Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:31])[CH:10]([NH:12][C:13]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)=[O:14])[CH3:11])[CH:5]=[CH:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:31])[CH:10]([NH:12][C:13]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=3)[N:16]=2)=[O:14])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(NC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1)C(O)Cc1cccc(Br)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(NC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1)C(=O)Cc1cccc(Br)c1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a solution of N-(4-(3-bromophenyl)-3-hydroxybutan-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxamide (300 mg, 0.6 mmol) in DCM (300 mL), Dess-Martin reagent (988 mg, 2.4 mmol) was added in portions. The reaction mixture was stirred overnight and filtered. The filtrate was evaporated, and the residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=5:1) to afford N-(4-(3-bromophenyl)-3-oxobutan-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxamide (200 mg, 67%) as a white solid. MS (ES+) C20H15BrF3N3O4 requires: 497, 499, found: 498 [M+H]+, 500 [M+2+H]+(1:1).
Reaction SMILES: [Na].[CH:2]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14](Br)[CH:15]=1.O>CN1CCCC1=O>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([O:8][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:15]=1
Reactant: OC1CCCCC1
Reactant: Brc1cncc(Br)c1
Agent: [Na]
Solvent: O
Solvent: CN1CCCC1=O
Product: Brc1cncc(OC2CCCCC2)c1
Temperature: 90 °C

Procedure:
Under an argon atmosphere, sodium (750 mg, 31.75 mmol) was added to refluxing cyclohexanol (15 mL). The mixture was refluxed until complete consumption of sodium. The remaining cyclohexanol was removed by a stream of argon to give a white solid, which was dissolved in N-methyl-pyrrolidinone (16 mL). After addition of 3,5-dibromopyridine (3 g, 12.66 mmol), the mixture was stirred and heated at 90° C. for 1 h, then cooled to room temperature, poured into cold (5° C.) water (60 mL), and extracted with diethyl ether (3×50 mL). The combined organic phases were washed with water (25 mL) and then brine (25 mL), then dried (MgSO4), filtered and concentrated by rotary evaporation to give 6.2 g of an orange oil, which was purified by column chromatography, eluting with cyclohexane/ethyl acetate (95/5, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 1.6 g (50%) of a light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]2[CH2:13][N:12]([CH2:14][CH3:15])[CH2:11][CH:10]2[OH:16])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].O>CO>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C@@H:9]2[CH2:13][N:12]([CH2:14][CH3:15])[CH2:11][C@H:10]2[OH:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CCCCN(C(=O)c1ccc(Cl)cc1)C1CN(CC)CC1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCN(C(=O)c1ccc(Cl)cc1)[C@@H]1CN(CC)C[C@H]1O
Yield: 89 %

Procedure:
A mixture of 7.0 g (0.015 mole) of trans-4-chlorobenzoic acid ester with 4-[(4-chlorobenzoyl)(n-butyl)amino]1-ethyl-3-pyrrolidinol, 0.9 g (0.016 mole) of potassium hydroxide, 15 ml of water and 60 ml of methanol was heated on a steam bath for 1 hr, then concentrated to approximately 10 ml volume under reduced pressure. The residue was partitioned between water and methylene chloride. The organic layer was separated, dried and concentrated under reduced pressure. The crystalline residue was recrystallized from isopropyl ether to give 4.3 g (89%) of white powder; m.p. 96.5°-98.0° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH:31]([CH3:33])[CH3:32])[CH3:14])=[CH:8][C:7]=1[CH3:34].[OH-].[Na+].Cl>CO.C1COCC1>[CH:31]([C:16]1[N:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:24][CH:25]=2)[O:19][C:15]=1[CH:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]([CH3:34])[CH:8]=1)[CH3:14])([CH3:32])[CH3:33]
Reactant: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(OC(F)(F)F)cc3)nc2C(C)C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OC(C)c2oc(-c3ccc(OC(F)(F)F)cc3)nc2C(C)C)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(4-{1-[4-Isopropyl-2-(4-trifluoromethoxy-phenyl)-oxazol-5-yl]-ethoxy}-2-methyl-phenyl)-propionic acid methyl ester in MeOH (1.0 mL) and THF (0.5 mL) is treated with NaOH (1.5 mL, 2.0 M) and stirred at room temperature for 2 hours. The mixture is neutralized to pH=6 with HCl (5 N) and extracted with EtOAc (20 mL×2), and the combined organics are dried (Na2SO4), concentrated and purified on silica gel chromatography column with EtOAc/Hexanes (50/50) to yield the acid as white solid (14 mg). MS (ES): 478.2; the structure is also confirmed by proton NMR.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][CH:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([NH2:23])=[O:22]>>[NH2:23][C:21](=[O:22])[CH:20]([NH:19][C:15](=[O:17])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)C(N)C(N)=O
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CC(C)(C)C(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 2-amino-3,3-dimethyl-butanamide hydrochloride (1:1) (CAN 359844-68-1) as starting materials, LC-MS (UV peak area/ESI) 100%, 346.2113 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[F:15][C:16]1[CH:17]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35](Cl)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:19]=[C:20]([F:27])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:27][C:20]1[CH:19]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=3[F:1])[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:17]=[C:16]([F:15])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: OB(O)c1cccc(C(F)(F)F)c1F
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2cccc(C(F)(F)F)c2F)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 31.8 %

Procedure:
2-Fluoro-3-trifluoromethylbenzeneboronic acid (54 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (21 mg, 32%) after purification by flash chromatography on silica gel (% EtOAc in hexane=12%˜80%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[N:8][C:7]=1[CH3:14])=[O:5].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O.C(Cl)(Cl)Cl>[CH2:19]([O:18][C:16]([NH:2][CH2:3][C:4]([C:6]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[N:8][C:7]=1[CH3:14])=[O:5])=[O:17])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: Cc1nc2sccn2c1C(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCC(=O)c1c(C)nc2sccn12
Yield: 43.3 %

Procedure:
To a solution of 4 g of 5-aminoacetyl-6-methylimidazo[2,1-b]thiazole hydrochloride in 50 ml of water is added a mixed solution of 3.2 g of ethyl chloroformate and 50 ml of ethyl acetate under stirring, and then 7.6 g of sodium bicarbonate is added. After the mixture is stirred at room temperature for 4 hours, chloroform and water are added to the resulting mixture. The chloroform layer is separated, washed with water and dried over magnesium sulfate, and then the chloroform is distilled off under reduced pressure. The residual oil is purified with a column chromatography using chloroform as a eluent to give 2 g of 5-ethoxycarbonylaminoacetyl-6-methylimidazo[2,1-b]thiazole.
Reaction SMILES: Br[C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[OH:21])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:11](=[O:12])[C:3]3[C:4]4[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]=3[O:21][C:15]=2[CH:16]=1
Reactant: Cc1ccc(NC(=O)c2c(Br)sc3c2CCCC3)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)Oc1sc3c(c1C(=O)N2)CCCC3
Yield: 41.4 %

Procedure:
In the same manner as in Example 18 and using 2-bromo-4,5,6,7-tetrahydro-N-(2-hydroxy4-methylphenyl)-benzo[b]thiophene-3-carboxamide (5.8 g), dimethyl sulfoxide (80 ml) and potassium carbonate (4.7 g), 1,2,3,4-tetrahydro-8-methyl[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one (1.87 g) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl>ClCCl>[N:11]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[CH:22][CH:23]=[CH:24][N:25]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ncccn3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cnc(-c2ccc(N3CCNCC3)cc2)nc1
Reaction time: 2 h

Procedure:
4-(4-Pyrimidin-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester 5.03 gm was dissolved in 25 ml dichloromethane and 10 ml of 4N HCl dioxane added. After stirring for 2 hrs, the mixture was then evaporated to obtain the title product.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.P(Cl)(Cl)Cl.[NH2:19][C:20]1[S:21][C:22]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=2[N:24]=1>O>[Cl:29][C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([NH:19][C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])[S:21][C:22]=2[CH:28]=1
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: Nc1nc2ccc(Cl)cc2s1
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=C(Nc1nc2ccc(Cl)cc2s1)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (0.30 g) of Preparation 1 in 75 mL xylenes is heated to reflux. PCl3 (0.07 mL) is added dropwise and the mixture stirred for 15 minutes. 2-Amino-6-chlorobenzothiazole (0.31 g) is added in one portion and the reaction refluxed overnight. The reaction is cooled to room temperature and H2O is added to quench excess PCl3. After stirring the solution for 30 minutes, a yellow solid is filtered, dried, and recrystallized from DMSO to give the title product (0.31 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: OB(O)c1ccccc1
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Product: CCCCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Purification by chromatography on silica gel (20% acetone in toluene to 60% acetone in toluene gradient) afforded 2-butyl-1-isobutyl-7-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p.>250° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=3)=[N:16][CH:17]=2)=[O:9])=[N:6][CH:7]=1.[CH3:25][S:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[F:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][NH:10][C:8](=[O:9])[C:5]3[CH:4]=[CH:3][C:2]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:34]=4)=[CH:7][N:6]=3)=[CH:17][N:16]=2)[CH:23]=[CH:22][N:21]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=C(NCc1ccc(-c2ccnc(F)c2)nc1)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cccc(-c2ccc(C(=O)NCc3ccc(-c4ccnc(F)c4)nc3)nc2)c1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a tube was added 5-bromo-N-((2′-fluoro-2,4′-bipyridin-5-yl)methyl)picolinamide 38-4 (38 mg, 0.10 mmol), 3-(methylsulfonyl)phenylboronic acid 43-1 (33 mg, 0.20 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol), toluene (0.4 mL), ethanol (0.1 mL) and 2M Na2CO3 (0.15 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours with the tube sealed. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 aqueous solution, H2O and brine. The organic phase was dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified with reverse phase HPLC to give N-((2′-fluoro-2,4′-bipyridin-5-yl)methyl)-5-(3-(methylsulfonyl)phenyl)picolinamide 43 as a white powder. MS m/z 463.10 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.63 (t, 1H, J=6.0 Hz), 9.06 (d, 1H, J=1.6 Hz), 8.75 (d, 1H, J=1.6 Hz), 8.42 (dd, J1=8.4 Hz, J2=2.0 Hz), 8.35 (d, 1H, J=5.2 Hz), 8.31 (m, 1H), 8.20-8.15 (m, 3H), 8.03-8.01 (m, 2H), 7.94 (dd, 1H, J1=8.2 Hz, J2=2.0 Hz), 7.85-7.80 (m, 2H), 4.62 (d, 2H, J=6.4 Hz), 3.30 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:5]=2[N:6]=1.[CH2:14]([O:16][P:17]([CH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([O:19][CH2:20][CH3:21])=[O:18])[CH3:15]>>[S:3]1[C:4]2[C:13]3[C:8]([CH2:7][C:5]=2[N:6]=[C:2]1[NH:1][C:27]([C:26]1[CH:30]=[CH:31][C:23]([CH2:22][P:17](=[O:18])([O:16][CH2:14][CH3:15])[O:19][CH2:20][CH3:21])=[CH:24][CH:25]=1)=[O:28])=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: Nc1nc2c(s1)-c1ccccc1C2
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2nc3c(s2)-c2ccccc2C3)cc1)OCC

Procedure:
Using 2-amino-4H-indeno[2,1-d]thiazol and 4[(diethoxyphosphoryl)methyl]benzoyl chloride, the procedure of Example 1 was otherwise repeated to provide the objective compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.Br[CH2:11][CH2:12][CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1>CN(C=O)C.O>[O:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[O:14][CH2:13][CH2:12][CH2:11][N:7]1[CH:8]=[CH:9][C:4](=[O:3])[CH:5]=[CH:6]1
Reactant: BrCCCOC1CCCCO1
Reactant: Oc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccn(CCCOC2CCCCO2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
Sodium hydride (946 mg of a 50% suspension in mineral oil, 19.7 mmol) was added to a solution of 4-hydroxypyridine (1.88 g, 19.7 mmol) in DMF (50 ml) and the mixture stirred for 30 minutes. 2-(3-Bromopropoxy)tetrahydropyran (4.0 g, 17.9 mmol), (J. Chem. Soc. 1963, 3440), was added and the mixture heated at 100° C. for 3 hours. The reaction mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5) to give 1-[3-(tetrahydropyran-2-yloxy)propyl]-1,4-dihydro-4-pyridone (1.5 g, 35%). 1H NMR Spectrum: (DMSOd6) 1.35-1.75(m, 6H); 1.95(t, 2H); 3.35-3.5(m, 2H); 3.65-3.8(m, 2H); 4.12(t, 2H); 4.57(s, 1H); 6.95(s, 2H); 7.94(s, 2H).
Reaction SMILES: [NH:1]([C:3]([C:5]1[N:6]=[CH:7][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][CH:10]=1)=[O:4])[NH2:2].[N:16]([O-])=O.[Na+].O.Cl>ClCCl>[N:1]([C:3]([C:5]1[N:6]=[CH:7][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][CH:10]=1)=[O:4])=[N+:2]=[N-:16]
Reactant: CCOC(=O)c1cnc(C(=O)NN)cn1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cnc(C(=O)N=[N+]=[N-])cn1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
A mixture of ethyl 5-(hydrazinecarbonyl)pyrazine-2-carboxylate (1.00 g, 4.76 mmol), sodium nitrite (1.76 g, 25.5 mmol), water (18 mL) and dichloromethane (18 mL) was cooled to 0to 5° C. (ice-bath) under vigorous stirring. 6M hydrochloric acid (7.4 mL) was added drop-wise over 30 minutes, keeping the temperature under 10° C. After stirring for a further 30 minutes, the organic layer was separated, dried over magnesium sulfate and concentrated under vacuum to afford the title compound (1.01 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[C@@H:8]([CH3:22])[CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][C@@H:8]([CH3:22])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN[C@@H](C)C1
Reaction time: 12 h

Procedure:
A suspension of 3.5 g (S)-2-Methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-ethyl ester and 0.4 g Pd/C (10%) in 56 ml ethyl acetate was stirred under an atmosphere of hydrogen (3 bar) for 12 h. The mixture was filtrated over a plug of Celite, washed with ethyl acetate and the combined wash solutions concentrated to give the title compound as colourless oil. Yield: 1.6 g.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]1[CH2:15][CH:14]=[CH:13][CH:12]=1)[CH2:8]2.CO.[CH3:18][C:19]([CH3:21])=O.N1CCCC1>C(OCC)C.O.C(O)(=O)C.O1CCCC1.C(O)C>[CH:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH:2]1[C:11]1[CH:15]=[CH:14][C:13](=[C:19]([CH3:21])[CH3:18])[CH:12]=1)[CH2:10]2
Reactant: C1=CCC(C2C3CC4CC(C3)CC2C4)=C1
Reactant: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)=C1C=CC(C2C3CC4CC(C3)CC2C4)=C1
Reaction time: 48 h

Procedure:
To 2-adamantylcyclopentadiene (6.06 g, 30.3 mmol) was added 50 mL methanol, 50 mL ethanol, 20 mL tetrahydrofuran, 36 mL acetone (0.49 mol) and 0.5 mL pyrrolidine (0.006 mol). After stirring for 48 hours, 5 mL of acetic acid were injected, followed by 200 mL H2O and 200 mL diethyl ether. The organic layer was isolated and the aqueous layer extracted with diethyl ether (3×40 mL). The combined organic layers were extracted with H2O (3×25 mL) and with 10% aqueous NaOH (3×25 mL), dried over MgSO4, filtered and rotavapped. The obtained yellow solid was further purified by overnight Soxhlet extraction by 150 mL methanol. The precipitate in the filtrate was isolated by filtration at 0° C., and in vacuo drying: 4.54 g (62.5%) of 3-(2-adamantyl)-6,6-dimethylfulvene, as a yellow powder. Elemental analysis calculated for C18H24: C, 89.94; H, 10.06. Found: C, 82.23, 82.23; H, 8.78, 8.82.
Reaction SMILES: [CH:1]1([Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH:14]1C[CH2:17][O:16][CH2:15]1.C[Si](C)(C)Cl>C[O-].[Na+]>[CH:1]1([Si:6]([O:11][CH3:12])([O:7][CH3:8])[O:9][CH:10]2[CH2:14][CH2:15][O:16][CH2:17]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CO[Si](OC)(OC)C1CCCC1
Reactant: OC1CCOC1
Agent: C[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CO[Si](OC)(OC1CCOC1)C1CCCC1
Yield: 54 %

Procedure:
In a 100 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 7.7 g (0.0404 mole) of cyclopentyl trimethoxysilane, 35.7 g (0.405 mole) of 3-hydroxy tetrahydrofurane and 53.0 mg (0.98 m mole) of sodium methoxide, which were then reacted with each other in an oil bath of 80° C. for 2 hours under stirring. After cooled, trimethylchlorosilane was added to neutralize the alkali. Then, 5.37 g (0.0218 mole) of cyclopentyl dimethoxy oxa-3-cyclopentyloxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. The yield was 54%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](O)=[O:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:39][NH:40][O:41][CH3:42].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([N:40]([O:41][CH3:42])[CH3:39])=[O:15])=[C:10]([C:17]3[CH:18]=[CH:19][C:20]([S:23](=[O:25])(=[O:26])[NH2:24])=[CH:21][CH:22]=3)[C:9]=2[CH3:27])=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: Cc1c(-c2ccc(S(N)(=O)=O)cc2)c(C(=O)O)n(C)c1-c1ccc(Cl)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 0 °C
Reaction time: 15 h
Yield: 76.7 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxylic acid (compound 49ε, 0.800 g, 1.98 mmol) in DMF (15 ml) was added HOBT (0.333 g, 2.17 mmol) at room temperature followed by the addition of N,O-dimethylhydroxylamine hydrochloride (0.386 g, 3.96 mmol). The reaction mixture was then cooled to 0° C., and to the cooled reaction mixture was added EDC (0.570 g, 2.97 mmol) and triethylamine (0.80 g, 1.10 ml, 7.92 mmol). The reaction mixture was then stirred at room temperature for 15 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue so obtained was taken in ethyl acetate (100 ml) and washed with saturated sodium bicarbonate solution (20 ml) followed by washing with brine (20 ml). The organic layer obtained was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtain a crude product. The crude product was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (0.680 g, 76.8%).