Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=C([O:4][C:5](=O)[NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:14]([CH3:25])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][N:19]=[C:18]([NH:23][CH3:24])[CH:17]=3)[C:10]([CH3:26])=[CH:9][C:8]=1[F:27])C.C(O)(=O)C.C(O)(=O)C.[F:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41].CN1CCCC1>C1COCC1>[F:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH:41][C:5]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:14]([CH3:25])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][N:19]=[C:18]([NH:23][CH3:24])[CH:17]=3)[C:10]([CH3:26])=[CH:9][C:8]=1[F:27])=[O:4]
Reactant: CC(C)(F)CCN
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)cc3nc2C)c(C)cc1F
Agent: CN1CCCC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1cc2nc(C)c(-c3cc(NC(=O)NCCC(C)(C)F)c(F)cc3C)cc2cn1
Yield: 70.9 %

Procedure:
Combine prop-1-en-2-yl(2-fluoro-4-methyl-5-(2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl)phenyl)carbamate (2.5 g, 6.6 mmol), 3-fluoro-3-methylbutan-1-amine diacetate (1.8 g, 7.9 mmol), and N-methylpyrrolidine (2.7 mL, 26.0 mmole) in THF (50 mL) and heat at 50° C. overnight. Evaporate under reduced pressure and partition between NaHCO3 and EtOAc. Wash the organic layer with brine, dry over Na2SO4, concentrate in vacuo, and purify by silica gel chromatography (50-100% EtOAc/DCM) to obtain the title compound (2.0 g, 71%). 1H NMR (400 MHz, DMSO-d6): δ 8.82 (s, 1H), 8.33 (s, 1H), 7.93 (d, J=8 Hz, 1H), 7.83 (s, 1H), 7.16 (d, J=8 Hz, 1H), 6.73 (m, 1H), 6.56 (m, 1H), 6.52 (s, 1H), 3.15 (m, 2H), 2.82 (d, J=5 Hz, 3H), 2.27 (s, 3H), 1.94 (s, 3H), 1.73 (m, 2H), 1.30 (d, J=21.6 Hz, 6H); MS (ESI) m/z: 428.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([Cl:12])(=[O:11])=[O:10].[N:15]1C=CC=CC=1.C(OC(=O)N[CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[C:42]3[O:41][CH:40]=[CH:39][C:38]=3[CH:37]=[C:36]([NH2:43])[CH:35]=2)[CH2:30][CH2:29]1)(C)(C)C>C(Cl)Cl>[ClH:12].[NH2:15][CH:32]1[CH2:33][CH2:28][CH2:29][CH2:30][N:31]1[C:34]1[C:42]2[O:41][CH:40]=[CH:39][C:38]=2[CH:37]=[C:36]([NH:43][S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:14])([F:13])[F:1])(=[O:11])=[O:10])[CH:35]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(N)cc3ccoc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: c1ccncc1
Solvent: ClCCl
Product: Cl
Product: NC1CCCCN1c1cc(NS(=O)(=O)c2ccccc2C(F)(F)F)cc2ccoc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(Trifluoromethyl)benzenesulfonyl chloride (89.0 mg, 0.36 mmol) and pyridine (219 mL) were added to tert-butyl[1-(5-amino-1-benzofuran-7-yl)piperidin-4-yl]carbamate (100.0 mg, 0.30 mmol; Intermediate 49) in DCM (1 mL). The mixture was shaken at room temperature for 1 h, solvent removed in vacuo and the residue was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. N-deprotection and conversion into the hydrochloride salt was performed by treatment with 2 M HCl in ether. This furnished 76.1 mg (57%) of the title product. HPLC 100%, RT: 1.834 (System A; 10-97% MeCN over 3 min). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.70-1.72 (m, 2H) 2.00-2.02 (m, 2H) 2.78 (t, J=11.30 Hz, 2H) 3.21 (s, 1H) 3.71 (d, J=12.56 Hz, 2H) 6.60 (d, J=1.88 Hz, 1H) 6.83 (d, J=2.20 Hz, 1H) 6.85-6.91 (m, J=1.88 Hz, 1H) 7.80-7.81 (m, 2H) 7.88-7.89 (m, 1H) 7.96-7.98 (m, 1H) 8.08-8.10 (m, 4H) 10.40 (s, 1H). LC-MS 440 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[F:16][C:17]1([F:21])[CH2:20][NH:19][CH2:18]1.[C:22]12([C:32](Cl)=[O:33])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[O:23]1)[CH2:29]2.C(N(CC)CC)C>C(#N)C>[F:16][C:17]1([F:21])[CH2:20][N:19]([C:4]([C:3]2[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:2]=2[NH:1][C:32]([C:22]23[CH2:31][CH:26]4[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]4)[O:23]2)[CH2:29]3)=[O:33])=[O:6])[CH2:18]1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(N)c1
Reactant: FC1(F)CNC1
Reactant: O=C(Cl)C12CC3CC(CC(C3)O1)C2
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(=O)N2CC(F)(F)C2)c(NC(=O)C23CC4CC(CC(C4)O2)C3)c1

