Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[C:5]([NH:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57])=[O:7]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)c(F)c2)c(O)n1
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
A solution of 3-fluoro-4-(1-phenoxyethyl)benzoic acid (300 mg, 1.2 mmol) in dichloromethane (15.0 mL) was added N-hydroxybenzotriazole (270 mg, 2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (384 mg, 2 mmol), triethylamine (202 mg, 2 mmol). The mixture was stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (270 mg, 1.8 mmol) was added and the mixture was stirred at room temperature for 12 hours. To the mixture, water (50 mL) was added. The mixture was then extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by preparative-TLC (silica gel, methanol/dichloromethane=1:20, 1% NH3) to give 3-fluoro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide as white solid (217 mg, 46%). LRMS (M+H+) m/z: calcd 394.17. found 394. HPLC purity (214 nm): 96%. 1H NMR (300 MHz, CD3OD): δ 7.57-7.49 (m, 3H), 7.16 (t, J=8.4 Hz, 2H), 6.85-6.82 (m, 3H), 6.09 (s, 1H), 5.68 (q, J=6.6 Hz, 1H), 4.45 (s, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 1.62 (d, J=8.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]([CH3:25])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH2:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br-].C1C(C(OOC(C)(C)C)=O)=CC=CC=1.O>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]([CH3:25])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1COC(c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)=N1
Agent: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Br-]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1coc(-c2ncn3c2CN(C)C(=O)c2c(Cl)cccc2-3)n1
Yield: 46.7 %

Procedure:
A solution of 6.80 g (0.0181 mol) of methyl (S)-2-(7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-3-yl)-4,5-dihydro-oxazole-4-carboxylate in 700 ml of hot benzene was treated with 2.86 g (0.0199 mol) of copperl bromide and 5.1 ml (0.0272 mol) of tert-butyl perbenzoate according to the method described in Tetr. Letters 1994, 35, 2481. The mixture was boiled at reflux for 20 min., cooled and treated with 300 ml of water. The mixture was filtered, extracted with dichloromethane and chromatographed over silica gel with ethyl acetate as the eluent. There were obtained 3.15 g (47%) of methyl 2-(7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)-oxazole-4-carboxylate as white crystals; m.p. 266°-268°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34](Cl)[O:35][CH:36]=2)=[O:31])[CH3:28])[CH:18]=[C:19]([F:26])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:19]1[CH:18]=[C:17]([CH:27]([NH:29][C:30]([C:32]2[N:33]=[C:34]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[O:35][CH:36]=2)=[O:31])[CH3:28])[CH:16]=[C:15]([F:14])[C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2ccc(C(F)(F)F)cc2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 23.6 %

Procedure:
4-Trifluoromethylbenzeneboronic acid (50 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (15 mg, 24%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>CS(C)=O>[Cl:18][C:19]1[N:20]=[N:21][C:22]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:23][CH:24]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of N-Boc-4-piperidinemethanol (1.0 g, 4.50 mmol) was added dropwise to a suspension of NaH (60% in mineral oil, 0.27 g, 6.76 mmol) in DMSO (2 mL). The mixture was stirred at ambient temperature for 1 h, then 30 minutes at 50° C. The mixture was cooled to ambient temperature and a solution of 3,6-dichloropyridazine (0.73 g, 4.73 mmol) in DMSO (4 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature overnight, poured onto water, then extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark reddish brown oil. The crude product was purified by chromatography on ISCO silica gel column eluted with a EtOAc:hexane gradient (0 to 30%) to give 0.85 g (56%) of 1,1-dimethylethyl 4-{[(6-chloro-3-pyridazinyl)oxy]methyl}-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.36 (d, 1H, J=9.0 Hz), 6.94 (d, 1H, J=9.1 Hz), 4.34 (d, 2H, J=6.6 Hz), 4.20-4.10 (m, 2H), 2.80-2.65 (m, 2H), 2.10-1.95 (m, 1H), 1.85-1.70 (m, 2H), 1.45 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 328 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:16]([O-])=O>C(=O)([O-])O.[Na+]>[NH2:16][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:12](=[O:15])(=[O:14])[NH2:13])[C:3]=1[O:2][CH3:1])[C:7]([OH:9])=[O:8]
Reactant: COc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
4-Methoxy-3-nitro-5-sulphamyl-benzoic acid (2.8 g) was dissolved in 1N sodium hydrogen carbonate solution (12 ml), and hydrogenated, using Pd-on-carbon as a catalyst, and the 3-amino-4-methoxy-5-sulphamyl-benzoic acid was isolated as described in EXample 1 B. After several recrystallizations from water and drying at 78° C in vacuo, the melting point was 210° C under decomposition.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:40][S:41]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:9]=2[S:8][C:7]=1[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)c(Cc3cccc4ccccc34)sc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCOS(C)(=O)=O)c(Cc3cccc4ccccc34)sc21
Reaction time: 8 h

