Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[C:8](=[O:20])[C:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([OH:11])[C:5]=2[CH:4]=1)[CH3:2].[CH:37](N(C(C)C)CC)(C)C.CO.C[Si](C=[N+]=[N-])(C)C>C(#N)C>[CH2:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[C:8](=[O:20])[C:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:10]([O:11][CH3:37])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1cc2c(O)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: CO
Product: CCc1cc2c(OC)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a mixture of 4′-{[2-ethyl-4-hydroxy-6-oxo-5-(2-phenylethyl)thieno[2,3-b]pyridin-7(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g), diisopropylethylamine (0.72 mL), methanol (2 mL) and acetonitrile (18 mL) was added trimethylsilyldiazomethane (2M hexane solution, 0.72 mL), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.28 g, 62%).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]([C:25]2[N:26]=[C:27]([N:30]3[CH2:33][CH:32](OS(C)(=O)=O)[CH2:31]3)[O:28][CH:29]=2)=[O:24])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([O-:42])(=[S:41])[CH3:40].[K+]>CN(C)C=O>[C:39]([S:41][CH:32]1[CH2:33][N:30]([C:27]2[O:28][CH:29]=[C:25]([C:23]([N:21]3[CH2:20][CH:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:22]3)=[O:24])[N:26]=2)[CH2:31]1)(=[O:42])[CH3:40]
Reactant: CC([O-])=S
Reactant: CC(C)(C)[Si](OC1CN(C(=O)c2coc(N3CC(OS(C)(=O)=O)C3)n2)C1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C3)co2)C1
Temperature: 80 °C
Reaction time: 7.5 h
Yield: 57.3 %

Procedure:
To a solution of 1-[4-(3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]-3-methanesulfonyloxyazetidine (1.56 g, 2.81 mmol) (obtained as described in Reference Example 74(2)) in dimethylformamide (80 ml) was added potassium thioacetate (1.92 g, 16.8 mmol) at room temperature and the mixture was stirred in an oil bath (80° C.) for 7.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:1) as the eluant to afford 3-acetylthio-1-[4-(3-t-butyldiphenylsilyloxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (863 mg, yield 57%) as a pale brown solid.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]([F:12])([F:11])[F:10])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CO>[CH2:21]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6]([C:9]([F:12])([F:10])[F:11])(=[O:7])=[O:8])[CH:20]=[CH2:19]
Reactant: CCCCNS(=O)(=O)C(F)(F)F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCN(CCCC)S(=O)(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
A mixture of N-butyltrifluoromethanesulfonamide (62.0 g, 0.302 mole), potassium carbonate (45.54 g, 0.330 mole) and methanol (250 ml) was refluxed with stirring for two hours. Allyl bromide (39.93 g, 0.330 mole) was then added and this mixture stirred under reflux for 24 hours, cooled, filtered, and the solvent evaporated in vacuo. The residue was fractionally distilled yielding 37.0 g (b.p. of 53°-58° C. at 0.07 torr) of the desired compound, N-allyl-N-butyltrifluoromethylsulfonamide.
Reaction SMILES: CO.[CH:3]1([C:9]2[C:17]3[C:16](=[O:18])[NH:15][C:14]([C:19]4[CH:24]=[CH:23][C:22]([N:25](S(C)(=O)=O)[S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][C:20]=4[O:34][CH3:35])=[N:13][C:12]=3[N:11]([CH3:36])[N:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[OH-].[Na+]>O>[CH:3]1([C:9]2[C:17]3[C:16](=[O:18])[NH:15][C:14]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:21][C:20]=4[O:34][CH3:35])=[N:13][C:12]=3[N:11]([CH3:36])[N:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COc1cc(N(S(C)(=O)=O)S(C)(=O)=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.4 %

Procedure:
To a 2 ml methanol solution of 100 mg (0.20 mg) of the compound obtained in Example 141, 1 ml of a 1M aqueous solution of sodium hydroxide was added, and the mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was diluted with water, and the dilution was washed with dichloromethane. The aqueous layer was acidified with a 2M aqueous solution of hydrochloric acid, and precipitated solids were collected by filtration, followed by drying and recrystallization to obtain 19 mg (22%) of the captioned compound.
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:21]#[CH:22])[CH:10]=[C:11]3[C:16]=2[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]3([CH3:20])[CH3:19])[CH3:5])[CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][C:28]=1[F:34]>[Cu]I.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.C(N(CC)CC)C>[CH3:23][O:24][C:25](=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:22]#[C:21][C:9]2[CH:10]=[C:11]3[C:16](=[C:7]([CH2:6][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:5])[CH:8]=2)[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]3([CH3:20])[CH3:19])=[CH:29][C:28]=1[F:34]
Reactant: C#Cc1cc(CN(C)C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(CN(C)C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following General Procedure B and using 8-[(cyclopropyl-methyl-amino)-methyl]-6-ethynyl-2,2,4,4-tetramethyl-chroman (Intermediate 11, 0.084 g, 0.28 mmol), 2-fluoro-4-iodo phenyl acetic acid methyl ester (U.S. Pat. No. 6,252,090, 0.091 g, 0.3 mmol), triethyl amine (3 mL), copper(I)iodide (0.027 g, 0.14 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.060 g, 0.085 mmol) followed by flash column chromatography over silica gel (230-400 mesh), the title compound was obtained as a yellow oil (0.083 g, 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:11](=[O:27])[C:10]=2[C:28](O)=[O:29])=[CH:5][CH:4]=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([NH:38][C:28]([C:10]1[C:11](=[O:27])[N:12]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[N:13]=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(-c2nn(CC3CC3)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Reactant: NCc1ccccc1
Product: COc1ccc(-c2nn(CC3CC3)c(=O)c(C(=O)NCc3ccccc3)c2-c2ccc(OC)cc2)cc1

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-cyclopropylmethyl-2H-pyridazin-3-one and benzylamine as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained quantitatively.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][C:6]#[N:7].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]([CH2:2][CH:3]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][C:6]#[N:7])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCC(CO)CCC#N
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(CCC#N)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 66 h
Yield: 82.7 %

Procedure:
To a mixture of 45.50 g (0.323 mol) of crude 4-(hydroxymethyl)heptanenitrile and 53.5 g of t-butyldimethylsilyl chloride in 450 mL of methylene chloride at 3°-4° C., under argon, was added a solution of 67.5 mL (50.1 g, 0.388 mol) of diisopropylethylamine in 67.5 mL of methylenechloride dropwise over 10 min. 3.94 g (32.2 mmol) of 4-dimethylaminopyridine was then added and after stirring at room temperature for 66 hr, the dark reaction mixture was washed with 150 mL of 2N hydrogen chloride solution, 150 mL of water and 150 mL of saturated brine, dried (MgSO4), filtered, and concentrated. The residue was redissolved in methylene chloride, 180 g of silica gel was added and the solvent was removed under vacuum. The residual powder was placed on top of a 23/8"×9" column of 270 of silica gel and eluted, sequentially, with 1 L of hexane, 1 L of 1:19 ethyl acetate:hexane and I L of 1:9 ethyl acetate:hexane; 500-mL fractions were collected. Fractions 3-7 were combined and concentrated in vacuo, and the residue was distilled to give 68.22 g (82.9%) of 4-(t-butyldimethylsiloxymethyl)heptanenitrile, bp 114°-117° C. (0.9-1.0 mm Hg).
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH:35]([OH:39])[CH:36]([CH3:38])[CH3:37])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[OH:39][CH:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:12]=[C:11]([OH:10])[CH:16]=[C:15]([OH:17])[CH:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOCOc1cc(C=Cc2cccc(C=CCCCC(O)C(C)C)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(O)CCCC=Cc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.3 ml of concentrated sulphuric acid in 2.5 ml of methanol with 126 mg (0.27 mmol) of 8-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}-2-methyloct-7-en-3-ol in 2.5 ml of THF, after purification on a silica column (ethyl acetate 40-heptane 60), a beige powder (m=60 mg; Y=63%) is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:3]1[C:4]2[NH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][C:2]=1[O:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Reactant: CCOC(=O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOc1ccc2c(c1)[nH]c1ccccc12
Yield: 33 %

Procedure:
2-Hydroxycarbazole (0.5 g, 2.7 mmol), ethyl 6-bromohexanoate (0.6 g, 2.7 mmol), and potassium carbonate (0.4 g, 3.0 mmol) in dimethyl formamide (10 ml) were heated to 120° C. for 24 h. Water was added and extraction with ethyl acetate was performed. The combined organic phases were washed with water and dried (sodium sulfate). The solvent was removed i. vac. and the residue was purified by column chromatography (silica gel, ethyl acetate: heptane=1:1) to give ethyl 6-(9H-carbazol-2 yloxy)-hexanoate (290 mg, 33%) as a colorless solid. MS (M−H+)324.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.C([N:27]=[C:28]=[S:29])(=O)C1C=CC=CC=1.O>CC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:28]([NH2:27])=[S:29])=[N:2]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Solvent: CC(C)=O
Solvent: O
Product: NC(=S)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A solution of Compound 2 (0.06 g, 0.26 mmol) in acetone mL) was added with benzoyl isothiocyanate (0.10 mL, 1.5 mmol), followed by stirring at room temperature for 1 hour. The crude product obtained by adding water to the mixture was collected by filtration, dissolved in ethanol (1 mL) and added with 1 mol/L aqueous sodium hydroxide solution (1 mL), followed by stirring at room temperature for 1 hour. The mixture was neutralized by adding 6 mol/L hydrochloric acid and the precipitated solid was collected by filtration. The residue was triturated in ethanol to obtain Compound 161 (54 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[C:5]([O:9]COC)=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+]>C1COCC1.Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([OH:9])=[C:6]([I:8])[CH:7]=1
Reactant: COCOc1cnc(Cl)cc1I
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnc(Cl)cc1I
Temperature: 60 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
2-Chloro-4-iodo-5-methoxymethoxy-pyridine (0.8 g, 2.7 mmol) was dissolved in THF (4 mL) and 3N HCl (6 mL). The mixture was heated to 60° C. with magnetic stirring. Heating was maintained for 3 hours. The mixture was cooled to room temperature and the pH was adjusted to 7 with the slow addition of saturated aqueous sodium bicarbonate. The result was extracted with EtOAc (3×50 mL) dried over Na2SO4, filtered and concentrated. The solid was suspended in EtOAc and stirred for 12 hours at room temperature. The mixture was filtered and the filtrate was concentrated to yield an off white solid (0.63 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ11.10 (br s, 1H), 7.89 (s, 2H).
Reaction SMILES: Br[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[Mg].[Cl:11][CH2:12][C:13]([C:15]1([Cl:18])[CH2:17][CH2:16]1)=[O:14].[Cl-].[NH4+]>C(OCC)C.O>[Cl:11][CH2:12][C:13]([C:15]1([Cl:18])[CH2:17][CH2:16]1)([OH:14])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3]
Reactant: C=C(Br)c1ccccc1
Reactant: O=C(CCl)C1(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: C=C(c1ccccc1)C(O)(CCl)C1(Cl)CC1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
##STR20## A solution of 5 g (25 mmol) of α-bromostyrene in 10 ml of absolute diethyl ether is added dropwise to a mixture of 0.7 g (30 mmol) of magnesium filings and 10 ml of diethyl ether under an argon atmosphere and with stirring at room temperature. After the addition has ended, the reaction mixture is refluxed for 1 hour. The resulting Grignard solution is added dropwise at room temperature with stirring to a solution of 3 g (20 mmol) of 1-chlorocyclopropyl chloromethyl ketone in 10 ml of diethyl ether. After the addition has ended, the mixture is refluxed for another 4 hours. The reaction mixture is subsequently treated with a saturated, aqueous ammonium chloride solution, the resulting mixture is poured into water, and this mixture is extracted repeatedly using diethyl ether. The combined organic phase are washed with saturated, aqueous sodium chloride solution, dried over sodium sulphate, and then concentrated by stripping off the solvent under reduced pressure. 5.0 g (97% of theory) of 1-chloro-2-(1-chlorocyclopropyl)-3-phenyl-but-3-en-2-ol are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15].[CH:34]([NH2:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:13]([CH3:33])[C:14]([C:16]1[S:32][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([C:29]([NH:37][CH:34]([CH3:36])[CH3:35])=[O:31])=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)=[O:15]
Reactant: CC(C)N
Reactant: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccc(C(=O)N(C)C)cc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-((2-chloro-4-(dimethylcarbamoyl)phenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with isopropylamine, HATU and DIPEA in THF to give 339 as a colorless solid after reverse phase HPLC. MS: (ESI+) 526.1
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.Cl[C:21]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:24]=[C:23]([S:32][CH3:33])[N:22]=1>O1CCCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([NH:10][C:25]2[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][N:22]=[C:23]([S:32][CH3:33])[N:24]=2)=[N:12]1
Reactant: Nc1n[nH]c2ccccc12
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(SC)nc1Nc1n[nH]c2ccccc12
Temperature: 25 °C
Yield: 86.8 %

