Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC([C@@]12C(C)(C)[C@@H](CC1)C=C2[C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]([CH3:30])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])=[CH:16][C:15]=1[O:31][CH3:32])=O.FC(F)(F)S(O[C:39]1[C@@H:40]2[C:45]([CH3:47])([CH3:46])[C@:43]([CH3:48])([CH:44]=1)[CH2:42][CH2:41]2)(=O)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][O:31][C:15]1[CH:16]=[C:17]([C:22]([CH3:23])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:30])[CH:18]=[C:19]([O:20][CH3:21])[C:14]=1[C:39]1[C@@H:40]2[C:45]([CH3:47])([CH3:46])[C@@:43]([CH3:48])([CH2:42][CH2:41]2)[CH:44]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C=C2OS(=O)(=O)C(F)(F)F
Reactant: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@@H]3CC[C@@]2(C(=O)OC)C3(C)C)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@]3(C)CC[C@H]2C3(C)C)c(OC)c1

Procedure:
The title compound was prepared by the general procedure described for compound 11a (HU-911), using pinacol arylboronate 3 (mixed with 4-alkyl resorcinol dimethylether 1) 0.755 g, enol triflate 19a 0.17 g (0.598 mmol), Pd(PPh3)4 0.041 g (0.036 mmol) and t-BuNF 0.9 ml (0.9 mmol, 1M solution in THF). The product was purified by silica gel column chromatography (petroleum ether/ether) to give oil 0.185 g (78%), which solidified upon standing at −20° C. mp 33-34° C.; 1H NMR (300 MHz, CDCl3) δ ppm 6.50 (s, 2H), 5.79 (d, J=3.00 Hz, 1H), 3.76 (s, 6H), 2.60 (d, J=3.51, 1H), 1.81 (m, 1H), 1.64 (m, 1H), 1.60 (m, 1H), 1.55 (m, 2H), 1.31 (m, 1H), 1.28 (s, 6H), 1.17-1.25 (m, 8H), 1.08 (s, 3H), 0.99 (s, 3H), 0.86 (t, J=6.69 Hz, 3H), 0.81 (s, 3H). Exact mass calculated for C27H42O2 m/e 398.32. found 398.82. Anal. calcd. for C27H42O2: C, 81.35; H, 10.62. Found: C, 81.50; H, 10.71.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].CCN(CC)CC.[C:15]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][O:17][CH2:16]1>C(Cl)Cl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:19]([CH2:18][O:17][CH2:16][C:15]([OH:22])=[O:21])=[O:20]
Reactant: CC(C)(S)CN
Reactant: O=C1COCC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(S)CNC(=O)COCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To an ice-cooled suspension of 1-amino-2-methyl-2-propanethiol hydrochloride (4.21 g, 29.7 mmol) in CH2Cl2 (50 mL) was added Et3N (4.56 mL, 32.7 mmol) followed by diglycolic anhydride (3.43 g, 29.6 mmol). After stirring at room temperature for 30 minutes the reaction was concentrated under vacuum. Cold 2N HCl (50 mL) was added to the residue. The mixture was extracted with EtOAc (5×30 mL). The combined organic extracts were washed with brine (30 mL) and dried over Na2SO4. Concentration and trituration with Et2O:hexane gave the title compound as a white solid (5.50 g, 84.2%). mp 81-82° C.; 1H NMR (300 MHz, CDCl3) δ 8.80 (br s, 1H), 7.48 (br s, 1H), 4.24 (s, 2H), 4.20 (s, 2H), 3.41 (d, J=6.4 Hz, 2H), 1.59 (s, 1H), 1.38 ((s, 6H); 13C NMR (75 MHz, CDCl3) δ 172.8, 170.4, 70.8, 68.4, 51.9, 44.9, 29.8; mass spectrum (API-TIS) m/z 239 (M+NH4), 222 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:12][C:3]1[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NS(C)(=O)=O)c1Cl

