Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:31][C@H:32]([C:37]2[CH:42]=[CH:41][C:40](Br)=[CH:39][C:38]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:33]([F:36])([F:35])[F:34])[N:3]=1.CC1(C)C(C)(C)OB(/[CH:58]=[CH:59]/[C:60]([O:62][CH2:63][CH3:64])=[O:61])O1.[CH2:66](O)C>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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:30][CH2:29][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19]/[C:20](/[CH:25]=[CH2:66])=[CH:21]/[CH:22]=[CH:23]\[CH3:24])=[O:17])[C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:31][C@H:32]([C:37]2[CH:42]=[CH:41][C:40](/[CH:58]=[CH:59]/[C:60]([O:62][CH2:63][CH3:64])=[O:61])=[CH:39][C:38]=2[N:44]2[CH:48]=[CH:47][C:46]([CH3:49])=[N:45]2)[C:33]([F:35])([F:34])[F:36])[N:3]=1
Reactant: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)O)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Reactant: CCO
Reactant: CCOC(=O)/C=C/B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=C/C(=C\C=C/C)COC(=O)N1CC2(CCN(c3cc(O[C@H](c4ccc(/C=C/C(=O)OCC)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)C[C@H]1C(=O)O
Temperature: 80 °C

Procedure:
To a solution of (S)-8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((benzyloxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (product of Step 3, Example 10m) (240 mg, 0.33 mmol) in ethanol (8 mL) was added (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (110 mg, 0.49 mmol), PdCl2(PPh3)2 (20 mg, 0.049 mmol) and KHCO3 (170 mg, 0.05 mmol). The reaction was heated to 80° C. for 2 h, cooled to RT, and filtered. The solvent was removed in vacuo. Purification via normal phase silica gel chromatography (CH2Cl2/heptane) provided ((S)-8-(2-amino-6-((R)-1-(4-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2-((((2E,4Z)-2-vinylhexa-2,4-dien-1-yl)oxy)carbonyl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([O:20]CC)=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:23][C:13]4=[N:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=[C:12]4[CH2:11]3)[C:9](=[O:24])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(F)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncc(F)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl (6S)-5′-fluoro-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (200 mg, 0.611 mmol) in THF (4 mL) and water (1 mL) was added 1 N lithium hydroxide (0.733 mL, 0.733 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The reaction mixture was acidified to pH 4 by addition of 1 N hydrochloric acid and concentrated to dryness in vacuo to give the title compound. MS: m/z=300.2 (M+1); 1H NMR (500 MHz, CD3OD) δ 9.21 (s, 1H), 8.90 (s, 1H), 8.07 (m, 1H), 7.78 (dd, 1H, J=7.8, 2.7 Hz), 3.87-3.78 (m, 2H), 3.72 (d, 1H, J=17.3 Hz), 3.61 (d, 1H, J=17.6 Hz).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([C:26]2[O:30][N:29]=[CH:28][C:27]=2[CH2:31][CH2:32][C:33](O)=[O:34])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([C:33](=[O:34])[CH2:32][CH2:31][C:27]3[CH:28]=[N:29][O:30][C:26]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1cnoc1-c1ccccc1)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A mixture of N-diphenylmethylpiperazine (0.85 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.55 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-diphenylmethyl-N′-[3-(5-phenyl-4-isoxazolyl)propionyl]piperazine (1.35 g, yield 93%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl3) δ: 2.26–2.42 (4H, m), 2.50–2.64 (2H, m), 2.94–3.08 (2H, m), 3.32–3.44 (2H, m), 3.56–3.68 (2H, m), 4.22 (1H, s), 7.12–7.54 (13H, m), 7.66–7.86 (2H, m), 8.21 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[CH2:9][CH2:8]3.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[CH2:9][CH2:8]3)=[O:24]
Reactant: CCCOC(=O)c1c(N)sc2c1CC1CCC2O1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CCCOC(=O)c1c(NC(=O)c2ccccc2C(F)(F)F)sc2c1CC1CCC2O1