Procedure:
2-Amino-4-(methylsulfonyl)benzoic acid (0.25 g) and 3,3-difluoro-azetidine hydrochloride (0.19 g) were reacted according to the method described in Example 332C. The resultant intermediate (0.14 g) was then reacted with 2-oxaadamantane-1-carbonylchloride (1.25 equiv) (prepared from 2-oxaadamantane-1-carboxylic acid and thionyl chloride as in Example 12) and triethylamine (2 equiv) in acetonitrile (10 mL). Evaporation of solvents and flash chromotography over silica gel (10% ethyl acetate/hexane) provided 110 mg of the title compound. 1H NMR (dimethylsulfoxide-d6, 300 MHz) δ 1.66-2.03 (m, 10H), 2.19 (br s, 2H), 3.25 (s, 3H), 4.43-4.57 (br, 2H), 4.63-4.70 (br, 2H), 7.66 (dd, 1H), 7.82 (d, 1H), 8.79 (d, 1H), 10.76 (s, 1H); MS (ESI+) m/z 455 (M+H)+.
Reaction SMILES: C([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([NH2:22])[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=O)C(C)(C)C.CCO.C1COCC1>O>[NH2:22][C:20]1[S:21][C:17]2[C:16]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)=[C:15]([C@H:9]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:8][OH:7])[C:24]([CH3:25])=[CH:23][C:18]=2[N:19]=1
Reactant: Cc1cc2nc(N)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2nc(N)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
A flask was charged with (S)-2-(2-Amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (2.15 g, 4.52 mmol), LiOH monohydrate (2.00 g, 47.4 mmol), H2O (4 mL), EtOH (absolute, 4.0 mL), and THF (8.0 mL). The reaction was placed under N2 and heated to 100° C. After 2 h, the reaction was cooled to 23° C., diluted with H2O, and extracted with EtOAc several times. The combined organic phases were dried (Na2SO4), filtered, and concentrated. The residue was treated with benzene and purified via chromatography on silica gel (80 g “gold” ISCO column; Hex/EtOAc) giving (S)-2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethanol (1.10 g, 62% yield). LCMS-ESI+: calc'd for C20H23ClN2O2S: 391.1 and 393.1 (M+H+); found: 391.2 and 393.2 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: 7.49-7.41 (m, 2H), 7.36-7.32 (m, 2H), 7.20 (d, J=7.3 Hz, 1H), 5.39 (s, broad, 2H), 4.52-4.50 (m, 1H), 3.85-3.70 (m, 2H), 2.63 (s, 3H), 0.99 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]([C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[C:28]([CH3:41])[CH:27]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2([O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:8]([CH3:25])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:42][O:43][C:44](=[O:53])[CH2:45][C:46]1[CH:47]=[N:48][CH:49]=[C:50](Br)[CH:51]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:42][O:43][C:44](=[O:53])[CH2:45][C:46]1[CH:47]=[N:48][CH:49]=[C:50]([C:29]2[CH:30]=[CH:31][C:26]([C:3]([CH2:4][CH3:5])([C:6]3[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]4([O:20][Si:21]([CH3:23])([CH3:24])[CH3:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)=[C:8]([CH3:25])[CH:7]=3)[CH2:1][CH3:2])=[CH:27][C:28]=2[CH3:41])[CH:51]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 140 °C
Yield: 62.6 %

Procedure:
A solution of 2-(4-{1-ethyl-1-[3-methyl-4-(1-trimethylsilanyloxy-cyclohexylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 35-(4); 57.6 mg, 0.10 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 30.1 mg, 0.13 mmol), tetrakistriphenylphosphine palladium (14.1 mg, 0.0122 mmol) and potassium phosphate (27.8 mg, 0.13 mmol) in N,N-dimethylformamide (0.27 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the mixture was purified by silica gel chromatography (45% ethyl acetate/hexane) to give the title compound (37.3 mg, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:32])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:15][CH2:14][C:13]([F:32])([F:12])[CH2:18][CH2:17]1)[C:22]1[CH:27]=[N:26][C:25]([C:28]([F:29])([F:30])[F:31])=[N:24][CH:23]=1)=[O:6]
Reactant: O=C(O)c1c(F)cccc1Cl
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1)c1c(F)cccc1Cl

