Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=C(C2C=CN=CC=2)C(C2C=CC(OCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=[N:3]1.[F:31][C:32]1[C:37]([F:38])=[C:36]([O:39][CH2:40][C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=2)[CH:35]=[CH:34][C:33]=1[C:51](=O)[CH2:52][C:53]1[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=1>>[F:38][C:37]1[C:32]([F:31])=[C:33]([C:51]2[C:52]([C:53]3[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=3)=[CH:1][N:2]([CH3:6])[N:3]=2)[CH:34]=[CH:35][C:36]=1[O:39][CH2:40][C:41]1[CH:50]=[CH:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccc3ccccc3n2)c(F)c1F
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)c(F)c2F)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-[2,3-Difluoro-4-(quinolin-2-ylmethoxy)-phenyl]-2-pyridin-4-yl-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.44 (bs, 2H), 8.22 (d, J=8.7 Hz, 1H), 8.06 (d, J=8.7 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.70 (m, 2H), 7.66 (s, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.08 (m, 3H), 6.88 (m, 1H), 5.48 (s, 2H); MS: (M+H m/z=429.1).
Reaction SMILES: Cl[C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].Cl.[O:22](C1C=CC(C(C)=CC(O)=O)=CC=1)C1C=CC=CC=1.[OH-].[K+]>>[O:14]([C:11]1[CH:12]=[CH:13][C:8]([C:2]([OH:22])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])=[CH:9][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(Cl)(CC(=O)O)c1ccc(Oc2ccccc2)cc1
Reactant: CC(=CC(=O)O)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(O)(CC(=O)O)c1ccc(Oc2ccccc2)cc1

Procedure:
1 g. of 3-chloro-3-p-phenoxyphenyl-butyric acid (obtainable by an addition reaction of HCl with 3p-phenoxyphenyl-2-butenoic acid) and 25 ml. of 20% potassium hydroxide solution are boiled for 10 minutes, cooled, washed with ether and acidified to give 3-p-phenoxyphenyl-3-hydroxybutyric acid, m.p. 137°-138°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)=[CH:4][C:5]([F:9])=[C:6]([NH2:8])[CH:7]=1.[CH3:18][N:19]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:12]=2)=[CH:4][C:5]([F:9])=[C:6]([NH2:8])[CH:7]=1
Reactant: Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cc(Oc3cc(F)c(N)cc3Cl)ccn2)cn1
Temperature: 90 °C
Yield: 77.3 %

Procedure:
5-Chloro-4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (1.177 g, 4.31 mmol) and 1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.166 g, 5.60 mmol) were dissolved in DMF (16.16 ml), cesium carbonate (4.21 g, 12.93 mmol) was added, followed by water (5.39 ml). Argon was bubbled through the mixture for 5 minutes, and then palladium tetrakistriphenylphosphine (0.249 g, 0.215 mmol) was added. The flask was fitted with a reflux condenser, flushed with argon, and heated in a 90° C. oil bath under a balloon of argon for 4 hours. The reaction mixture was then cooled to RT and diluted with a 4:1 mixture of ethyl acetate and THF. The solution was extracted with 10% aqueous LiCl (2×150 mL) and brine (100 mL), dried (MgSO4), evaporated under reduced pressure and purified via silica gel chromatography (ethyl acetate/hexanes) to yield 5-chloro-2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine as a tan solid (1.062 g, 77% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.31 (d, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.20 (d, 1H), 7.13 (d, 1H), 6.92 (d, 1H), 6.52 (dd, 1H), 5.49 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 319.1 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:13][CH3:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN
Reactant: O=Cc1ccc2[nH]ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNCc1ccc2[nH]ccc2c1
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Indole-5-carbaldehyde (1.0 g, 6.9 mmol) was dissolved in anhydrous methanol (15 mL). Methylamine (9.9 mL of 2M solution in methanol, 19.8 mmol) was added and the reaction was stirred for 3 hr. The solution was concentrated to a yellow oil and then dissolved into anhydrous methanol (20 mL). Sodium borohydride (262 mg, 6.9 mmol) was added and the mixture was stirred overnight. Water (1 mL) was added and the solution was concentrated. Sodium hydroxide (5 mL, 1N) was added and the product was extracted with ethyl acetate (3×20 mL), dried over MgSO4 and concentrated to afford the title compound as a brown oil (980 mg, 91%). 1H NMR (200 MHz, CDCl3) δ 8.60 (s, 1H), 7.56 (s, 1H), 7.35-7.15 (m, 3H), 6.55 (m, 1H), 3.85 (s, 2H), 2.49 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][N:4]=1.Cl.[C:12]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][N:19]([CH3:20])[CH2:18][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:21])=[N:4][CH:5]=1)#[N:8]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cn1
Temperature: 60 °C
Yield: 117.6 %

