Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@:9]([OH:19])([C@H:16](O)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.CCN(CC)CC.CS(Cl)(=O)=O.C[O-].[Na+]>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@:9]1([CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[C@H:16]([CH3:17])[O:19]1
Reactant: C[C@@H](O)[C@](O)(Cn1cncn1)c1cc(F)ccc1F
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H]1O[C@@]1(Cn1cncn1)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a solution of (2R,3R)-2-(2,5-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (53.0 g, 197 mmol) and Et3N (54.8 mL, 394 mmol) in CH2Cl2-EtOAc (1:3, 400 mL) cooled in an ice-bath was added MsCl (17.5 mL, 227 mmol) dropwise over a period of 15 min. After stirring for 30 min at 0° C., the mixture was warmed to room temperature and quenched with water (200 mL). EtOAc (200 mL) was added and the organic layer was washed with water and brine, dried over MgSO4 and evaporated under reduced pressure. The obtaining residue was dissolved in MeOH (500 mL) and cooled in an ice-bath. A solution of NaOMe (41.8 g, 28% in MeOH, 217 mmol) was added dropwise and after the completion of the addition, the mixture was stirred for 15 min at 0° C. MeOH was evaporated under reduced pressure and the resulting residue was dissolved in EtOAc (500 mL). The EtOAc solution was washed with water and brine, dried over MgSO4 and evaporated under reduced pressure. The obtaining solid was recrystalized from t-BuOMe-hexane to give pure (2R,3S)-2-(2,5-Difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)-methyl]-oxirane (43.5 g, 88%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.C([Li])CCC.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1.C(Cl)(Cl)Cl>[C:18]1([S:24]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
4.8 mg of indole-3-carboxylic acid was dissolved in 1 mL of tetrahydrofuran, 0.042 mL of n-butyllithium (1.58 M hexane solution) was added to the solution at 0° C., the resulting mixture was stirred for 30 minutes. Then 5.3 mg of benzenesulfonyl chloride was added to the mixture, and the resulting mixture was stirred at 0° C. overnight. Water and chloroform were added to the mixture, the organic layer was separated and concentrated under reduced pressure, and the residue was purified by HPLC to obtain 1.0 mg of 1-(phenylsulfonyl)-1H-indole-3-carboxylic acid.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:11][C:10]2[C:5](=[C:6]([Cl:13])[CH:7]=[CH:8][C:9]=2[Cl:12])[CH2:4]1.C([N:17]1[CH2:21][CH2:20][NH:19][C:18]1=O)(=O)C>P(Cl)(Cl)(Cl)=O>[Cl:13][C:6]1[CH:7]=[CH:8][C:9]([Cl:12])=[C:10]2[C:5]=1[CH2:4][N:3]([NH:2][C:18]1[NH:19][CH2:20][CH2:21][N:17]=1)[CH2:11]2
Reactant: NN1Cc2c(Cl)ccc(Cl)c2C1
Reactant: CC(=O)N1CCNC1=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(Cl)c2c1CN(NC1=NCCN1)C2
Yield: 50.9 %

Procedure:
5.9 g (0.025M) of 2-amino-4,7-dichloroisoindoline hydrochloride and 3,6 g (0.028M) of 1-acetylimidazolidin-2-one are heated to 100° C. over 2 hours in 50 ml of phosphorus oxychloride. The Cl3OP is evaporated off and the residue dissolved in 100 ml of ethanol and heated to the boiling point for 1 hour to eliminate the acetyl group. The solvent is drawn off in the vacuum, the residue picked up in water, alkalized with dilute sodium hydroxide solution, and extracted with chloroform. The chloroform is evaporated, and ethyl ether added, yielding 3.4 g of 4,7-Dichloro-2-(2-imidazolin-2-ylamino)-isoindoline as a base, which is converted with ethanolic hydrochloric acid into the hydrochloride.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])=O)C.[CH2:17]([O:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23]CBr)C.[Na].C(=O)(O)[O-].[Na+]>C(O)C.CO.OS(O)(=O)=O.O>[CH3:17][O:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH2:4][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16]
Reactant: CCOC(=O)C1CCc2ccccc2C1=O
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: COC(=O)CCCCC1CCc2ccccc2C1=O
Yield: 31.9 %