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2-chloro-6-fluorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound. LCMS (MH+): m/z=466.1, tR (minutes, Method F)=2.97. [α]D20=+36.00 (c=1.50 mg/mL,CHCl3)
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH:10]1[C@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14][C@@H:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=2[F:32])[CH2:12][NH:11]1)#[N:9].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+]>ClCCl>[C:33]([N:11]1[CH2:12][C@H:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=2[F:32])[CH2:14][CH2:15][C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]1[C:8]#[N:9])(=[O:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1C#N
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.8 %

Procedure:
Triethylamine (1.29 mL, 9.25 mmol) was added to a solution of tert-butyl [(3R,6S)-2-cyano-6-(2,3-difluorophenyl)azepan-3-yl]carbamate (0.65 g, 1.85 mmol) in dichloromethane (20 mL) at 0° C. Acetic anhydride (0.53 mL, 5.55 mmol) was added and the mixture was allowed to warm to ambient temperature. After 16 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (99% dichloromethane/ethyl acetate→70% dichloromethane/ethyl acetate) gave the title compound (144 mg). MS 394.1 (M+1).
Reaction SMILES: C(C1C2C(=CC(OC)=CC=2)CCC1C(CC1C=CC=CC=1)=O)#N.[C:24]([CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28][CH:27]1[C:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=1)=O)#[N:25]>>[CH3:45][C:41]1[CH:40]=[C:39]([CH2:38][CH:36]2[CH:27]3[CH:26]([C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:29][CH2:28]3)[CH2:24][NH:25]2)[CH:44]=[CH:43][CH:42]=1
Reactant: Cc1cccc(CC(=O)C2CCc3ccccc3C2C#N)c1
Agent: COc1ccc2c(c1)CCC(C(=O)Cc1ccccc1)C2C#N
Product: Cc1cccc(CC2NCC3c4ccccc4CCC23)c1

Procedure:
Following the procedures described in Step 2 of Example 6, replacing 1-cyano-6-methoxy-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalene (the product of Step 1 of Example 6) with the product of Step 1 above, 1-cyano-2-(3-methylphenyl)methylcarbonyl-1,2,3,4-tetrahydronaphthalene, the title compound was prepared; MS DCI-NH3M/Z: 278 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:8]=[C:9]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[C:10]=1[N:11]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH3:12])=[O:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:11]([CH3:12])[C:10]2[C:9]([CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)=[CH:8][C:7]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])(=[O:15])=[O:14])=[CH:21][CH:20]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(CN3CCN(C)CC3)cc(-c3ccccc3)cc2C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(CN3CCN(C)CC3)cc(-c3ccccc3)cc2C(=O)O)cc1
Yield: 88 %

Procedure:
A mixture of 0.965 g (1.72 mmol) of the product of Example 74 and 8.6 mL (8.59 mmol) of 1N NaOH in 8.6 mL of THF and 8.6 mL of methanol was heated to reflux for 18 h. The reaction mixture was cooled and neutralized with 3N HCl. The organic solvents were removed and the resulting aqueous solution was extracted with dichloromethane. The organic layer was separated, washed with water and brine, dried over Na2CO3 and concentrated in vacuo. The residue was triturated with ether to provide 0.829 g (89%) of the desired product as a cream solid. Electrospray Mass Spec 548.1 (M+H)+
Reaction SMILES: [C:1](=[O:11])(SCC)[O:2][CH2:3][O:4][C:5](=[O:7])[CH3:6].S(Cl)([Cl:15])(=O)=O>>[C:1]([Cl:15])(=[O:11])[O:2][CH2:3][O:4][C:5](=[O:7])[CH3:6]
Reactant: CCSC(=O)OCOC(C)=O
Reactant: O=S(=O)(Cl)Cl
Product: CC(=O)OCOC(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 112.4 %

Procedure:
To the thioester from Step 3 (2.50 g, 14.0 mmol) cooled to 0° C. is added sulfuryl chloride (1.5 mL, 18.25 mmol) over 2 min. The reaction mixture is stirred at 0° C. for 30 min then at RT for 2.5 h. The reaction mixture is concentrated and then dried on house vacuum overnight to afford 2.4 g of the desired crude product, which is used without further purification. 1H NMR (CDCl3) δ 5.83 (s, 2H), 2.19 (s, 3H);
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[S:11][C:12]([CH3:15])=[N:13][N:14]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>>[CH3:1][O:2][N:3]=[C:4]([C:10]1[S:11][C:12]([CH3:15])=[N:13][N:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1nnc(C)s1
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1nnc(C)s1
Yield: 71.2 %

