Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[O:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11]1.Cl>ClCCl>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:18][C:13]=2[CH2:12][CH2:11]1
Reactant: CCC(=O)Cl
Reactant: c1ccc2c(c1)CCO2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc2c(c1)CCO2
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
To a solution of propionyl chloride (0.72 mL, 8.30 mmol) in dichloromethane (10 mL), aluminum chloride (835 mg, 6.25 mmol) was added at 0° C. under an argon atmosphere and stirred for 10 minutes, then a solution of 1,2-dihydrobenzofuran (500 mg, 4.15 mmol) in dichloromethane (11 mL) was added dropwisely at the same temperature. After stirring for 5 minutes, the resultant mixture was added with 1N HCl at 0° C. and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (n-hexane/ethyl acetate), and 1-(2,3-dihydrobenzofuran-5-yl)propan-1-one (716 mg, yield 98%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[CH:26]=CC=[CH:23][N:22]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:39]1C=CC=C[N:40]=1)CCC>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[N:22]=[CH:23][N:40]([CH3:39])[CH:26]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1cc2cc(-c3ccccn3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2cc(-c3cn(C)cn3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(1-methyl-1H-imidazol-4-yl)naphthalen-2-yl)acetic acid (64) was prepared in a similar fashion to compound 63 with the substitution of 1-methyl-4-(tributylstannyl)-1H-imidazole for 2-(tributylstannyl)pyridine in step 1. The title compound (0.026 g) was isolated as an amorphous white powder. LCMS-ESI+ (m/z): [M+H]+ calcd for C27H28ClN2O3: 463.98; found: 463.86. 1H-NMR: 400 MHz, (CD3CN) δ: 6.46 (br s, 1H); 8.24 (br s, 1H); 7.73 (br s, 1H); 7.65 (s, 1H); 7.62-7.51 (m, 4H); 7.36-7.25 (m, 2H); 5.21 (s, 1H): 3.85 (s, 3H); 2.56 (s, 3H); 0.97 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1([C:5]2[C:6]([F:25])=[CH:7][C:8]3[C:18](=[O:19])[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:10]4[C@@H:11]([CH3:15])[CH2:12][O:13][C:14]=2[C:9]=34)[CH2:4][CH2:3]1.[C:26](OC(=O)C)(=[O:28])[CH3:27].O>C(Cl)Cl>[C:26]([NH:1][C:2]1([C:5]2[C:6]([F:25])=[CH:7][C:8]3[C:18](=[O:19])[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:10]4[C@@H:11]([CH3:15])[CH2:12][O:13][C:14]=2[C:9]=34)[CH2:3][CH2:4]1)(=[O:28])[CH3:27]
Reactant: CCOC(=O)c1cn2c3c(c(C4(N)CC4)c(F)cc3c1=O)OC[C@@H]2C
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cn2c3c(c(C4(NC(C)=O)CC4)c(F)cc3c1=O)OC[C@@H]2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
In 33 ml of methylene chloride was suspended 6.43 g of ethyl (S)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine- 6-carboxylate. To the resulting suspension was added 2.27 g of acetic anhydride with ice-cooling. The resulting mixture was stirred at room temperature for 1 hour, and 30 ml of water was added to the reaction mixture. The resulting crystals were collected by filtration to obtain 5.85 g (yield: 81.1%) of ethyl (S)-10-(1-acetylaminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH2:13]([N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1)[CH2:14][CH2:15][CH2:16][CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:13]([N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CCCCCn1cccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCn1cccc1C1=CC(=O)c2ccccc2C1=O
Yield: 26 %

Procedure:
6.32 millimol of 1,4-naphthoquinone and 3.16 millimol of N-pentylpyrrole were stirred in 50 ml of chloroform in a round-bottomed flask for 5 hours at room temperature, the reaction being catalysed by addition of a few milligrams of para-toluenesulphonic acid. The reaction medium was diluted with 50 ml of chloroform and then washed four times with 50 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The product 2-(1-pentyl-1H-pyrrol-2-yl)-[1,4]-naphthoquinone was thus isolated, in the form of an oil, in a yield of 26% after purification by chromatography on a column of silica.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+]>[Cl-].[Mg+2].[Cl-]>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: [NH4+]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: [Cl-]
Agent: [Mg+2]
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 48 h

