Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[O:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[O:1][CH2:13][CH2:14]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl 4-oxocyclohexanecarboxylate (31.8 g) in toluene (100 mL) was added ethylene glycol (36.5 mL) and p-toluenesulfonic acid monohydrate (0.426 g). The two phase mixture was stirred rapidly at ambient temperature for 72 hours. The reaction was diluted with water (900 mL) and extracted with ether (900 mL). The organic layer was washed with saturated sodium bicarbonate solution and brine, and then dried over anhydrous sodium sulfate. After filtration, the title compound was obtained by concentration under high vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11]Br>C(O)(=O)C>[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed a solution of 1-(4-bromophenyl)ethanone (10.0 g, 50.25 mmol, 1.00 equiv) in acetic acid (50 mL). This was followed by the addition of a solution of bromine (8.2 g, 1.05 equiv) in acetic acid (50 mL) dropwise with stirring at 60° C. over 90 min. The resulting solution was stirred for 3 h at 60° C. The resulting mixture was concentrated under vacuum. The crude product was re-crystallized from petroleum ether/ethyl acetate in the ratio of 7:1. This resulted in 9.3 g (67%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7](C)=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].[C:18](OC)(=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O-:31])=[O:30].C(SCCCCCCCCCC(NC1C=CC=CC=1SCCCC(OCC)=O)=O)(C)C>>[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:32])([OH:31])=[O:30]
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Reactant: CCOC(=O)CCCSc1cccc(C)c1N
Agent: CCOC(=O)CCCSc1ccccc1NC(=O)CCCCCCCCCSC(C)C
Product: O=C(O)CCCCCCCCCCC(=O)Nc1ccccc1SCCCC(=O)O

Procedure:
When amine (11) is acylated with acid chloride (7) as per procedure Step (E), and the resultant diester (ethyl 4-(2-(11-carbomethoxyundecanoylamino)phenylthio)butyrate 12 is hydrolyzed in Step I as per procedure (F), the title compound, 13 m.p. 113.5°-115° C. is obtained.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=O)[S:17][C:13]=3[CH:12]=2)[CH:2]=1.N1C=CC=CC=1.[NH2:34][OH:35].Cl>CCO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:27]=[CH:26][C:14]3[N:15]=[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=[N:34][OH:35])[S:17][C:13]=3[CH:12]=2)[CH:2]=1
Reactant: O=C1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cccnc43)cc2s1
Temperature: 88 °C
Yield: 71.1 %