Procedure:
To a solution of 5.0 g (22.9 mmol) 1-oxo-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl ester (1a) (Pradeep, K., and Saravanan, K., Tetrahedron 54 (1998) 2161-2168) and 5.79 g ethyl-5-bromo-pentanoate (27.7 mmol) in 10 mL ethanol at reflux is added a freshly prepared solution of 0.53 g sodium in 15 mL ethanol. After 10 h at reflux enough water is added for the precipitate to dissolve. The solvent is evaporated, the residue is dissolved in a solution of 3.85 g KOH in 7 mL MeOH and 5 mL H2O and refluxed for another 10 h. After cooling the solution is poured into 25 mL ice-cold 4N HCl and extracted with CH2Cl2. Evaporation of the solvent leaves a residue of crude 5-(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pentanoic acid (1b) which is dissolved in 100 mL MeOH. A few drops of H2SO4 are added and the solution is refluxed over night. After addition of some sodiumbicarbonate-solution the solvent is evaporated and the residue is subjected to column-chromatography yielding 1.9 g methyl-(5-(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pentanoate) (1c). To a solution of 1.6 g (23 mmol) hydroxylamine hydrochloride in 40 mL MeOH is added 15 mL of a solution of 0.8 g (35 mmol) of sodium in 30 mL of MeOH. To this, a solution of 3.0 g (11.5 mmol) methyl-(5-(1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pentanoate) (1c) in 20 mL MeOH is added, followed by the remaining 15 mL of the sodium methylate solution. After stirring for 6 h at rt the solvent is evaporated, acidified with 2N HCl and extracted with CH2Cl2. After evaporation the residue is purified by column-chromatography yielding 2.2 g of the title compound as an oil, MS (APCI): 260.1 (M−1).
Reaction SMILES: [CH3:1][CH:2]([O:9][C:10]1([OH:21])[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:22](Br)[C:23]#[CH:24]>>[CH2:24]([O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([O:9][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])([OH:21])[CH:11]([O:19][CH3:20])[CH:12]=1)[C:23]#[CH:22]
Reactant: C#CCBr
Reactant: COC1C=C(C(=O)O)C=CC1(O)OC(C)CCCC(C)C
Product: C#CCOC(=O)C1=CC(OC)C(O)(OC(C)CCCC(C)C)C=C1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(1,5-dimethylhexyl)oxy]vanillic acid with propargyl bromide, there is obtained p-[(1,5-dimethylhexyl)oxy]vanillic acid propargyl ester; nD24 = 1.5151.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][NH2:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2cccc(Br)c2)CCOCC1
Product: O=C(NCC1(c2cccc(Br)c2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 34 %

Procedure:
This compound was synthesized from (4-(3-bromophenyl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (40 mgs, 34% yield). 1H NMR (300 MHz, CDCl3) δ 8.30-8.22 (m, 2H) 7.86 (d, J=3.7 Hz, 1H), 7.60 (t, J=3.7 Hz, 1H), 7.52-7.44 (m, 2H), 7.38-7.30 (m, 2H), 3.90 (m, 2H), 3.71 (d, J=3.3 Hz, 2H), 3.64 (m, 2H), 2.13 (m, 2H), 2.02 (m, 2H). MS (ESI) m/z: Calculated for C22H19BrF3N3O3: 509.06. found: 509.9 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:12][CH:13]([Cl:17])[C:14](Cl)=[O:15]>C1C=CC=CC=1>[CH:1]1([NH:4][C:14](=[O:15])[CH:13]([Cl:17])[Cl:12])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(NC1CC1)C(Cl)Cl
Yield: 81.3 %