Procedure:
Ethyl 2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetate (syn isomer) (0.4 g.) and 1 N aqueous solution of sodium hydroxide (2.1 ml.) were treated according to a similar manner to that of Example 1(a) (5) to give 2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetic acid (syn isomer) (0.25 g.), mp 168° to 171° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]=[CH:7][NH:6][C:5]2=[O:13].[H-].[Na+].[CH3:16][SH:17]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:17][CH3:16])[N:8]=[CH:7][NH:6][C:5]2=[O:13]
Reactant: CS
Reactant: O=c1[nH]cnc2cc(Cl)c(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc2nc[nH]c(=O)c2cc1Cl
Temperature: 120 °C

Procedure:
Under a nitrogen atmosphere in a flame dried flask equipped with a magnetic stirrer and a reflux condenser, a mixture of 1.00 g (0.00465 mol) of 6,7-dichloroquinazolin-4(3H)-one and 18 ml of dimethylformamide was treated at room temperature with 0.56 g (0.012 mol) of 50% sodium hydride in mineral oil. Foaming began immediately and most of the solids dissolved. When the foaming had subsided, 1.8 ml (0.0176 mol) of 47% methyl mercaptan in dimethyl formamide was added to the stirred mixture. The mixture was heated at 120° C. for six hours. When the reaction mixture was again at room temperature, a small amount of insoluble matter was filtered, and was rinsed with a few ml of dimethylformamide. The filtrate was washed three times with 10 ml portions of hexane. The filtrate was then poured into 300 ml of ice and water. By the addition of 2N hydrochloric acid, the aqueous solution was adjusted to pH 2. There formed a fine colorless precipitate which was filtered, washed with water, air dried and pressed on a clay plate to furnish the title compound: yield 0.97 g (92%); m.p. 292°-295° C. (dec.); mass spectrum m/e 226 (parent peak and molecular ion with expected isotope pattern), 193 (-33) among others; 1H--NMR(DMSO-d6) 2.6 ppm (singlet, 3H, SCH3), 7.45 (singlet, 1H, aromatic H), 8.0 (singlet, 1H, aromatic H), 8.15 (singlet, 1H, N=CH--N).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:10]([O:21][CH2:22][CH3:23])[C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18](O)=[O:19])[CH:12]=2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:55][C:56]1[CH:57]=[C:58]([CH:60]=[CH:61][C:62]=1[CH3:63])[NH2:59]>CN(C=O)C.C(OCC)(=O)C>[CH3:55][C:56]1[CH:57]=[C:58]([NH:59][C:18]([C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:10]3[O:21][CH2:22][CH3:23])=[CH:15][CH:14]=2)=[O:19])[CH:60]=[CH:61][C:62]=1[CH3:63]
Reactant: CCOn1c(-c2c(Cl)cccc2Cl)cc2ccc(C(=O)O)cc21
Reactant: Cc1ccc(N)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOn1c(-c2c(Cl)cccc2Cl)cc2ccc(C(=O)Nc3ccc(C)c(C)c3)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-(2,6-dichlorophenyl)-1-ethoxy-1H-indole-6-carboxylic acid (230 mg, 660 μmol) in DMF (5 mL) was added HATU (375 mg, 990 μmol), triethylamine (137 μL, 99 mg, 980 μmol) and 3,4-dimethylaniline (80 mg, 660 μmol). After stirring the mixture for 72 h at ambient temperature, the solution was poured into ethyl acetate and extracted with water once and brine five times. The organic layer was dried, filtered, and solvent removed under reduced pressure. The residual material was chromatographed with a 10-60% gradient of heptane/ethyl acetate to afford 2-(2,6-dichlorophenyl)-1-ethoxy-1H-indole-6-carboxylic acid (3,4-dimethylphenyl)-amide. 1H NMR (DMSO-d6, 400 MHz): δ 10.16 (s, 1H), 8.19 (s, 1H), 7.71 (m, 4H), 7.58 (m, 3H), 7.12 (d, J=8.2 Hz, 1H), 6.60 (s, 1H), 4.14 (q, J=7.1 Hz, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.12 (t, J=7.1 Hz, 3H). MS (m/z) 453.0 (M+1); Retention time=1.72 min (Method 10). Anal. Calcd.: C, 66.23; H, 4.89; N, 6.18. Found: C, 66.34; H, 4.97; N, 6.06.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12](Br)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][NH2:19]>C(O)C.O1CCOCC1>[C:1]1([S:7]([C:10]2[CH:15]=[C:14]([Br:16])[N:13]=[C:12]([NH:19][CH3:18])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1cc(Br)nc(Br)c1
Reactant: CN
Solvent: C1COCCO1
Solvent: CCO
Product: CNc1cc(S(=O)(=O)c2ccccc2)cc(Br)n1
Yield: 61 %

