Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][C@H:20]([CH3:39])[C@H:21]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=1.N1C=CN=C1.C(OCC)(=O)C>CN(C=O)C>[Si:5]([O:19][C@H:20]([CH3:39])[C@H:21]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:22]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-Butylchlorodiphenylsilane (2.0 ml) was added in four portions to a solution of tert-butyl [(1R,2R)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]carbamate (610 mg) and imidazole (817 mg) in DMF (3 ml) in a nitrogen atmosphere, and the reaction solution was stirred at room temperature for three hours. Ethyl acetate was added to the reaction solution, which was then sequentially washed with water, 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:diethyl ether 49:1 to 19:1) to obtain 684 mg of the title compound.
Reaction SMILES: [C:1]1([CH:7]2[NH:10][C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C1COCC1>[C:1]1([CH:7]2[CH2:8][CH2:9][NH:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccccc2)N1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc(C2CCN2)cc1
Temperature: 25 °C

Procedure:
To 0.5 g (3.4 mmol) 4-phenyl-2-azetidinone in 5 mL anhydrous THF under nitrogen was added a solution of lithium aluminium hydride (1 M in THF, 11.9 mmol) dropwise, and the mixture was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature, 20% aqueous ammonium chloride was added and the mixture was filtered through a pad of celite. The filtrate was extracted with EtOAc (2×10 mL), the organic layers were combined and dried over Na2SO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, DCM/7 N ammonia in MeOH 92:2 to 94:6), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH2:14][CH3:15])[CH2:9][C:10](OC)=[O:11])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[OH-].[NH4+:18]>O>[Cl:1][C:2]1[C:7]2[C@H:8]([CH2:14][CH3:15])[CH2:9][C:10](=[O:11])[NH:18][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CCC(CC(=O)OC)c1c(Cl)ncnc1Cl
Agent: [OH-]
Solvent: O
Product: CC[C@@H]1CC(=O)Nc2ncnc(Cl)c21
Temperature: 200 °C

Procedure:
Dissolve methyl 3-(4,6-dichloropyrimidin-5-yl)pentanoate (10.00 g, 38.01 mmol) in 28% ammonium hydroxide in water (95 mL) and seal in a 350 mL tube. Heat the reaction mixture to 200° C. for 2 hours. Cool the reaction mixture in an ice bath, then filter and wash with cold water. Dry the solids under vacuum to give the racemate. Chiral separation (Chiralpak AS-H, 100% ethanol w/0.2% dimethyl ethylamine) provides the title compound as enantiomer 2 (3.19 g, 40%) (>99% ee). MS (ES) m/z=212 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([O:17]CC)=[O:16])=[CH:11][N:10]1[CH3:20].O1CCCC1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](=[O:14])[C:12]([C:15]([OH:17])=[O:16])=[CH:11][N:10]1[CH3:20]
Reactant: CCOC(=O)c1cn(C)n(-c2ccccc2OC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1-n1c(=O)c(C(=O)O)cn1C
Yield: 83.2 %

Procedure:
In the same manner as in Reference Example 65 and using ethyl 2-(2-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (2.5 g, 9.2 mmol), tetrahydrofuran (6 mL), methanol (5 mL) and 4N aqueous sodium hydroxide solution (8 mL) as starting materials, the title compound (1.9 g, 85%) was obtained as a white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[C:8]([O:10]C)=[O:9].Cl>CO>[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]([C:12]1[CH:13]=[CH:14][C:15]([N:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)C(CCCCl)c1ccc(N(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1ccc(C(CCCCl)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 23.5 h
Yield: 191.1 %