Procedure:
To a solution of cyclopropylamine (28.6 g, 0.5 mol) and 50 ml of triethylamine in 200 ml of anhydrous benzene was added dropwise with stirring and ice-bath cooling dichloroacetyl chloride (73.7 g, 0.5 mol). The solution was stirred 2 hr at room temperature. The benzene solution was washed successively with 10% HCl, H2O and saturated NaCl solution and dried over anhydrous MgSO4. The solvent was distilled affording 68.3 g (82%) of white crystalline product, m.p. 125-71/4. Recrystallization from ethanol-benzene yielded purified product; m.p. 130°-2°.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]([F:19])([F:18])[O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].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>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:14]2[CH:13]=[CH:12][C:11]([O:10][C:9]([F:8])([F:18])[F:19])=[CH:16][CH:15]=2)[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)CCN1
Yield: 41.9 %

Procedure:
To a mixture of (R)-2-methylpiperazine (3.0 g, 30 mmol), 4-trifluoromethoxy bromo benzene (6.6 g, 27.5 mmol) and sodium tert-butoxide (3.56 g, 37.5 mmol) in dry toluene (50 mL) under nitrogen atmosphere, were added Pd(OAc)2 (0.28 g, 12.5 mmol) followed by BINAP (0.62 g, 1 mmol) and refluxed for 16 h. Then the reaction mixture was concentrated and the crude compound was purified by column chromatography on silica gel using chloroform and methanol as eluent to give the title compound as a dark brown liquid (3 g, 38%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]1[CH2:36][C@H:35]1[C:37]1[CH:38]=[CH:39][C:40]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[C:41]([NH:43][CH:44]=[O:45])[CH:42]=1>C1COCC1>[CH2:1]([N:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=[O:27])=[O:28])[CH:21]=1)[CH2:36][C@@H:35]([C:37]1[CH:38]=[CH:39][C:40]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[C:41]([NH:43][CH:44]=[O:45])[CH:42]=1)[OH:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCNCc2ccccc2)c1)C1CCCC1
Reactant: O=CNc1cc([C@@H]2CO2)ccc1OCc1ccccc1
Solvent: C1CCOC1
Product: O=CNc1cc([C@@H](O)CN(CCCCCCOCCCCc2cccc(S(=O)(=O)C3CCCC3)c2)Cc2ccccc2)ccc1OCc1ccccc1
Yield: 27.1 %

Procedure:
N-Benzyl-6-{4-[3-(cyclopentylsulfonyl)phenyl]butoxy}hexan-1-amine (40 mg) was dissolved in dry THF (0.25 ml) and {5-[(2R)-2-oxiranyl]-2-[(phenylmethyl)oxy]phenyl}formamide (23 mg) (Organic Process Research & Development 1998, 2, 96-99), added. The reaction mixture was heated in a microwave oven for 3 h at 150°. The solvent was removed and the residue purified on a silica SPE bond elut cartridge, eluting with EtOAc-cyclohexane mixtures to give the title compound, (17 mg) LCMS RT=3.1 min
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1.C(#N)C.[Mn]([O-])(=O)(=O)=[O:26].[K+].S(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:26])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1
Reactant: CC(C)c1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 30 °C

Procedure:
A vial was charged with 6-chloro-5-[4-(propan-2-yl)phenyl]-1H-indole-3-carbaldehyde, 1 mL acetonitrile, and 500 uL of a 1.0M solution of potassium permanganate in water. The vial was sealed and heated to 30° C. for 16 hrs. Sodium bisulfite (72 mg, 1.0 mmol) was then added and the reaction heated to 30° C. for 1 hr. The reaction was then filtered, and the solvent removed in vacuo. The residue was then purified by reverse phase prep HPLC to give the title compound. MS (AP−) 312 (M−H)−. RT=2.378 Column Xbridge C18 2.1×50 mm 5 μm, Temperature 50° C. Mobile Phase A=0.05% NH4OH in water. Mobile Phase B=100% acetonitrile. Gradient: Initial 5% B Time 0.00 mins, 5% B Time 0.50 mins, 5% B Time 3.40 mins, 100% B Time 4.20 mins, 100% B Time 4.21 mins, 5% B Time 4.70 mins, 5% B Flow rate, 0.8 mL/min Injection volume 2 μL. Agilent 1200 HPLC/1956 MSD/SEDEX 75 ELSD Ionization Mode API-ES Polarity Negative.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:37][CH3:38])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:37][CH3:38])[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(COc2nn(Cc3ccccc3)cc2CO)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.3 %

Procedure:
A mixture of [1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazol-4-yl]methanol (0.30 g), activated manganese dioxide (1.00 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 20 hrs. Manganese dioxide was removed by filtration, and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carbaldehyde (0.24 g, yield 80%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 151-152° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=4[Cl:29])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1.[C:31]([Cu])#[N:32]>>[Cl:29][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:31]#[N:32])=[CH:30][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Reactant: N#C[Cu]
Product: COC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(C#N)cc2OCC3)c(Cl)c1

Procedure:
Following Example 53, methyl 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate and CuCN gave methyl 3-chloro-4-(8-cyano-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=2)[C:23]([OH:25])=O)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:28]=[CH:27][CH:26]=[C:22]([C:23]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:25])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[O:11])=[C:4]([F:29])[CH:3]=1
Reactant: C1COCCN1
Reactant: Cn1cc(C(=O)CC(c2cccc(C(=O)O)c2)c2ccc(Cl)cc2F)ccc1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1cc(C(=O)CC(c2cccc(C(=O)N3CCOCC3)c2)c2ccc(Cl)cc2F)ccc1=O

Procedure:
In analogy to example 207, step 2, 3-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)benzoic acid (example 320, step 4) was coupled with morpholine using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a colourless foam, MS (ESI+): m/z=483.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]([CH2:16][OH:17])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]([CH2:16][O:17][S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C=Cc1ccccc1C2CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C=Cc1ccccc1C2COS(=O)(=O)c1ccc(C)cc1
Yield: 79.8 %

Procedure:
To a solution of 2-methoxy-5-hydroxymethyldibenzo[a,d]cycloheptene (10.5 g) in dry dichloromethane (150 ml) was added p-toluenesulphonyl chloride (8.1 g), pyridine (6.6 g) and 4-dimethylamino pyridine (300 mg). The reaction mixture was refluxed for 15h, cooled, washed with water (2×200 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica chromatography using 15% ethyl acetate in hexane as eluent to give the title compound as an oil (13.5 g). δ(360 MHz, CDCl3), 2.44 (3H, s, Ar--CH3), 3.78 (3H, s, OCH3), 4.19-4.31 (3H, m CH-CH2 --OSO2Ar). 6.58 (1H, d, J=11.9 Hz, Ar--CH=CH--Ar), 6.65 (1H, d, J=11.9 Hz, Ar--CH=CH--Ar), 6.68 (1H, d, J=2.7, CH=C(OCH3)--CH), 6.85 (1H, dd, J=8.4 and 2.7 Hz, CH=C(OCH3)--CH) and 7.16-7.42 (9H, m, aromatics). m/e 406 (M+).
Reaction SMILES: P([O:5][C:6]([C@@:9]1([O:32][C:33]2[CH:38]=[C:37]([F:39])[C:36]([F:40])=[C:35]([F:41])[CH:34]=2)[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[C:20]([O:30][CH3:31])[N:19]=3)=[N:16][N:17]=[C:10]12)([CH3:8])[CH3:7])(O)(O)=O>C(O)C>[CH3:31][O:30][C:20]1[N:19]=[C:18]([C:15]2[N:11]3[CH2:12][CH2:13][CH2:14][C@@:9]([C:6]([OH:5])([CH3:8])[CH3:7])([O:32][C:33]4[CH:38]=[C:37]([F:39])[C:36]([F:40])=[C:35]([F:41])[CH:34]=4)[C:10]3=[N:17][N:16]=2)[CH:23]=[CH:22][C:21]=1[N:24]1[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]1
Reactant: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)OP(=O)(O)O)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1nc(-c2nnc3n2CCC[C@]3(Oc2cc(F)c(F)c(F)c2)C(C)(C)O)ccc1-n1cnc(C)c1
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To 2-{(8R)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-8-(3,4,5-trifluorophenoxy)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}propan-2-ol monophosphate (213.4 g) was added ethanol (350 mL), the mixture was dissolved at 60° C., and the insoluble material was removed by filtration. 2-Propanol (700 mL) was added to the filtrate at 60° C., and the mixture was stirred for 30 min, and at 0° C. for 30 min. The crystals were collected by filtration, washed with 2-propanol (250 mL) and dried at 60° C. under reduced pressure to give the title compound (184 g).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([Cl:20])=[CH:15][CH:16]=2)[N:11]=1>O>[Cl:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:4]3[N:3]=[CH:2][S:1][CH:5]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1cscn1
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cscn1
Yield: 77.2 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 4-thiazolecarboxylic acid (4.8 g), N,N'-carbonyldiimidazole (7.5 g) and 2-amino-7-chloro-1,8-naphthyridine (4.8 g). The product obtained by precipitation in water is purified by recrystallization in dimethylformamide (350 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-4-thiazolecarboxamide (6 g), m.p. 325° C., is thereby obtained.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[C:20]([C:24]#[N:25])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.Cl.[CH2:28]([NH2:32])[CH:29]([CH3:31])[CH3:30]>CO>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[C:20]([C:24](=[NH:25])[NH:32][CH2:28][CH:29]([CH3:31])[CH3:30])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:3])=[O:26])[O:10]1
Reactant: CC(C)CN
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cncc(C#N)n3)cc(C)c21
Agent: Cl
Solvent: CO
Product: Cc1cc(Oc2cncc(C(=N)NCC(C)C)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.8 %