Procedure:
The immobilized Serratia marcescens prepared in the above (1) (60 g) was packed in a jacketed column (4 cm×8 cm) and incubated at 37° C. for 48 hours to activate the immobilized cells (aspartase activity: 1,582,000 μmole/hr). After activation, 1M ammonium fumarate solution containing 1mM magnesium chloride (pH 8.5, 1,000 ml) was passed through the column at 37° C. at the flow rate of 150 ml/hr. The effluent was adjusted to pH 2.8 to give L-aspartic acid (127 g).
Reaction SMILES: C[C:2]1([C:11]2[CH:16]=[CH:15][C:14](C(F)(F)F)=[CH:13][CH:12]=2)OC2C=CC=CC=2[O:3]1.[N+]([O-])(O)=[O:22].O>ClC(Cl)C>[O:22]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:2][O:3]1
Reactant: CC1(c2ccc(C(F)(F)F)cc2)Oc2ccccc2O1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(Cl)Cl
Product: c1ccc2c(c1)COO2
Temperature: 20 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of 2-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-benzodioxole (5.6 g) in dichloroethane (15 ml) was added over 10 minutes to vigorously stirred nitric acid (50% w/v, 25 ml) keeping the temperature at 15°-20° C. by means of a cooling bath. The resulting reaction mixture was stirred for a further 1 hour at 20° C., poured into water (200 ml) and extracted with methylene chloride (3×100 ml). After drying over anhydrous sodium sulphate, the extract was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methylene chloride as eluant, affording the pure product benzodioxole as a pale yellow oil (5.3 g, 82%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:19].O>C(OCC)C>[Br:19][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCCCCCCCCCCc1ccccc1
Solvent: O
Solvent: CCOCC
Product: BrCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In diethylether (200 mL), 10-phenyl-1-decanol (10 g) was dissolved, phosphorus tribromide (4.0 mL) was carefully added thereto, at 0° C., followed by stirring at room temperature for 6 hours. Water was added carefully to the reaction solution, followed by extraction with tert-buthylmethylether. The organic layer was washed with water, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (7.0 g) having the following physical property values.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].C(N(CC)CC)C.Cl[C:15]([CH3:22])([CH:17]([N:20]=[O:21])[CH2:18][CH3:19])[CH3:16]>C(#N)C>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:15]([CH3:22])([C:17](=[N:20][OH:21])[CH2:18][CH3:19])[CH3:16]
Reactant: NCCCCN
Reactant: CCC(N=O)C(C)(C)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(=NO)C(C)(C)NCCCCN

Procedure:
To a stirred solution of 1,4-diaminobutane (0.26 g; 2.9 mmol) and triethylamine (0.33 g; 3.2 mmol) in acetonitrile (5 ml) was added a solution of 2-chloro-2-methyl-3-nitrosopentane (0.485 g; 3.24 mmol) in acetonitrile (5 ml). After stirring for ca 10 minutes the product began to precipitate. The reaction mixture was stirred overnight and the product was filtered off and dried in vacuo to give a white powder, (0.5 g; 86%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][CH:26]([C:22]2[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH:16]([CH3:15])[CH3:32])[CH:25]=[CH:24][CH:23]=2)[CH2:27][CH2:28]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COc1cccc(OCCCCCl)c1
Product: COc1cccc(OCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-(4-chlorobutoxy)-3-methoxybenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:20][OH:21])[C:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:20]=[O:21])[C:9]([N:12]3[CH2:17][C@H:16]([CH3:18])[O:15][C@H:14]([CH3:19])[CH2:13]3)=[C:10]([F:11])[C:5]=2[O:4][N:3]=1
Reactant: C[C@@H]1CN(c2c(CO)cc3c(N)noc3c2F)C[C@H](C)O1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@H]1CN(c2c(C=O)cc3c(N)noc3c2F)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of {3-amino-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-7-fluoro-1,2-benzisoxazol-5-yl}methanol (Intermediate 7, 200 mg, 0.67 mmol) in CH2Cl2/CH3CN mixture (4 mL, 1:1 v/v) was added NMO (119 mg, 1.0 mmol) followed TPAP (23 mg, 0.06 mmol) and mixture stirred for 2 h at room temperature. The reaction mixture filtered thorough a silica gel bed and washed with EtOAc. The organic phase concentrated under reduced pressure to give the title compound as a yellow solid. Yield: 100 mg, (50%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([CH:30]=O)[C:24]=2[O:23][CH2:22][CH2:21]1>>[O:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([CH2:30][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)[C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: O=Cc1cccc2c1OCCO2
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc5c4OCCO5)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2,3-dihydro-1,4-benzodioxine-5-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(2,3-dihydro-1,4-benzodioxin-5-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]3[CH2:25][CH2:24][N:23]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[C:22]3=[O:32])=[C:16]([Cl:33])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:33][C:16]1[CH:15]=[C:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=2)[CH:19]=[CH:18][C:17]=1[CH2:20][CH:21]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[C:22]1=[O:32]
Reactant: CC(C)(C)OC(=O)c1cccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)c1
Yield: 94.4 %

