Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:32])[C@@H:19]([C:20]#[C:21][C:22]([OH:24])=[O:23])[C@H:18]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CN(C1C=CC=CN=1)C.[Cl:42][C:43]([Cl:47])([Cl:46])[CH2:44]O>C(Cl)Cl>[CH3:16][C:17]1([CH3:32])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH2:44][C:43]([Cl:47])([Cl:46])[Cl:42])=[O:23])[C@H:18]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Reactant: OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
6.2 g of dicyclohexylcarbodiimide were introduced into a solution of 7.15 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 80 mg of 4 dimethylamino-pyridine in 35 ml of methylene chloride and the reaction mixture was stirred for 10 minutes after which 4.5 g of 2,2,2-trichloroethanol were added. The mixture was stirred for 1 hour and was filtered. The filtrate was washed with N hydrochloric acid, then with water until neutral, dried and evaporated to dryness. The 14 g of oil residue were chromatographed over silica gel and eluted with a 97-3 mixture of benzene-ethyl acetate to obtain 9 g of tert.butyl (1R,cis) 2,2-dimethyl-3-(2,2,2-trichloroethoxycarbonylethynyl)-cyclopropane-carboxylate melting at 70°-71° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]([NH:18][C:19](=[O:21])[CH3:20])=[C:6]([Br:22])[CH:5]=1)(=[O:3])[CH3:2].[Li+].[CH3:24][CH:25]([N-]C(C)C)[CH3:26].C(Br)C=C>C1COCC1>[C:1]([C:4]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]([N:18]([CH2:26][CH:25]=[CH2:24])[C:19](=[O:21])[CH3:20])=[C:6]([Br:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(=O)Nc1cc(OCc2ccccc2)c(C(C)=O)cc1Br
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCN(C(C)=O)c1cc(OCc2ccccc2)c(C(C)=O)cc1Br
Temperature: -78 °C
Yield: 57.7 %

Procedure:
A solution of N-(4-acetyl-5-benzyloxy-2-bromo-phenyl)-acetamide (1.03 g, 2.85 mmol) in anhydrous THF (20 ml) under nitrogen was cooled to −78° C. followed by the dropwise addition of LDA (2.1 ml, 2M solution, 4.3 mmol). The reaction was continued to stir for an hour at −78° C. and then quenched with allyl bromide (0.44 ml, 2.85 mmol). The reaction was allowed to warm to room temperature and continued to stir overnight. The solution was partitioned between EtOAc and water. The organics were collected and washed with water, brine and then dried (MgSO4). Purification by column chromatography in hexane/EtOAc (1:1) afforded a white solid (0.662 g, 58%). LC/MS: RT=2.703 min. 402/404 (MH+).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)#[N:11]>C1COCC1>[OH:17][CH2:16][C:15]1[CH:19]=[CH:20][C:12]([C:10]#[N:11])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Boron trifluoride diethyl etherate (0.85 mL, 6.8 mmol) was added to a solution of 4-cyanobenzoic acid (1.0 g, 6.8 mmol) and THF (10 mL). At room temperature, borane-tetrahydrofuran complex (1.0 M, 13.6 mL) was added to the reaction mixture drop-wise with no observed exotherm. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The resulting residue was taken up in ethyl acetate (50 mL), washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (0.900 g, 95% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)[C:12]=1[F:31])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C(F)(F)F)c2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (97 mg, 0.161 mmol) in DCM (7 ml) was added TFA (3 ml) and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was quenched with saturated sodium bicarbonate and the organic layer was separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-[(4-chloro-3-{[3-cyano-5-(trifluoromethyl)phenyl]oxy}-2-fluorophenyl)methyl]-1H-imidazole-5-carboxamide (45 mg, 0.095 mmol, 59% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.82 (s, 1H), 7.69 (s, 1H), 7.47-7.53 (m, 2H), 7.35-7.42 (m, 2H), 4.63 (s, 2H). LC-MS (ES+) m/z 473.07, [M+H].