Procedure:
0.42 g (0.00112 mol) of 4-benzenesulphonyl-2,6-dibromopyridine and 1.4 ml of 8M methylamine in ethanol were stirred at room temperature in a mixture of 11 ml of ethanol and 11 ml of dioxane for 48 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:10. The product-containing fractions were suspended in 25 ml of diethyl ether, treated in an ultrasound bath and diluted with 45 ml of hexane. The suspension was suction filtered and the filter material was dried in a high vacuum. There was obtained 0.224 g (61%) of (4-benzenesulphonyl-6-bromopyridin-2-yl)-methylamine as white crystals; m.p.: 145-148° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+].CCOCC.[Cl:28][CH2:29][C:30](Cl)=[O:31]>O>[Cl:28][CH2:29][C:30]([N:7]([CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16])=[O:31]
Reactant: CCc1cccc(C)c1NCC1OCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCc1cccc(C)c1N(CC1OCCO1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3-Dioxolan-2-ylmethyl)-2-ethyl-6-methylaniline (7.5 grams), sodium carbonate (5.0 grams), ether (100 ml) and water (40 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture was cooled to a temperature of about 0°C and chloroacetyl chloride (4.5 grams) was added, with stirring, over a period of about 15 minutes. After the addition was completed stirring was continued for a period of about one hour. After this time the resulting solution was washed with water and the washed solution was dried over anhydrous magnesium sulfate and stripped of solvent under reduced pressure to yield the desired product N-α-chloroacetyl-N-(1,3-dioxolan-2-ylmethyl)-2-ethyl-6-methylaniline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].C(O[C:14](=[O:16])[CH3:15])(=O)C.[C:17]([OH:20])(=O)[CH3:18].B(F)(F)F.CC([O-])=O.[Na+]>O>[CH3:1][C:2]1[C:3]([CH3:9])=[C:4]([CH3:8])[CH:5]=[CH:6][C:7]=1[C:17](=[O:20])[CH2:18][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Reactant: Cc1cccc(C)c1C
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: O
Product: CC(=O)CC(=O)c1ccc(C)c(C)c1C
Temperature: 3 °C
Reaction time: 2 h

Procedure:
50 g of 1,2,3-trimethylbenzene (Aldrich Chemical Co., 90+% pure) and 160 mL of acetic anhydride are placed in a 1 L flask under positive nitrogen and chilled at 3° C. in an ice-bath. 462 mL of boron trifluoride acetic acid is added while maintaining the temperature below 5° C. The reaction mixture is stirred via mechanical stirrer for two hours. The reaction mixture is warmed to room temperature and stirred for two hours. The reaction mixture is heated to 65° C. for 20 hours followed by cooling to room temperature. The reaction mixture is poured into a solution containing 900 mL of water and 208 g of sodium acetate anhydrous. (It is important to add the reaction solution to the sodium acetate.) This mixture is heated to reflux for 30 minutes, followed by cooling to room temperature. This mixture is extracted with 800 mL of methylene chloride. The resulting water layer is extracted with 200 mL of methylene chloride. The combined methylene chloride layers are dried over 146 g of sodium sulfate. The dark brown organic fraction is acidic pH and smells strongly of acetic acid. The liquid is transferred to a 4 L separatory funnel. Saturated sodium bicarbonate (aq) is added 100 mL at a time (a total of 2100 mL is added) to neutralize the sample. Addition of the sodium bicarbonate is done slowly because the sample foams and much gas evolves in the neutralization process. The mixture is filtered through a cake of sodium sulfate (anhydrous) and is evaporated to give 150 g of a very dark brown viscous liquid. This material is distilled, 150° C. and 0.01 mm Hg, to yield 24.3 g of 1-(2',3',4'-trimethylphenyl)-1,3-butanedione. This material is distilled again, at 0.01 mm Hg using a mirrored column and a receiver cow to collect fractions. A total of four fractions are collected with a total weight of 15.53 g. All fractions are green in color. Results of this distillation are: