Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23](Cl)(=[O:25])=[O:24])[CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.O>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)(=[O:25])=[O:24])[CH:3]=1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Cl)cc1CS2(=O)=O
Reactant: C1COCCN1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)N3CCOCC3)cc1CS2(=O)=O

Procedure:
A mixture of Example 49j (0.2 g, 0.45 mm) and morpholine (0.08 mL, 0.9 mmol) in dry ethyl acetate (25 mL) was stirred overnight at room temperature, treated with water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous HCl (50 mL), water, brine, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound. Yield: 0.19 g, (86%); 1H NMR (DMSO-d6): δ 2.80 (s, 3H, CH3), 3.0 (t, 4H, 2CH2), 3.7 (s, 4H, 2CH2), 5.5 (s, 2H, CH2), 8.0 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.2 (s, 2H, Ar). MS: m/e (EI+) 487 (M+).
Reaction SMILES: CS(Cl)(=O)=O.[N:6]([CH2:9][C@H:10]1[C:15]2[C:16]([CH3:22])=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:14]=2[CH2:13][C@@H:12]([CH2:23]O)[O:11]1)=[N+:7]=[N-:8].[CH2:25]([N:27](CC)[CH2:28][CH3:29])[CH3:26]>C(Cl)Cl.C(OCC)C>[N:6]([CH2:9][CH:10]1[C:15]2[C:16]([CH3:22])=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:14]=2[CH2:13][CH:12]([CH2:23][N:27]2[CH2:28][CH2:29][CH2:26][CH2:25]2)[O:11]1)=[N+:7]=[N-:8]
Reactant: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CN=[N+]=[N-]
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C)c2c1CC(CN1CCCC1)OC2CN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.146 mL, 1.89 mmol) is added dropwise to a solution of 0.453 g (1.72 mmol) of [1R,3S] 1-azidomethyl-3,4-dihydro-3-hydroxymethyl-5-methoxy-8-methyl-1H-2-benzopyran, the product of Step 4 of Example 142, and 0.36 mL (2.58 mmol) of triethylamine in 15 mL of methylene chloride at 0° C. The reaction mixture is stirred for 30 min at 0° C. then transferred to a separatory funnel and diluted with 45 mL of diethyl ether. The layers are separated and the organic layer is washed with 2×20 mL of water, 2×20 mL of 1 N hydrochloric acid and 20 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in 20 mL of N,N-dimethyl formamide (DMF) and an excess amount of pyrrolidine is added to this solution. The reaction mixture is heated at 95° C. for 2.5 h then poured into 75 mL of water. The aqueous solution is extracted with 3×40 mL of diethyl ether. The combined ether extracts are washed with 2×30 mL of water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluted to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH:10]1[CH2:13][CH2:12][CH2:11]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:10]2[CH2:13][CH2:12][CH2:11]2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: BrC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1cnn(C2CCC2)c1
Temperature: 25 °C

Procedure:
To a cooled (0 C) stirred solution of 4-bromo-1H-pyrazole (5.360 g, 36.47 mmol) in DMF (50 mL) was added sodium hydride (1.925 g, 80.23 mmol) slowly. The mixture was allowed to stir in the ice bath 30 min and bromocyclobutane (3.433 ml, 36.47 mmol) was added. The vessel was sealed and the reaction mixture heated at 95 C for 23 h. The mixture was allowed to cool to rt and diluted with 200 mL EtOAc, washed with 500 mL water, then 2×100 mL water, sat NaHCO3, then the organic layer dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a CH2Cl2 in hexanes gradient. (I2 stain for visualization). The title compound was collected as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[NH:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[H-].[Na+].I[CH2:26][CH2:27][CH3:28]>CN(C=O)C>[N:16]1([CH2:15][CH2:14][CH2:13][CH2:12][C:11]2[N:10]([CH2:26][CH2:27][CH3:28])[C:3]3[CH:4]=[C:5]([C:8]#[N:9])[CH:6]=[CH:7][C:2]=3[N:1]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCCI
Reactant: N#Cc1ccc(N)c(NC(=O)CCCCN2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(CCCCN2CCCCC2)nc2ccc(C#N)cc21
Temperature: 25 °C

