmol), (1H-imidazol-4-yl)-methanol (602 mg, 6.1 mmol) and cesium carbonate (2.86 g, 8.8 mmol) in 40 ml of acetonitrile was refluxed overnight. The reaction mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. Chromatography on Si—NH2 (Isolute) using ethyl acetate as an eluent gave the title compound as a yellowish solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]([NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH2:28])[CH:24]=3)[N:19]=2)[CH2:9]1>>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]([NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:28][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[CH:24]=3)[N:19]=2)[CH2:9]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1ccc2nc(NC3COc4ccccc43)ccc2c1
Product: CN(C)S(=O)(=O)Nc1ccc2nc(NC3COc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from dimethylsulfamoylchloride and rac-N2-(2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine; MS: m/e=385.6 (M+H+).
Reaction SMILES: Cl.[NH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=1)=[NH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:48]=[CH:47][C:27]2[C:28](=O)[C:29](=[CH:42]N(C)C)[CH2:30][N:31]=[C:32]([C:33]3[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=3[F:41])[C:26]=2[CH:25]=1.Cl>O.CO>[Cl:23][C:24]1[CH:48]=[CH:47][C:27]2[C:28]3[N:2]=[C:3]([NH:5][C:6]4[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=4)[N:4]=[CH:42][C:29]=3[CH2:30][N:31]=[C:32]([C:33]3[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=3[F:41])[C:26]=2[CH:25]=1
Reactant: COc1cccc(F)c1C1=NCC(=CN(C)C)C(=O)c2ccc(Cl)cc21
Reactant: COc1cc(NC(=N)N)ccc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2OC)=NC3)ccc1C(=O)O
Temperature: 52.5 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Into a reactor was added 6 (3.81 kg, 15.5 mol), potassium carbonate (4.3 kg, 31.1 mol), 9 (5.27 kg, 14.1 mol) and methanol (63 L). The suspension was warmed to 50 to 55° C. and stirred for a minimum of 24 h until ≧96.0% conversion was obtained by HPLC analysis. Methanol (10 L) and water (37 L) were added while maintaining the temperature between 50 and 55° C. The pH of the mixture was adjusted to 3.0 to 4.0 using 7% w/w HCl (prepared from 7.0 kg of concentrated HCl and 24 L of water) while maintaining the temperature between 50 and 55° C. The suspension was cooled to 20 to 25° C. over a minimum of 1 h and stirred for at least 60 min. The resulting suspension was filtered and washed with water (2×26.3 L) at 50 to 55° C. and methanol (2×10 L) at 20 to 25° C. The wet cake was dried at 45 to 50° C. under vacuum to provide 5.85 kg (80% yield) of Formula (II). 1H NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 10.22 (s, 1H), 8.72 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.80 (dd, J=2.4, 8.9 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.39 (m, 3H), 7.21 (s, 1H), 6.89 (s, 2H), 3.82 (s, 6H); MS (ESI) m/z MS (ESI) m/z 517.2 (M−H+, 45%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])=[CH:9][C:10]([CH3:15])([CH3:14])[O:11]2)=[CH:6][C:5]=1[C:17]([CH3:25])=[C:18]([F:24])[C:19](OCC)=[O:20])[CH3:2].[H-].[CH2:27]([Al+]CC(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])=[CH:9][C:10]([CH3:14])([CH3:15])[O:11]2)=[CH:6][C:5]=1/[C:17](/[CH2:25][CH3:27])=[C:18](/[F:24])\[CH2:19][OH:20])[CH3:2]
Reactant: CC(C)C[Al+]CC(C)C
Reactant: CCOC(=O)C(F)=C(C)c1cc2c(cc1OCC)OC(C)(C)C=C2C
Agent: [H-]
Product: CCOc1cc2c(cc1/C(CC)=C(/F)CO)C(C)=CC(C)(C)O2

Procedure:
Following General Procedure L, ethyl 3-(7-ethoxy-2,2,4-trimethyl-2H-chromen-6-yl)-2-fluoro-but-2-enoate (Compound 80,226 mg, 0.62 mmol) and diisobutylaluminum hydride (1 M in dichloromethane, 1.87 mL, 1.87 mmol) were reacted to give the title compound as yellow solid after purification by flash chromatography (silica gel, 1:4 ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([O:27][CH3:28])[C:21]=3[S:20][C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[N:29]#CBr>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([O:27][CH3:28])[C:21]=3[S:20][C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:10][CH2:9]1)#[N:29]
Reactant: N#CBr
Reactant: COc1cccc2c1Sc1ccccc1C21CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: COc1cccc2c1Sc1ccccc1C21CCN(C#N)CC1

