Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:13]([Cl:14])=[C:12]([Cl:15])[S:11][C:10]=1[Cl:16])[CH3:5].C(N(CC)CC)C.[F:24][CH:25]([F:35])[C:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][N:28]([CH3:34])[N:27]=1>ClCCl.O>[CH3:1][O:2][N:3]([CH:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[C:13]([Cl:14])=[C:12]([Cl:15])[S:11][C:10]=1[Cl:16])[CH3:5])[C:31]([C:30]1[C:26]([CH:25]([F:35])[F:24])=[N:27][N:28]([CH3:34])[CH:29]=1)=[O:32]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)[C@@H]1C[C@H]1c1c(Cl)sc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a stirred solution of trans O-Methyl-N-{1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]ethyl}-hydroxylamine (0.25 g; 0.83 mmol) prepared as described in example P17 and triethylamine (0.15 mL; 1.08 mmol) in dichloromethane (5.0 ml) at ambient temperature was added dropwise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.16 g; 0.83 mmol). The reaction mixture was stirred for 16 hours at ambient temperature then poured in water (3 ml) and extracted with dichloromethane (3×1 ml). Combined organic layers were washed with water (1 ml), brine and dried over anhydrous sodium sulphate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (elution gradient: cyclohexane/ethyl acetate 99:1 to 30:70) to afford 0.32 g (84% of theory) of trans 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-{1-[2-(2,4,5-trichloro-thiophen-3-yl)-cyclopropyl]-ethyl}-amide as white solid (m.p. 110° C.-113° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C[Si](Cl)(C)C.C([Li])CCC.CN(C)[CH:22]=[O:23].Cl>C1COCC1.CCCCCC>[NH2:5][C:4]1[CH:3]=[C:2]([F:1])[C:8]([CH:22]=[O:23])=[C:7]([F:9])[CH:6]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CN(C)C=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Nc1cc(F)c(C=O)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,5-difluoroaniline (12.9 g, 0.1 mol) in anhydrous THF (400 mL) was cooled at −78° C. and treated with nbutyllithium (2.5 M in hexane, 84 mL, 0.21 mol, 2.1 equv.) dropwise over 25 min. After stirring at −78° C. for 30 min, trimethylsilyl chloride (1.0 M in THF, 210 mL, 0.21 mol, 2.1 equiv.) was added dropwise over 30 min. The temperature was allowed to rise to 23° C. and stirred overnight. After re-cooling to −78° C., additional n-butyllithium (2.5 M in hexane, 44 mL, 0.11 mol, 1.1 equiv.) was added dropwise over 20 min, and the reaction mixture was stirred at that temperature for 5 hours to form the anion. Then dimethylformamide (11.6 ml, 0.15 mol, 1.5 equiv.) was added dropwise over 20 min. The temperature was allowed to rise to 23° C. and stirred overnight. The mixture was cooled in an ice-bah and acidified to pH=1 by slow addition of aqueous HCl (1.0 M, 220 mL, 0.22 mol). After stirring 15 min, the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed (brine), dried (Na2SO4), filtered and evaporated to dry. The residue was purified by chromatography on a silica gel column, eluting with a gradient increasing in polarity from 0 to 50% ethyl acetate in hexane. Relevant fractions were combined to give the title compound.
