Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:43])[F:42])=[CH:36][N:35]=1)[C:28]#[N:29].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([C:28]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:12])[N:29]=2)[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:42])[F:43])=[CH:36][N:35]=1
Reactant: N#Cc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (0.90 g), 3-chloro-4-(3-chloro-5-trifluoromethylpyridine-2yloxy)benzonitrile (0.80 g), anhydrous iron (III) chloride (0.40 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][CH:14]2[C:26]([NH2:28])=[O:27])=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]2[C:26]([NH2:28])=[O:27])=[CH:4][CH:3]=1
Reactant: NC(=O)C1CN(Cc2ccccc2)CCN1CCCC=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)C1CNCCN1CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 76.3 %

Procedure:
A solution of 56.9 parts of 1-[5,5-bis(4-fluorophenyl)-4-pentenyl]-4-(phenylmethyl)-2-piperazinecarboxamide in 400 parts of methanol was hydrogenated in a Parr apparatus and at 50° C. with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in 2-propanone and the whole was acidified with a mixture of hydrochloric acid and 2-propanol. After the addition of 2,2'-oxybispropane, the supernatant liquid was decanted and the precipitate was stirred in 2,2'-oxybispropane. The precipitated product was filtered off and dissolved in water. After washing with 2,2'-oxybispropane, the aqueous layer was treated with ammonium hydroxide and the product was extracted with trichloromethane. The extract was washed with a sodium chloride solution, dried, filtered and evaporated (under trichloromethane), yielding 35.2 parts (76.3%) of 1-[5,5-bis(4-fluorophenyl)pentyl]-2-piperazinecarboxamide as a residue (int. 34).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:11][C:12](=[O:33])[CH:13]([C:23](=[O:32])[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[NH2:35][OH:36]>C(O)C>[CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:11][C:12](=[O:33])[CH:13]([C:23](=[O:32])[NH:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[NH:22])[NH:35][OH:36])=[CH:19][CH:20]=1)[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: NO
Reactant: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C#N)cc1)C(=O)NCc1ccccc1)C1CCCCC1
Solvent: CCO
Product: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)NO)cc1)C(=O)NCc1ccccc1)C1CCCCC1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A suspension of [2-(R,S)-benzylcarbamoyl-3-(4-cyano-phenyl)-propionylamino]-(S)-cyclohexyl-acetic acid methyl ester (9 g, 19.5 mmol) and hydroxylamine (3.22 g, 97.5 mmol) in ethanol (180 ml) was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, evaporated in vacuo, solved in ethanol and poured in ice-water. The precipitate was collected by suction and dried at 50° C. in vacuo to give 7.9 g (82%) of the desired product. mp.: 101-104° C., MS m/z: 495 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:4]=1.CC1C2C(=CC=CC=2)C=CC=1OC1CCNCC1.Br[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=1)=[O:47].ClCCCC(C1C=CC(F)=CC=1)=O>>[F:21][C:2]([F:1])([F:20])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([C:48]3[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=3)=[O:47])[CH2:16][CH2:15]2)[CH:4]=1
Reactant: COc1ccc(C(=O)CCCCCBr)cc1
Reactant: FC(F)(F)c1cc(OC2CCNCC2)cc2ccccc12
Agent: Cc1c(OC2CCNCC2)ccc2ccccc12
Agent: O=C(CCCCl)c1ccc(F)cc1
Product: COc1ccc(C(=O)CCCCCN2CCC(Oc3cc(C(F)(F)F)c4ccccc4c3)CC2)cc1