Procedure:
A 5 N sodium hydroxide solution (0.5 mL) was added to a solution of methyl 5-chloro-2-(4-dimethylaminophenyl)pentanoate (175 mg) in methanol (2 mL), and the reaction solution was stirred at room temperature for 23.5 hours. Thereafter, 1 N aqueous hydrochloric acid (2.5 mL) was added to the reaction solution, and the reaction solution was concentrated under reduced pressure to obtain 317 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17](O)=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:27][NH2:28]>>[Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([NH:28][CH3:27])=[O:18])[CH:14]=[N:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN
Reactant: O=C(O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Agent: Cl
Product: CNC(=O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was reacted with methylamine hydrochloride via General Procedure B to yield 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylpyridine-3-carboxamide. Crude 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylpyridine-3-carboxamide (41 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 10.6 mg of 344. MS (Q1) 472.0 (M)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[C:19](N(OC)C)=[O:20])[CH:5]=[CH:6][CH:7]=1.[CH3:25][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[C:19](=[O:20])[CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1nc(C)c2ccccc2c1-c1cccc(F)c1
Solvent: C1CCOC1
Product: CC(=O)c1nc(C)c2ccccc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 4-(3-fluorophenyl)-N-methoxy-N,1-dimethylisoquinoline-3-carboxamide (257 mg, 0.792 mmol) in tetrahydrofuran (1 mL) was added 1.4 M methylmagnesium bromide in tetrahydrofuran (3.4 mL, 4.8 mmol). The reaction was stirred at room temperature overnight, quenched with sat. ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to dryness to afford the desired product (0.221 g, 100%). LCMS calculated for C18H15FNO (M+H)+: m/z=280.1; Found: 280.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([C:18]([O:20]CC)=O)[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH:5]1[OH:17]>CO.N>[CH2:10]([N:7]1[CH2:8][CH2:9][C:4]2([C:18](=[O:20])[NH:1][CH2:2][CH2:3]2)[CH:5]([OH:17])[CH2:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C1(CCN)CCN(Cc2ccccc2)CC1O
Agent: N
Solvent: CO
Product: O=C1NCCC12CCN(Cc1ccccc1)CC2O
Temperature: 45 °C
Reaction time: 8 h

Procedure:
Into a 10000-mL 3-necked round-bottom flask was placed a solution of ethyl 4-(2-aminoethyl)-1-benzyl-3-hydroxypiperidine-4-carboxylate (220 g, 718.02 mmol, 1.00 equiv) in methanol (2000 mL) and ammonia (2000 mL). The resulting solution was stirred overnight at 45° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol to obtain the title compound.
Reaction SMILES: [CH:1]([C:3]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]([NH-:16])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=O.[NH:17]1[C:21]2[N:22]=[CH:23][CH:24]=[C:25]([C:26]([OH:28])=[O:27])[C:20]=2[CH:19]=[CH:18]1.[CH3:29][N:30]([CH3:44])[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:36]=[C:37]([NH2:43])[C:38]([NH2:42])=[CH:39][C:40]=1[F:41]>CN(C)C=O>[NH:17]1[C:21]2[N:22]=[CH:23][CH:24]=[C:25]([C:26]([OH:28])=[O:27])[C:20]=2[CH:19]=[CH:18]1.[CH3:44][N:30]([CH3:29])[CH2:31][CH2:32][CH2:33][O:34][C:35]1[C:40]([F:41])=[CH:39][C:38]2[N:42]=[C:1]([C:3]3[C:15]4[C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH:8]([NH-:16])[C:7]=4[CH:6]=[CH:5][CH:4]=3)[NH:43][C:37]=2[CH:36]=1
Reactant: [NH-]C1c2ccccc2-c2c(C=O)cccc21
Reactant: CN(C)CCCOc1cc(N)c(N)cc1F
Agent: O=C(O)c1ccnc2[nH]ccc12
Solvent: CN(C)C=O
Product: CN(C)CCCOc1cc2[nH]c(-c3cccc4c3-c3ccccc3C4[NH-])nc2cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Stir, at room temperature under argon, a mixture of 100 mg of (4-formyl-9H-fluoren-9(R,S)-yl)amide of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid, prepared as in Example 234, 65 mg of 4-(3-dimethylaminopropoxy)-5-fluorobenzene-1,2-diamine, prepared in the previous stage, and 46 mg of ferric trichloride in 5 ml of anhydrous dimethylformamide. After 48 hours, evaporate the reaction medium to dryness and then purify the residue by flash chromatography on silica gel (20-40 μm), eluting with a mixture of dichloromethane and ammonia as a 7N solution in methanol (95/5 then 9/1 by volume). In this way, we obtain 42 mg of {4-[6-(3-dimethylaminopropoxy)-5-fluoro-1H-benzimidazol-2-yl]-9H-fluoren-9(R,S)-yl}amide 1H-pyrrolo[2,3-b]-pyridine-4-carboxylic acid, in the form of a yellow solid with the following characteristics:
Reaction SMILES: [CH:1]1([CH:4]=[O:5])[CH2:3][CH2:2]1.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.C([Li])CCC>>[CH:1]1([CH:4]([C:7]2[CH:8]=[N:9][CH:10]=[N:11][CH:12]=2)[OH:5])[CH2:3][CH2:2]1
Reactant: O=CC1CC1
Reactant: Brc1cncnc1
Agent: [Li]CCCC
Product: OC(c1cncnc1)C1CC1