Reaction SMILES: C([Li])CCC.Br.[CH2:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17])[CH3:8].[CH2:18]([N:20]([C:29]#[N:30])[C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])[CH3:19].C1COCC1>CCCCCC>[CH3:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=1[N:9]([CH2:7][CH3:8])[C:29]([N:20]([C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])[CH2:18][CH3:19])=[NH:30]
Reactant: CCN(C#N)c1c(C)cccc1C
Reactant: CCNc1c(C)cccc1C
Agent: Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN(C(=N)N(CC)c1c(C)cccc1C)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (20.5 mL, 1.6 M in hexane, 32.8 mmol) was added dropwise to a stirred suspension of N-ethyl-2,6-dimethylaniline hydrobromide (3.8 g, 16.5 mmol) in hexane (40 mL) at 0° C. The reaction mixture was stirred for 1 h at room temperature and cooled subsequently to −80° C. N-Ethyl-N-cyano-2,6-dimethylaniline (2.92 g, 16.8 mmol) was added drop wise at −80° C. after which the reaction mixture was allowed to slowly warm up to room temperature. The resulting reaction mixture was stirred for 2 h at room temperature, during which hexane (60 mL) and THF (20 mL) were added to form a homogeneous solution. The reaction mixture was quenched and washed with water (100 mL). The organic layer was separated, the aqueous layer was extracted with diethyl ether (100 mL) and the combined organic layers were dried with Na2SO4. Filtration and rotatory evaporation of the volatiles yielded the desired guanidine as a yellow waxy material. Yield: 5.3 g (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1>>[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[CH2:44][CH2:43][N:42]([C:22]([C:21]3[CH:20]=[CH:19][C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:30])([F:31])[F:29])[C:9]=5[CH:17]=4)=[CH:26][CH:25]=3)=[O:24])[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: Clc1cccc(N2CCNCC2)c1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2cccc(Cl)c2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(3-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=625.96 (M+H+); retention time=1.06 minutes.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10](=[O:26])[NH:11][C@H:12]([C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C>[C:5]([O:9][C:10](=[O:26])[NH:11][C@H:12]([C:17](=[O:25])[C:18]1[CH:19]=[CH:20][C:21]([N:1]=[N+:2]=[N-:3])=[CH:22][CH:23]=1)[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(F)cc1)C(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](C(=O)c1ccc(N=[N+]=[N-])cc1)C(C)(C)C
Temperature: 120 °C
Yield: 15 %

Procedure:
Sodium azide (37.9 g, 0.58 mol) was added to a solution of [1(S)-(4-fluorobenzoyl)-2,2-dimethylpropyl]-carbamic acid tert-butyl ester (6.0 g, 19.4 mmol) in DMF (400 mL), and the mixture heated at 120° C. for 24 hours. The solvent was removed in vacuo and the residual solid taken up in ethyl acetate (200 ml). The organic phase was washed with 1M Na2CO3 (1×400 ml) and brine (1×400 mL), dried over MgSO4, filtered and the solvent removed in vacuo to give a yellow solid. Purification by column chromatography (SiO2, 6:1 iso-hexane:ethyl acetate) afforded the title compound as a yellow solid (1.96 g) and [1(S)-(4-Azidobenzoyl)-2,2-dimethylpropyl]-carbamic acid tert-butyl ester as an orange solid (0.97 g) (47% combined yield).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12]2)=[CH:7][C:5]=1[NH2:6])([O-])=O.O.Cl>[Fe].C(O)C>[O:17]=[C:14]1[CH:15]=[CH:16][N:11]([C:8]2[CH:9]=[CH:10][C:4]([NH2:1])=[C:5]([NH2:6])[CH:7]=2)[CH:12]=[CH:13]1
Reactant: Nc1cc(-n2ccc(=O)cc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(-n2ccc(=O)cc2)cc1N
Yield: 86.2 %

Procedure:
First, 5.515 g of 2-nitro-5-(4-oxo-4H-pyridin-1-yl)-aniline was added to a suspension containing 7.975 g of iron powder, 20 ml of water, and 78 ml of ethanol, followed by adding 2 ml of 2N hydrochloric acid. The resultant mixture was refluxed by heating for 6 hours. Then, 1.092 g of iron powder and 2 ml of 2N hydrochloric acid were added to the mixture. The resultant mixture was refluxed for another 1 hour. After the reaction, the reaction mixture was hot filtered using celite, and a residue on the celite was thoroughly washed with warm ethanol. The mother liquor and the washings were combined together and concentrated to dryness. The residue thus obtained was subjected to silica gel column chromatography, and fractions eluted with 5% methanol in chloroform were collected. The collected fractions were combined and evaporated. The residue was recrystallized with isopropanol-methanol (1:1) to give 4.137 g of orange crystals of 4-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Br:15].[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:12][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([Br:15])[C:2]=1[NH2:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Br)c(N)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(N)c(N)c(Br)c1
Temperature: 60 °C
Yield: 56.2 %

Procedure:
A suspension of methyl 4-amino-3-bromo-5-nitrobenzoate (10 g, 36.3 mmol) and tin(II) chloride (33 g, 14.5 mmol) in methanol (100 mL) was heated to 60° C. and maintained for 4 hours. The reaction mass was cooled to ambient temperature and concentrated to obtain a residue; the residue was basified using saturated aqueous sodium bicarbonate until pH was 11 and the aqueous layer was extracted with dichloromethane (3×200 mL). The combined organic layers were washed with aqueous saturated sodium chloride (200 mL), dried over anhydrous sodium sulfate and concentrated to obtain methyl 3,4-diamino-5-bromobenzoate as an off-white solid (5 g, 58%). 1HNMR (CDCl3): δ ppm 7.74 (s, 1H), 7.35 (s, 1H), 4.18 (broad s, 2H), 3.85 (s, 3H) and 3.38-3.56 (broad s, 2H).