Procedure:
The title compound was prepared from the product of Example 34A and commercially available 2-trifluoromethyl-benzoyl chloride according to the procedure described for Example 1C. 1H NMR (DMSO-d6, 300 MHz) δ 0.92 (t, J=7.5 Hz, 3H), 1.64-1.71 (m, 3H), 1.98-2.15 (m, 3H), 2.58 (d, J=17.0 Hz, 1H), 3.11 (dd, J=16.6, 4.4 Hz, 1H), 4.16 (t, J=6.4 Hz, 2H), 4.69-4.74 (m, 1H), 5.14-5.16 (m, 1H), 7.80-7.94 (m, 4H), 11.40 (br s, 1H); MS (ESI+) m/z 440 (M+H)+. Anal. calcd. for C21H20F3NO4S: C, 57.40; H, 4.59; N, 3.19. Found: C, 57.44; H, 4.47; N, 3.14.
Reaction SMILES: [CH3:1][CH:2]1[O:6][C:5]([C:8]2[CH:9]=[C:10]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)([CH3:7])[CH2:4][O:3]1.Cl.[NH2:25][OH:26]>>[CH3:1][CH:2]1[O:6][C:5]([C:8]2[CH:9]=[C:10]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[N:25][OH:26])[CH3:22])=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)([CH3:7])[CH2:4][O:3]1
Reactant: CC(=O)c1ccc(Sc2cccc(C3(C)COC(C)O3)c2)cc1
Reactant: NO
Agent: Cl
Product: CC(=NO)c1ccc(Sc2cccc(C3(C)COC(C)O3)c2)cc1
Yield: 82 %

Procedure:
Using an analogous procedure to that described in Example 68, 4'-[3-(2,4-dimethyl-1,3-dioxolan-4-yl)phenylthio]acetophenone was reacted with hydroxylamine hydrochloride to give 4'-[3-(2,4-dimethyl-1,3-dioxolan-4-yl)phenylthio]acetophenone oxime in 82% yield as a gum.
Reaction SMILES: Cl[C:2]([F:27])([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C>C(O)C.[Pd]>[F:27][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NC(C)C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC(C)C
Yield: 89.8 %

Procedure:
This compound was prepared as described in Example 54: 2.7 g (0.006 mol) of product of Example 60, 0.65 g (0.006 mol) of triethylamine and 0.12 g of Pd/C (10%) in 30 ml of ethanol were reacted affording an oil residue which was kugelrohr distilled at 80 Pa, pot temperature 104° C., to give 2.07 g (89.8%) of product as a white solid; mp 53°-55° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=2)[N:5]=1)([OH:3])=[O:2].[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:22]=CC=C[CH:18]=1.C(O)C=C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:22]([O:2][C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=2)[N:5]=1)=[O:3])[CH:17]=[CH2:18]
Reactant: O=C(O)c1ccc2cc([N+](=O)[O-])ccc2n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C=CCO
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of 2-carboxy-6-nitroquinoline (1.5 g; 6.8 mM) in THF (30 ml) was added triphenylphosphine (2.7 g; 10.2 mM), allyl alcohol (0.7 ml; 10.2 mM) and DEAD (1.63 ml; 10.2 mM). After stirring at ambient temperature for 30 minutes, the mixture was extracted with ethyl acetate and purified by subjecting to flash chromatography, eluting with ethyl acetate/petroleum ether (40/60) to give 2-allyloxycarbonyl-6-nitroquinoline (1.2 g; 71%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:25])=[CH:9][C:10]([O:23][CH3:24])=[CH:11][C:12]=3[C:13]2([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])O)=[CH:4][CH:3]=1.[N:26]([Si](C)(C)C)=[N+:27]=[N-:28].C([O+]([B-](F)(F)F)CC)C>C1(C)C=CC=CC=1>[N:26]([C:13]1([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]2[CH:11]=[C:10]([O:23][CH3:24])[CH:9]=[C:8]([F:25])[C:7]=2[O:6][C:5]2[C:14]1=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=2)=[N+:27]=[N-:28]
Reactant: CCOC(=O)CC1(O)c2cc(Br)ccc2Oc2c(F)cc(OC)cc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC[O+](CC)[B-](F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(N=[N+]=[N-])c2cc(Br)ccc2Oc2c(F)cc(OC)cc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of ethyl 2-(7-bromo-4-fluoro-9-hydroxy-2-methoxy-9H-xanthen-9-yl)acetate (1.0 g, 2.432 mmol) in toluene (25 ml) was added azidotrimethylsilane (0.560 g, 4.86 mmol). The solution was cooled to 0° C. and (diethyloxonio)trifluoroborate (0.308 ml, 2.432 mmol) was added drop wise. The mixture was stirred overnight at RT. The solution was quenched with MeOH (10 ml) and diluted with EtOAc. The organic phase was separated, washed with saturated aqueous sodium bicarbonate solution and brine, and then concentrated to afford crude ethyl 2-(9-azido-7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-yl)acetate (1 g, 2.292 mmol, 94% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7 %