Procedure:
To a solution of methyl 3-amino-2-chlorobenzoate (517 mg, 2.79 mmol) and pyridine (0.25 mL, 3.06 mmol) in 8 mL CH2Cl2 was added methanesulfonylchloride (0.24 mL, 3.06 mmol). After washing with 1M HCl, methyl 2-chloro-3-[(methylsulfonyl)amino]benzoate was isolated as a solid in quantitative yield. 1H NMR (400 MHz, CDCl3), δ 7.77 (dd, 1H, J=8.2, 1.6 Hz), 7.61 (dd, 1H, J=7.9, 1.6 Hz), 7.33 (t, 1H, J=7.9 Hz), 7.16 (s, 1H), 3.91 (s, 3H), 2.99 (5, 3H); ESI-MS 262 (M−H). Methyl 2-chloro-3-[(methylsulfonyl)amino]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(methylsulfonyl)amino]benzoic acid as a solid, which was used without further purification. ESI-MS 248 (M−H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:18]([O:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
A mixture of 3-methyl-2-nitrophenol (50 g, 0.326 mol), K2CO3 (45 g, 0.326 mol) and benzylbromide (61.4 g, 42.6 mL, 0.359 mol) in dry DMF (200 mL) was stirred at 90° C. for 3 hours under nitrogen. Most of the DMF was removed at reduced pressure and the residue was partitioned between water (300 mL) and ether (300 mL). The organic layer was washed with brine and dried (Na2SO4). Removal of the solvent provided (70 g, 88%) of 3-benzyloxy-2-nitrotoluene as an orange oil.
Reaction SMILES: [Mg].[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[C:13](Cl)(=[O:15])[CH3:14].S(=O)(=O)(O)O>C(O)C.ClC(Cl)(Cl)Cl>[C:4]([CH:3]([C:13]([CH3:14])=[O:15])[C:2]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:5])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C(C(C)=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
5 ml of tetrachloromethane were added to 24.3 g (1 mol) of magnesium turnings in 50 ml of dry ethanol under nitrogen and in the absence of moisture. After the beginning of gas evolution, a solution of 177.7 g (1 mol) of tert-butyl acetoacetate in 100 ml of dry ethanol was slowly added dropwise, the reaction mixture being kept at the reflux temperature. Stirring was carried out for a further 4 hours at this temperature, after which the mixture was cooled. 78.5 g (1 mol) of acetyl chloride was slowly added dropwise at 10° C. Stirring was continued for a further 4 hours at room temperature and hydrolysis was then effected with a mixture of 450 ml of ice-water and 25 ml of concentrated sulfuric acid. The organic phase was separated off, dried, and evaporated down under reduced pressure. 192.3 g of >96% pure tert-butyl 2-acetylacetoacetate were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:31][C:14]2[N:15]=[CH:16][C:11]3[CH:10]=[C:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[C:22](=[O:23])[N:21]([CH3:24])[C:12]=3[N:13]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: NC1CCCCC1
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NC3CCCCC3)nc21
Temperature: 134 °C

Procedure:
A mixture of 0.100 g (0.26 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.300 g (3.00 mmol) of cyclohexylamine was heated to the boiling point (134° C.). The resulting solution was heated at reflux for 2 minutes. Most of the excess amine was evaporated at reduced pressure. The remaining gum was dissolved in 2 mL of ethyl acetate hot. Petroleum ether (2 mL) was added, and the crystals that separated from the cooled solution were filtered and washed with water; wt 0.090 g. Recrystallization from ethyl acetate gave pure crystalline product; 0.048 g; mp 242°-244° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][CH2:9][CH:10]([CH3:13])[CH2:11][OH:12])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[CH2:24][C:25](Cl)=[O:26].[OH-].[K+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH:10]([CH3:13])[CH2:11][O:12][CH2:24][C:25]2=[O:26])=[CH:14][CH:15]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(CNCC(C)CO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CC(C)COCC2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of 3-(4-methoxy-benzylamino)-2-methyl-propan-1-ol (4.14 g, 19.8 mmol) in dichloromethane (60 ml) was added triethylamine (2.20 g, 21.8 mmol) and chloroacetyl chloride (2.46 g, 21.8 mmol) at 0° C. The mixture was stirred at 0° C. for one hour and partitioned between 0.5N—HCl and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved into 2-propanol (66.7 ml), then potassium hydroxide (2.22 g, 39.6 mmol) was added at 0° C. The mixture was stirred for 16 hours and partitioned between saturated ammonium chloride aqueous solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=1/1 to 1/3) to afford 4-(4-methoxy-benzyl)-6-methyl-[1,4]oxazepan-3-one as white solid (4.35 g, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O-:16])=O)[CH:7]=[C:8]([C:10]([O:12]C)=[O:11])[CH:9]=1)([O-:3])=[O:2].[OH-].[NH4+:18].N>O>[NH2:18][C:14]([C:6]1[CH:7]=[C:8]([CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:10]([OH:12])=[O:11])=[O:16]
Reactant: COC(=O)c1cc(C(=O)[O-])cc([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: N
Agent: [OH-]
Solvent: O
Product: NC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1

