Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[CH:10]=2)O1.Br[C:23]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[N:26][N:25]2[CH2:35][CH2:36][CH2:37][C:24]=12.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2]>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]2[C:23]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]4[CH2:19][CH2:20]4)=[O:17])[CH:10]=3)=[C:24]3[CH2:37][CH2:36][CH2:35][N:25]3[N:26]=2)=[CH:33][CH:32]=1
Reactant: Fc1ccc(-c2nn3c(c2Br)CCC3)cc1
Reactant: CC1(C)OB(c2ccnc(NC(=O)C3CC3)c2)OC1(C)C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2c(-c3ccc(F)cc3)nn3c2CCC3)ccn1)C1CC1
Temperature: 120 °C
Yield: 46.9 %

Procedure:
140 mg (0.50 mmol) of N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]cyclopropanecarboxamide and 172 mg (1.2 eq 0.60 mmol) of 3-bromo-2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole are dissolved in 3.5 mL 1,4-dioxan. To this are added 36 mg of bis(tricyclohexylphosphine)-palladium(II)dichloride (0.05 mmol, 0.1 eq) and 1.2 mL sodium carbonate solution (2M in H2O). The reaction mixture is flushed for 5 mins with argon and then sealed. Next the mixture is heated for 12 mins at 120° C. in the microwave (CEM Explorer). After cooling, insoluble components are filtered off and the salt residue washed with 1,4-dioxan. The organic phase is evaporated and the crude product purified by silica gel chromatography (eluent cyclohexane/ethyl acetate). 85 mg (43%) of N-{4-[2-(4-fluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]pyridin-2-yl}cyclopropanecarboxamide are obtained as a colourless solid.
Reaction SMILES: [I-].[C:2]([CH2:10][CH2:11][N+](C)(C)C)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O>[C:3]1([C:2]([CH:10]=[CH2:11])=[O:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[N+](C)(C)CCC(=O)c1ccccc1
Agent: [I-]
Solvent: O
Product: C=CC(=O)c1ccccc1
Yield: 94 %

Procedure:
N-(2-benzoylethyl)-N,N,N-trimethylammonium iodide (5.0 g) was suspended in water (400 ml) and the mixture passed through the CMR (15 ml/min; 90°-95° C.; atmospheric pressure) and the hot product collected in a mixture of ice (250 g) and diethyl ether (100 ml), in a flask which was cooled in an ice bath. The ether phase was separated and the aqueous extracted with ether (3×150 ml). The pooled organic phase was dried over anhydrous sodium sulphate and evaporated to dryness, affording phenylvinyl ketone as a colourless oil (1.95 g; 94% yield) in high purity, according to the 1H NMR spectrum; cf ref.15, where a yield of 51% was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:15](=O)[C:16]([N:18]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]#[C:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:17])[CH:9]2C(O)=O)=[CH:4][C:3]=1[O:36][CH3:37].C(O)(=O)C.N>C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].O>[Br:1][C:2]1[C:3]([O:36][CH3:37])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:15]4[C:16](=[O:17])[N:18]([C:31]([CH3:33])([CH3:34])[CH3:32])[CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]=4[C:25]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[C:9]3[C:10]=2[CH:11]=1
Reactant: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCOCC#Cc1cccs1)C(C)(C)C)CC2
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cc2c(cc1Br)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCOC3
Temperature: 105 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
A solution of 257 mg of 7j in a mixture of 5 ml of acetic anhydride and 100 mg of sodium acetate was heated at 105° C. for 30 min. The reaction mixture was cooled, diluted with 20 ml of water and stirred for 1 hr at RT. Then, acetic acid was neuralized by addition of cold conc. ammonia. The product was extracted with ethyl acetate and the organic layer was washed twice with water, dried, concentrated and the crude material was purified by chromatography over silica gel, using a gradient of heptane/ethyl acetate. The material isolated was triturated with diethyl ether, to give 120 mg of 7k;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][S:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:47])[CH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:47])[CH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[C:12]([CH2:13][S:14][CH2:15][CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[C:11]([CH3:23])[O:10][N:9]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)[CH3:25]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1onc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4noc(C)c4CSCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 3-(4-bromo-phenyl)-5-methyl-4-phenethylsulfanylmethyl-isoxazole and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3]C1.Cl>CC(C)=O>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]2[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]2)=[CH:11]1
Reactant: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-(1H-3-indolyl)cyclohexanone ethylene ketal (66.4 g, 0.258 mol) is dissolved in 350 mL of acetone and 350 mL of 10% hydrochloric acid solution and allowed to stir at room temperature for 6 hours. The acetone is removed under reduced pressure and the mixture is made basic with concentrated ammonium hydroxide. The mixture is extracted with chloroform. The organic fraction is dried with sodium sulfate and volatiles are removed under reduced pressure. The resulting solid is taken up in hot ethyl acetate and upon cooling and filtration a crystalline solid is obtained (36.89 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: Cc1cccc(Cl)c1N
Reactant: Cc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2c(C)cccc2Cl)cc1
Yield: 89.3 %