Procedure:
When in the procedure of Example 18, 4-(4-trifluoromethyl-2-naphthalenyloxy)piperidine is substituted for 4-(1-methyl-2-naphthalenyloxy)piperidine and 6-bromo-1-(4-methoxyphenyl)-1-hexanone substituted for 4-chloro-1-(4-fluorophenyl)-1-butanone, 6-[4-(4-trifluoromethyl-2-naphthalenyloxy)-1-piperidyl]-1-(4-methoxyphenyl)-1-hexanone is obtained.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][CH:6]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][CH2:8]O>>[Br:2][CH2:8][CH2:7][CH:6]([CH3:5])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: BrP(Br)Br
Reactant: CCCCC(C)CCO
Product: CCCCC(C)CCBr
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Phosphorus tribromide (10.44 g, 38.5 mmol) is added dropwise to 95% 3-methyl-1-heptanol (7.7 g, 56.3 mmol) at 0° C. and the mixture is stirred for 5 h at 100° C. The mixture is allowed to cool, poured onto ice, and extracted several times with hexane. The extract is washed with sodium carbonate solution, dried over magnesium sulfate, and evaporated down.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH:16]([CH3:19])[CH2:17][CH3:18])=[CH:11][CH:10]=1)[CH3:6])[CH3:2].I([O-])(=O)(=O)=[O:21].[Na+].CCOCC>CO.O>[CH2:1]([O:3][N:4]=[C:5]([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH:16]([CH3:19])[CH2:17][CH3:18])=[O:21])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCON=C(C)COc1ccc(SC(C)CC)cc1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CCON=C(C)COc1ccc(S(=O)C(C)CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(1-methylpropylthio)phenoxyacetone O-ethyloxime (7.1 mmol) in 10 ml of methanol at 0° is added, dropwise over 5 min., sodium periodate (1.67 g, 7.8 mmol) in 13 ml of water. The mixture is stirred for 3 hours while warming to RT. The reaction is worked up by addition of water and extraction with ether. The combined organic extracts are washed with saturated sodium thiosulfate, with water and with brine, dried and solvent evaporated off to give 4-(1-methylpropylsulfinyl)phenoxyacetone O-ethyloxime.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([NH2:32])([C:30]#[N:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH2:26][C:27]([C:30]#[N:31])([NH:32][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([O:6][C:2]([F:1])([F:16])[CH:3]([F:4])[F:5])=[CH:15][CH:14]=2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(O)c1ccc(OC(F)(F)C(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2ccc(OC(F)(F)C(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 28.5 h
Yield: 85.5 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uoronium hexafluorophosphate (1.60 g, 4.20 mmol) was added to a solution of 4-(1,1,2,2-tetrafluoro-ethoxy)-benzoic acid (1.00 g, 4.20 mmol), 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (995 mg, 4.42 mmol) and N,N-diisopropylethylamine (1.46 ml, 8.39 mmol) in DMF (8.8 ml) at 0° C. The mixture was gradually warmed to room temperature and stirred for 28.5 hours. An aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate three times. The organic layers were sequentially washed with H2O (×2) and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:AcOEt=90:10→30:70) to give 4-cyano-4-[4-(1,1,2,2-tetrafluoro-ethoxy)-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester as a light brown powder (1.60 g, 86%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C@@H:22]([C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[CH2:23][CH2:24][OH:25].C(N(CC)C(C)C)(C)C>C(#N)C>[OH:25][CH2:24][CH2:23][C@@H:22]([NH:21][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:26]1[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: Cc1ccc([C@H](N)CCO)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CCO)c4ccc(C)nc4)c3C2)c(C#N)c1
Yield: 33.3 %

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (60 mg, 0.21 mmol) and (R)-3-amino-3-(6-methylpyridin-3-yl)propan-1-ol (35 mg, 0.21 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (73 μL, 0.42 mmol) was subjected to microwave irradiation at 180° C. for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel column (0-30% MeOH/CH2Cl2) followed by preparative HPLC (100×20.2 mm, C18 column; 20-50% CH3CN-water [10 mM Et2NH]) to yield an off-white solid (29 mg).
Reaction SMILES: [CH:1]([N:4](CC)[CH:5](C)C)(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[O:18])=[CH:13][CH:12]=1.ClN1C(=O)CCC1=O.CNC>C(#N)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([N:4]([CH3:5])[CH3:1])(=[O:18])=[N:19][C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])=[CH:15][CH:16]=1
Reactant: O=C(NS(=O)c1ccc(Br)cc1)C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CN(C)S(=O)(=NC(=O)C(F)(F)F)c1ccc(Br)cc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
N,N-Diisopropylethylamine (14 μL) is added to a mixture of N-(4-bromobenzenesulfinyl)-2,2,2-trifluoroacetamide (50 mg), N-chlorosuccinimide (25 mg), and dimethylamine solution (2 M in tetrahydrofuran; 0.16 mL) in acetonitrile (2 mL) at −10° C. under an argon atmosphere. The reaction mixture is stirred at −10° C. for 15 min, warmed to room temperature and stirred for 3 h. The reaction mixture is extracted with dichloromethane and the combined extracts are washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound. The crude product is used for the next step without further purification. LC (method 1): tR=1.07 min; Mass spectrum (ESI+): m/z=359, 361 [M+H]+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][CH2:9][CH2:10][NH2:11].Cl.N1(S([N:31]=[N+:32]=[N-])(=O)=O)C=CN=C1.S(=O)(=O)(O)[O-].[K+]>CO.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].O>[N:11]([CH2:10][CH2:9][CH2:8][C@H:7]([NH:6][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([OH:14])=[O:13])=[N+:31]=[N-:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Reactant: [N-]=[N+]=NS(=O)(=O)n1ccnc1
Agent: [Cu+2]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCN=[N+]=[N-])C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium bicarbonate (1.99 g, 23.68 mmol) was added to a mixture of Boc-Orn-OH (Compound tk56) (1.0 g, 4.31 mmol) and copper sulfate pentahydrate (21 mg, 0.086 mmol) in methanol (20 mL)-water (6 mL) at room temperature, followed by addition of 1H-imidazole-1-sulfonyl azide hydrochloride synthesized by the method described in the literature (Org. Lett., 2007, 9, 3797) (1.08 g, 5.17 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was cooled in an ice bath, followed by addition of a saturated aqueous potassium bisulfate solution (8 mL). The resulting mixture was extracted with ethyl acetate (three times), and the organic phase was concentrated under reduced pressure. The resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (S)-5-azido-2-((tert-butoxycarbonyl)amino)pentanoic acid (Compound tk69) (1.19 g, quant.).
Reaction SMILES: Cl.[C:2]([CH2:7][N:8]1[C:20]2[CH2:19][CH2:18][CH:17]([N:21]([CH3:23])[CH3:22])[CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)([O:4]CC)=[O:3].Cl>>[CH3:22][N:21]([CH3:23])[CH:17]1[CH2:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:7][C:2]([OH:4])=[O:3])[C:20]=2[CH2:19][CH2:18]1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CC(N(C)C)CC2
Agent: Cl
Product: CN(C)C1CCc2c(c3ccccc3n2CC(=O)O)C1

