Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:37][C:34]2[CH:33]=[CH:32][C:31]([O:30][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:36][CH:35]=2)=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 8 h

Procedure:
In the same manner as described in Referential Example 13, 3.0 g of p-dodecyloxybenzoic acid chloride and 2.0 g of p-benzyloxyphenol were dissolved in 50 ml of tetrahydrofuran, 1.5 g of triethylamine was added to the solution, and reaction was carried out at room temperature overnight. The obtained 4-benzyloxyphenyl 4-dodecyloxybenzoate was isolated, and reduction was carried out under a hydrogen pressure of 25 kg/cm2 by using Pd/C as the catalyst to obtain 2.3 g of 4-hydroxyphenyl 4-dodecyloxybenzoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:21][CH:20]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:30][N:31]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.NO>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]#[C:28][CH3:29])=[CH:21][CH:20]=2)([C:14]([NH:31][OH:30])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCOc1ccc(SCC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(SCC2(C(=O)NO)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of 0.204 g (0.49 mmol) of 4-(4-But-2-ynyloxy-phenylsulfanylmethyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester, 0.079 g (0.58 mmol) of 1-hydroxybenzotriazole in 2.5 mL of DMF was added 0.112 g (0.84 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and stirred at room temperature for 1 h. Then added 0.3 mL of 50% aqueous hydroxylamine and stirred for 18 h. The resulting mixture was diluted with EtOAc, washed with H2O, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1.5% MeOH/CH2Cl2 to provide 0.077 g (36%) of the desired product as a white solid. Electrospray Mass Spec: 435.2 (M+H)+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[C:11]([CH3:15])[N:10]=[C:9]([S:16][CH3:17])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1CCCCC1.CC(O)=O.[CH2:28]([O:30][C:31](=[O:38])[CH2:32][C:33](OCC)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31]([C:32]1[C:33](=[O:34])[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]2[N:8]=[C:9]([S:16][CH3:17])[N:10]=[C:11]([CH3:15])[C:12]=2[CH:13]=1)=[O:38])[CH3:29]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CSc1nc(C)c(C=O)c(NC2CCCC2)n1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2c(C)nc(SC)nc2n(C2CCCC2)c1=O
Yield: 39.4 %

Procedure:
A solution of 4-cyclopentylamino-6-methyl-2-methylsulfanyl-pyrimidine-5-carbaldehyde (20.8 g, 0.083 mol), piperidine (8.2 mL) and AcOH (9.4 mL) in malonic acid diethyl ester (150 mL) was stirred at 130° C. for 72 hours. TLC (petroleum ether/EtOAc 4:1) indicated about half of the starting material was consumed. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography (silica gel, petroleum ether/EtOAc 4:1) to yield the title compound (11.3 g, 39.4%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=O)[NH:8]2)=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[F:19][C:20]([F:34])([F:33])[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)[NH2:22].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:13])[NH:22][CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=3)[C:20]([F:34])([F:33])[F:19])[NH:8]2)=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: CCOC(=O)c1cc2cc(C(=O)O)[nH]c2cc1Cl
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of the crude 6-chloro-5-(ethoxycarbonyl)-1H-indole-2-carboxylic acid product (1.9 g) and 2,2,2-trifluoro-1-[3-trifluoromethylphenyl]ethanamine (1.12 g, 4.60 mmol) in N,N-dimethylformamide (15 ml) was admixed with 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (953 ng, 4.60 mmol) and stirred at room temperature for 4 days. The reaction solution was admixed with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with sat, sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. Column chromatography purification on silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 10% ethyl acetate to 25% ethyl acetate).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[C:12]([O:27][CH2:28][C:29]2[N:30]([CH2:34][CH3:35])[N:31]=[CH:32][N:33]=2)=[N:13][N:14]2[C:19]=1[CH:18]=[N:17][N:16]=[C:15]2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26]>>[CH2:34]([N:30]1[C:29]([CH2:28][O:27][C:12]2[C:11]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:19]3[N:14]([C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])=[N:16][N:17]=[CH:18]3)[N:13]=2)=[N:33][CH:32]=[N:31]1)[CH3:35]
Reactant: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1Br
Reactant: OB(O)c1ccncc1
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1-c1ccncc1
Yield: 21 %