Procedure:
A mixture of 6-bromomethylnicotinonitrile (Advanced Chemical Intermediates, 1.39 g; 7.06 mmol), sarcosine tert-butyl ester hydrochloride (1.54 g; 8.47 mmol) and K2CO3 (2.34 g; 17.0 mmol) in MeCN (25 mL) heated at 60° C. for 18 hours. The solvent was evaporated in vacuo. The residue was dissolved in a mixture of DCM and water and then poured through a hydrophobic frit. The filtrate was evaporated to afford the title product (2.17 g, quantitative). 1H NMR (CDCl3, 400 MHz) δ 8.82 (1 H, d, J=2 Hz), 7.95-7.92 (1 H, dd, J=8.4, 2 Hz), 7.73 (1 H, d, J=8 Hz), 3.91 (2 H, s), 3.28 (2 H, s), 2.41 (3 H, s), 1.48 (9 H, s).
Reaction SMILES: CS(O[CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O>N1CCCC1>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][CH:6]([N:8]3[CH2:9][CH2:10][CH2:6][CH2:7]3)[CH2:7]2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: CS(=O)(=O)OC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: C1CCNC1
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCCC3)C2)cc1
Yield: 53 %

Procedure:
5 g (0.0174 mole) of methanesulfonic acid 1-(4-nitro-phenyl)-pyrrolidin-3yl ester (2) were heated 2 hours at 85° C. in 30 ml of pyrrolidine. The mixture was then poured on ice water until crystallization occurred. After filtrating and drying, the obtained yellow powder was chromatographed with an eluent consisting of dichloromethane/methanol (98/2). 2.6 g of derivative (1) was thus obtained (yield 53%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][Br:14])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccn2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccn2)cc1

Procedure:
4-(2-Pyridyl)toluene, 2 mL (1.98 g, 11.7 mmol), N-bromosuccinimide (NBS), 2.5 g (14.0 mmol), and α,α′-azobis(isobutyronitrile) (AIBN), 23 mg (0.14 mmol) were suspended in 35 mL tetrachloromethane, and refluxed for 24 hours. The product was filtered, and the solvent removed from the filtrate by rotary evaporation. Equal amounts of chloroform and water were added and the product extracted. The chloroform layer was separated and dried, and the solvent removed. 4-(2-Pyridyl)benzyl bromide, 2 g, was obtained as a sticky yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:17]=[C:16]([CH3:38])[CH:15]=2)=[CH:9][C:8]=1[CH3:39])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:39][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:17]=[C:16]([CH3:38])[CH:15]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Oc3ccccc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2Oc2ccccc2)c1
Yield: 109.9 %

Procedure:
A solution of 3-{2-methyl-4-[3-methyl-5-(2-phenoxy-4-trifluoromethyl-phenoxy)-phenoxy]-phenyl}-propionic acid ethyl ester (0.137, 0.249 mmol) in ethanol (8 mL) is treated with 5 N NaOH (2 mL) and heated to reflux until saponification is completed. The mixture is cooled, and the solvent is removed in vacuo to afford a residue that is acidified with 1 N HCl. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 0.143 g (100%) of the title compound. 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C30H25O5F3 523.1732, found 523.1721.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(Cl)c2)o1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cccc(Cl)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-(3-chloro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.10 min; [M+H]+=425.02.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:21]([O-])=[O:22].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:21]=[O:22])[C:5]([N:7]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:8]1[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=CO
Product: CCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 1 h
Yield: 41.3 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-n-butyl-3-D-ribofuranosylurea are dissolved in 10 ml of formic acid, and 1.5 g of sodium nitrite are added gradually thereto at 0° to 5° C. for one hour under stirring. The mixture is further stirred at the same temperature for one hour. After the reaction, the mixture is treated in the same manner as described in Example 5-(2). 1.4 g of 1-(2-chloroethyl)-1-nitroso-3-n-butyl-3-D-ribofuranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][O:10][Si](C(C)(C)C)(C)C)[N:5]=[C:4]([N+:24]([O-:26])=[O:25])[N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[N+:24]([C:4]1[N:3]=[C:2]2[O:10][CH2:9][CH2:8][CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:6]2[N:5]=1)([O-:26])=[O:25]
Reactant: CC(C)(C)[Si](C)(C)OCCC(c1ccccc1)n1nc([N+](=O)[O-])nc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1nc2n(n1)C(c1ccccc1)CCO2
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-1-(3-(tert-butyldimethylsilyloxy)-1-phenylpropyl)-3-nitro-1H-1,2,4-triazole (510 mg, 1.16 mmol) in tetrahydrofurane (11.6 mL) was added under an atmosphere of nitrogen at room temperature 1 M tetrabutyl ammonium fluoride solution in tetrahydrofurane (3.47 mL, 3.47 mmol). The yellow solution was stirred at room temperature over night. Water was added and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a light yellow solid (174 mg, 61%) after column chromatography on silica gel using a gradient from heptane/ethyl acetate 4:1 to 1:1 (v/v) as eluent. MS ISP (m/e): 247.2 (100) [(M+H)+], 264.1 (36). 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.42-7.38 (m, 3H), 7.09 (d, 2H), 5.61 (t, 1H), 4.56 (m, 2H), 2.77 (m, 1H), 2.42 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O>>[C:18]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: OB(O)c1ccccc1-c1ccccc1
Product: Oc1ccc2ncn(-c3ccccc3-c3ccccc3)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and biphenyl-2-ylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=288.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:33].CCO.[OH-].[NH4+:38]>O>[NH2:38][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:33]
Reactant: [NH4+]
Reactant: O=S(=O)(c1cnc(Cl)c(F)c1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ncc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 125 °C
Yield: 53.7 %

Procedure:
A 100-mL pressure vessel was charged with 2-(4-(4-((6-chloro-5-fluoro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.725 g, 1.389 mmol), 5 mL of EtOH, and concentrated ammonium hydroxide (10 mL, 257 mmol). The vessel was sealed and the mixture was heated to 125° C. for 18 h. After that time, the mixture was diluted with water and extracted with CH2Cl2 (3×100 mL). The combined extracts were dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (0 to 70% EtOAc in hexanes) and to give 2-(4-(4-((6-amino-5-fluoro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.375 g) as a white solid. 1H NMR (400 MHz, CD3OD) δ=8.18 (d, J=1.4 Hz, 1H), 7.62 (dd, J=1.9, 10.5 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.01 (d, J=9.0 Hz, 2H), 3.35-3.29 (m, 4H), 3.19-3.14 (m, 4H). m/z (ESI, +ve ion) 503.1 (M+H)+. GK-GKRP IC50 (Binding)=0.163 μM; GK-GKRP EC50 (LC MS/MS-2)=0.299 μM.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[OH-:10].[Na+].[Cl-]>ClCCl>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][C:4](=[O:10])[CH:5]([CH3:9])[CH3:6])[CH:3]=[CH:4][C:5]=1[CH3:9]
Reactant: Cc1ccc(N)cc1O
Reactant: [OH-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a mixture of 5-amino-2-methylphenol (30 g, 244 mmol), 10% NaOH (210 mL) and dichloromethane (120 mL) was added at 0° C. slowly isobuyryl chloride (25.5 mL, 244 mmol) in dichloromethane (50 mL). The mixture was stirred at room temperature overnight. The aqueous layer was separated and extracted with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 37.2 g of N-(3-hydroxy-4-methyl-phenyl)-isobutyramide (78%). 1H NMR (300 MHz, CDCl3 ppm): δ: 1.21 (d, J=7.03 Hz, 6 H), 2.17(s, 3 H), 2.53 (m, 1 H), 2.58 (s, 3 H), 6.81(dd, J=2.05 Hz, 7.91 Hz, 1H), 6.97 (d, J=7.91 Hz, 1H), 7.38 (d, J=2.05 Hz, 1 H), 8.14 (bs, 1 H), 8.58 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][C@@H:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:31][C@@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](Nc1c([N+](=O)[O-])c(Cl)nc2ccccc12)c1ccccc1
Yield: 87.3 %

Procedure:
The method described in Part A of Example 4 was used to treat 2,4-dichloro-3-nitroquinoline (20.6 g, 85.1 mmol) in DMF (100 mL) with triethylamine (35 mL, 0.225 mol) and (R)-(+)-α-methylbenzylamine (13.3 mL, 102 mmol). After the precipitate was isolated by filtration, it was washed with water and diethyl ether to provide 24.35 g of 2-chloro-3-nitro-N-[(1R)-1-phenylethyl]quinolin-4-amine as an orange solid.
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:33])[C:5](=O)[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[NH:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:9]=1.[NH3:34]>C(O)C>[NH2:34][C:5]1[C:4](=[O:33])[C:3](=[O:2])[C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[NH:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:9]=1
Reactant: N
Reactant: COc1ccc(C(NCCC2CCCCC2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Solvent: CCO
Product: COc1ccc(C(NCCC2CCCCC2)c2cccc(Nc3c(N)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1d), 3-methoxy-4-{3-[(4-methoxyphenyl)-(2-cyclohexylethylamino)methyl]phenylamino}-3-cyclobutene-1,2-dione (630 mg) [prepared as described in step (c) above] and a solution of ammonia in ethanol (2N, 2.8 ml) were reacted, to give the title compound (536 mg) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][CH:13]([C:16]#[N:17])[CH2:12][CH2:11]1)[C:3](=[O:9])OC(C)(C)C.FC(F)(F)C(O)=O.[N:25]1[O:26][N:27]=[C:28]2[CH:33]=[C:32](C(Cl)=O)[CH:31]=[CH:30][C:29]=12>ClCCl>[C:16]([C@@H:13]1[CH2:12][CH2:11][C@H:10]([N:2]([CH3:1])[C:3]([C:32]2[CH:31]=[CH:30][C:29]3=[N:25][O:26][N:27]=[C:28]3[CH:33]=2)=[O:9])[CH2:15][CH2:14]1)#[N:17]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(C#N)CC1
Reactant: O=C(Cl)c1ccc2nonc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)c1ccc2nonc2c1)[C@H]1CC[C@@H](C#N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butyl methyl-(4-cyanocyclohexyl)carbamate (710 mg, 3 mmol) was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (3 ml) was added. The solvent was evaporated after 2 hours, the residue was re-dissolved in a 4N HCl (3 ml) solution in dioxane and the solvent evaporated. Dichloromethane (30 ml) and NEt3 (2 ml) were added to the residue followed by a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (548 mg, 3 mmol) in dichloromethane (10 ml). After stirring the mixture for 1 hour at room temperature, the organic phase was washed with 1N HCl and conc. NaHCO3 solution, dried over magnesium sulfate, and concentrated under vacuum. The material was purified on a silica gel column eluting with ethyl acetate/chloroform (1:1) to give 170 mg of N-(cis-4-cyanocyclohexyl)-N-methyl-[2,1,3]-benzoxadiazole-5-carboxamide as a white solid and as the less polar isomer. Mp=222-223° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 7.93 (d, 1H, J=9.0 Hz); 7.85 (s, 1H), 7.42 (d, J=9.0 Hz, 1H); 4.65-4.50 and 3.55-3.40 and 3.15-2.80 (m, 5H) and 2.20-1.30 ppm (m, 8H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@H:14]([C:23]([N:25]([CH2:35][C:36]1[C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[S:39][CH:40]=1)[C@@H:26]([CH3:34])[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:24])[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[S:39]1[CH:40]=[C:36]([CH2:35][N:25]([C@@H:26]([CH3:34])[CH:27]([O:28][CH2:29][CH3:30])[O:31][CH2:32][CH3:33])[C:23](=[O:24])[C@@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: CCNC(=O)NN(C)CC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N(Cc1csc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 57 mg (0.32 mmol) was coupled with (S)-tert-butyl 3-amino-4-((benzo[b]thiophen-3-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-4-oxobutanoate (Compound IV-18) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[OH:16])[CH2:3][CH2:2]1>[Pd].C(O)C.[H][H]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[C:8]([OH:16])[CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(O)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)c(O)c1
Reaction time: 12 h
Yield: 105 %

Procedure:
10% Palladium on carbon (10 mg, 0.892 mmol) was added to 2-morpholino-5-nitrophenol (prepared as described herein above; 200 mg, 0.892 mmol) in ethanol (20 mL), hydrogen gas was added (40 psi), and the reaction allowed to proceed for 12 h at room temperature. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture filtered through Celite®, and the solvent removed in vacuo. The residue was purified by flash column chromatography (2% CH3OH/CH2Cl2) to provide the title compound 5-amino-2-morpholinophenol (200 mg, 0.937 mmol, 105% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20]COC)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>C(#N)C>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH3:20])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:24]=[CH:25][C:2]([NH:1][C:41]([NH:40][C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)=[O:42])=[CH:3][CH:4]=1)#[N:18]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2cc1C#N
Yield: 68 %

Procedure:
4-(4-Aminophenoxy)-6-cyano-7-methoxyethoxyquinoline (150 mg) was added to 5.0 ml of toluene and 2.5 ml of acetonitrile, and the mixture was heated to reflux. After then adding 4-fluorophenyl isocyanate (0.12 ml), the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and washed with ethyl acetate/toluene=1/1 to obtain 150 mg of the title compound as light brown crystals (68% yield).