Procedure:
(R)-2-((6-((3H-Imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone from Example 54 (70 mg, 0.19 mmol) was stirred in EtOH. Pyridine (100 μL, excess) and NH2OH.HCl (100 mg, excess) were added and the resulting mixture was heated at 88° C. for 1 h. LCMS showed that the reaction was complete. The mixture was then cooled to rt and purified by HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (R)-2-((6-((3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanone oxime (53 mg, 73%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.60 (s, 1H), 8.38 (d, J=4.0 Hz, 1H), 8.13-8.27 (m, 1H), 8.09 (dd, J=0.8, 7.9 Hz, 1H), 7.58-7.76 (m, 1H), 7.10-7.39 (m, 3H), 5.49 (s, 2H), 4.33-4.77 (m, 1H), 2.69-2.95 (m, 1H), 1.92-2.38 (m, 2H), 1.26-1.86 (m, 5H). LCMS (ESI) m/z 393 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[O:7][CH2:8][CH:9]([N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])[CH:5]2[O:4][CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:28][S:29]([O:1][CH:2]1[CH2:3][O:4][CH:5]2[CH:9]([N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])[CH2:8][O:7][CH:6]12)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1C1COC2C(O)COC21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
Under a N2 atmosphere, to a solution of 2-(6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)isoindoline-1,3-dione (2.35 g, 8.54 mmol) in dichloromethane (40 mL) were added triethylamine (1.30 g, 12.8 mmol) and N,N-dimethylpyridin-4-amine (209.2 mg, 1.7 mmol) and the mixture was cooled to 0° C. and then methanesulfonyl chloride (0.8 mL, 10.0 mmol) was added to the mixture. The resulting mixture was stirred at 0° C. for 30 min, then moved to room temperature overnight. The mixture was diluted with dichloromethane (100 mL), washed with 1M HCl (100 mL), water (100 mL) and brine (100 mL). The separated organic phase was dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/200) to give the title compound as a white solid (2.35 g, 77.9%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[C:12]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[N:13]2[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20].[P:30]([O-:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33]>C(Cl)(Cl)(Cl)Cl>[P:30]([O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:12]1[N:13]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]2[C:10]([N:11]=1)=[C:9]([Cl:8])[N:17]=[CH:16][N:15]=2)([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:37]
Reactant: CCOP([O-])OCC
Reactant: CC(C)(C)Cn1c(-c2ccccc2O)nc2c(Cl)ncnc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOP(=O)(OCC)Oc1ccccc1-c1nc2c(Cl)ncnc2n1CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (1.1 mmol) was added slowly to an ice-cooled solution of 6-chloro-N9-neopentyl-8-(2-hydroxyphenyl)purine (1 mmol) and diethyl phosphite (1 mmol) in carbontetrachloride. The reaction was stirred at room temperature overnight. Triethylamine hydrochloride was precipitated as a white solid mass. Extraction and chromatography gave diethyl 2-(6-Chloro-N9-neopentylpurin-8-yl)phenyl phosphate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].F[P-](F)(F)(F)(F)F.[NH2:30][N+:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.CN1CCCC1=O.CN(CCN(C)C)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:36]3[N:31]([N:32]=[CH:33][CH:34]=[CH:35]3)[N:30]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)Cc2ccc(S(C)(=O)=O)cc2)cc1
Reactant: N[n+]1ccccn1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCOc1ccc(C2=NN3N=CC=CC3C2c2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 1 h

Procedure:
Titanium tetrachloride (3.45 mL) was added to a stirred mixture of 1-(4-ethoxyphenyl)-2-(4-methanesulfonyl-phenyl)-ethanone (10.0 g), N-amino-pyridazinium hexafluorophosphate (7.95 g) in dichloromethane (150 mL) at about 20° C. N-Methyl-pyrrolidinone (3.0 mL) was added at about 20° C. TMEDA (6.7 mL) was then added over a period of about 4 hours at about 20° C. After stirring the mixture for about 1 hour, a second portion of TMEDA (12.3 mL) was added over about 20 minutes, and the reaction mixture was stirred at about 20° C. for about 16 hours.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]([F:20])([F:19])[F:18])=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]#[N:30]>CN(C)C=O>[C:29]([CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]([F:20])([F:18])[F:19])=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2)#[N:30]
Reactant: N#CCCl
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(O)c2n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCC#N)c2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of 4.00 g (13.9 mmol) of ethyl 7-hydroxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate, 4.23 g (30.6 mmol) of potassium carbonate, 1.26 g (16.7 mmol) of chloroacetonitrile and 60 ml of dimethylformamide was stirred at room temperature for 2 hours. Insoluble matters were filtered off. The filtrate was poured onto ice water followed by extraction with diethyl ether. The extract was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 4.50 g of ethyl 7-cyanomethoxy-1-methyl-4-trifluoromethyl-2-indolecarboxylate.
Reaction SMILES: [F:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:3]=O.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>[Cu](Cl)Cl.C(Cl)Cl>[F:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)/[CH:3]=[N:17]/[S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=CC(F)c1ccccc1
Agent: Cl[Cu]Cl
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/C(F)c1ccccc1
Temperature: 23 °C
Reaction time: 0.03 h
Yield: 30.1 %