Procedure:
1.02 g (7.2 mmol) of 2-chloro-6-methylaniline, 1.23 g (7.2 mmol) 4-bromotoluene, 1.15 g (12 mmol) sodium tert-butoxide, 160 mg (0.7 mmol) tri-tert-butyhphosphine and 130 mg (0.23 mmol) bis-dibenzylideneacetone-palladium(0) are reacted in 50 ml toluene under nitrogen at 90° C. for 20 minutes and at 60° C. over night. Aqueous workup (3N HCl, with hyflo, washing the organic phase with water) and flash-chromatography on silica using heptan/toluene (4:1) as the eluent affords 1.49 g of N-(2′-chloro-6′-methylphenyl)-4-methylaniline.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:29]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][C:37]1=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>ClC(Cl)C>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: c1ccc(CN2CCC(N3CCc4ccccc4C3)CC2)cc1

Procedure:
1,2,3,4-Tetrahydroisoquinoline (700 mg, 5.3 mmol), acetic acid (3.2 g, 5.3 mmol), sodium triacetoxyborohydride (2.2 g, 11 mmol) and benzylpiperidone (1.0 g, 5.3 mmol) were stirred at room temperature for 3.5 hours in dichloroethane (7 ml). The reaction solution was alkalified by adding sodium hydroxide aqueous solution, the reaction product was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and then dried with anhydrous sodium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 900 mg (3.0 mmol, 56% in yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH2:21]([N:23]([CH2:35][CH3:36])[C:24]([C:26]1[S:27][C:28]([C:31]([NH:33][NH2:34])=[O:32])=[CH:29][CH:30]=1)=[O:25])[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH2:35]([N:23]([CH2:21][CH3:22])[C:24]([C:26]1[S:27][C:28]([C:31]([NH:33][N:34]=[C:18]([C:3]2[C:2]([OH:1])=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:5]([CH3:17])[N:4]=2)[CH3:19])=[O:32])=[CH:29][CH:30]=1)=[O:25])[CH3:36]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: CCN(CC)C(=O)c1ccc(C(=O)NN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCN(CC)C(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(F)(F)F)cc3)c2O)s1
Yield: 53.2 %

Procedure:
1-[4-Hydroxy-1-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (28 mg, 0.10 mmol, synthesized in accordance with WO2004/108683), 5-hydrazinocarbonylthiophene-2-carboxylic acid diethylamide (24 mg, 0.10 mmol) prepared in Reference Synthetic Example 1 and p-toluenesulfonic acid (6 mg) were heated with 2-propanol (4 mL) for 14 hours with reflux. After cooling, the solvent was evaporated, and the resulting solid was recrystallized from 2-propanol-diethyl ether-n-hexane to give 27 mg of the desired product (yield 53%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:7](=[O:25])[C:6]2([NH:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]2)[CH2:40][CH2:39]1)=[O:37])[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2].Cl.C(Cl)Cl.CO>CO.C(O)(C)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:7](=[O:25])[C:6]2([NH:35][C:36]([N:38]1[CH2:39][CH2:40][CH:41]([N:44]2[CH2:45][CH2:46][NH:47][CH2:48][CH2:49]2)[CH2:42][CH2:43]1)=[O:37])[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2]
Reactant: CCOc1ncccc1C1(NC(=O)N2CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOc1ncccc1C1(NC(=O)N2CCC(N3CCNCC3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Temperature: 25 °C