Procedure:
The ammonium salt of 3-(aminocarbonyl)-5-nitrobenzoic acid (Compound I or C-I) is prepared from 5-nitro-1,3-benzenedicarboxylic acid, 1-methyl ester (“MME”) with ammonium hydroxide. The reaction is preferably carried out in an aqueous solvent, e.g., ammonia in water, and at elevated temperatures. Preferably, the reaction mixture contains a molar excess of ammonia relative to MME. In one embodiment, the product, C-I, is obtained as a solid, centrifuged or filtered, washed with cold aqueous ammonia then by cold water and finally dried.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]1(=[O:54])[NH:48][C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12>O1CCCC1>[C:44]1(=[O:54])[N:48]([CH2:23]/[CH:22]=[CH:21]\[CH2:20][O:19][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC/C=C\COC1CCCCO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C/C=C\COC1CCCCO1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.1 %

Procedure:
Under a nitrogen atmosphere diethylazodicarboxylate (1.6 ml, 10 mmol) was added to a cooled (0° C.) solution of cis-4-tetrahydropyranyloxy-2-butene-1-ol (1.7 g, 10 mmol), triphenyl phosphine (2.2 g, 10 mmol) and phthalimide (1.47 g, 10 mmol) in anhydrous tetrahydrofuran (50 ml). When the addition was completed (5 min) the reaction mixture was allowed to warm at room temperature and was stirred 12 h. Then the mixture was concentrated in vacuo, diluted with ethyl acetate (200 ml) and washed with brine (150 ml). After usual work-up (the aqueous phase was extracted three times with 100 ml portions of ethyl acetate), the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo) the product was purified by flash chromatography on silica gel (ethyl acetate:hexane; 2:8) to give 1.9 g of the title compound (64%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=1>>[CH:9]1([O:8][C:6]2[N:5]=[C:4]3[CH2:14][CH2:15][CH2:16][C:3]3=[C:2]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=3)[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Clc1cc(OC2CCCC2)nc2c1CCC2
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(OC3CCCC3)nc3c2CCC3)cc1
Yield: 79.8 %

Procedure:
Following general procedure B2, 4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.070 g, 0.29 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.080 g, 0.44 mmol) to afford the title compound (0.088 g, 78%) as a yellow foam. MW=380.48. APCI MS m/z 381 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][C:8]1[C:9]([N:15]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6].[C:25](#[N:27])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][C:8]1[C:9]([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:26][CH2:25][N:27]3[CH2:4][CH2:3][CH2:2][CH2:24][CH2:23]3)[CH2:17][CH2:16]2)=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=1)=[O:6]
Reactant: CC#N
Reactant: O=C(Nc1cc(Cl)cnc1N1CCCNCC1)c1cccc(Cl)c1
Product: O=C(Nc1cc(Cl)cnc1N1CCCN(CCN2CCCCC2)CC1)c1cccc(Cl)c1
Temperature: 175 °C
Yield: 9 %