Procedure:
This was prepared in 21% yield using a similar procedure to that described in Example 18 except using pyridine-4-boronic acid instead of 3-trifluoromethylbenzeneboronic acid and 3-bromo-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-7-(2-fluorophenyl)pyrazolo[1,5-d][1,2,4]triazine instead of 3-bromo-7-(2-fluorophenyl)-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine. Data for title compound: mp=214-217° C.; 1H NMR (360 MHz, CDCl3) δ 1.35 (3H, t, J=7.2 Hz), 4.12 (2H, q, J=7.2 Hz), 5.60 (2H, s), 7.31 (1H, t, J=9.2 Hz), 7.42 (1H, t, J=7.6 Hz), 7.62 (2H, d, J=6.0 Hz), 7.68 (1H, m), 7.82 (1H, m), 7.90 (1H, s), 8.72 (2H, d, J=5.6 Hz), 9.53 (1H, s); MS (ES+) m/e 417 [MH]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1cccc(Cl)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4cccc(Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(3-chloro-phenyl)-1-methyl-propyl]-amine (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([O:4][CH:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH:12]=[C:11]([C:17]1[NH:21][N:20]=[N:19][N:18]=1)[C:10]2=[O:22])[CH3:6])(=O)C.[OH-].[Na+].Cl>>[OH:4][CH:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][CH:12]=[C:11]([C:17]1[NH:21][N:20]=[N:19][N:18]=1)[C:10]2=[O:22])[CH3:6]
Reactant: CC(=O)OC(C)c1ccc2occ(-c3nnn[nH]3)c(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(O)c1ccc2occ(-c3nnn[nH]3)c(=O)c2c1

Procedure:
A solution of 0.300 part of 6-(1-acetoxyethyl)-3-(1H-tetrazol-5-yl)chromone in 4 parts by volume of 1N-NaOH is stirred at room temperature for 1 hour and then acidified with 1N-hydrochloric acid. The resulting precipitates are recovered by filtration and recrystallized from ethanol to obtain 0.100 of 6-(1-hydroxyethyl)-3-(1H-tetrazol-5-yl)chromone as colorless crystals melting at 234°-236° C (decomposition with foaming).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](=O)[CH3:5].[C:13]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:25]([O:24][C:22]([C:21]1[C:4]([CH3:5])=[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:2][C:13]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[O:23])[CH3:26]
Reactant: CC(=O)C(N)c1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccncc2)[nH]c(-c2ccccc2)c1C
Temperature: 0 °C
Yield: 16.3 %

Procedure:
A mixture of 1-amino-1-phenyl-propan-2-on hydrochloride (10.5 g, 50.5 mmol), ethyl isonicotinoylacetate (8.1 g, 42.1 mmol), and ammonium acetate (6.5 g, 84.2 mmol) in acetic acid (50 mL) was heated under reflux temperature for 6 hours. After cooling, the mixture was diluted with ice-water (50 mL). The whole was extracted with CH2Cl2 (30 mL×3), and the combined organic layers were dried over MgSO4, and concentrated in vaciio. The residue was purified by flash chromatography eluting with hexane-ethyl acetate (2 : 1) to afford the title product (2.1 g, 16% yield) as a pale yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])N(CCO)N=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22](=[O:29])[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:8]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNc1ccccn1
Product: COc1ccc(C2=NN(c3ccccn3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 2-pyridylhydrazine as described for compound 35. Purified by chromatography (ethyl acetate) and crystallized from ethyl acetate/diethyl ether. M.p. 147°-148° C.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[NH:14]([CH2:16]C(O)=O)[CH3:15].C(=O)=O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:9])[CH2:15][N:14]([CH3:16])[C:7](=[O:8])[C:6]=2[CH:13]=1
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: CNCC(=O)O
Agent: O=C=O
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccc(Br)cc2C1=O
Temperature: 0 °C