Procedure:
Dissolve 3′-chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-3-carboxylic acid tert-butyl ester (Preparation 82) (506 mg, 1.08 mmol) in methylene chloride (5 mL). Add trifluoroacetic acid (5 mL) and stir at room temperature for 1 hour. Concentrate and redissolve in methylene chloride. Pour into 1N NaOH. Extract with ether. Acidify aqueous phase to pH 1. Extract with ether. Dry over sodium sulfate, filter and concentrate to yield 420 mg (94%) of the title compound as a white solid. Mass spectrum (apci) m/z=410.3
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)=[CH:6][C:3]=1[CH2:4][OH:5].C1N=CN([C:22](N2C=NC=C2)=[S:23])C=1>CC(C)=O>[CH3:10][C:9]1[C:2]2[NH:1][C:22](=[S:23])[O:5][CH2:4][C:3]=2[CH:6]=[C:7]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]2)[CH:8]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Cc1cn(-c2cc(C)c(N)c(CO)c2)cn1
Solvent: CC(C)=O
Product: Cc1cn(-c2cc(C)c3c(c2)COC(=S)N3)cn1
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixed solution of 2-amino-3-methyl-5-(4-methylimidazol-1-yl)benzylalcohol (135 mg), N,N'-thiocarbonyldiimidazole (116 mg) and acetone (3.1 ml) was heated under stirring under nitrogen atmosphere for 2 hours. The mixture was distilled under reduced pressure to give a residue. The residue was column chromatographed(chloroform: methanol=30:1) to give 95 mg (59.0%) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].N1C=CC=CC=1.[C:11]([C:14]1[CH:39]=[CH:38][C:17]([CH2:18][NH:19][C:20]2[C:30]3[CH2:29][CH2:28][N:27]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH2:26][CH2:25][C:24]=3[CH:23]=[CH:22][C:21]=2[Cl:37])=[CH:16][CH:15]=1)(=O)[CH3:12]>C(O)C>[Cl:37][C:21]1[CH:22]=[CH:23][C:24]2[CH2:25][CH2:26][N:27]([C:31](=[O:36])[C:32]([F:35])([F:33])[F:34])[CH2:28][CH2:29][C:30]=2[C:20]=1[NH:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14]([C:11](=[N:4][O:3][CH3:2])[CH3:12])=[CH:39][CH:38]=1
Reactant: CC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(C)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 82.6 %

Procedure:
Add O-methylhydroxylamine hydrochloride (10 mg, 0.12 mmol) and pyridine (0.02 mL, 0.24 mmol) to a solution of 6-(4-acetyl-benzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (50 mg, 0.12 mmol) in ethanol (10 mL). Heat the mixture to reflux for 1.5 h. Remove the solvent in vacuo and partition the residue between DCM and 0.1N aqueous HCl. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5 to 1:1 gradient over 30 min). Concentrate in vacuo to obtain 7-chloro-6-[4-(1-methoxyimino-ethyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (45 mg, 83%). MS (ES+) m/z: 454 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Br:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][C:28](=[O:34])[NH:29]2>>[Br:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1/[C:27](=[CH:14]/[C:11]1[NH:10][C:7]3[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[C:5](=[O:16])[C:6]=3[C:12]=1[CH3:13])/[C:28](=[O:34])[NH:29]2
Reactant: O=C1Cc2c(Br)cccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Product: Cc1c(/C=C2\C(=O)Nc3cccc(Br)c32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Yield: 74.5 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 4-bromo-1,3-dihydro-indol-2-one as starting materials to give (S,Z)-2-(4-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 22 (43 mg, yield 74.5%) as a yellow solid.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([N:13]([CH2:29][CH2:30]O)[C:14]([NH:16][C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])=[O:18])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH2:6]([N:13]1[CH2:29][CH2:30][N:16]([C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][C:24]=2[C:25]([F:27])([F:28])[F:26])=[O:18])[C:14]1=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(NC(=O)N(CCO)Cc1ccccc1)c1cnccc1C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cnccc1C(F)(F)F)N1CCN(Cc2ccccc2)C1=O
Temperature: 20 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
Methanesulfonyl chloride (0.17 ml) was added to an ice-cooled mixture of 1-benzyl-1-(2-hydroxyethyl)-3-(4-trifluoromethyl-3-pyridylcarbonyl)urea (0.70 g), and triethylamine (0.64 ml) in dichloromethane, then stirred for 3 hours at 20° C. The mixture was washed (water), dried (magnesium sulfate), evaporated and the residue purified by silica-gel chromatography, eluting with n-hexane/ethyl acetate (3:2), to give 1-benzyl-3-(4-trifluoromethyl-3-pyridylcarbonyl)-2-imidazolidinone (0.63 g, Compound S-15).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[N:19]/[OH:20])/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH3:17])[C:10]=1[OH:18].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:20]/[N:19]=[C:8](/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])\[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH3:17])[C:10]=1[OH:18])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(/C(=N\O)c2ccccc2F)c(O)c1C
Product: COc1ccc(/C(=N\OC(C)=O)c2ccccc2F)c(O)c1C