Procedure:
Using the general method of Example 1, cyclopropanecarboxaldehyde (19 g, 0.27 mol) was reacted with 5-bromopyrimidine (43.2 g, 0.27 mol) and n-butyl lithium (108.6 ml of 2.5M, 0.27 mol) to give the product as a pale yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH2:36][CH2:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH2:36][CH2:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CCCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ccc2c(c1CN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-6-propoxy-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0210 g, 0.0405 mmol) in methylene chloride (1 mL) was added with trifluoroacetic acid (1 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate, thereby made basic, and then extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-7-(piperazin-1-ylmethyl)-6-propoxybenzofuran-3(2H)-one (0.0160 g, 94%).
Reaction SMILES: [N:1]1([C:7]2[C:16]([F:17])=[C:15]3[C:10]([C:11](=[O:24])[C:12]([C:21]([OH:23])=[O:22])=[CH:13][N:14]3[CH:18]3[CH2:20][CH2:19]3)=[C:9]([CH3:25])[C:8]=2[F:26])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28].Cl>[OH-].[Na+]>[C:27]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:16]([F:17])=[C:15]3[C:10]([C:11](=[O:24])[C:12]([C:21]([OH:23])=[O:22])=[CH:13][N:14]3[CH:18]3[CH2:19][CH2:20]3)=[C:9]([CH3:25])[C:8]=2[F:26])[CH2:2][CH2:3]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N1CCN(c2c(F)c(C)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1

Procedure:
To a solution of 7-(1-piperazinyl)-1-cyclopropyl-6,8-difluoro-5-methyl-1, 4-dihydro-4-oxoquinoline-3carboxylic acid (42 mg) in 5% sodium hydroxide (2 ml) is added acetic anhydride (0.1 ml) at room temperature. After the mixture is made acidic with dilute hydrochloric acid, the resultant is extracted with dichloromethane and the extract is dried over magnesium sulfate. After concentrating, the obtained residue is recrystallized from ethanol to give 7-(4-acetyl-1-piperazinyl)-1-cyclopropyl-6,8-difluoro-5-methyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (30 mg), as white powder, m.p. 217°-220° C.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][C:18]([O:27][C:28](=[O:30])[CH3:29])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)C1C=CC=CC=1>N.CO.[Pd]>[C:28]([O:27][C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][CH2:12][NH2:11])[CH2:20][CH2:19]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC1(c2ccccc2)CCN(CCCNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: N
Solvent: CO
Product: CC(=O)OC1(c2ccccc2)CCN(CCCN)CC1
Reaction time: 4 h
Yield: 99.6 %

Procedure:
A mixture of N-benzyloxycarbonyl-3-(4-acetoxy-4-phenylpiperidin-1-yl)propylamine (3.0 g, 7.3 mmol) and 10% Pd-C (0.3 g) in 1M ammonia in methanol(50 mL) was hydrogenated at 70 psi at room temperature for 4 h. The catalyst was removed by filtration and the solvent was evaporated to leave the product as a viscous oil (2.01 g, 99%), the 1H-NMR showed it to be very pure and was used in the next step without any purification.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)=[O:13].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].Cl>CS(C)=O.O>[CH3:20][N:17]1[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:15][CH2:16]1
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CN1CCN(C(=O)CCc2ccccc2O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1ccccc1CCC(=O)N1CCN(C)CC1
Temperature: 80 °C
Reaction time: 3.75 h
Yield: 9.3 %