Procedure:
A solution of 39.5 g of 5-bromoisatoic acid anhydride and 14.5 g of sarcosine in 150 ml of dimethyl sulphoxide is heated to 100° C. while stirring. In so doing, a vigorous evolution of carbon dioxide occurs from 70° C. and this has finished after ca 30 minutes. The mixture is stirred at 100° C. for a further 30 minutes and thereafter the mixture is poured into 900 ml of ice-water (temperature 5° C.) and the separated material is filtered off under suction. The crystals are washed with water and subsequently dried at 50° C. over phosphorus pentoxide in a vacuum drying cabinet. There is obtained 7-bromo-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione in the form of light beige crystals. A sample recrystallised from methanol has a melting point of 260°-261° C.
Reaction SMILES: [CH:1]1([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[S:16]([NH2:19])(=[O:18])=[O:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20]([N:22]=[C:23]=[S:24])[CH3:21]>>[CH:1]1([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[S:16]([NH:19][C:23]([NH:22][CH2:20][CH3:21])=[S:24])(=[O:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: NS(=O)(=O)c1cnccc1NC1CCCCCCC1
Reactant: CCN=C=S
Product: CCNC(=S)NS(=O)(=O)c1cnccc1NC1CCCCCCC1

Procedure:
The procedure is identical to that of Example 5, using (4-(cyclooctylamino)pyrid-3-yl)sulfonamide and ethylisothiocyanate as the starting materials. Yield is similar. Melting point: 196°-198° C.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>ClCCl>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[O:26])=[CH:28][CH:29]=1)([O-:20])=[O:19]
Reactant: c1cc2c(s1)CCCCN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCc2sccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 10.71 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 19.4 ml of triethylamine in 150 ml of dichloromethane under argon is added in small portions 4-nitrobenzoyl chloride (exothermic). The mixture is stirred for 3 hours at 25° C. and then washed with water, sodium bicarbonate solution, brine and dried (Na2SO4). The solvent is removed, the residue dried under vacuum and recrystallized by dissolving in hot ethyl acetate and diluting with hexane. Chilling overnight and filtering gives 16 g of light brown crystals, m.p. 141°-142° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]2[CH2:21][CH2:22][CH2:23][C@H:19]2[CH2:18][N:14]2[CH2:15][CH2:16][CH2:17][C@H:13]2[CH3:12])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(Br)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure C (see example 32) from 4-bromo-2-fluoro-benzoic acid (CAS 112704-79-7) and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (FIA) 369/371 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[CH:7]1.[C:15]([O-:18])(=[S:17])[CH3:16].[K+]>CC(C)=O>[C:15]([S:17][CH2:2][CH2:3][O:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[CH:7]1)(=[O:18])[CH3:16]
Reactant: CC([O-])=S
Reactant: ClCCOCn1cnc2cccnc21
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SCCOCn1cnc2cccnc21
Yield: 45.8 %

Procedure:
A suspension of 0.7 g (3.3 mmol) 3-(2-Chloro-ethoxymethyl)-3H-imidazo[4,5-b]pyridine and 378 mg (3.3 mmol) potassium thioacetate in 15 ml acetone was heated to reflux for 12 hours. The orange suspension was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, gradient of 0 to 10% methanol in DCM) to afford 380 mg (46%) of the desired product MS(ISP): 252.1 [MH]+; 1H-NMR (CDCl3): 2.28 (s, 3H), 3.05 (t, 2H), 3.69 (t, 2H), 5.72 (s, 2H), 7.27 (m, 1H), 8.09 (dd, 1H), 8.20 (s, 1H), 8.43 (dd, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[F:9])[CH3:2].[OH:10]O>C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-:10])=[CH:5][C:4]=1[F:9])[CH3:2]
Reactant: OO
Reactant: CCc1ccncc1F
Solvent: CC(=O)O
Product: CCc1cc[n+]([O-])cc1F
Temperature: 25 °C
Yield: 100 %