Procedure:
To a 500 mL RBF containing 2-fluoro-2-phenylacetaldehyde (320.00 mg, 2316.5 μmol) was added DCM (10 mL) and the mixture was allowed to stir at 23° C. for 2 min. At this time, (R)-2-methylpropane-2-sulfinamide (364.99 mg, 3011.5 μmol) was added in one portion to the mixture followed by copper(II) chloride (856.51 mg, 6370.4 μmol) at 5:30 pm. The reaction was allowed to stir overnight and then filtered through a plug of celite over silica gel. The solvent was removed and the crude residue was purified on a silica gel column (15 to 35% EtOAc in hexanes) to give the product (168 mg, 30%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:29]2[O:30][CH2:31][O:32][C:28]=2[CH:27]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][CH2:23][CH2:24][O:25][C:26]3[CH:34]=[CH:33][C:29]4[O:30][CH2:31][O:32][C:28]=4[CH:27]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: BrCCCOc1ccc2c(c1)OCO2
Product: CCOC(=O)N1CCC(c2cn(CCCOc3ccc4c(c3)OCO4)c3ccccc23)CC1
Reaction time: 15 h

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 2.2 g (8.1 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 2.68 g (10 mmol) of 5-(3-bromo-propoxy)-benzo[1,3]dioxole. After standard work-up, 3.8 g (100% of yield) of the expected product was obtained.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:37][CH:36]=2)[C:31]([F:45])=[CH:30][N:29]=1.[CH3:46][O:47][C:48]([C:50]1[O:51][C:52]2[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][C:53]=2[CH:54]=1)=[O:49]>>[F:45][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:37][CH:36]=2)=[N:33][C:28]([NH:59][C:56]2[CH:57]=[CH:58][C:52]3[O:51][C:50]([C:48]([O:47][CH3:46])=[O:49])=[CH:54][C:53]=3[CH:55]=2)=[N:29][CH:30]=1
Reactant: CC(C)Oc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(OC(C)C)cc4)n3)ccc2o1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-[4-(isopropoxy)phenyl]-4-pyrimidineamine and 2-methoxycarbonyl-5-aminobenzofuran were reacted to yield 5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.04 (d, 1H, J=1.8 Hz), 7.49-7.41 (m, 4H), 7.35 (dd, 1H, J=2.4 and 8.7 Hz), 7.14 (bs, 1H), 6.90 (d, 2H, J=9.3 Hz), 6.70 (bs, 1H), 4.56 (2q, 1H, J=5.7 Hz), 3.98 (s, 3H), 1.37 (d, 6H, J=5.7 Hz); LCMS: ret. time: 25.52 min.; purity: 98%; MS (m/e): 437 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[H][H]>CCO.CCOC(C)=O.O=[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2cccnc2)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(-c2cccnc2)c1
Yield: 100 %