Procedure:
55.3 mg (0.07 mmol) of tert-butyl 4-[1-({[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3,-dihydro-1H-indol-3-yl]amino}carbonyl)piperidin-4-yl]piperazine-1-carboxylate were initially charged in 4 ml of methanol, and 1.0 ml of 5-6 M hydrochloric acid in isopropanol was added. The mixture was stirred at room temperature. The progress of the reaction was monitored by TLC (silica gel, CH2Cl2/MeOH 9:1). After complete conversion, the alcoholic solvent residues were removed, and the residue was taken up in dichloromethane and, using 1 N aqueous sodium hydroxide solution, adjusted by extraction to pH 9. The organic phase was separated from the aqueous phase, and the aqueous phase was reextracted with dichloromethane (2×). The combined organic phase was dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was crystallized from diethyl ether. Alternatively, the residue can also be purified either by conventional column chromatography on a normal phase (NP-SiO2 cartridge, Chromabond) using dichloromethane/methanol as mobile phases or by preparative HPLC (RP, mobile phases acetonitrile/water, 0.01% TFA). After crystallization, 15.9 mg (0.023 mmol, 33%) of N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-O-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-piperazin-1-ylpiperidine-1-carbox amide were isolated.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[C:11]([CH3:21])=[C:12]([S:17](Cl)(=[O:19])=[O:18])[CH:13]=[C:14]([CH3:16])[CH:15]=1>>[Cl:9][C:10]1[C:11]([CH3:21])=[C:12]([S:17]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:19])=[O:18])[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cc(Cl)c(C)c(S(=O)(=O)Cl)c1
Reactant: Cc1noc(N)c1Br
Product: Cc1cc(Cl)c(C)c(S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 71 %

Procedure:
3-Chloro-2,5-dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 3-chloro-2,5-dimethylbenzenesulfonyl chloride according to the procedures described in Example 30. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 148-150° C., yield 71%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1CCCCC1.CCOCC.C1(N)CCCCC1>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2)c(Cl)c1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2ccccc2)c(Cl)c1