Procedure:
To a mixture of 4-ethyl-3-fluoropyridine (R. P. Dikinson et al., Bioorg. Med. Chem. Lett., 1996, 6, 2031, 28.51 g, 205.9 mmol) and 30% hydrogen peroxide (30 ml) in acetic acid (300 ml) was heated at reflux temperature for 3 h. After cooling to room temperature, the resulting mixture was concentrated. The residue was diluted in dichloromethane (300 ml) and dried (MgSO4). Removal of solvent gave 32.30 g (100%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]([C:12]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:24][S:25](O)(=[O:27])=[O:26]>C(Cl)Cl>[C:14]([C:13]1[CH:16]=[C:17]([C:20]([F:23])([F:21])[F:22])[CH:18]=[CH:19][C:12]=1[N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:5]=[C:4]([S:25]([Cl:24])(=[O:27])=[O:26])[CH:3]=[C:2]([F:1])[C:11]1=2)#[N:15]
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cccc(F)c21
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Cl)cc(F)c21
Reaction time: 1.5 h
Yield: 21.1 %

Procedure:
To a vial charged with 2-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)benzonitrile (0.445 g, 1.381 mmol) was added DCM (5.52 ml). The resulting solution was cooled in an ice water bath prior to the addition of chlorosulfonic acid (0.367 ml, 5.52 mmol), faster than dropwise. After 90 mins of stirring LC-MS of the resulting yellow/brown suspension indicated two peaks (˜2:1) with desired product mass as the main mass (M+23) with consumption of starting material. The mixture was added to ice, diluted with water and extracted with EtOAc (2×). The combined organics were dried under reduced pressure and purified with a 40 HP spherical silica column (15 m spherical, Interchim) ramping EtOAc in heptane (0-35%, 10% DCM throughout) yielding near complete separation of isomers. NMR analysis of the first eluted peak confirmed the desired regiochemistry 4-(2-cyano-4-(trifluoromethyl)phenyl)-5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.123 g, 0.292 mmol, 21.17% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.91-4.02 (m, 2 H) 4.37 (br. s., 2 H) 6.97 (dd, J=9.10, 1.56 Hz, 1 H) 7.20 (d, J=8.61 Hz, 1 H) 7.64 (dd, J=9.10, 7.34 Hz, 1 H) 7.77 (dd, J=8.61, 2.15 Hz, 1 H) 7.97 (d, J=1.76 Hz, 1 H). m/z (ESI) 443.1 (M+Na)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([N:15](C(O)=O)[CH2:16]C2C=CC=CC=2)[CH3:14])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.CCOCC>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([NH:15][CH3:16])[CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]([C@@H]1CCN(Cc2ccccc2)C1=O)N(Cc1ccccc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN[C@@H](C)[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 0 °C