Procedure:
A suspension of 3-(2-fluoro-5-nitrophenyl)pyridine (26 g, 119 mmol) in EtOH (200 ml) and EtOAc (200 ml) was treated with PtO2 (1.35 g, 6 mmol) then exposed to 50 psi hydrogen until uptake ceased (circa 3 hours). The reaction was filtered through glass-microfibre filter paper and concentrated to gave 3-(2-fluoro-5-aminophenyl)pyridine (22.4 g) as a dark oil which solidified on standing: δH (360 MHz, CDCl3) 3.65 (2H, s), 6.65-6.72 (2H, m), 6.99 (1H, dd, J 9 and 9), 7.33-7.37 (1H, m), 7.84-7.86 (1H, m), 8.58 (1H, d, J 4), 8.76 (1H, m).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=O)[C:5](F)=[CH:6][CH:7]=1.O.[NH2:24][NH2:25].O>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:25][N:24]=[C:9]2[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: COc1c(Br)ccc(F)c1C(=O)c1ccc2ccccc2c1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: COc1c(Br)ccc2[nH]nc(-c3ccc4ccccc4c3)c12
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A total of 1.63 g of (3-bromo-6-fluoro-2-methoxy-phenyl)-naphthalen-2-yl-methanone was dissolved in 15 ml of pyridine, 2.2 ml of hydrazine monohydrate was added, followed by stirring at 100° C. for 6 hours. Water was added to the reaction mixture, and then it was extracted with ethyl acetate for two times. The organic layer was sequentially washed with 1 N hydrochloric acid, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was removed by distillation. Then, the resulting crystals were washed with hexane once and dried in vacuo, to give 0.923 g of the title compound as brown crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([CH3:25])=[C:15]([CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.CN(C)[CH:33]=[O:34].O>O1CCCC1>[CH3:25][C:14]1[S:13][C:12]([C:4]2[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=2)[CH:33]=[O:34])=[N:16][C:15]=1[CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: Cc1sc(-c2cc(Br)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc(-c2cc(C=O)cc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
Under a nitrogen atmosphere at −78° C., to a solution (80 mL) of the compound (7.3 g, 17 mmol) obtained in Example 95a in tetrahydrofuran was added n-butyllithium (1.6M hexane solution, 16 mL, 25 mmol), and the mixture was stirred at the same temperature for 1 hr. Anhydrous N,N-dimethylformamide (2.6 mL, 33 mmol) was added to the reaction mixture, and the mixture was stirred overnight while allowing to spontaneously warm to room temperature from −78° C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=80/20) to give the title compound (1.6 g, 24%) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[C:8]2[CH3:15].[CH2:16]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:12]([C:9]3[NH:10][C:11]4[C:7]([C:8]=3[CH3:15])=[CH:6][CH:5]=[CH:4][C:3]=4[O:2][CH3:1])=[O:14])=[CH:31][CH:32]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCC(Oc2ccc(N)cc2)C1
Reactant: COc1cccc2c(C)c(C(=O)O)[nH]c12
Product: CCOC(=O)N1CCC(Oc2ccc(NC(=O)c3[nH]c4c(OC)cccc4c3C)cc2)C1

Procedure:
With a procedure similar to the example above, 3-{4-[(7-methoxy-3-methyl-1H-indole-2-carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 7-methoxy-3-methyl-1H-indole-2-carboxylic acid and 3-(4-amino-phenoxy)-pyrrolidine-1-carboxylic acid ethyl ester. LCMS calcd for C24H27N3O5 (m/e) 437, obsd 438 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:20](Cl)(=[O:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18].CCN(C(C)C)C(C)C.[CH:33]([O:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)([CH3:35])[CH3:34]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:20]([NH:41][C:40]2[CH:39]=[CH:38][C:37]([O:36][CH:33]([CH3:35])[CH3:34])=[CH:43][CH:42]=2)(=[O:22])=[O:21])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[Cl:18]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)Cl)cc2Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Oc1ccc(NS(=O)(=O)c2cc(Cl)c(Oc3ccc([N+](=O)[O-])cc3Cl)c(Cl)c2)cc1
Temperature: 40 °C
Yield: 63 %