Procedure:
A solution of 1'-benzyl-4-methoxythioxanthene-9-spiro-4'-piperidine (15.48 g.) and cyanogen bromide (4.68 g.) in methylene chloride (155 ml.) is stirred at ambient temperature overnight. The solvent is evaporated in vacuo, the residual gum dissolved in toluene and subjected to chromatography on magnesium silicate (200 g.), eluting consecutively with petroleum ether (b.p. 60°-80° C.) (5 × 200 ml.), toluene (5 × 200 ml.) and chloroform (5 × 200 ml.). The combined chloroform fractions are evaporated in vacuo and the residual gum is triturated with ice-cold ether to give 1'-cyano-4-methoxythioxanthene-9-spiro-4'-piperidine, m.p. 145°-146° C. on recrystallisation from toluene/ether 1/2.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([N:15]([CH3:17])[CH3:16])=[O:14].Cl[C:22]1[CH:31]=[CH:30][N:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26]([CH3:32])=[N:27]2>>[CH3:16][N:15]([CH3:17])[C:13](=[O:14])[C:12]1[CH:18]=[CH:19][CH:20]=[C:10]([S:9][C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[NH:1][C:22]2[C:23]3[C:28](=[N:27][C:26]([CH3:32])=[CH:25][CH:24]=3)[N:29]=[CH:30][CH:31]=2)[CH:11]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2cccc(C(=O)N(C)C)c2)c(N)c1
Product: Cc1ccc(Sc2cccc(C(=O)N(C)C)c2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 88b (0.175 g, 0.610 mmol) was reacted with the product from Example 1d (0.109 g, 0.61 mmol) for 24 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.1552 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.40 (s, 3H) 2.75 (s, 6H) 2.92 (s, 3H) 6.34 (d, J=6.99 Hz, 1H) 7.11-7.53 (m, 7H) 7.76 (d, J=8.82 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 8.94 (d, J=8.82 Hz, 1H); MS (ESI+) m/z 429.0 (M+H)+; (ESI−) m/z 427.0 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:6]=1[CH:7]=[O:8].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:5]2[C:6]([CH:7]=[O:8])=[C:2]([Cl:1])[N:3]=[C:4]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:18][CH:17]=1
Reactant: O=Cc1[nH]c(-c2ccccc2)nc1Cl
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc(Br)cc1
Yield: 71.5 %

Procedure:
3.0 g of 4-chloro-5-formyl-2-phenylimidazole (Chem. Pharm. Bull. 1976, 24(5), 960), 7.0 g of 4-bromobenzyl bromide and 11.7 g of K2CO3 are stirred at RT for 20 h in 200 ml of DMF. The reaction mixture is then poured onto 500 ml of water, and the precipitate is filtered off with suction and chromatographed on silica gel using DIP. 3.9 g of an amorphous foam are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([CH:19]=[O:20])[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1.Cl.[NH2:22][OH:23]>C(O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3([C:19]([NH:22][OH:23])=[O:20])[CH2:18][CH2:17][CH2:16]3)[NH:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=CC1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NO)C1(C2NCCc3c2[nH]c2ccc(Cl)cc32)CCC1

Procedure:
A solution of 1.2 g of the compound obtained in Step A in 120 ml of ethanol, 0.54 ml of triethylamine and 0.27 g of hydroxylarnine hydrochloride is stirred for 6 hours and then concentrated under reduced pressure. Chromatography on silica gel (dichloromethane/ethyl acetate: 98/2) enables the expected product to be isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)(CC=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[CH:26]([OH:29])(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=2)([CH2:26][OH:29])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)(c2ccc(Br)cc2)CC1
Reactant: CC(C)O
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1.78 g of 4-(4-bromo-phenyl)-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester from Step 3 (4.85 mmol, 1 eq) in 25 mL of isopropanol was added NaBH4 (0.201 g, 5.33 mmol, 1.1 eq). The mixture was stirred at room temperature for 20 h and then quenched by the addition of aqueous HCl (20 mL) to pH ˜3. The solvent was removed by rotary evaporation and the resulting aqueous mixture was extracted with three 50 mL portions of ethyl acetate. The organic extracts were combined and washed with saturated brine and dried over Na2SO4. Filtration and concentration by rotary evaporation gave the crude product which was purified by flash column chromatography eluting with a gradient of 5-20% ethyl acetate in hexane to give 1.36 g of the title compound 4-(4-bromo-phenyl)-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester 49 as a pale foam. 1H NMR (300 MHz, CDCl3): δ 7.38-7.18 (m, 4H), 4.35-4.19 (br. d, 2H), 2.83-2.76 (t, 2H), 2.70-2.58 (m, 1H), 1.86-1.78 (d, 2H), 1.70-1.58 (m, 3H), 1.50 (s, 9H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:9]=2[CH:8]=1)=[O:6].Cl[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][C:14]([O:16][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][C:9]=2[CH:8]=1)=[O:6]
Reactant: COC(=O)c1cc2cc(O)ccc2s1
Reactant: ClCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cc(OCc3cccnc3)ccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
Sodium hydride (0.24 g. of 50% dispersion in mineral oil) was added portionwise to a solution of 5-hydroxybenzo[b]thiophene-2-carboxylic acid methyl ester (1.04 g.) in dry N,N-dimethylformamide (10 ml.) and the mixture was stirred at room temperature for 30 minutes. 3-Chloromethylpyridine (0.65 g.) in dry N,N-dimethylformamide (5 ml.) was then added and the mixture was stirred at room temperature for 1 hour, and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed well with water and dried (Na2SO4). Evaporation of the solvent gave a solid which was washed with petrol and crystallized from isopropanol to give 5-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylic acid methyl ester (0.80 g.), m.p. 126°-127° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:12][CH2:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[ClH:16].[N:17]([O-])=[O:18].[Na+]>O>[ClH:16].[CH2:1]([N:5]([CH2:12][CH2:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N:17]=[O:18])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=N[O-]
Reactant: CCCCN(CCCC)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCN(CCCC)c1ccc(N=O)cc1

Procedure:
A solution of N,N-dibutylaniline (10.25 g; 0.05 moles; Aldrich No.: 30,446-8, 97%) in a mixture of concentrated HCl (15 ml; Aldrich No.: 25,814-8, 37%) and distilled water (20 ml) was cooled to −5° C. to −15° C. in a freezing mixture (ice+salt) (Solution A). Sodium nitrite (3.62 g; 0.052 moles; Aldrich No: 43,089-9, granular, 99.5%, DuPont product) was dissolved at room temperature in distilled water (10 ml) and cooled to and kept at 0° C. (Solution B). Cold (0° C.) Solution B was gradually added over 1-2 hours to a magnetically stirred Solution A (at −5 to −15° C.) and the reaction temperature was carefully monitored and not allowed to rise above 0° C. During addition, the reaction mixture changes from pale red to almost black. The mixture was then allowed to attain room temperature over two to three hours. During this time, a dark crystalline mass was deposited. The crystals were collected on Buchner funnel and washed with acetone.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13]>O>[N+:12]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][C:1]2=[O:11])=[CH:6][CH:7]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCCc2ccccc21
Solvent: O
Product: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h

Procedure:
Under ice-cooling, 1-tetralone (15.0 g, 0.103 mol) was gradually added dropwise to fuming nitric acid (100 ml). The reaction mixture was stirred for 30 minutes, which was poured into water. Resulting crystalline precipitate was collected by filtration and washed with water, which was dissolved in ethyl acetate. The solution was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/isopropyl ether to give 7-nitro-1-tetralone. This compound was dissolved in ethanol (100 ml), to which 5% Pd.-C (50% hydrous, 1 g) was added. The mixture was stirred for 2 hours at room temperature under hydrogen atmosphere. The reaction mixture was subjected to filtration, and the filtrate was concentrated. The concentrate was purified by means of a silica gel column chromatography (hexane/ethyl acetate, 3:2), followed by recrystallization from ethyl acetate/isopropyl ether to give 1.70 g (yield from 1-tetralone, 10%) of the above-titled compound, m.p.141-143° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.Cl>CC(C)=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:11][S:8]([C:6]2[S:7][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:10])=[O:9])=[O:23])=[CH:17][CH:16]=1
Reactant: COc1ccc(S(N)(=O)=O)s1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Cl)cc2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
To a solution of 5-methoxy-2-thiophenesulfonamide (7.6 g, 39.4 mmole) in 23 ml of acetone was added aqueous sodium hydroxide (46 ml of 1N, 46 mmole) followed by a solution of 4-chlorophenyl isocyanate (7.91 g, 51.3 mmole) dissolved in 23 ml of acetone. This mixture was stirred at room temperature for 18 hrs. and filtered. The filtrate was acidified with hydrochloric acid (47.5 ml of 1N, 47.5 mmole) and stirred vigorously for 30 min. The resultant precipitate was filtered and washed with water The material was slurried with a minimal amount of ethanol and filtered to produce 8.4 g of a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]1=[N:23]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[OH2:37]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH2:12][CH:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][C:14](=[O:37])[NH:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: O=[N+]([O-])c1ccc(CC2C(=NO)CCc3ccccc32)cc1OCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1CCc2ccccc2C(Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)N1
Temperature: 25 °C