Procedure:
N,N-diisopropylethylamine (19.4 g) and 3-aminoindazole (6.66 g) were added to a tetrahydrofuran (0.2 L) solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (12.22 g), and stirred with heating under reflux for 15 hours. After cooled to room temperature, the reaction solution was evaporated under reduced pressure, water (50 mL) was added to the residue and the precipitated solid was collected through filtration, washed with distilled water and ethyl acetate in that order, and dried to give the title compound as a white solid (14.3 g).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH2:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH:38]=[CH2:39]>ClCCl>[CH2:37]([N:40]1[CH2:45][CH2:44][N:43]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:42][CH2:41]1)[CH:38]=[CH2:39]
Reactant: C=CCN1CCNCC1
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: C=CCN1CCN(Cc2cc3c(cn2)ncn3-c2cc(O[C@H](C)c3ccccc3C(F)(F)F)c(C(N)=O)s2)CC1

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 126.2 mg of 1-allylpiperazin in 2.5 ml dichloromethane give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[CH:6][CH:7]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[N:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Br)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(-c2nnn[nH]2)nc1
Temperature: 120 °C

Procedure:
A mixture of 3-bromo-6-cyano-pyridine (2 g, 10.9 mmol), sodium azide (0.85 g, 13 mmol), and ammonium chloride (0.59 g, 11 mmol) in N,N-dimethylformamide (20 mL) was heated for 1 h at 120° C. The reaction mixture was diluted with ethyl acetate (˜100 mL) and the product was isolated by filtration and then washed with ethyl acetate to give the title compound, an off-white amorphous solid which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[C:29]([CH3:31])[CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:27]2[CH:28]=[C:29]([CH3:31])[CH:30]=[C:25]([CH3:24])[CH:26]=2)=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Cc1cc(C)cc(O)c1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cc(C)cc(C)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3,5-dimethylphenol: 1H-NMR (CDCl3) δ 8.54 (1H, dd, J=2.6, 0.3 Hz), 8.24 (1H, d, J=7.3 Hz), 8.16 (1H, d, J=3.0 Hz), 8.00 (2H, dd, J=6.6, 1.8 Hz), 7.42 (2H, d, J=8.4 Hz), 6.94 (1H, s), 6.77 (2H, s), 5.42–5.32 (1H, m), 3.90 (3H, s), 2.36 (6H, s), 1.58 (3H, d, J=7.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:10][CH:9]2[C:11](O)=[O:12])=[CH:4][CH:3]=1.[CH3:17][NH2:18]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:10][CH:9]2[C:11](=[O:12])[N:18]([CH3:17])[C:14]3=[O:16])=[CH:4][CH:3]=1
Reactant: CN
Reactant: Nc1ccc(C2(C(=O)O)CC2C(=O)O)cc1
Solvent: CO
Product: CN1C(=O)C2CC2(c2ccc(N)cc2)C1=O
Temperature: 100 °C
Reaction time: 168 h

Procedure:
A mixture of 220 mg of 1-(4-aminophenyl)-1,2-cyclopropanedicarboxylic acid, 10 ml of methanol and 0.26 ml of methylamine (40%) is stirred in a glass bomb tube for 7 days at 100° C. The mixture is concentrated in vacuo and the residue is chromatographed over a column of silica gel with a 4:6 mixture of hexane/ethyl acetate. Recrystallisation from ethyl acetate/petroleum ether affords yellow crystals of the title compound, which is identical with the title compound of Example 3(a).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH2:14]O)=[CH:11][C:10]([CH3:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K]>CN(C=O)C>[CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])=[CH:11][C:10]([CH3:16])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CCO)n(Cc2ccccc2)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [H-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CCN2C(=O)c3ccccc3C2=O)n(Cc2ccccc2)n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
2-(2-Benzyl-5-methyl-2H-pyrazol-3-yl)-ethanol (848 mg, 3.92 mmol) was dissolved in DMF (21 ml) and cooled to −20° C. followed by the addition of sodium hydride (218 mg, 5.02 mmol). Stirring was continued at rt for 30 minutes. The reaction mixture was again cooled to −20° C. and toluene-4-suofonyl chloride (pTs-Cl, 966 mg, 5.02 mmol) was added. The cooling bath was removed and stirring was continued for 2 h at rt and 30 minutes at 50° C. followed by the addition of potassium phthalimid (1.7 g, 9.2 mmol). Stirring at 50° C. was continued for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up in DCM (30 ml) filtered again and the filtrate was washed with water (30 ml). The phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give 80 mg (6%) of 2-[2-(2-benzyl-5-methyl-2H-pyrazol-3-yl)-ethyl]-isoindole-1,3-dione. LC-MS: tR=0.95 min; [M+H]+=346.31.