Procedure:
Prepared analogous to Example 42 from 4-(2-chloro-4-biphenylyl)-4-oxo-butyric acid. Melting point 87°-88° C. (from cyclohexane/ether); melting point of the cyclohexylamine salt: 156°-157° C. (from acetone/ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].O1CCO[CH:13]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C(=O)C>[F:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]3([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=1)[NH:6][C:4]2=[O:5]
Reactant: NC(=O)c1cc(F)ccc1N
Reactant: OC1(c2ccc(C3OCCO3)cc2)CCCC1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1[nH]c(-c2ccc(C3(O)CCCC3)cc2)nc2ccc(F)cc12
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A suspension of 2-amino-5-fluorobenzamide (135 mg, 0.88 mmol), 1-(4-[1,3]dioxolan-2-yl-phenyl)-cyclopentanol (206 mg, 0.88 mmol) and sodium disulfite (170 mg, 0.89 mmol) in N,N-dimethylacetamide (2 ml) is heated to 150° C. and stirred at this temperature for 3 hours. The reaction mixture is allowed to reach room temperature and poured into ice water. The resulting precipitate is collected by filtration and washed with water. It is chromatographed on a silica gel column with methanol/dichloromethane as eluent to afford 6-fluoro-2-[4-(1-hydroxy-cyclopentyl)-phenyl]-3H-quinazolin-4-one as white solid; HPLC/MS 1.80 min (A), [M+H] 325;
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:18])=[CH:5][C:6]([NH:10]C(=O)OC(C)(C)C)=[N:7][C:8]=1[CH3:9].C1C=NC2N(O)N=NC=2C=1.N1C(C)=CC(C)=CC=1C.[CH3:38][O:39][C:40]1[CH:54]=[CH:53][C:43]([CH2:44][N:45]2[CH:49]=[C:48]([C:50](O)=[O:51])[CH:47]=[N:46]2)=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:10][C:6]1[N:7]=[C:8]([CH3:9])[C:3]([CH2:2][NH:1][C:50]([C:48]2[CH:47]=[N:46][N:45]([CH2:44][C:43]3[CH:53]=[CH:54][C:40]([O:39][CH3:38])=[CH:41][CH:42]=3)[CH:49]=2)=[O:51])=[C:4]([CH3:18])[CH:5]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: COc1ccc(Cn2cc(C(=O)O)cn2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: COc1ccc(Cn2cc(C(=O)NCc3c(C)cc(N)nc3C)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl 5-(aminomethyl)-4,6-dimethylpyridin-2-ylcarbamate (80.0 mg, 0.318 mmol) in DCM (3 ml) were added HOAt (87.0 mg, 0.637 mmol), collidine (0.127 ml, 0.955 mmol), 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (73.9 mg, 0.318 mmol) and HATU (81.0 mg, 0.212 mmol). After stirring for 2 h at rt, all volatiles were removed in vacuo. The crude intermediate was purified by column chromatography (CombiFlash Companion, 12 g SiO2, TBME to TBME+10% MeOH), dissolved in DCM (3 ml) and TFA (1 ml), kept for 14 h at rt, and concentrated. Purification by column chromatography (CombiFlash Rf, 13 g RediSep Rf C18, MeCN:water 5:95+0.1% TFA to MeCN) afforded the title compound as. 1H-NMR (DMSO-d6, 400 MHz): 2.37 (s, 3H), 3.73 (s, 3H), 4.27 (d, 2H), 5.24 (s, 1H), 6.64 (s, 1H), 6.91 (d, 2H), 7.23 (d, 2H), 7.70 (br, s, 2H), 7.84 (s, 1H), 8.14-8.19 (m, 2H), 13.59 (s, 1H). LCMS RtK=0.71 min, [M+H]+=366.4.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11]C(=O)C(C)(C)C)[CH:9]=[CH:10][C:4]=2[C:3]=1[Br:18].[OH-].[K+]>C(O)C>[Br:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[Br:18]
Reactant: CC(C)(C)C(=O)Oc1ccc2c(Br)c(Br)sc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc2c(Br)c(Br)sc2c1
Yield: 101 %

Procedure:
Dissolve 2,2-dimethyl-propionic acid 2,3-dibromo-benzo[b]thiophen-6-yl ester (32 g, 82 mmol) in ethanol (725 mL), add 50% aqueous solution of potassium hydroxide (39 mL, 328 mmol) and heat to reflux for 4 hours. Concentrate in vacuo to ½ volume, partition between ethyl acetate (500 mL) and saturated aqueous ammonium chloride (500 mL), separate layers, wash organic with saturated aqueous ammonium chloride (2×500 mL), and brine (300 mL). Dry with sodium sulfate, filter, and concentrate in vacuo to give 25.5 g of 2,3-dibromo-benzo[b]thiophen-6-ol (100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([SH:15])=[N:6][C:5]=2[N:16]=1.[CH3:17][C:18]1[C:22]([CH2:23]Cl)=[C:21]([CH3:25])[O:20][N:19]=1>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:15][CH2:23][C:22]3[C:18]([CH3:17])=[N:19][O:20][C:21]=3[CH3:25])=[N:6][C:5]=2[N:16]=1
Reactant: C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: Cc1noc(C)c1CCl
Product: Cc1noc(C)c1CSc1nc(N[C@H](C)CO)c2sc(N)nc2n1

Procedure:
The titled compound was prepared from the product of example 4, step (b), and 3,5-dimethyl-4-chloromethylisoxazole using the method of example 4, step (c) to give a white powder (0.016 g)
Reaction SMILES: C([C:6]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O-:21])=[O:20])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])(OCC)=O.S(=O)(=O)(O)O.C(O)(=O)C>O>[C:7]1(=[O:12])[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)C1(CCCCCCC(=O)[O-])CCCCC1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCCCCCC1CCCCC1=O