Procedure:
A solution of [6-(6-cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (200 mg, 0.57 mmol) in methanol (4.7 mL) was bubbled through gaseous HCl for 40 minutes at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The solvent was removed under reduced pressure. To the residue was added methanol (2.5 mL) and ammonia solution (28%, 0.27 mL). The reaction mixture was refluxed for overnight. LC-MS showed all material converted to methyl imidate while the ethyl ester group was also hydrolyzed to free acid. The solvent was removed under reduced pressure. Half of the residue (0.28 mmol) was dissolved in methanol (2 mL) and isobutylamine (0.29 mL, 2.9 mmol) was added. The reaction mixture was refluxed overnight. The pH was adjusted to pH 3 with aqueous HCl (6 N). Prep-HPLC separation (C18 column) gave the title compound (11 mg, 10%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.90 (1H, s), 8.58 (1H, s), 7.25 (1H, s), 7.14 (1H, s), 5.65 (1H, dd), 3.15 (1H, m), 3.02 (2H, m), 2.60 (3H, s), 2.30 (1H, m), 1.78 (1H, m), 0.95 (3H, d), 0.94 (3H, d). MS found (electrospray): (M+H)+=399.2.
Reaction SMILES: [F:1][C:2]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]CC)=O)[N:6]=1.Cl.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33][NH2:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33][NH:34][C:10]([C:7]1[N:6]=[C:5]([CH2:4][C:3]2[CH:15]=[CH:16][C:17]([F:20])=[C:18]([F:19])[C:2]=2[F:1])[O:9][N:8]=1)=[O:12]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(Cc2ccc(F)c(F)c2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccc(F)c(F)c2F)n1

Procedure:
This compound was prepared according to method F from ethyl 5-(2,3,4-trifluorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.089 g; 0.311 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.080 g; 0.346 mmol), HATU (0.131 g; 0.346 mmol), N,N diisopropylethylamine (0.149 mL; 0.865 mmol), in DMF (3 mL). The crude mixture was purified by flash column chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and by preparative HPLC method 2 to yield 0.013 (9%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,3,4-trifluorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.