Procedure:
A mixture of 9.9 g. of 9-carbethoxymethyl-3-(dimethylamino)-1,2,3,4-tetrahydrocarbazole hydrochloride (Example 14) in 50 ml. of 6-N hydrochloric acid was heated on a steam bath for one and one-half hours, cooled, and the resulting solids were collected by filtration to give, after recrystallization from ethyl alcohol-water, 6.26 g. of 3-(dimethylamino)-9-carboxymethyl-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. 316°-319° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:17][O:18][C:19]1[CH:28]=[CH:27][C:22]2[NH:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=1>>[Cl:8][C:6]1[N:7]=[C:2]([N:23]2[C:22]3[CH:27]=[CH:28][C:19]([O:18][CH3:17])=[CH:20][C:21]=3[O:26][CH2:25][CH2:24]2)[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(C1CCC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1ccc2c(c1)OCCN2
Product: CCC(C1CCC1)n1cc(Cl)nc(N2CCOc3cc(OC)ccc32)c1=O

Procedure:
Prepared in a similar fashion as described for Example aaa using 3,5-dichloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone and 7-methoxy-3,4-dihydro-2H-1,4-benzoxazine as the starting materials to give an oil. 1H NMR (300 MHz, CDCl3): δ 6.91 (d, J=9.5 Hz, 1H), 6.69 (s, 1H), 6.46-6.41 (m, 2H), 4.92-4.82 (m, 1H), 4.34-4.31 (m, 2H), 4.20-4.16 (m, 2H), 3.76 (s, 3H), 2.64-2.50 (m, 1H), 2.24-2.12 (m, 1H), 1.96-1.40 (m, 7H), 0.84 (t, J=7.5 Hz, 3H); HRMS (ESI) m/z 390.1595 [(M+H)+, calcd for C20H25N3O3Cl 390.1584].
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[C:14]([I:15])[C:9]=2[O:8][N:7]=1)=[O:4].S(OC)(O[CH3:23])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:18][C:2]([F:17])([F:1])[C:3]([N:5]([C:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[C:14]([I:15])[C:9]=2[O:8][N:7]=1)[CH3:23])=[O:4]
Reactant: Cc1ccc2c(NC(=O)C(F)(F)F)noc2c1I
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2c(N(C)C(=O)C(F)(F)F)noc2c1I
Temperature: 50 °C