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (800 mg) was dissolved in dichloroethane (16 ml), added with 1,2,3,4-tetrahydroquinoline (0.50 ml), sodium triacetoxyborohydride (1.7 g) and acetic acid (2.3 ml) and stirred at room temperature for 24 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (20 ml) and extracted twice with ethyl acetate (20 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=10:1) to obtain 90.6 mg of the title compound. Yield: 7%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]([OH:6])[CH3:5].C(N(CC)CC)C.[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CCOC(C)=O>[Si:15]([O:6][C@H:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:7])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](C)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
To the mixture of (R)-2-Hydroxy-propionic acid methyl ester (1.0 g, 9.6 mmol), triethyl amine (4.0 mL, 28.81 mmol) in tetrahydrofuran (12 mL), was added tert-butyldiphenylsilylchloride (3.68 mL, 14.4 mmol) at room temperature and allowed the reaction mixture to stir for 12 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (80 mL) and washed with water (70 mL) and brine (70 mL). The EtOAc layer was dried over Na2SO4 and solvent was evaporated in vacuo to afford methyl (2R)-2-{[tert-butyl(diphenyl)silyl]oxy}propanoate (3.28 g). The above crude material was sufficiently pure for the next step and used without further purification. The crude material was diluted with THF-MeOH—H2O (1:1:1, 20 mL) and added LiOH. H2O (1.17 g, 28.0 mmol). The reaction mixture was stirred for over night at room temperature. The reaction mixture neutralized with conc. HCl and concentrated in vacuo. The residue was diluted with 75 mL water and extracted with EtOAc (3×50 mL), the combined EtOAc layers were dried over Na2SO4 and evaporated in vacuo. The crude carboxylic acid was purified by Isco silica gel flash column using EtOAc to obtain the carboxylic acid (0.6 g). 1H NMR (CDCl3) δ 7.70-7.60 (m, 4H), 7.50-7.38 (m, 6H), 4.32 (q, J=6.6 Hz, 1H), 1.30 (d, J=7.0 Hz, 9H); LC-MS [M−H]+ 327.2
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.Br[CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: OP(O)CCCCc1ccccc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CP(=O)(O)CCCCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 71.6 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (2.0 g, 0.01 mole) in chloroform (40 ml) was added triethylamine (3.2 ml, 0.022 mole) and cooled in an ice bath to 0° C. Trimethyl silyl chloride (2.8 ml, 0.022 mole) was added to the above solution dropwise, followed by benzyl bromoacetate (1.6 ml, 0.011 mole). The ice bath was removed and the mixture stirred at room temperture for 5 hours and poured into 10% aqueous HCl (30 ml) and crushed ice (20 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil (3.5 g) was dissolved in 30 ml ether; hexane was added dropwise to get a turbid solution and left at room temperature overnight to complete the crystallization. The resulting product was cooled in the freezer for 2 hours, filtered and the solid was washed very thoroughly with hexane (50 ml), ether (50 ml) and again very thoroughly with hexane (50 ml), ether (50 ml) in that order. The solid was vacuum dried to get 2.48 g (71%) of title compound, m.p. 68°-70° C. TLC: Silica gel, CH2Cl2 :MeOH:HOAc (20:1:1) shows a single spot at Rf =0.25.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].CCN(CC)CC.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:4][CH2:1][C:2]#[CH:3])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: C#CCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNS(=O)(=O)c1ccc(C)cc1

Procedure:
To solution of propargylamine (2.00 g, 36.29 mmol) and Et3N (7.30 g, 72.59 mmol) in CH2Cl2 was added in small portions p-toluenesulfonyl chloride (6.90 g, 36.29 mmol) (J. T. Baker) at 0° C. After 5 min the mixture was filtered and the filtrate was concentrated to a residue that upon direct application on a silica gel column with a 0-40% EtOAc in hexanes gradient yielded 4-Methyl-N-(prop-2-ynyl)-benzenesulfonamide. (Yield 7.30 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23](Br)=[CH:22][C:20]=2[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:14][C:15]1[CH2:16][C:17]([C:27]([N:29]([CH2:33][CH2:34][CH3:35])[CH2:30][CH2:31][CH3:32])=[O:28])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:8]3[CH:7]=[C:6]4[C:5](=[CH:10][CH:9]=3)[C:3](=[O:4])[O:2][CH2:1]4)=[CH:22][C:20]=2[N:21]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc4c(c3)COC4=O)cc2N=C(N)C1
Temperature: 100 °C