Procedure:
5- [(3-Hydroxypropyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 4) (403 mg) was dissolved in dichloromethane (6 ml). Triethylamine (300 μl) was added followed by methanesulfonyl chloride (150 μl ) and the mixture was stirred overnight. Sodium bicarbonate (aqueous) was added and the phases were separated. The aqueous phase was extracted twice with dichloromethane, the organic phases were combined, washed with brine, dried, filtered and evaporated to give the subtitle compound (0.57 g).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][C:5]1([CH3:21])[CH2:10][CH:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:18])[CH2:8][C:7]([CH3:20])([CH3:19])[NH:6]1>CN(C)C=O>[OH:3][CH2:2][CH2:1][N:6]1[C:7]([CH3:20])([CH3:19])[CH2:8][CH:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:18])[CH2:10][C:5]1([CH3:21])[CH3:4]
Reactant: C1CO1
Reactant: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1
Solvent: CN(C)C=O
Product: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1CCO
Temperature: 190 °C

Procedure:
To a small autoclave is charged a solution of 6.6 g (0.15 mole) of ethylene oxide and 25.2 g (0.1 mole) of N-(2,2,6,6-tetramethylpiperidin-4-yl)-epsilon-caprolactam, in 100 ml of N,N-dimethylformamide. The autoclave is heated for four hours at 190° C. during which time the pressure dropped from 100 psi (7 kg/cm2) to 70 psi (4.9 kg/cm2). The reaction mixture is then distilled in vacuo (50° C./2 mm) to remove the solvent. The residue is crystallized from 300 ml of heptane:toluene (2:1) to give the above-named product in a yield of 13.7 g as a white solid melting at 141°-142° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH2:13][C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CC(C)=O>[C:14]([CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:15]
Reactant: N#CCBr
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OCC#N)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
To a solution of methyl 3-hydroxybenzoate (5.00 g, 32.9 mmol) in acetone (60 mL) were added bromoacetonitrile (2.63 mL, 39.4 mmol) and potassium carbonate (6.81 g, 49.3 mmol), and the mixture was stirred at 60° C. for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=10/90→20/80), and the fraction containing the object product was concentrated under reduced pressure to give the title compound (5.43 g, 86%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([CH2:15][OH:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH:15]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:6]2[CH2:5][C:4]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:2]([Cl:1])[CH:3]=1)=[O:16]
Reactant: CCOC(=O)c1cc2c(CO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2c(C=O)cccc2n1Cc1ccc(Cl)c(Cl)c1
Yield: 94.9 %

Procedure:
Ethyl N-(3,4-dichlorobenzyl)-4-hydroxymethylindole-2-carboxylate (5.17 g) and 2,3-dichloro-5,6-dicyanobenzoquinone (3.10 g) were stirred in dioxane (100 ml) at ambient temperature, overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in dichloromethane (100 ml) and filtered. The filtrate was concentrated in vacuo and the residue purified by column chromatography using 10% ethyl acetate:iso-hexane as eluent to give product as a yellow solid (4.88 g, 95%); NMR δ(CD3SOCD3) 1.30 (t, 3H), 4.30 (q, 2H), 5.90 (s, 2H), 6.85 (m, 1H), 7.90 (m, 1H), 8.00 (m, 1H), 10.22 (s, 1H); M/z (+) 376.3 (MH+).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:37])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=2[Cl:36])=[O:22])[CH2:17]1>>[Cl:36][C:27]1[CH:28]=[CH:29][C:30]([C:32]([F:35])([F:33])[F:34])=[CH:31][C:26]=1[C:25]([NH:24][CH2:23][C:21](=[O:22])[NH:20][CH:18]1[CH2:19][N:16]([CH:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:9]3[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[CH2:3][CH2:4]2)[CH2:17]1)=[O:37]
Reactant: Cc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)ccc1Cl)NC1CNC1
Product: Cc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cc(C(F)(F)F)ccc4Cl)C3)CC2)cn1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(6-methyl-pyridin-3-yl)-cyclohexanone, as prepared in Example 13 Step B, and N-(azetidin-3-ylcarbamoylmethyl)-2-chloro-5-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH:40]([F:42])[F:41])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][C:31]([CH3:38])([C:34]([O:36]C)=[O:35])[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH:40]([F:41])[F:42])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][C:31]([CH3:38])([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: COC(=O)C1(C)CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C(=O)O)CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylate (500 mg, 0.83 mmol) in methanol (10 mL) was added a solution of potassium carbonate (700 mg, 5.06 mmol) in water (5 mL). The resulting solution was stirred at 60° C. overnight and acidified with 1 N HCl to pH 2. The solids were collected by filtration. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (30.0% MeCN up to 35.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 30.0% in 2 min); Detector, UV 254/220 nm. This resulted in 26.6 mg of 1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)-4-methylpiperidine-4-carboxylic acid as a white solid. LCMS (Method 20) [M+H]+=588.2, RT=2.79 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 12.5 (br, 1H), 9.76 (s, 1H), 9.34 (d, 1H, J=6.8 Hz), 8.69-8.68 (m, 2H), 8.32 (s, 1H), 7.63 (dd, 1H, J=2.8, 8.8 Hz), 7.56 (d, 1H, J=2.8 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.29 (dd, 1H, J=4.4, 7.2 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.28-5.18 (m, 2H), 3.96-3.93 (m, 1H), 3.74-3.70 (m, 1H), 3.26-3.23 (m, 1H), 3.01-2.95 (m, 1H), 1.98-1.93 (m, 2H), 1.46-1.30 (m, 2H), 1.18 (s, 3H).
Reaction SMILES: C([Li])CCC.[Cl-].[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH2:17][PH3+].[CH:19]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=O>CCCCCC.O1CCCC1.O>[N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1/[CH:17]=[CH:19]/[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: [PH3+]Cc1ccc2ccccc2n1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COC(=O)c1cccc(/C=C/c2ccc3ccccc3n2)c1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
2.5M Butyl lithium in hexane (8.8 ml) is added over 5 minutes to a stirred solution of quinolin-2-ylmethylphosphonium chloride (9.66 g, 22 mmol) in dry tetrahydrofuran (250 ml) at -75° C. The mixture is stirred for 1 hour at -75° C. then a solution of methyl 3-formylbenzoate (3.28 g, 20 mmol) in tetrahydrofuran (25 ml) is added dropwise over 10 minutes. After stirring for a further 30 minutes at -75° C., the mixture is warmed to room temperature, diluted with water and extracted with ethyl acetate. The extract is dried and evaporated and the residue is purified by chromatography on silica eluting with ethyl acetate-hexane (1:3).
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].[F:8][C:9]([CH:12]([C:16]([F:18])=[O:17])[C:13]([F:15])=[O:14])([F:11])[F:10].S(F)(OCC)(=O)=O>CCOCC>[CH2:1]([C:12]([C:9]([F:11])([F:10])[F:8])([C:13]([F:15])=[O:14])[C:16]([F:18])=[O:17])[CH3:2]
Reactant: CCN(CC)CC
Reactant: O=C(F)C(C(=O)F)C(F)(F)F
Agent: CCOS(=O)(=O)F
Solvent: CCOCC
Product: CCC(C(=O)F)(C(=O)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A solution of 9.2 g (0.09 mol) of triethylamine in 25 ml of ether was added dropwise to a stirred solution of 17.6 g (0.10 mol) of trifluoromethylmalonyl fluoride in 50 ml of ether at -80°C. To the resulting suspension of solid was added 14.1 g (0.11 mol) of ethyl fluorosulfate and the mixture was then allowed to warm to 25°C with stirring. The homogeneous reaction mixture developed two layers after standing overnight. Distillation gave 15 g (74%) of ethyltrifluoromethylmalonyl fluoride, bp 54°-56°C (260 mm), identified by ir.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH2:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]1COC[CH2:19]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:18]([CH3:19])=[N:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Product: Cc1nnc(C2CCN(C(=O)OC(C)(C)C)CC2)o1
Temperature: 50 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 9.0 g of 4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (see reference WO 9703986 A1 19970206) (37 mmoles, 1 eq.) in 40 ml of THF, were added 8.1 ml of (55.4 mmoles, 1.5 eq.). The reaction mixture was then stirred at 50° C. for 4 hours under nitrogen. The solvent was removed under reduced pressure, the residue dissolved in 40 ml of toluene, and 400 mg of para toluene sulfonic acid were added. The mixture was then heated at 100° C. under nitrogen for 18 hours, the volatiles were removed under reduced pressure and the residue was partitioned between methylene chloride and an aqueous solution of sodium bicarbonate. The organic phase was dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride/methanol as eluant (98:2 v/v to 95:5 v/v) to afford 8.07 g of the title compound as a white solid (81%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]([CH3:17])=[N:14][C:13]=1[CH3:18].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]([CH3:17])=[N:14][C:13]=1[CH3:18]
Reactant: COC(=O)c1ccc(Cl)c(-c2[nH]c(C)nc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(C)c(-c2cc(C(=O)O)ccc2Cl)[nH]1
Yield: 90 %