Procedure:
A mixture of 0.035 g (0.096 mmol) of 3-chloro-N-(5-chloro-2-[1,4]diazepan-1-yl-pyridin-3-yl)-benzamide in 0.053 g (0.29 mmol) of 2-pyridino-1-ethylchloride hydrochloride in acetonitrile (2 mL) is heated at 175° C. in a microwave reactor for 30 minutes. The mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.004 g (9%) of the title compound (108) as a red solid. [M+H]+=476.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([N:11]([CH2:12][CH3:13])[CH2:9][CH3:10])=[CH:4][CH2:3]1
Reactant: CCNCC
Reactant: CN1CCC(=O)CC1
Solvent: CCOCC
Product: CCN(CC)C1=CCN(C)CC1
Reaction time: 96 h
Yield: 59.9 %

Procedure:
The starting substance is prepared as follows: To 1000 g of Klinosorb-4 molecular sieve 1000 ml of dry diethyl ether, 226 g of 1-methyl-4-piperidone and 219 g of dry diethylamine are added. The reaction mixture is kept at room temperature for 4 days and then filtered off. The Klinosorb-4 is washed with ether, the filtrate and the washing are combined, the solvent is distilled off and the residue is purified by distillation in vacuo to give 1-methyl-4-diethylamino-1,2,5,6-tetrahydropyridine with a yield of 59.9%, bp.: 88°-106° C./1.5 kPa; nD20 =1.4825.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]1[O:1][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1O
Reactant: ClCc1ccncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3Cl)cc2c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
A mixture of 0.78 g of 2-hydroxy-5-(trifluoromethyl)benzaldehyde, 0.89 g of 3-chloro-4-(chloromethyl)pyridine, 1.94 g of potassium carbonate and 15 ml of DMF was stirred at 80° C. for 3 hours and subsequently at 150° C. for 4 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.72 g of 3-chloro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 6”).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].[Br:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[S:22](Cl)(=[O:24])=[O:23]>>[Br:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[S:22]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:2]([OH:1])[CH:3]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1Br
Reactant: COc1ccc(N)cc1O
Product: COc1ccc(NS(=O)(=O)c2c(F)c(F)c(F)c(F)c2Br)cc1O

Procedure:
The title compound was prepared in a manner similar to that described in Example 6 of WO 97/30677, beginning with 3-hydroxy-4-methoxyaniline and 2-bromo-3,4,5,6-tetrafluorophenylsulfonyl chloride (Example D, above).
Reaction SMILES: O.C1O[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)[O:4]C1.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(C(O)=O)(F)(F)F>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH:12]=1
Reactant: c1cncc(C2CCC3(CC2)OCCO3)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CCC(c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.2 %

Procedure:
Water (1 mL) was added to a cod solution of 4-(3-pyridyl)cyclohexanone ethylene acetal (4.79 g, 21.9 mmol) in CF3CO2H (20 mL). After stirring room temperature for 6 h, the reaction mixture was added dropwise to sat. NaHCO3. aq. The resulting mixture was adjusted to pH 8 with 2M NaOH aq. and extracted with CH2Cl2, After drying and consentration, the crude product was purified by column chromatography (Hexane/EtOAc=1/1→0/1) to yield 4-(3-pyridyl)cyclohexanone (3.23 g, 84%) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][C:10](=O)[CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:17][CH2:18][C:19]#[C:20][CH3:21].O1CCCC1>C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10]3[N:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:11]=3[C:12](=[O:14])[CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1CC(=O)CC(c2ccc(F)cc2)C1
Reactant: CC#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc2c1C(=O)CC(c1ccc(F)cc1)C2
Temperature: 220 °C
Reaction time: 6 h
Yield: 28.9 %

Procedure:
To a mixture of 5-(4-fluorophenyl)cyclohexane-1, 3-dione (0.98 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml) was added triethylamine (0.48 g), and the mixture was refluxed for 14 hours and cooled. Insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred for 6 hours at 220° C. and cooled, to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtoAc/hexane) to give oil of 7-(4-fluorophenyl)-4methyl-5,6,7,8-tetrahydroquinolin-5-one (0.35 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].[Cu][C:13]#[N:14]>CCOC(C)=O>[CH3:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:13]#[N:14])[CH:3]=2)[NH:7][CH:6]=1
Reactant: Cc1c[nH]c2ccc(Br)cc12
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2ccc(C#N)cc12
Temperature: 200 °C
Reaction time: 5 h
Yield: 81.1 %