Procedure:
To 100 mg of 3,5-Dichloro-4-(2-Chloro-4-Nitrophenoxy)Benzene-1-Sulfonyl Chloride (0.23 m.mol) was added 0.2 ml of DIEA, 5 ml of dichloromethane and 150 mg of 4-isopropoxyaniline. The mixture was maintained at 40° C. for 4 hours. The solvent was evaporated and the residue dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na2SO4 and the solvent evaporated. The residue as purified using radial silica-gel chromatography using 1:4 ethyl acetate:hexane as solvent. The purity of the product by LC/MS was 97.19%. M−1 (530) was seen in the mass spectrum. The yield of the product was 80.3 mg or 63% yield.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:33])[C@H:8]([NH:15]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:9][S:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCCCC1>CC#N>[CH:1]1([O:6][C:7](=[O:33])[C@H:8]([NH2:15])[CH2:9][S:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)SC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC1CCCC1
Solvent: C1CCNCC1
Solvent: CC#N
Product: CC(C)(C)SC[C@@H](N)C(=O)OC1CCCC1
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
(S)-3-tert-Butylsulfanyl-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid cyclopentyl ester (1.63 g, 3.50 mmol) was dissolved in a CH3CN (25 ml) at 0° C. Piperidine (21 ml) was added to the solution. After stirring for 30 minutes, the solvent was removed in vacuo to give a residue. Purification by column chromatography (EtOAc eluent) gave the product as a colourless oil (628 mg, 73% yield). 1H NMR (300 MHz, CDCl3), δ: 1.30 (9H, s, (CH3)3), 1.55-1.95 (8H, m, CH2×4), 2.75 (1H, dd, CH, J=7.2, 12.3 Hz), 2.95 (1H, dd, CH, J=4.8, 12.3 Hz), 5.25 (1H, m, CH).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:10]=1>>[CH3:25][C:23]1[NH:22][N:21]=[C:20]([NH:19][C:11]2[N:10]=[C:9]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:18]3[C:13]([CH:12]=2)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:24]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccccc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-phenoxy-isoquinolin-3-yl)-amine. LC-MS: m/e 317 (MH+). 1H NMR(DMSO): δ 2.12(s, 3H), δ 5.56(s, 1H), δ 7.22(s, 1H), δ 7.32(m, 5H), δ 7.51(m, 2H), δ 7.65(m, 2H), δ 8.15(d, 1H), δ 9.05(s, 1H).
Reaction SMILES: [C:1]([O-:7])([O-])([O:3][CH2:4][CH3:5])[CH3:2].[CH3:8][C:9]([CH3:18])=[CH:10][CH2:11][CH2:12][C:13](O)([C:15]#[CH:16])[CH3:14].C(O)(=O)C(C)C>>[CH3:14][C:13]([CH2:12][CH2:11][CH:10]=[C:9]([CH3:18])[CH3:8])=[C:15]=[CH:16][CH2:2][C:1]([O:3][CH2:4][CH3:5])=[O:7]
Reactant: CCOC(C)([O-])[O-]
Reactant: C#CC(C)(O)CCC=C(C)C
Solvent: CC(C)C(=O)O
Product: CCOC(=O)CC=C=C(C)CCC=C(C)C
Yield: 96 %

Procedure:
A mixture of 65.6 g of ethyl ortho-acetate, 30.4 g of dehydrolinalool and 1.5 g of isobutyric acid was reacted at 130° to 140°C. for 8 hours. Distillation was conducted after the reaction in the same manner as in the preceeding Examples, and a fraction boiling at 92 to 94°C. under 0.5 mm Hg was collected. Ethyl 5,9-dimethyl-3,4,8-decatrienoate was obtained in a yield of 96%.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:22])[CH2:6][CH2:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[C:10]=1[O:19][CH3:20].O>CO>[O:21]=[C:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[C:10]=1[O:19][CH3:20])[CH2:7][CH2:6][C:5]([OH:22])=[O:4]
Reactant: COC(=O)CCC(=O)c1ccc(OC)c(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)CCC(=O)O)c(OC)c1OC
Temperature: 25 °C
Yield: 88.4 %

Procedure:
5.95 g of sodium hydroxide was dissolved in 200 mL of methanol in a 500 mL round bottom flask. The reaction mixture was cooled to room temperature and 55 (6.78 g, 22.90 mmol) was added followed by 20 mL of water and 100 mL of methanol and the reaction mixture was refluxed for 30 min. The solvent was evaporated under reduced pressure and the reaction mixture was neutralized with dilute hydrochloric acid and the reaction mixture was extracted with ether (100×3) and the combined organic phases were washed with water and dried over sodium sulfate and solvent evaporated under reduced pressure. The crude product was purified by column chromatography (20:80 EtOAc:Hexanes) to yield 5.43 g of 56 as tan colored solid (94%).