Procedure:
(1E,4E)-2-Amino-8-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide was prepared as follows, substituting 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one for 4-(methoxycarbonyl)phenylboronic acid. (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) was then used. 1H NMR (400 MHz, CDCl3) δ 7.96-8.00 (m, 1H), 7.78-7.82 (m, 1H), 7.72-7.74 (m, 1H), 7.52-7.55 (m, 1H), 7.38-7.42 (m, 1H), 7.30-7.35 (m, 1H), 6.85 (s, 1H), 5.37 (s, 2H), 3.60-3.71 (m, 2H), 3.39-3.53 (m, 4H), 2.85 (m, 2H), 1.59-1.75 (m, 4H), 0.90-0.99 (m, 6H); m/z (APCI-pos) M+1=418.2.
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C([Si](C)(C)O[CH2:34][CH:35]=[O:36])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C[O:60][CH2:59][CH2:58]1>>[OH:60][CH2:59][CH2:58][N:26]([CH:23]1[CH2:24][CH2:25][N:20]([C:17]2[S:18][CH:19]=[C:15]([C:7]3[CH:6]=[CH:5][C:4]4[C:3]([CH3:27])([CH3:2])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]=4[CH:8]=3)[N:16]=2)[CH2:21][CH2:22]1)[CH2:34][CH2:35][OH:36]
Reactant: C1CCOC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N(CCO)CCO)CC4)n3)ccc21

Procedure:
The preparation is carried out starting from 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrobromide and (tertbutyldimethylsilanyloxy)acetaldehyde. The protecting group is cleaved off as already described by means of a 1M TBAF/THF solution. The product was purified by means of reversed-phase chromatography and converted into the hydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11].[Li]CCCC.C[O:18]B(OC)OC.OO>C1COCC1.O.C(O)(=O)C>[CH2:10]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[OH:18])[CH3:11]
Reactant: CCOc1ccc(F)cc1Br
Reactant: COB(OC)OC
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(F)cc1O
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
The 2-bromo-1-ethoxy-4-fluoro-benzene (3.1 g) described in example 1.1 was dissolved in THF (25 ml). The solution was cooled to −75° C. and a solution of n-BuLi (9.73 ml, 1.6 M in hexane) was added slowly. The mixture was stirred for 30 min at −75° C. Trimethylborate (1.62 g) was added within 5 min. Acetic acid (1.27 g) and a 30% solution of H2O2 (1.51 g) were added sequentially. The mixture was stirred for 30 min at 0° C. and for 3 h at room temperature. Water was added and the mixture was extracted with ethyl acetate. The crude product was purified by column chromatography (n-hexane/ethyl acetate) to yield 1.77 g of 2-ethoxy-5-fluoro-phenol as a colorless oil. MS: 156 ([M]+).
Reaction SMILES: C(C1CN([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33][CH3:34])=[O:32])[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)N(C2C=CC=CC=2)C=1)=O.[CH2:42]([P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])P(=O)(OCC)OCC.[CH3:59][N:60]([CH3:63])C=O.[H-].[Na+]>O>[CH2:56]([O:55][P:51](/[CH:42]=[CH:27]/[C:26]1[C:22]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33][CH3:34])=[O:32])[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:23][N:60]([C:63]2[CH:38]=[CH:39][CH:16]=[CH:17][CH:18]=2)[CH:59]=1)([O:52][CH2:53][CH3:54])=[O:58])[CH3:57]
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(CON4CC(C=O)=CN4c4ccccc4)cc3OC)c(C)o2)c1
Reactant: CN(C)C=O
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)OC)c3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 57 %

Procedure:
To a mixture of methyl 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-2-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (0.85 g), tetraethyl methylenediphosphonate (0.49 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.07 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate as colorless crystals (0.59 g, yield 57%) from a fraction eluted with ethyl acetate-hexane (4:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 141-142° C.