Procedure:
A vessel was charged with 5-bromo-3-methyl-1H-indole (1.06 g, 5.05 mmol), copper (I) cyanide (542.83 mg, 6.0608 mmol), and degassed NMP (10 mL), sealed and heated to 200° C. with stirring for 5 h, then at 110° C. for 16 h. The cooled reaction was diluted with EtOAc and the organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/heptane gradient (0 to 100% EtOAc) to afford 640 mg (81.1%) of 3-methyl-1H-indole-5-carbonitrile (192): 1H NMR (400 MHz, CDCl3): δ 8.22 (br s, 1H), 7.91 (s, 1H), 7.42-7.35 (m, 2H), 7.07 (s, 1H), 2.32 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[CH3:18])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:25]1[S:26][C:27]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:28]=2[N:29]=1>C(O)CCC>[CH3:35][O:34][C:32]1[CH:31]=[CH:30][C:28]2[N:29]=[C:25]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]([CH3:23])([C:19]([O:21][CH3:22])=[O:20])[CH3:18])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:26][C:27]=2[CH:33]=1
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc(-c2ccc(N)cc2)cc1
Solvent: CCCCO
Product: COC(=O)C(C)(C)NC(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC)cc4s3)cc2)cc1

Procedure:
As shown in Reaction Scheme 12, a mixture of methyl N-[(4′-aminobiphenyl-4-yl)carbonyl]-2-methylalaninate (100 mg, 0.32 mmol), 2-chloro-6-methoxybenzothiazole (83 mg, 0.42 mmol, commercially available), and 1-butanol (4.0 mL) was heated at 90° C. overnight. The solvent was evaporated under reduced pressure to afford crude methyl N-({4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-2-methylalaninate; LC-MS m/z 476.2 (MH+), retention time 3.25 minutes.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[O:22][CH3:23])=[NH:11])[S:7][CH:8]=1.[CH2:24]([S:28](Cl)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27].CN1CCOCC1>C1COCC1>[CH3:21][O:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([O:22][CH3:23])[C:14]=1[CH2:13][NH:12][C:10]([NH:9][C:6]1[S:7][CH:8]=[C:4]([CH2:3][NH:2][S:28]([CH2:24][CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])[N:5]=1)=[NH:11]
Reactant: CCCCS(=O)(=O)Cl
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc(CN)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCS(=O)(=O)NCc1csc(NC(=N)NCc2c(OC)cccc2OC)n1

Procedure:
Reaction of 100 mg (0.33 mmol) N-[4-(aminomethyl)-1,3-thiazole-2-yl]-N′-(2,6-dimethoxybenzyl)guanidine hydrochloride, Example 154 free base, with 60.4 mg butane sulfonic acid chloride in 5 ml THF with addition of 480 mg polymer-bound NMM (1.7 mmol/g; Argonaut) and chromatography of the crude product on silica gel dichloromethane/methanol 0-2%) yielded 46 mg; ESI-MS [M+H+]=442.05.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1(=[O:21])[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>CS(O)(=O)=O.C1(C)C=CC=CC=1>[C:14]([O:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:15])[C:13]1[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:21]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCCCCCCCCO
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCCC
Yield: 103.4 %

Procedure:
567 g of nonyl alcohol produced in Example 1 was combined with 280 g of phthalic anhydride, 200 g of toluene and 5.5 g of methanesulfonic acid. The reaction was set up for reflux through a Dean-Stark trap using a nitrogen purge and slow stiffing. The reactor contents were refluxed for 5 hours. Residual catalyst was neutralized with a 10% NaCO3 solution and the product was water washed. The product was purified by vacuum stripping and distillation to yield 818 g of dinonyl phthalate.