Procedure:
The compound (1.04 g) obtained in Example 61-2 was dissolved in DMF (31.2 ml) and added with 60% sodium hydride (0.166 g) and 1-iodopropane (0.405 ml) while the whole was being stirred under ice-cooling. The solution was warmed to room temperature and stirred for 15 hours. The reaction solution was poured in ice-cold water and subjected to separation/extraction with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was again dissolved in a 4 mol/l hydrogen chloride/dioxane solution (10 ml) and the whole was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and a saturated saline solution. Then, the resultant was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified′through silica gel column chromatography (chloroform), thereby obtaining the subject compound (451.8 mg) as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:14][CH2:15][C:16](Cl)=[O:17].Cl>CCOC(C)=O.O>[Cl:14][CH2:15][C:16]([C:5]1[CH:4]=[C:3]([CH3:9])[C:2]([F:1])=[CH:7][C:6]=1[F:8])=[O:17]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(F)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(=O)CCl)c(F)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 2,4-difluorotoluene was added 6.3 g (47.3 mmol) of AlCl3, and 3.4 mL (42.6 mmol) of chloroacetyl chloride at 0° C. After the mixture was stirred for 10 min. at 0° C. and then at 45° C. for 30 min. The mixture was allowed to cool to r.t., about 16 mL of conc. HCl, 25 mL of water, and 100 mL of EtOAc were added. The organic layer was separated and washed with brine and sat. NaHCO3 (2×), and dried over Na2SO4. The solution was filtered and concentrated to give 9.0 g of 2-chloro-1-(2,4-difluoro-5-methylphenyl)ethanone as a colorless solid that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:70]1([CH2:76][CH2:77][NH2:78])[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([C:25](=[O:26])[NH:78][CH2:77][CH2:76][N:70]4[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]4)[CH3:27])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Reactant: NCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NCCN2CCCCC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (2 mL) was added 2-piperidin-1-yl-ethylamine (24 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (7 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[OH:22][CH2:23][C@@H:24]1[O:28][C:27]([C:29]2[NH:33][C:32]([C:34]3[CH:35]=[C:36]([OH:46])[CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=3)=[CH:31][CH:30]=2)=[N:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:22][CH2:23][C@@H:24]1[O:28][C:27]([C:29]2[NH:33][C:32]([C:34]3[CH:35]=[C:36]([CH:37]=[C:38]([O:40][C@@H:41]([CH3:45])[CH2:42][O:43][CH3:44])[CH:39]=3)[O:46][C:2]3[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=3)=[CH:31][CH:30]=2)=[N:26][CH2:25]1
Reactant: COc1ccc(CN(C)S(=O)(=O)c2ccc(Cl)cn2)cc1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
5-Chloro-N-(4-methoxybenzyl)-N-methylpyridine-2-sulfonamide (427 mg, 1.31 mmol) synthesized in Example (121b) and 3-{5-[(5R)-5-(hydroxylmethyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-[(1S)-2-methoxy-1-methylethoxy]phenol (568 mg, 1.64 mmol) synthesized in Example (125g) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (361 mg, 2.61 mmol) was added, followed by stirring at 100° C. for 2 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (40 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-3.5%) to afford the desired compound (228 mg, yield 27%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][CH2:17][C@@H:18]([C:20]([O:22]CC2C=CC=CC=2)=[O:21])[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[O:16][CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[N:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1COC(c2ccccc2OCc2ccccc2)=N1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1COC(c2ccccc2OCc2ccccc2)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixture of benzyl ester (1) (25.7 mg, 0.0664 mmol) in 1:1 THF/H2O (3 mL) at 0° C. was added LiOH (9 mg, 0.348 mmol, 1.5 equiv.). The reaction mixture was stirred for 1 h at room temperature. The desired product (3) was obtained in 99% yield after purification by column chromatography (CH2Cl2/MeOH=85:15). FABMS: 298 (M+1); HREIMS calcd. for C17H15NO4 298.1079, found 298.1078.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.Br[C:17]1[C:18]([NH2:24])=[N:19][CH:20]=[C:21]([Br:23])[N:22]=1.CCN(CC)CC>CS(C)=O>[NH2:24][C:18]1[C:17]([NH:1][CH2:2][C@H:3]2[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]2)=[N:22][C:21]([Br:23])=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)C1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(Br)cnc2N)C1
Temperature: 150 °C
Reaction time: 9 h
Yield: 69.9 %

Procedure:
(R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (26 g, 124.83 mmol) was dissolved in DMSO (300 ml), and 3,5-dibromopyrazine-2-amine (37.8 g, 149.79 mmol) and Et3N (20.9 ml, 149.79 mmol) were added, followed by stirring at 150° C. for 9 hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (EA:Hex=1:1), to give (R)-tert-butyl 2-(((3-amino-6-bromopyrazine-2-yl)amino)methyl)morpholine-4-carboxylate (33.9 g, 70%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[C:18]([NH:20][CH:21]3[CH2:23][CH2:22]3)[N:17]3[N:24]=[CH:25][C:26]([CH:27]=[O:28])=[C:16]3[N:15]=2)=[CH:11][CH:10]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.O>CN(C=O)C>[CH:21]1([NH:20][C:18]2[N:17]3[N:24]=[CH:25][C:26]([CH:27]=[O:28])=[C:16]3[N:15]=[C:14]([C:12]3[S:13][C:9]([CH2:8][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:10][CH:11]=3)[CH:19]=2)[CH2:23][CH2:22]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(CBr)s3)nc12
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(CN4CCCC4)s3)nc12
Temperature: 60 °C
Yield: 50.5 %

Procedure:
Potassium carbonate (30 mg, 0.20 mmol) was added to 5-(5-(bromomethyl)thiophen-2-yl)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (25 mg, 0.07 mmol) dissolved in DMF (0.7 mL). Pyrrolidine (6μL, 0.07 mmol) was added and the reaction was heated to 60° C. for 4 h. Water (3 mL) was added and the orange precipitate was filtered and dried in vacuo to give 7-(cyclopropylamino)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (13 mg, 54%) which was used without further purification. LCMS (ES): >85% pure, m/z 368 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([NH:4][C:5]([C:7]1[N:8]([CH3:13])[CH:9]=[C:10]([NH2:12])[N:11]=1)=[O:6])[CH3:3].[CH3:14][N:15]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=[C:16]1[C:23](Cl)=[O:24]>C1COCC1.C(Cl)Cl>[CH3:3][N:2]([NH:4][C:5]([C:7]1[N:8]([CH3:13])[CH:9]=[C:10]([NH:12][C:23]([C:16]2[N:15]([CH3:14])[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[N:17]=2)=[O:24])[N:11]=1)=[O:6])[CH3:1]
Reactant: Cn1cc([N+](=O)[O-])nc1C(=O)Cl
Reactant: CN(C)NC(=O)c1nc(N)cn1C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)NC(=O)c1nc(NC(=O)c2nc([N+](=O)[O-])cn2C)cn1C
Temperature: -20 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
The amine from above was dissolved in dry THF (20 mL) and cooled to -20° C. The stirring reaction mixture was placed under argon and a solution of 1-methyl-4-nitroimidazole-2-carbonyl chloride (2.18 g, 11.5 mmol) in dry CH2Cl2 (10 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred overnight then concentrated to dryness and water was added. The suspension was filtered and the solid was washed with carbon tetrachloride and water, then dried in-vacuo (80° C.) to provide N-(N',N'-dimethylamino)-1-methyl-4-[1-methyl-4-nitroimidazole-2-carboxamido]imidazole-2-carboxamide as a pale yellow crystalline solid, 2.18 g (68.8% yield). A sample for analysis was obtained by recrystallization from water: mp 239° C. (dec.). TLC (5% MeOH/CHCl3) Rf 0.66. 1H--NMR (CDCl3); δ2.69 (s, 6H, N(CH3)2), 4.07 (s, 3H, N--CH3), 4.21 (s, 3H, N--CH3), 7.43 (s, 1H, NH). IR (nujol: υ3397 and 1678 cm-1. MS(El) m/z (rel. intensity) 336 (M+, 100), 293 (M+1-N(CH3)2, 85).
Reaction SMILES: [CH:1]([S:14]([CH2:16][C:17]([O-:19])=O)=[O:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:20]>>[CH:1]([S:14]([CH2:16][C:17]([NH2:20])=[O:19])=[O:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C([O-])CS(=O)C(c1ccccc1)c1ccccc1
Product: NC(=O)CS(=O)C(c1ccccc1)c1ccccc1

Procedure:
Lafon also disclosed the use of an intermediate, a racemic mixture of benzhydrylsulphinylacetic acid to prepare an isomer of modafinil in U.S. Pat. No. 4,927,855, referring to French patent 2,326,181B. The racemic mixture of the acid was reacted with the (−)-α-methylbenzylamine to provide the (−)-benzhydrylsulphinylacetate of (−)-methylbenzylamine which is acidified with concentrated hydrochloric acid to provide (−)benzyhydrylsulphinylacetic acid. The levo-acid thus produced was then reacted with methylsulfate in water and sodium bicarbonate to provide methyl(−)benzhydrylsulphinylacetate. The acetate was then amidated with ammonia gas to provide (−)benzhydrylsulphinylacetamide.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:35][N:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)N>>[CH3:1][CH:2]([CH3:34])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:36]([CH3:35])[C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(C(F)(F)F)cc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]propanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 562.2 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][C@H:11]([CH2:16][OH:17])[C@H:12]([CH2:14][CH3:15])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:17][CH2:16][C@@H:11]([NH:10][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:7])[C@@H:12]([CH3:13])[CH2:14][CH3:15]
Reactant: CC[C@H](C)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-thiophenesulfonyl chloride (1 g, 5.48 mmol) in CH2Cl2 (5 mL) and (S)-isoleucinol (642 mg, 5.48 mmol) was added Hunig's base (1.05 mL, 6.02 mmol). The reaction mixture was stirred at 25° C. for 24 h. The solvent was removed and the oil was dissolved in EtOAc (100 mL). The solution was washed with water (2×100 mL), brine (1×100 mL), and dried over Na2SO4. The desired sulfonamide (m/z=264.0 (M+H), rt=0.79 min) was isolated by semi-preparative RP-HPLC using the conditions outlined for example 195.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-]>CC(OC)(C)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C@H:6]2[CH2:7][C@@H:12]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccc(Br)cc1
Solvent: COC(C)(C)C
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a 1-neck, 1-L round bottom flask equipped with a magnetic stirrer was added 265 mL methyl tert-butyl ether. The flask was evacuated and flushed with nitrogen three times. 2,2′-Isopropylidenebis[(4R)-4-tert-butyl-2-oxazolidine] (2.39 g, 8.03 mmol) was added, followed by copper(I) tridluoromethanesulfonate benzene complex (4.49 g, 8.03 mmol). The green suspension was stirred at room temperature for about 2 hours and was then filtered. The filtrate was added to a 4-neck, 5-L, round bottom flask equipped with a mechanical stirrer, thermocouple, nitrogen bubbler, and addition funnel. Then, 4-bromostyrene (150 g, 0.803 mol) was added to this solution and the reaction was cooled to 0° C. via an ice/water bath. Ethyl diazoacetate (167 mL, 1.606 mol) was dissolved in 1675 mL of MTBE and the solution was evacuated/flushed with nitrogen three times. This solution was then added to an addition funnel and added dropwise to the reaction mixture. A slight exotherm was observed. The ethyl diazoacetate was allowed to add slowly over the weekend and the reaction slowly warmed to room temperature. The reaction was poured into a large extractor and diluted with 4 L MTBE. The organics were washed with 2×1 L 3% aq. ammonium hydroxide and 2 L brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was dissolved in heptane and a small amount of dichloromethane, injected onto an ISCO 1500 g column prepacked in heptane. The column was eluted with 100% heptane over 1 column volume, 0-20% ethyl acetate/heptane over 6.5 column volumes, and held at 20% ethyl acetate/heptane over 8 column volumes. The product containing fractions were collected and concentrated to give 191 g (yield 88%) of the title compound. 1H NMR (500 MHz, (CDCl3): 7.42 (d, 2H), 7.01 (d, 2H), 4.21 (q, 2H), 2.49 (m, 1H), 1.88 (m, 1H), 1.62 (m, 2H), 1.25 (t, 3H).
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:4]=[C:3]2[S:12]([NH:15][CH2:16][NH:17][C:2]=12)(=[O:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26](OCC)=[O:27]>CN(C=O)C>[Cl:7][C:6]1[C:5]([S:8]([NH2:11])(=[O:9])=[O:10])=[CH:4][C:3]2[S:12](=[O:14])(=[O:13])[N:15]([CH2:25][CH2:26][OH:27])[CH2:16][NH:17][C:2]=2[CH:1]=1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)NCNS2(=O)=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc2c(cc1Cl)NCN(CCO)S2(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a solution of hydrochlorothiazide (ONBIO, Inc., Ontario, Canada) (13.82 g, 46.4 mmol) in DMF (50 mL) was added cesium carbonate (7.51 g, 23.0 mmol) and ethyl bromoacetate (7.69 g, 46.1 mmol) and the mixture was stirred for 18 hours at room temperature. The solids were removed via suction filtration, and the solvent was evaporated under vacuum. The resulting residue was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was recrystallized from ethyl acetate/ether to give the title product (10.9 g, 61% yield) as white needles: mp 199-203° C.; 1H NMR (400 MHz, d6-DMSO) δ 8.07 (s, 1H), 8.01 (s, 1H), 7.53 (s, 2H), 7.08 (s, 1H), 4.97 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 1.19 (t, J=7.1 Hz, 3H); Mass spectrum (API-TIS) m/z 384 (MH+), 401 (MNH4+), 784 (2MNH430).
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CCCCCC.[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21]>>[C:1]1([CH2:21][C:20]([O:23][CH2:24][CH3:25])=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)Cc1cccc2ccccc12

Procedure:
Ethyl 1-naphthaleneacetate was prepared by the general experimental method from 1-naphthaleneboronic acid (172 mg, 1.00 mmol). After workup by column chromatography (hexane/ethyl acetate, 5:1), ethyl 1-naphthaleneacetate is obtained as a colourless liquid in a yield of 77% of theory. 1H NMR (600 MHz, CDCl3): δ=8.04 (d, J=8.3 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.80-7.84 (m, 1H), 7.55-7.58 (m, 1H), 7.50-7.54 (m, 1H), 7.43-7.47 (m, 2H), 4.16-4.20 (m, 2H), 4.09 (s, 2H), 1.23-1.27 (m, 3H) ppm; 13C NMR (151 MHz, CDCl3): δ=171.7, 133.9, 132.2, 130.8, 128.8, 128.1, 128.0, 126.4, 125.8, 125.6, 123.9, 61.0, 39.4, 14.3 ppm; MS (70 eV), m/z (%): 214 (100) [M+], 141 (34), 115 (45), 89 (9), 63 (6); IR (NaCl): ν=3047 (w), 2981 (m), 1733 (s), 1173 (m), 1029 (m) cm−1, elemental analysis: (theor): C=78.48, H=6.59, (exp): C=78.35, H=6.86.