Procedure:
Methyl 4-chloro-3-(2,4-dimethyl-1H-imidazol-5-yl)benzoate (compound 50.3, 270 mg, 1.02 mmol) was dissolved in methanol (20 mL) and aqueous NaOH (2 M, 6 mL) then heated to 50° C. for 16 hrs. The volatile solvents were removed under reduced pressure and the resulting aqueous phase was acidified to pH 5-6 with aqueous HCl (2M). The precipitated solids were filtered, and dried to yield 230 mg (94%) of the title compound as a white solid. m/z (ES−) 249 (M−H)−
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:6][S:5][CH:4]=1.Br[C:13]1[C:17]([CH2:18][CH2:19]CC)=CS[CH:14]=1.C[O-].[Na+].OS([O-])(=O)=O.[Na+]>CO.C(O)CCCCC.C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3]1[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:6][S:5][CH:4]=1)[CH2:14][CH2:13][CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1cscc1Br
Reactant: CCCCc1cscc1OC
Agent: C[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCCCCCO
Product: CCCCCCOc1cscc1CCCC

Procedure:
10 g of 3-methoxy-4-butylthiophene, prepared from 3-bromo-4-butylthiophene by reaction with sodium methylate in methanol with catalysis by CuO, b.p. 54° C./0.26 mbar, were dissolved as in Example 14 in 50 cm3 of 1-hexanol and 30 ml of toluene, and 1 g of NaHSO4 was added. After distilling off 6 cm3 of azeotrope, the batch was worked up as in Example 14. Yield 8.5 g of 3-hexyloxy-4-butylthiophene of b.p. 112° to 116° C./0.26 mbar, which corresponds to 60% of theory.
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.O[CH2:20][C:21]([NH:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:26])([CH3:23])[CH3:22]>ClCCCl.C(Cl)Cl>[CH3:20][C:21]1([CH3:23])[CH2:22][O:26][C:25]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=2)=[N:24]1
Reactant: CC(C)(CO)NC(=O)c1ccc2ccccc2n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)COC(c2ccc3ccccc3n2)=N1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
To an oven dried 250 mL round bottomed flask was weighed p-Toluene sulfonyl chloride (1.049 g, 5.5 mmol) and N,N-dimethylaminopyridine (39.1 mg, 0.32 mmol). A magnetic stirbar was added and the flask was placed under N2 atmosphere. The flask was charged with DCE (20 mL) and triethylamine (3.2 mL, 23 mmol). The N-(1-hydroxy-2-methylpropan-2-yl)quinoline-2-carboxamide (1.112 g, 4.55 mmol) was dissolved in DCE (15 mL) and added to the flask dropwise via syringe. The reaction mixture was stirred at 0° C. for 15 min, before a reflux condenser was fitted to the flask and heated to reflux for 16 h. The reaction mixture was cooled to room temperature, transferred to a separatory funnel and diluted with DCM (70 mL). The organic phase was washed with saturated NaHCO3 solution (2×70 mL), H2O (2×70 mL), and Brine (1×70 mL). Dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography eluting with 20%→30% acetone in hexanes to afford 4,4-dimethyl-2-(quinoline-2-yl)-oxazoline in 47% yield (484 mg, 2.14 mmol) according to the reaction
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[CH:14]=[N:15][NH:16][C:17]=2[C:18]3=[O:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:12]2[C:13]2[CH:14]=[N:15][NH:16][C:17]=2[CH:18]3[OH:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1c2[nH]ncc2C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CCCC1C(O)c1[nH]ncc12
Yield: 77.7 %

Procedure:
To a solution of 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-dien-7-one (58 mg, 0.16 mmol) in 2:1 MeOH/THF (3 mL) was added NaBH4 (12 mg, 0.33 mmol) in portions. After sixteen hours the reaction was quenched with half saturated KHSO4 and then diluted with EtOAc and water. The separated organic phase was washed with water (10 mL), brine (10 mL), dried over MgSO4 filtered and concentrated to yield 12-(4-chloro-benzenesulfonyl)-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-dien-7-ol (44 mg, 76%) as a white fluffy solid. MS (ES) m/e 354.0. (M+H)