Procedure:
A solution of 1-(3-benzyloxy-4-nitrobenzyl)-3,4-dihydro-1H-naphthalen-2-one oxime (600 mg, 1.49 mmol) in 10 mL CHCl3 is cooled to −50° C. PCl5 (310 mg, 1.49 mmol) is added portionwise over 10 minutes to maintain the temperature below −30° C. The suspension is stirred until it becomes a solution then is warmed to RT and stirred for 2 hours. Water is added and the solution is extracted with CH2Cl2. The organic layer is washed with water, 5% NaOH and brine then is dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 14-100% EtOAc/hexane as eluent to give the title compound as a yellow solid. 1H NMR (CDCl3): 7.85-7.83 (d, J=8.59 Hz, 1H), 7.45-7.20 (m, 8H), 7.09-7.07 (d, J=7.58 Hz, 1H), 6.88-6.86 (dd, J=1.52 Hz, 8.34 Hz, 2 H), 5.80-5.79 (d, J=4.80 Hz, 1H), 5.22-5.14 (q, J=12.12, 2H), 4.74-4.69 (m, 1H), 3.37-3.32 (q, J=5.56 Hz, 1H), 3.19-3.08 (m, 2H), 3.04-2.97 (m, 1H), 2.81-2.65 (m, 2H). (M−1)−=401.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI.[Cl-].[NH4+]>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[N:16]([CH3:1])[S:15]2(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCC1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Potassium t-butoxide (1.83 g, 14.9 mmol) was added to a solution of 2-phenylmethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (4 g, 14.9 mmol) in 150 ml of THF at 0° C. and the mixture was stirred for 1 hour at the same temperature. To the above mixture was added 10.58 g (74.6 mmol) of methyl iodide, and the reaction mixture was stirred at 0° C. for 0.5 hour, at room temperature for 6 hours, and decomposed with saturated ammonium chloride solution. The resulting mixture was extracted with methylene chloride and the organic layer was washed with brine, dried, and concentrated in vacuo to afford 4.19 g (quantitative) of 2-phenylmethyl-5-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IX: R1 =propyl; R2 =H; R3 =CH3).
Reaction SMILES: [C:1]1([CH:7]([NH:14][CH:15]2[CH2:20][CH2:19][N:18](C(OCC)=O)[CH2:17][CH2:16]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:8]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)N1CCC(NC(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1ccc(C(NC2CCNCC2)c2ccccc2)cc1

Procedure:
A solution of ethyl 4-[(diphenylmethyl)amino]-1-piperidinecarboxylate (42 g) and sodium hydroxide (50 g) in methanol (300 mL) was refluxed for 24 hours. This reaction mixture was diluted with water and extracted with chloroform. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure to give N-(diphenylmethyl)-4-piperidinamine. This product was converted to the dihydrochloride using 4N-HCl solution in ethanol and the precipitate was collected by filtration and dried to provide 31 g of the title compound. Yield 73%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Br[CH:21]([C:23]1[CH:24]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:27][CH:28]=1)[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: CC(Br)c1cccc(C(F)(F)F)c1
Product: CC(C)C[C@H](CO)Nc1nc(SC(C)c2cccc(C(F)(F)F)c2)nc2nc(N)sc12
Yield: 81 %

Procedure:
The title compound was synthesized as a mixture of two diastereomers by general method A from the reaction of (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (30 mg, 0.1 mmol) with 3-(1-bromoethyl)trifluoromethylbenzene (15.5 μL, 0.1 mmol) to give 38 mg (81% yield) as an oil.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OC([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=O)(C)(C)C.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH2:61])[CH2:59][CH3:60])=[CH:54][CH:53]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[NH2:32][C:33]1([C:48]([NH:61][CH:58]([C:55]2[CH:54]=[CH:53][C:52]([Cl:51])=[CH:57][CH:56]=2)[CH2:59][CH3:60])=[O:50])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: CCC(N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.209 g) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (0.181 g), 1-(4-chlorophenyl)propan-1-amine (0.085 g) and DIPEA (0.262 mL) in DMA (10 mL) at 25° C. under nitrogen. The resulting solution was stirred at 60° C. for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. This crude material was then treated with a 20% solution of TFA in DCM (10 mL) and stirred at room temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness. This material was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)propyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide as a white solid (0.138 g, 66.8