Reaction SMILES: C([Li])(C)(C)C.I/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].CN(P(N(C)C)N(C)C)C.I[CH2:26][C:27]1[C:36]([CH3:37])=[C:35]([O:38][C:39](=[O:41])[CH3:40])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([F:42])[CH:33]=2)[N:28]=1.Cl>[Cu](I)I.O.O1CCCC1.CCOCC.CCCCC>[CH2:26]([C:27]1[C:36]([CH3:37])=[C:35]([O:38][C:39](=[O:41])[CH3:40])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([F:42])[CH:33]=2)[N:28]=1)/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC/C=C/I
Reactant: CC(=O)Oc1c(C)c(CI)nc2ccc(F)cc12
Agent: I[Cu]I
Agent: CN(C)P(N(C)C)N(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCCCC/C=C/Cc1nc2ccc(F)cc2c(OC(C)=O)c1C
Temperature: -35 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
5.99 ml of a pentane solution of 9.34 mmols of t-butyl lithium was added to 1.11 g (4.67 mmols) of trans-1-iodo-1-octene, 15 ml ether solution in an atmosphere of argon at -78° C. and stirred at the same temperature for 2 hours. 400 mg (2.10 mmols) of copper iodide was added to the reaction solution, after which it was heated up to -35° C. and stirred at the same temperature for 45 minutes. 941 mg (5.25 mmols) of hexamethylphosphorus triamide was added to the solution and stirred at -35° C. for 10 minutes, to which 10 ml of a tetrahydrofuran solution of 628 mg (1.75 mmols) of 2-iodomethyl-3-methyl-4 acetoxy-6-fluoroquinoline was added, followed by stirring at the same temperature for 30 minutes. The reaction solution was added to a solution of 2 ml of 1N hydrochloric acid and 100 ml of water, followed by filtration through Celite. The resultant filtrate was extracted with chloroform, washed with water and dried with anhydrous sodium sulfate. The solvent was distilled off under the reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane : ethyl acetate=15:1) to obtain 120 mg (yield 20 %) of 2-(trans-2-nonenyl)-3-methyl-4-acetoxy-6-fluoroquinoline.
Reaction SMILES: ClCCCl.[CH3:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[O:8][N:7]=1.[I:20]N1C(=O)CCC1=O.OS(O)(=O)=O>O>[I:20][C:10]1[C:6]([CH3:5])=[N:7][O:8][C:9]=1[C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1
Reactant: Cc1cc(-c2ccc([N+](=O)[O-])cc2)on1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCCl
Product: Cc1noc(-c2ccc([N+](=O)[O-])cc2)c1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with 10 mL of 1,2-dichloroethane. To the stirring solution were added 3-methyl-5-(4-nitrophenyl)-1,2-oxazole (0.27 g, 1.30 mmol), N-iodosuccinimide (0.28 g, 1.24 mmol), followed by concentrated H2SO4 (0.2 mL) at 0° C. and stirred at room temperature for 4 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with sodium thiosulphate solution (30 mL), water (30 mL) and saturated brine solution (10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as yellow solid (0.40 g, yield: 93.7%). 1H NMR (300 MHz, CDCl3): δ 8.29-8.32 (dd, 2H), 8.18-8.21 (dd, 2H), 2.33 (s, 3H).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:9][CH2:8][CH:7]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:6]2.CC(C)([O-])C.[K+].[F:44][C:45]1[CH:46]=[C:47]2[C:52](=[C:53]([F:55])[CH:54]=1)[O:51][CH2:50][C:49]([CH:56]=O)=[CH:48]2.Cl>C1COCC1.O>[F:44][C:45]1[CH:46]=[C:47]2[C:52](=[C:53]([F:55])[CH:54]=1)[O:51][CH2:50][C:49]([CH:56]=[CH:13][C:12]1[CH:11]=[C:10]3[C:5]([CH2:6][CH:7]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:8][O:9]3)=[CH:4][C:3]=1[F:2])=[CH:48]2
Reactant: O=CC1=Cc2cc(F)cc(F)c2OC1
Reactant: CCCCCC1COc2cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c(F)cc2C1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC1COc2cc(C=CC3=Cc4cc(F)cc(F)c4OC3)c(F)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.2 g (17.7 mmol) of (6-fluoro-3-pentylchroman-7-ylmethyl)triphenylphosphonium bromide are dissolved in 50 ml of THF, and 2.0 g (17.8 mmol) of potassium tert-butoxide are added with ice cooling. After 1 h, a solution of 6,8-difluoro-2H-chromene-3-carbaldehyde in 50 ml of THF is slowly added dropwise, and the batch is left to stir overnight at room temp. The solution is subsequently added to water, acidified using dil. hydrochloric acid and extracted three times with MTB ether. The combined org. phases are washed with sat. sodium chloride soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is chromatographed on silica gel with heptane/toluene (1:1) and recrystallised from heptane at −20° C., giving 6,8-difluoro-3-[2-(6-fluoro-3-pentylchroman-7-yl)vinyl]-2H-chromene as yellow crystals.