Procedure:
10% sodium hydroxide aqueous solution (6.70 g) was added to a solution containing 3-(2-hydroxyphenyl)-1-(4-methylpiperazino)-1-propanone (2.07 g) obtained in Example 3(1) in dimethylsulfoxide (21 ml). The mixture was heated up to 80° C. and 1-bromooctadecane (2.78 g) was added thereto. After being stirred for 3.75 hours at 80° C., the reaction mixture, with water added thereto, was neutralized with 1N hydrochloric acid. The deposited solid was corrected by filtration and washed with water. This solid was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=50:1 to 10:1), thereby yielding the entitled compound (0.39 g) as white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@H:7]([OH:9])[CH3:8])=[CH:3][CH:2]=1.C([Li])CCC.[C:15]12([C:25](Cl)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>C1COCC1.CCCCCC>[C:15]12([C:25]([O:9][C@@H:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH3:8])=[O:26])[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: C[C@@H](O)c1ccncc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@@H](OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccncc1
Yield: 88.1 %

Procedure:
The method followed that described in Example 1, but using (+)-(R)-1-(4-pyridyl)ethanol (369 mg, 3.0 mmol) in THF (12 ml), n-butyllithium (2.5 M, 1.2 ml, 3.0 mmol) in hexane, and 1-adamantanecarbonyl chloride (656 mg, 3.3 mmol) in THF (3 ml). Chromatography, on elution with petrol-ether-triethylamine 200:50:1, afforded the title compound (754 mg, 88%). [α]D +25.8° (c 1, CHCl3); IR νmax 1730 cm-1 ; 1H-NMR (CDCl3) δ1.50 (3H, d, J 6.6 Hz, CHCH3), 1.73 and 1.93 (12H, 2s, adamantyl CH2), 2.04 (3H, s, adamantyl CH), 5.80 (1H, q, J 6.6 Hz, OCH), 7.23 (2H, d, J 6.1 Hz, Py 3 and 5H), 8.58 (2H, d, J 6.1 Hz, Py 2 and 6H); MS m/z 285 (M+). By passing hydrogen chloride gas through a solution of the product in ether, the hydrochloride was obtained, m.p. 164°-166° C. Anal. Calcd: C, 67.17; H, 7.52; N, 4.35. Found: C, 67.58; H, 7.51; N, 4.36%.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH3:15][CH2:16][N:17](C(C)C)[CH:18](C)[CH3:19].C(NCC)C.O>C1COCC1>[NH2:6][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([N:17]([CH2:18][CH3:19])[CH2:16][CH3:15])[CH:7]=1
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Solvent: CCNCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)c1cc(N)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dinitro-5-fluoroaniline (1.6 g, 8.0 mmol) in 20 mL of THF, a mixture of DIPEA (1.1 g, 8.8 mmol) and diethylamine (644 mg, 8.8 mmol) in 5 mL of THF was added slowly. The reaction mixture was stirred at room temperature for 1 h. Water (100 mL) was added to give the desired product as a yellow precipitate. The product was collected by filtration and washed with water (200 mL). The filtrate was concentrated to dryness in vacuo to give the desired product (1.8 g, 90% yield) as a bright yellow solid: 1H-NMR (300 MHz, CDCl3) δ 1.96 (t, 6H, J=7.2 Hz), 3.24 (q, 4H, J=7.2 Hz), 6.08 (s, 1H), 8.75 (s, 1H); 13C NMR (75 MHz, CDCl3) δ12.1, 45.7, 102.7, 123.3, 128.2, 131.6, 147.8, 149.4; ESI MS m/z 255.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]3[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:16]N1C(=O)CCC1=O>C(#N)C.CCOCC>[I:16][C:15]1[N:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(-c2cn3ccccc3n2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: Ic1c(-c2ccccc2)nc2ccccn12
Yield: 97 %