Procedure:
A stirred mixture of 380 g. of mixed methyl and ethyl esters of 7-(2-carbethoxycyclohexan-1-on-2-yl)heptanoate (Example 10), 202 ml. of concentrated sulfuric acid, 970 ml. of glacial acetic acid, and 970 ml. of water is refluxed for 22.5 hours. The cooled reaction mixture is treated with 380 g. of sodium carbonate and 2 liters of water and is extracted with ether. Acidic material is partitioned from the ether extract with 1.0M sodium carbonate. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ether. The extract is washed successively with water and saturated sodium chloride, dried, and evaporated to give an oil.
Reaction SMILES: Cl.[O:2]([CH2:9][C:10](=[NH:12])[NH2:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]([SH:17])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:13][C:14]1[S:17][N:11]=[C:10]([CH2:9][O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)COc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Clc1nc(COc2ccccc2)ns1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a solution of 2-phenoxyethanimidamide hydrochloride (2.00 g, 10.7 mmol) and perchloromethyl mercaptan (1.15 ml, 10.7 mmol) in dichloromethane (40 ml) was added dropwise a solution of sodium hydroxide (2.15 g, 53.7 mmol) in water (6 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=9:1) to give 1.66 g (68.3%) of the desired product as an oil.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[CH:23]=O)[CH:16]=[CH:15]1>O1CCCC1.C(OCC)(=O)C>[C:3](/[CH:5]=[CH:23]/[C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[NH:14][CH:15]=[CH:16]2)#[N:4]
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#C/C=C/c1cccc2cc[nH]c12
Reaction time: 0.25 h

Procedure:
Sodium hydride, 60% dispersion in mineral oil (0.10 g, 2.5 mmol) is added in portions over 10 minutes to a stirred solution of diethyl cyanomethylphosphonate (0.44 g, 2.5 mmol) in tetrahydrofuran (10 ml) cooled in ice. The mixture is stirred for 15 minutes then a solution of 7-indole carboxaldehyde (0.30 g, 2.1 mmol) in tetrahydrofuran (2 ml) is added dropwise. The mixture is stirred for 30 minutes, diluted with ethyl acetate, washed with water, dried and evaporated. The residue is chromatographed on silica in ethyl acetate-hexane (1:3) to give the product.
Reaction SMILES: [C:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[CH2:14]1[O:42][C:41]2[CH:40]=[CH:39][C:18]([C:19]([N:21]3[C:30]4[C:25](=[CH:26][C:27]([C:31]5[CH:36]([CH3:37])[S:35][C:34](=[O:38])[NH:33][N:32]=5)=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:17][C:16]=2[O:15]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([N:33]1[N:32]=[C:31]([C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:21]([C:19](=[O:20])[C:18]2[CH:39]=[CH:40][C:41]4[O:42][CH2:14][O:15][C:16]=4[CH:17]=2)[CH2:22][CH2:23][CH2:24]3)[CH:36]([CH3:37])[S:35][C:34]1=[O:38])=[O:11]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)CCCN2C(=O)c1ccc2c(c1)OCO2
Reactant: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1SC(=O)N(C(=O)C2CC3CCC2(C)C3(C)C)N=C1c1ccc2c(c1)CCCN2C(=O)c1ccc2c(c1)OCO2
Reaction time: 4 h

Procedure:
A solution of 26 g of (-)-camphanic acid chloride in 100 ml of methylene chloride is added dropwise at 0°, with stirring, to a suspension of 48 g of 5-[1- (3,4-methylenedioxybenzoyl)-1,2,3, 4-tetrahydroquinol-6- yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in 800 ml of methylene chloride to which 20 ml of triethylamine have been added, and the reaction mixture is stirred for 4 hours. It is then washed with dilute hydrochloric acid and subsequently with bicarbonate solution. The organic phase is separated off and worked up in conventional manner to give 3-[(-)-camphanoyl]-5-[1-(3,4-methylenedioxybenzoyl)-1,2,3, 4- tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4- thiadiazin-2-one as a mixture of diastereoisomers, m.p. 216°-217° .