Reaction SMILES: [OH-].[Na+:2].CO.[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13]>C(O)(C)C>[CH3:5][C:6]1[CH:7]=[N:8][C:9]([CH2:15][S+:16]([O-:28])[C:17]2[N-:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH3:27])=[CH:23][C:24]=3[N:25]=2)=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13].[Na+:2]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)O
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 10 °C
Yield: 31.4 %

Procedure:
3.47 g of sodium hydroxide and 105 ml of methanol were taken into a round bottom flask and stirred for dissolution. 30 g of esomeprazole was taken into a separate round bottom flask and dissolved in 150 ml of isopropanol and this solution was added to the above sodium hydroxide solution. The combined mixture was stirred for 1.5 hours, and distilled completely at 55° C. The residue was dissolved in 30 ml of isopropanol with stirring and the solution was cooled to 10° C. The mixture was stirred at 10° C. for 1 hour and filtered. The compound was dried at 34° C. for 5 hours to yield 10 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[N:18][N:19]3[CH3:24])=[CH:11][C:10]1=[O:25])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[CH3:7][CH:6]([CH3:8])[CH2:5][C@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[N:18][N:19]3[CH3:24])=[CH:11][C:10]1=[O:25])[C:3]([OH:26])=[O:2]
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc3c2cnn3C)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc3c2cnn3C)=CC1=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of (S)-4-methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (30 mg, 0.08 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (3.6 mg 0.08 mmol). The mixture was stirred at room temperature for 3.5 h and then partitioned between ethyl acetate and water. The aqueous phase was acidified with 1N aqueous hydrochloric acid (pH=1), and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-4-methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid as an off-white solid. A mixture of (S)-4-methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid in dichloromethane (5 mL) was treated with 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.025 g, 0.13 mmol), N,N-diisopropylethylamine (0.033 g, 0.26 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.056 g, 0.13 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3.5 h. The mixture was partioned between dichloromethane and water. The organic layer was collected and concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 20% to 100% ethyl acetate/hexanes) which afforded (S)-4-Methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (0.025 g, 57%) as an off-white solid.