Procedure:
(S,S)-1-benzyl-2-oxo-3-[1'-(carboxybenzylamino)ethyl]pyrrolidine (0.51 g, 1.44 mmol) is dissolved in tetrahydrofuran (20 ml) under a N2 atmosphere. LAH (0.32 g, 8.43 mmol) is added and the reaction mixture is refluxed for 12 hours. The reaction mixture is cooled to 0° C., diluted with Et2O and quenched with 15% aqueous NaOH. The resulting mixture is filtered through a celite pad which is then washed carefully with Et2O. The filtrate is washed with 15% aqueous NaOH and the aqueous layer extracted with Et2O. The combined Et2O layers are dried over MgSO4, filtered and concentrated under a stream of N2 to give crude (R,S)-1-benzyl-3-[1'-(methylamino)ethyl]pyrrolidine: 1H NMR (300 MHz, CDCl3) δ 1.04 (d, J is 6 Hz, 3H), 1.52 (m, 1H), 1.93 (m, 1H), 2.17 (m, 1H), 2.25 (dd, J is 16, 8 Hz, 1H), 2.37 (s, 3H), 2.33-2.49 (m, 2H), 2.56 (dd, J is 15, 8 Hz, 1H), 2.77 (dd, J is 8, 8 Hz, 1H), 3.58 (d, J is 12.8 Hz, 1H), 3.60 (d, J is 12.8 Hz, 1H), 7.23-7.36 (m, 5H). This crude material is suitable for use in Step 5.
Reaction SMILES: [C:1]([CH:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)#[N:2].[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[CH:28]([CH:32]([CH3:34])[CH3:33])[C:29](O)=[O:30].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C)C=O>[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[CH:28]([CH:32]([CH3:34])[CH3:33])[C:29]([O:18][CH:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=1)=[O:30]
Reactant: CC(C)C(C(=O)O)c1cc2ccccc2s1
Reactant: N#CC(O)c1ccc(F)c(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C(C(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1)c1cc2ccccc2s1
Reaction time: 2 h

Procedure:
To a stirred solution of α-cyano-4-fluoro-3-phenoxybenzyl alcohol (437 mg, 1.8 mmol), 2-(2-benzothienyl)-3-methylbutanoic acid (2.0 mmol) and 4-dimethylaminopyridine (0.65 mmol) in 20 ml of methylene chloride and 2 ml of dimethylformamide is added N,N'-dicyclohexylcarbodiimide (2.0 mmol). The reaction mixture is stirred, under nitrogen, for two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous sodiun bicarbonate, water and saturated aqueous sodium chloride, dried over calcium sulfate and solvent evaporated to give α-cyano-4-fluoro-3-phenoxybenzyl 2-(2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[C:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[O:4][Si](C)(C)C.[CH2:15]([O:22][C:23]1[C:28]2[C:29]([O:32][CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38]([CH2:41]OCC)[CH2:37][CH2:36]3)=[N:30][O:31][C:27]=2[CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C.[Cl-].[Mg+2].[Cl-]>[CH2:15]([O:22][C:23]1[C:28]2[C:29]([O:32][CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:9]4([C:3]([O:2][CH3:1])=[O:4])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]4)[CH2:37][CH2:36]3)=[N:30][O:31][C:27]=2[CH:26]=[CH:25][CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOCN1CCC(CCOc2noc3cccc(OCc4ccccc4)c23)CC1
Reactant: COC(O[Si](C)(C)C)=C1CCOCC1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: COC(=O)C1(CN2CCC(CCOc3noc4cccc(OCc5ccccc5)c34)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
[Methoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane (2.2 g, 10.0 mmol, EXAMPLE 1, step 3) was added to the mixture of 4-(benzyloxy)-3-{2-[1-(ethoxymethyl)piperidin-4-yl]ethoxy}-1,2-benzisoxazole (3.4 g, 8.4 mmol, EXAMPLE 7, step 4) and magnesium chloride (40 mg, 0.42 mmol) in acetonitrile (16.0 mL) at ambient temperature. After being stirred at room temperature for 3 h, the mixture was concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 2:3) to give 3.2 g (75%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].[C:10](OC(=O)C)(=[O:12])[CH3:11]>ClCCl>[C:10]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: C#Cc1ccc(N)cc1
Solvent: ClCCl
Product: C#Cc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1.0 g of 4-ethynylaniline and 2.4 mL of acetic anhydride in 5.0 mL of dichloromethane was stirred at room temperature for 18 hours. The solution was evaporated in vacuo at 40° C. The resulting semi solid mixture was suspended in hexanes and filtered. The hexanes filtrate was washed twice with water and dried over sodium sulfate. After filtering it was combined with the hexanes insoluble residue, dissolved in dichloromethane and purified by column chromatography in the same solvent to yield 0.96 g of 1-acetamido-4-ethynylbenzene.