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[O:14])[CH:6]=[C:5]([CH3:26])[N:4]=1.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1.Cl.CO.CCOC(C)=O>CCO.O.CCOC(C)=O>[ClH:27].[ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[CH:30][CH:29]=3)=[CH:18][CH:17]=2)=[O:14])[CH:6]=[C:5]([CH3:26])[N:4]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Cc1cc(Nc2cccc(C(=O)Nc3ccc(N)cc3)c2)nc(N)n1
Agent: Cl
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cccc(C(=O)Nc3ccc(Nc4ccnc5ccccc45)cc3)c2)nc(N)n1
Temperature: 20 °C

Procedure:
To a solution of compound B3 (150 mg, 0.37 mmol) in EtOH (15 mL) and H2O (7.5 mL) was added 4-chloroquinoline (73 mg, 0.45 mmol) and stirred until it dissolved, then 2 drops of c. HCl was added. The reaction mixture was refluxed for 20 h, diluted with EtOAc, brought to boil and cool to 20° C. The resulting precipitate was filtered and recrystallized from MeOH/EtOAc/Charcoal/Celite to give Cpd. FF1 (195 mg, 96%) as a yellow solid.; M.P (MeOH/EtOAc)>300° C.; 1H NMR [(CD3)2SO] δ 13.72 (v br, 2H, 2×N+H), 10.91 (brs, 1H, NH), 10.96 (brs, 1H, NH), 10.56 (s, 1H, HN), 8.79 (d, J=8.5 Hz, 1H, ArH), 7.50 (d, J=6.9 Hz, 1H, ArH), 8.14-7.99 (m, 6 H, ArH & NH2), 7.83 (m, 3H, ArH), 7.55 (t, J=7.9 Hz, 1H, ArH), 7.49 (d, J=8.8 Hz, 2H, ArH), 6.78 (d, J=6.9 Hz, 1H, ArH), 6.24 (s, 1H, ArH), 2.30 (s, 3H, ArH), mass APCl+476.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][CH:15]2[NH:18]C(=O)OC(C)(C)C)=[CH:10][CH:9]=1)#[N:2].[ClH:29]>O1CCOCC1.C(#N)C>[NH2:18][CH:15]1[C:16]2[CH:17]=[C:8]([O:7][CH2:6][C:5]3[CH:4]=[C:3]([CH:28]=[CH:27][CH:26]=3)[C:1]#[N:2])[CH:9]=[CH:10][C:11]=2[CH2:12][CH2:13][CH2:14]1.[ClH:29]
Reactant: CC(C)(C)OC(=O)NC1CCCc2ccc(OCc3cccc(C#N)c3)cc21
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: N#Cc1cccc(COc2ccc3c(c2)C(N)CCC3)c1
Reaction time: 2 h

Procedure:
The tert-butyl 7-(3-cyanobenzyloxy)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (0.045 g) was taken up in 4 M HCl in dioxane (2 mL) at r.t. After stirring for 2 h. the reaction was concentrated under reduced pressure to give a residue. This residue was taken up in acetonitrile and reconcentrated under reduced pressure two times to give crude 3-{[(8-amino-5,6,7,8-tetrahydronaphthalen-2-yl)oxy]methyl}benzonitrile as HCl salt (0.035 g) as a solid residue.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OC([C:17]2[CH:29]=[CH:28][C:20]3[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=3[CH:18]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:6]1[N:7]=[C:2]([C:17]2[CH:29]=[CH:28][C:20]3[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=3[CH:18]=2)[CH:3]=[CH:4][CH:5]=1
Reactant: CC(=O)Nc1nc2ccc(C3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: Nc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc2ccc(-c3cccc(N)n3)cc2s1
Temperature: 95 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
6-Bromopyridin-2-amine (0.5 g, 3 mmol) was dissolved in 1,4-dioxane (6 mL). Then N-(6-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzo[d]thiazol-2-yl)acetamide (1.0 g, 3.1 mmol), 2M Na2CO3 (3 mL, 6 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.4 g, 0.4 mmol) were added to the mixture. The flask was fitted with a reflux condenser, placed into a pre-heated (95° C.) bath, and allowed to stir under an inert atmosphere overnight. The flask was removed from the heat bath and allowed to cool to ambient temperature. The mixture was diluted with 5:1 DCM/MeOH and saturated NaHCO3. The aqueous layer was extracted with 5:1 DCM/MeOH three times, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (1-5% MeOH/DCM) to give N-(6-(6-aminopyridin-2-yl)benzo[d]thiazol-2-yl)acetamide (0.23 g, 28% yield) as a light yellow solid. MS (ESI pos. ion) m/z: 285 (MH+). Calculated exact mass for C14H12N4OS: 284.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH3:12]>>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([NH2:12])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: N
Product: Nc1ncccc1C(F)(F)F
Temperature: 175 °C
Reaction time: 72 h

Procedure:
10 g of 2-chloro-3-trifluoromethylpyridine was dissolved in 100 mL of 25% aqueous ammonia, and stirred in a sealed-tube at 175° C. for 3 days. The reaction mixture was cooled back to room temperature, and was extracted with diethyl ether. The organic layer was washed with water and with saturated brine in the subsequent order, and then dried over anhydrous sodium sulfate. After filtering the insolubles, the filtrate was concentrated under reduced pressure to obtain 8.73 g of 3-(trifluoromethyl)-2-pyridinamine [34-1] as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[OH:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[C:21]([C:25](O)=[O:26])[NH:22]2)=[CH:18][CH:17]=1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:25]([C:21]3[NH:22][C:23]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[C:16]([OH:15])[CH:24]=4)=[O:26])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Solvent: CC#N
Product: O=C(c1cc2ccc(O)cc2[nH]1)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 4-(4-fluorobenzyl)piperidine [J. Med. Chem., 35, 4903. (1992)] and 6-hydroxy-1H-indole-2-carboxylic acid in acetonitrile at room temperature. The reaction mixture is concentrated and the residue is purified by column chromatography using Kiesel gel 60 as adsorbent (Merck) and toluene:methanol=4:1 as eluent. Mp.: 180-182° C. (toluene).
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:41](COCC[Si](C)(C)C)[CH:40]=[N:39][C:5]=2[C:6]([CH2:30][C:31]2[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:38])=[N:7][C:8]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[CH:12][C:11]=1[CH3:29])#[N:2].O.C(=O)(O)[O-:52].[Na+]>S(=O)(=O)(O)O>[Cl:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:38])[C:31]=1[CH2:30][C:6]1[C:5]2[N:39]=[CH:40][NH:41][C:4]=2[C:3]([C:1]([NH2:2])=[O:52])=[C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)=[CH:12][C:11]=2[CH3:29])[N:7]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2ncn(COCC[Si](C)(C)C)c2c1C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(N2CCNCC2)ccc1Nc1nc(Cc2c(Cl)cccc2Cl)c2nc[nH]c2c1C(N)=O
Temperature: 95 °C
Reaction time: 0.33 h

Procedure:
To a solution of the product of Example 26B (194 mg, 0.27 mmol) in concentrated sulfuric acid (5 mL) was added water (1 mL) at 0° C. and the mixture was stirred at 95° C. for 20 minutes. After cooling to ambient temperature, water (3 mL) was added. The mixture was adjusted to pH 8-9 with saturated sodium bicarbonate solution and extracted with dichloromethane (3×20 mL). The organic layers were concentrated under vacuum and the residue was purified via preparative HPLC using a gradient of 10/90 to 75/25 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 13.62 (br, 1 H), 11.4 (br, 1 H), 9.58 (br, 1 H), 8.66 (s, 2 H), 8.58 (s, 1 H), 7.75-7.57 (m, 3 H), 7.45 (d, J=9 Hz, 1 H), 6.78 (d, J=2.4 Hz, 1 H), 6.34 (dd, J=9, 2.4 Hz, 1 H), 4.70 (s, 2 H), 3.26-3.22 (m, 8 H), 2.23 (s, 3 H). MS: 510 (M+H+).
Reaction SMILES: [O:1]1[CH:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:2]1[C:3]([O:5]C)=[O:4].[OH-].[Na+]>C1(C)C=CC=CC=1>[O:1]1[C@@H:7]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C1OC1C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(O)[C@@H]1O[C@H]1C1CCCCC1
Reaction time: 48 h

Procedure:
500 ml of toluene containing 100 g of racemic methyl 2,3-epoxy-3-cyclohexylpropionate, was added to 500 ml of a 1M tris-HCl buffer solution (pH 8.0) containing lipase (derived from hog pancreas, manufactured by Wako Pure Chemical Industries, Ltd.) in a concentration of 5 g/l, and asymmetric hydrolysis reaction was carried out at 30° C. for 48 hours at a stirring speed of 600 rpm. After the reaction, a 1N sodium hydroxide aqueous solution was added to the reaction solution to adjust the pH of the aqueous phase to 10, whereupon the aqueous phase was separated. The aqueous phase was then adjusted to pH 2 with a 1N hydrochloric acid solution, and then, extracted twice with 300 ml of t-butyl methyl ether. The organic layer was concentrated under reduced pressure to obtain 42.5 g of (2R,3S)-2,3-epoxy-3-cyclohexylpropionic acid as crude crystals. The crude crystals were dissolved in 200 ml of a solution of toluene/n-heptane=1/2 (v/v) and heated and dissolved for 20 minutes with stirring at 60° C. The solution was gradually cooled from 60° C. to 20° C. and then cooled with ice for 30 minutes, whereupon precipitated crystals were collected by filtration to obtain 40.2 g of crystals of (2S,3R)-2,3-epoxy-3-cyclohexylpropionic acid (98.6% ee [α]D2=−20.8 (c 1.04, CHCl3)).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([O:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:21]=2)[NH:18][C:17]([C:29]2[S:30][CH:31]([CH2:34][C:35](O)=[O:36])[CH2:32][N:33]=2)=[CH:16]3)=[CH:8][CH:7]=1)(=[O:4])=[O:3].O.O[N:40]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[CH3:1][S:2]([CH2:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([O:22][CH:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[CH:21]=2)[NH:18][C:17]([C:29]2[S:30][CH:31]([CH2:34][C:35]([NH2:40])=[O:36])[CH2:32][N:33]=2)=[CH:16]3)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)Cc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: CS(=O)(=O)Cc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(N)=O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of {2-[5-({6-[(methylsulfonyl)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (200 mg) in N,N-dimethylformamide (5 mL) were added 1-hydroxybenzotriazole monohydrate (84 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (105 mg), and 25% aqueous ammonia (2 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) and crystallized from acetonitrile. The obtained crystals were recrystallized from ethyl acetate and diethyl ether to give the title compound (136 mg, yield 68%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1.C([O:25][CH:26]=[C:27]([C:33](OCC)=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])C.C[O-].[Na+]>C(O)C>[CH2:31]([O:30][C:28]([C:27]1[CH:33]=[N:1][C:2]2[N:3]([N:4]=[CH:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)=[CH:9][CH:8]=2)[C:26]=1[OH:25])=[O:29])[CH3:32]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1n[nH]cc1-c1ccc(Cc2ccc3c(c2)OCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2c(-c3ccc(Cc4ccc5c(c4)OCO5)cc3)cnn2c1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-amino-4-[4-(3,4-methylenedioxyphenylmethyl)phenyl]pyrazole (1.5 g) in ethanol (10 ml) was added diethyl ethoxymethylenemalonate (2.07 ml), and the mixture was heated and refluxed for 12 hours. To the mixture was added sodium methoxide (829 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 day. The solvent was distilled away under reduced pressure, and thereto was added water (50 ml) under ice-cooling. The mixture was adjusted to acid with 10% hydrochloric acid, and the precipitate was separated by filtration, washed with water to give the title compound (2.1 g) at a quantitative yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(O)[CH:10]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:38])([CH3:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:26][C:25]=2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:37])([CH3:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:26][C:25]=2[O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CN(Cc3ccccc3)CCC2(O)CCCc2ccccc2)c(OCc2ccccc2)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCC(C)(C)c1ccc(C2=C(CCCc3ccccc3)CCN(Cc3ccccc3)C2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a -5° C. solution of 3.0 g. (4.85 mmols.) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-phenylpropyl)-4-piperidinol in 5 ml. of pyridine is slowly added 2.89 g. (24.3 mmols.) of thionyl chloride. The reaction mixture is then allowed to slowly warm to 25° C. and is stirred 12 hours longers. The reaction mixture is quenched by slow addition to 200 ml. of cold 20% potassium carbonate. The quenched mixture is extracted with 250 ml. of ether, the extract washed once with 200 ml. 20% potassium carbonate, dried over magnesium sulfate and evaporated. THe residue is purified via column chromatography on 300 g. silica gel eluted with 50% ether-cyclohexane to yield the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([Si:7]([CH3:28])([CH3:27])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][O:18][CH3:19])[C:11]=1[C:20](=[CH2:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:6])[CH3:5].[CH3:29]S(C)=O>>[CH3:3][C:4]([Si:7]([CH3:27])([CH3:28])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][O:18][CH3:19])[C:11]=1[C:20]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:29][CH2:26]1)([CH3:5])[CH3:6]
Reactant: CS(C)=O
Reactant: C=C(C(=O)OCC)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C1(c2c(CO[Si](C)(C)C(C)(C)C)cccc2OCOC)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH 60% disp in mineral oil (140 mg, 3.49 mmol) was added and the reaction mixture was stirred for 30 minutes at room temperature. A solution of ethyl 2-(2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-{[(methyloxy)methyl]oxy}phenyl)-2-propenoate (Intermediate 132, 830 mg) in dry dimethyl sulfoxide (5 mL) was added and the reaction mixture was stirred for 30 minutes at room temperature The reaction was quenched with ice, diluted with brine (10 ml) and water (10 ml) and extracted with ethyl acetate (2×30 ml). The organic layer was washed with water (3×15 ml) and brine (1×20 ml), dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 50 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluent. This afforded the title compound as a colourless oil (780 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([Cl:51])[C:37]=1[OH:52]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:40]1[CH:41]=[C:36]([Cl:35])[C:37]([OH:52])=[C:38]([Cl:51])[CH:39]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Yield: 102.7 %

Procedure:
Following general procedure D, tert-butyl 4-(5-(3-acetyl-6-bromoquinolin-4-ylamino)pyridin-2-yl)piperazine-1-carboxylate (55 mg, 0.104 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (36 mg, 0.125 mmol) to afford the desired product (65 mg, 72%) as an green oil: ESI MS m/z 608, [C31H31Cl2N5O4+H]+
Reaction SMILES: [OH:1][CH:2]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([CH3:25])[CH:17]=2)([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:7][C:6]=1[CH3:26].Cl.[NH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36].C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:12]([C:11]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:21])=[C:18]([CH3:25])[CH:17]=1)([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[C:27]([CH3:30])([CH3:28])[CH3:29])=[C:6]([CH3:26])[CH:7]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)O)c(C)c1
Reactant: CS(=O)(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(C(=O)NCCS(C)(=O)=O)c(C)c1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a mixture of 4-(1-{4-[2-(hydroxy)-3,3-dimethyl-butoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzoic acid, Example 1, (0.53 g, 1.29 mmol), 2-aminoethylmethylsulfone hydrochloride (0.21 g, 1.29 mmol), HOBt (0.19 g, 1.43 mmol), Et3N (0.72 mL, 5.19 mmol) and CH2Cl2 (10 mL) is added EDCI (0.249 g, 1.29 mmol) and stirred overnight. The reaction is diluted with CH2Cl2 (50 mL), washed with 1M HCl (2×30 mL), H2O (20 mL), satd NaHCO3 (2×20 mL), and brine (20 mL). The organic layer is MgSO4 dried, concentrated, and chromatographed (75% EtOAc/Hex) to give the title compound (0.51 g, 76%).