Procedure:
Treat a solution of 2-phenylimidazo[1,2-a]pyridine (50 mg, 0.257 mmol) in acetonitrile (1.25 mL) with N-iodosuccinimide (NIS) (69 mg, 0.309 mmol) at room temperature for 5 hours. Dilute the mixture with ether (10 mL), wash with a saturated aqueous solution of NaHCO3 (15 mL) and NaHSO3 (40%, 15 mL), dry (Na2SO4) and concentrate in vacuo. A yellow solid is obtained, 80 mg, 97% yield. MS(ES+): m/z=321.0 (M+H)+
Reaction SMILES: [CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[SH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:35]([C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)=[CH2:36]>C(O)(=O)C>[CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[S:21][CH2:36][CH2:35][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Cc1ccccc1
Reactant: C=Cc1ccncc1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCCc2ccncc2)c1Cc1ccccc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 4-benzyl-3-mercapto-5-sulfamylbenzoic acid (3.25 g), sodium hydrogen carbonate (2.0 g), sodium dithionite (2.0 g), 4-vinylpyridine (1.5 ml) and saturated sodium hydrogen carbonate (33 ml) is stirred at 70° C. for 4 hours. After cooling, the mixture is acidified with 4 N acetic acid. The separated material is collected by filtration and washed with water. After drying and recrystallization twice from aqueous ethanol, 4-benzyl-3-(4-pyridylethylthio)-5-sulfamylbenzoic acid is obtained as a hemihydrate with a melting point of 180° -182° C..
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=O)=[N:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:17][N:16]=2)[CH:15]=1
Reactant: O=C(NNc1ccc(F)cn1)N1CCCCC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc2nnc(N3CCCCC3)n2c1
Reaction time: 2 h
Yield: 48 %

Procedure:
Hexachloroethane (826 mg, 3.92 mmol) was added portionwise to a solution of Intermediate 3a (466 mg, 1.95 mmol), triphenylphosphine (1.03 g, 3.92 mmol) and triethylamine (1.1 mL, 7.83 mmol) in dry THF (30 mL) at RT, and the mixture stirred for 2 h. The resulting precipitate was filtered off and the filtrate evaporated. The residue was purified by SCX-2, eluting with MeOH followed by 2M NH3 in MeOH, to give the title compound as pale orange coloured gum (206 mg, 48%). LCMS (Method 1): Rt 2.44 min, m/z 221 [MH+].
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:9]([OH:10])[N:8]=[N:7][C:5]=2[CH:6]=1.[CH3:11][N:12]([CH3:15])C=O>>[CH2:1]1[CH2:2][CH2:3][CH:11]([N:12]=[C:15]=[N:7][CH:5]2[CH2:4][CH2:3][CH2:2][CH2:1][CH2:6]2)[CH2:5][CH2:6]1.[CH:1]1[CH:2]=[CH:3][C:4]2[N:9]([OH:10])[N:8]=[N:7][C:5]=2[CH:6]=1
Reactant: CN(C)C=O
Agent: On1nnc2ccccc21
Product: C(=NC1CCCCC1)=NC1CCCCC1
Reaction time: 24 h

Procedure:
These reactions were done in a 96-well plate. The reagents are given per well. Sulfonamide benzoic acid IIIp (4 mg, 0.012 mmol) in 300 μl N,N-dimethylformamide and polystyrene-DCC resin (15 mg, loading ca. 1.27 mmol/g) were combined with HOBt (2 mg, 0.015 mmol) and amine B (0.010 mmol). The reaction was shaken for 24 h, then polystyrene-(polystyrene)-trisamine resin (9 mg, loading ca. 4.36 mmol/g) was added and shaken overnight. The reaction was filtered and the N,N-dimethylformamide evaporated.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(O)C>[Cl:13][C:14]1[CH:15]=[C:16]([N:17]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2cccc(Cl)c2)C1=O
Yield: 81.2 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 3-chloroaniline (0.469 mL; 4.36 mmol) in ethanol (3 mL). 1-(3-chlorophenyl)-2-oxopyrrolidine-3-carboxylic acid 0.282 g (81%) was obtained as a solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[Cl:18][C:19]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[CH:21][C:20]=1[CH:34]([CH3:44])[CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40]>>[Cl:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH:22]=[CH:21][C:20]=1[CH:34]([CH3:44])[CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(C)CNC(=O)OC(C)(C)C)c(Cl)c1
Yield: 55.8 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-on (3.0 g, 9.7 mmol) was reacted with tert-butyl 2-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (5.7 g, 14 mmol) to afford the desired product (2.7 g, 56%) as a brown solid: ESI MS m/z 499 [C26H27ClN2O4S+H]+.