Procedure:
To 2,2,2-trifluoro-N-(7-iodo-6-methylbenzo[d]isoxazol-3-yl)acetamide in acetone (5.0 mL) at RT was added dimethyl sulfate (766 mg, 6.07 mmol) and potassium carbonate (1.40 g, 10.12 mmol). The mixture was heated at 50° C. in an oil bath for 5 h, then cooled to RT, filtered through a pad of Celite and rinsed with additional acetone (2×5 mL). The filtrate was concentrated to dryness to provide 2,2,2-trifluoro-N-(7-iodo-6-methylbenzo[d]isoxazol-3-yl)-N-methylacetamide. MS (ESI, pos. ion) m/z: 385.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[F:1][C:2]([F:13])([F:14])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(c1ccc(O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(C)(C)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-(2,2,2-trifluoro-1,1-dimethylethyl)phenol (408 mg, 2.0 mmol, WO 9708144A1) and potassium carbonate (552 mg, 4.0 mmol) in N,N-dimethylformamide (DMF) (30 ml) was added ethyl bromoacetate (334 mg, 2.0 mmol) and the mixture was stirred for 3 hours at ambient temperature. The reaction was partitioned with water and a 1:10 by volume mixture of ethylacetate/hexane, and the organic layer was separated and dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was passed through a silica gel chromatography column and eluted with a 1:1 by volume mixture of ethyl acetate/hexane to furnish ethyl [4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetate. Then, ethyl [4-(2,2,2-trifluoro-1,1-dimethylethyl)phenoxy]acetate was treated with 2M aqueous sodium hydroxide (3.0 ml) and methanol (3.0 ml) for 2 hours at room temperature and was quenched with 2M aqueous hydrogen chloride to acidify the mixture adjusting to pH 1. Crude product was extracted with ethyl acetate, and then the organic layer was dried over magnesium sulfate. After filtration, solvent was evaporated under reduced pressure to give 345 mg (66% yield) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[C:20](=[NH:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20](=[N:33][C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc2nc(Br)cnc2n1COCC[Si](C)(C)C
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1cc2nc(N=C(c3ccccc3)c3ccccc3)cnc2n1COCC[Si](C)(C)C
Temperature: 100 °C
Yield: 35.9 %

Procedure:
2-Bromo-6-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (0.340 g, 0.993 mmol), benzhydrylideneamine (0.18 mL, 1.09 mmol), Cs2CO3 (648 mg, 1.99 mmol), Pd(OAc)2 (22 mg, 0.099 mmol) and BINAP (62 mg, 0.099 mmol) were dissolved in THF (10 mL) and heated at 100° C. for 64 hr, cooled to RT, partitioned between EtOAc and brine. The organic layer was dried (MgSO4), filtered, concentrated, and purified by SiO2 chromatography (40 g SiO2, hexanes/EtOAc 0-35% EtOAc) to give 158 mg of benzhydrylidene-[6-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-amine as a yellow liquid (36% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][S:12]([CH3:11])(=[O:14])=[O:13])=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(C(=O)O)cc1
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cc1

Procedure:
4-Aminobenzoic acid is reacted with methanesulfonyl chloride (Compound 19) to give N-(4-carboxyphenyl)methanesulfonamide. 2-Triethylsilyl-4-furaldehyde (Compound 18) is reacted with N-(4-carboxyphenyl)methanesulfonamide and lithium diisopropylamide. The resulting 4-[1-hydroxy-2-N-(4-carboxyphenyl)sulfonamido]-ethyl-2-triethylsilylfuran is esterified with dodecanoyl chloride in the presence of triethylamine. Oxidizing this ester with singlet oxygen, under conditions as in Example 1, gives the title furanone.
Reaction SMILES: [C:1]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11]Cl)[N:10]=1)(=[O:4])[CH2:2][CH3:3].[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([CH2:11][C:9]3[N:10]=[C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])[S:7][CH:8]=3)[CH2:14][CH2:15]2)=[CH:20]1
Reactant: CCC(=O)Nc1nc(CCl)cs1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Reaction time: 6 h
Yield: 70.7 %

Procedure:
A mixture of 2-propionylamino-4-chloromethylthiazol (5.11 g), 3-(4-piperidyl)indole (5 g), sodium hydrogen carbonate (2.31 g) and N,N-dimethylformamide (25 ml) was heated at 102° to 103° C. with bubbling nitrogen gas and stirring for 6 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was subjected to column chromatography on silica gel and the column was eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the desired compound were combined and concentrated and ethanol was added thereto. The solution was concentrated again and the residue was triturated with diisopropyl ether to give 4-[4-(3-indolyl)piperidinomethyl]-2-propionylaminothiazole (6.50 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.FC(F)(F)C(O)=O.[NH:35]1[CH2:38][CH:37]([CH2:39][C:40]([OH:42])=[O:41])[CH2:36]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][N:35]1[CH2:38][CH:37]([CH2:39][C:40]([OH:42])=[O:41])[CH2:36]1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=C(O)CC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (100.0 mg, 0.267 mmol) and 2-(azetidin-3-yl)acetic acid trifluoroacetic acid (88.1 mg, 0.384 mmol) according to Reference R and the general procedure for reductive amination to give 2-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidin-3-yl)acetic acid as a tan solid. MS (ESI) m/z: Calculated: 473.2; Observed: 474.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(-c2cc(C)c(Cl)c(C)c2)nc1

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 2-bromo-5-methyl-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=0.90 min; Mass spectrum (ESI+): m/z=232/234 (Cl) [M+H]+.