Procedure:
E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone oxime (20.0 g) is warmed on a steam bath for one hour with 12 ml of acetic anhydride. The acetic anhydride is evaporated in vacuo and the product is distributed between ether and H2O, then the ether is washed with 10% NaHCO3. Evaporation and trituration of the crystalline product with hexane gives E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone O-acetyl oxime, mp 83°-86° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.C1C=CC(N[S:45]([C:48]([F:51])([F:50])[F:49])(=[O:47])=[O:46])=CC=1>O>[F:49][C:48]([F:51])([F:50])[S:45]([O:26][C:9]1[CH:8]=[C:7]2[C@@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH:18]=3)[O:13][C:12]2=[CH:11][CH:10]=1)(=[O:47])=[O:46]
Reactant: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1O2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
A vial charged with (S)-2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (0.200 g, 0.572 mmol) and potassium carbonate (0.087 g, 0.630 mmol) was treated with 2 mL DMF and was allowed to stir for 15 minutes. The reaction mixture was cooled to 0° C. and n-phenyltriflamide (0.245 g, 0.630 mmol) was added. After stirring for one hour the reaction mixture was poured into water and extracted with EtOAc. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography gave (S)-2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (0.183 g, 0.380 mmol, 66.4% yield)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][CH2:10][CH2:11][N:12]1[CH2:18][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:15][C@@H:14]([NH:25]C(=O)OC(C)(C)C)[C:13]1=[O:33]>ClCCl>[NH2:25][C@@H:14]1[CH2:15][CH2:16][C@@H:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:18][N:12]([CH2:11][CH2:10][O:9][CH3:8])[C:13]1=[O:33]
Reactant: COCCN1C[C@H](c2ccccc2)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN1C[C@H](c2ccccc2)CC[C@@H](N)C1=O
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl (3R,6S)-1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-ylcarbamate (41 mg, 0.113 mmol) in dichloromethane (5 mL). After 1 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 263 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.32 (t, J=7.3 Hz, 2H), 7.25-7.22 (m, 1H), 7.18 (d, J=8.3 Hz, 2H), 3.83-3.76 (m, 3H), 3.56-3.49 (m, 3H), 3.35 (s, 3H), 3.34-3.30 (m, 1H), 2.77-2.72 (m, 1H), 2.13-2.10 (m, 1H), 2.03-1.94 (m, 2H), 1.74-1.68 (m, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[F:10][C:11]([F:40])([C:30]([F:39])([F:38])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[N:21][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[F:40][C:11]([F:10])([C:30]([F:38])([F:39])[C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])[CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[N:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2])=[CH:27][CH:28]=2)=[N:19][CH:18]=1
Reactant: Oc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Reactant: C=CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C=CCCCCCCOc1ccc(-c2ncc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cn2)cc1
Temperature: 25 °C

Procedure:
A suspension of 8-bromo-1-octene (1.00 g, 5.24 mmol), 4-[5-(5,5,6,6,7,7,8,8,8-nonafluorooctyloxy)-pyrimidin-2-yl]-phenol (2.54 g, 5.50 mmol) and cesium carbonate (3.40 g, 10.47 mmol) in acetone (40 ml) was heated under reflux for 12 h, cooled to room temperature, washed with water and the organic layer extracted into ethyl acetate/hexane (3 times). The combined organic extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residues were purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (9:1)] to yield a colorless solid, which was recrystallized from ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[N:17]=[C:16]([CH3:25])[C:15]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][N:8]2[C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[N:17]=[C:16]([CH3:25])[C:15]=2[CH3:26])=[CH:4][CH:3]=1
Reactant: N#Cc1c[nH]c2cc(Br)ccc12
Reactant: Cc1nc2ccc(Cl)cc2c(Cl)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(Cl)cc2c(-n2cc(C#N)c3ccc(Br)cc32)c1C

Procedure:
A solution of 6-bromo-1H-indole-3-carbonitrile (0.5 g, 2.26 mmol), 4,6-dichloro-2,3-dimethylquinoline (0.56 g, 2.49 mmol) and cesium carbonate (2.21 h, 6.79 mmol) in DMF (11.2 mL) was heated at 140° C. overnight. After this time the solvent was evaporated in vacuo and the residue was purified by flash column chromatography to give 6-bromo-1-(6-chloro-2,3-dimethylquinolin-4-yl)-1H-indole-3-carbonitrile as white solid. Mass Spectrum (ESI) m/e=411 (M+1).