Reaction SMILES: C([NH:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[CH2:12][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[NH2:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[CH2:12][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(NCc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(Cc2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.98 g (22.43 mmol) of tert-butyl 1-[3-(benzylamino)benzyl]cyclopropanecarboxylate were dissolved in 50 ml of ethanol and 50 ml THF, and 0.48 g (0.45 mmol) of palladium (10% on carbon) were added. At RT, the mixture was stirred under a hydrogen atmosphere at atmospheric pressure for 2 h. The reaction mixture was then filtered off with suction through kieselguhr, the residue was washed with THF and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.66 g (65.9% of theory) of the title compound.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:8]=2[N:7]=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[C:33]2[C:28](=[C:29](Br)[CH:30]=[CH:31][CH:32]=2)[N:27]=[N:26][C:25]=1[C:35]([NH2:37])=[O:36]>>[NH2:23][C:24]1[C:33]2[C:28](=[C:29]([C:12]3[CH:11]=[CH:10][C:9]4[N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=[N:7][C:8]=4[CH:13]=3)[CH:30]=[CH:31][CH:32]=2)[N:27]=[N:26][C:25]=1[C:35]([NH2:37])=[O:36]
Reactant: CC(C)(C)n1cnc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: NC(=O)c1nnc2c(Br)cccc2c1N
Product: CC(C)(C)n1cnc2cc(-c3cccc4c(N)c(C(N)=O)nnc34)ccc21

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 1-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole and 4-amino-8-bromocinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 1.85 (s, 9 H), 7.58 (m, 1 H), 7.76-7.83 (m, 1 H), 7.88 (d, J=8 Hz, 1 H), 7.91-7.96 (m, 2 H), 8.29 (m, 1 H), 8.32 (s, 1 H); ESI-MS m/z [M+H]+ 361.3.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[S:15][C:16](I)=[C:17]([CH3:19])[CH:18]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].CCN(CC)CC.[CH2:28]([O:31][CH3:32])[C:29]#[CH:30]>CN(C=O)C.[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>[OH:1][C:2]1[C:3]2[C:13]([C:14]3[S:15][C:16]([C:30]#[C:29][CH2:28][O:31][CH3:32])=[C:17]([CH3:19])[CH:18]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9]
Reactant: C#CCOC
Reactant: Cc1cc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)sc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC#Cc1sc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)cc1C
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
4-hydroxy-3-(5-iodo-4-methylthien-2-yl)-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (200 mg, 0.48 mmol, Example 222) was dissolved in DMF (2.4 ml). Et3N 0.133 ml, 0.96 mmol) and methyl propargyl ether (0.202 ml, 2.4 mmol) were added and the mixture was degassed with N2 for 2 min. CuI (9.1 mg, 0.048 mmol) and PdCl2(PPh3)2 (17 mg, 0.024 mmol) were added, the vessel was capped and the reaction was heated at 60° C. with stirring for 2.5 h. The reaction mixture was then cooled and filtered through a plug of silica gel eluting with CH2Cl2→EtOH. The organics were removed by rotary evaporation and the residue was purified by RP-HPLC to give the title compound. MS (ESI) m/z 357.0 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.49 (s, 1H), 6.92 (s, 1H), 4.38 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].Br[CH2:13][CH2:14][CH2:15][CH2:16]Br>CS(C)=O.C(OCC)(=O)C.CCCCCC>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:10]#[N:11])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: N#CCc1ccccn1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CC1(c2ccccn2)CCCC1
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
To a suspension of sodium hydride (60%) (0.745 g, 18.644 mmol) in dimethyl sulfoxide (10 mL) was dropwise added a mixture of pyridin-2-yl-acetonitrile (429) (1 g, 8.475 mmol) and 1,4-dibromo-butane (1.831 g, 8.475 mmol) dissolved in dimethyl sulfoxide-ether (10 mL, 1:1) at 0° C. and the reaction mixture was stirred for 30 min at the same temperature and then stirred at room temperature for 4 h. After completion of the reaction (monitored by silica TLC, Rf=0.4, in 10% ethyl acetate/hexane) the mixture was quenched with HCl (1N, 10 mL). The reaction mixture was diluted water (20 mL) and extracted with ethyl acetate (2×50 mL) combined extracts were washed with water (20 mL) and brine (2×20 mL). The organic phase was thereafter dried and concentrated in vacuo to get a crude mass which was purified by combi-flash to get 1-pyridin-2-yl-cyclopentanecarbonitrile (430) (1.2 g, 82%) as a color less liquid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[CH2:22]([N:27]=[C:28]=[O:29])[CH2:23][CH2:24][CH2:25][CH3:26]>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:28](=[O:29])[NH:27][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: O=C1c2ccccc2SCCC1CO
Reactant: CCCCCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCNC(=O)OCC1CCSc2ccccc2C1=O

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (264 mg, 1.27 mmol) in 16 ml of tetrahydrofuran were added, at 0° C., triethylamine (0.2 ml, 1.4 mmol) and n-pentyl isocyanate (492 μl, 4.9 mmol). The mixture was heated under reflux for 15 hours, concentrated and purified by column chromatography on silica gel (eluent: 4:1 diisopropyl ether/hexane). The product was obtained in a yield of 145 mg (35%).