Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])CC2)[S:9][CH:10]=1)=[O:5])[CH3:2].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.C(O)C>CN(C)C=O>[Si:18]([O:17][CH:14]1[N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:16][CH2:15]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCOC(=O)c1csc(N2CCC(O)CC2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1csc(N2CCC2O[Si](C)(C)C(C)(C)C)n1
Reaction time: 0.17 h
Yield: 103.3 %

Procedure:
To a solution of 1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-4-hydroxypiperidine (1.00 g, 3.90 mmol) (obtained as described in Reference Example 13(2)) in dimethylformamide (50 ml) were added t-butyldimethylsilyl chloride (1.2 g, 7.96 mmol) and imidazole (0.6 g, 8.8 mmol) in an ice bath. The reaction mixture was brought to room temperature in 10 minutes and then stirred for 18 hours. After checking the completion of the reaction, ethanol was added thereto in an ice bath, and the reaction mixture was then stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1) as the eluant to afford 4-t-butyidimethylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (1.38 g, yield 95%) as a pale yellow oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.Cl.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:29])=[CH:23][CH:22]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)Cc1ccncc1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.1 %

Procedure:
Triethylamine 1.75 ml (12.6 mill) was added to a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.95 g (5.0 mill) and 4-pyridylacetic acid hydrochloride 0.96 g (5.5 mill) and stirred at 0° C. for 30 min. WSC 1.35 g (7.04 mill) was added thereto, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 24 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After the drying agent was removed by filtration, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(4-pyridylacetyl)-1,8,8trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 0.39 g (10.3 mill) and refluxed under heating for 3 hours. The reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform acetone=10:1) to obtain the product as orange colored oily material. Yield: 0.35 g (Yield 27.1%)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][CH2:5][N:6]([CH3:9])[CH2:7][CH:8]=1.[I:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O>>[I:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:1][CH2:2][C:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH:4]=1
Reactant: Oc1ccccc1I
Reactant: CN1CC=C(CO)CC1
Product: CN1CC=C(COc2ccccc2I)CC1
Yield: 74 %

Procedure:
The title compound was prepared from 4-(hydroxymethyl)-1-methyl-1,2,3,6-tetrahydropyridine (D9) and 2-iodophenol, using a procedure similar to that of Description 1 in 74% yield.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:32]3[CH2:39][C:38](=[O:40])[NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:32]3[C:39](=[CH:20][C:3]4[NH:4][C:5]5[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]6[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]6)[C:7](=[O:19])[C:6]=5[C:2]=4[CH3:1])[C:38](=[O:40])[NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Product: Cc1c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 46.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]-pyrimidin-6-one as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (44 mg, 46.8%) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH2:8]Cl.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=2[N:23]=1>C(Cl)(Cl)Cl>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: COc1cccc(C=CCCl)c1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Product: COc1cccc(C=CCN2CCc3nc(N)sc3CC2)c1
Yield: 21 %

Procedure:
Prepared from 3-methoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. -Yield: 21% of theory, Melting point: 120°-124° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)=[N:11][OH:12])[CH:5]=2)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1ccccc1C(CC(=NO)c1ccncc1)c1cccc(Br)c1
Product: Cc1ccccc1C(CC(=NO)c1ccncc1)c1cccc(-c2cccc(S(C)(=O)=O)c2)c1

Procedure:
In analogy to example 22, from 3-(3-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime (example 11) and (3-methylsulfonylphenyl)boronic acid was prepared the title compound as a mixture of E and Z isomers (3:1) as a white foam, MS (ESI+): m/z=471.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7](OS(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[CH:23]=1.[Br-].[C:25]([CH2:27][CH2:28][CH2:29][Zn+])#[N:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([CH2:29][CH2:28][CH2:27][C:25]#[N:26])[C:6]=2[CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(=O)oc3ccc(Cl)cc23)cc1
Reactant: N#CCCC[Zn+]
Agent: [Br-]
Solvent: C1CCOC1
Product: N#CCCCc1cc(=O)oc2ccc(Cl)cc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
Toluene-4-sulfonic acid 6-chloro-2-oxo-2H-1-benzopyran-4-yl ester (1.05 g, 3 mmol) is dissolved in THF (30 mL) under nitrogen and [P(o-tolyl)3]2PdCl2 (120 mg, 0.15 mmol) is added 3-cyanopropylzinc bromide (9 mL of a 0.5 M solution in THF, 4.5 mmol) is added and the resulting yellow solution is stirred at 60° C. for 2 hrs. Silica gel is added to the dark red reaction mixture, which is concentrated in vacuo and purified by flash column chromatography eluting with CH2Cl2 and gradually increasing polarity to 1% MeOH—CH2Cl2 to give a residue which is triturated with Et2O to give the title compound (0.54 g, 73%) as a cream solid. 1H NMR (DMSO-d6, 400 MHz) d 7.92 (1H, d, J=2 Hz), 7.68 (1H, dd, J=9, 2 Hz), 7.46 (1H, d, J=9 Hz), 6.47 (1H, s), 2.90 (2H, t, J=7 Hz), 2.63 (2H, t, J=7 Hz), 1.94 (2H, q, J=7 Hz). LCMS (MeCN—H2O, MeCN—H2O, Luna 3 m C18(2) 30×4.6mm; (ESI Pos.) calcd for C13H10ClNO2 m/z [M+H]=248; found [no mass ion detected].
Reaction SMILES: [I:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:23]1[O:24][C:11]2([CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([CH2:3][C@@H:2]([I:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)[O:21][CH2:22]1
Reactant: C[C@]12CC[C@H](I)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C[C@]12CC[C@H](I)CC1=CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Yield: 87.3 %

Procedure:
More specifically, 3β-iodoandrost-5-en-17-one (11) (11.83 g, 29.7 mmol), ethylene glycol (20 ml) and p-toluene sulfonic acid (200 mg) in benzene (250 ml) were refluxed under a Dean-Stark trap for 72 hrs. The solution was washed with saturated sodium bicarbonate, water, then dried over magnesium sulfate. Evaporation and recrystallization from ether afforded 11.5 g (87.3%) of 3β-iodoandrost-5-en-17-one-17-ethyleneketal (12): mp 140°-141° C., IR (KBr): 3010, 2940, 1470, 1425, 1375 cm-1 ; 1H NMR (CDCl3): δ5.44 (brd J=6 Hz, 1H, H-6), 3.91 (s, 4H, ketal), 1.07 (s, 3H, C-19 Me), 0.88 (s, 3H, C-18 Me); MS (m/e): 442 (M+, 1), 380 (35), 315 (57), 253 (67), 227 (11), 105 (24), 99 (100), 91 (35), 55 (27), 41 (33).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][NH2:26]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH2:25][C:21]1[S:20][CH:24]=[CH:23][CH:22]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: NCc1cccs1
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1cccs1
Yield: 89 %

Procedure:
The compound prepared in Example 3 was reacted with thiophen-2-ylmethyl-amine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 89%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2[N:9]([CH2:13][C:14]3[N:19]=[CH:18][N:17]4[N:20]=[C:21]([CH2:23]O)[N:22]=[C:16]4[C:15]=3[CH2:25][CH2:26][CH3:27])[CH:10]=[CH:11][N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.COCCN(S(F)(F)[F:38])CCOC.C([O-])(O)=O.[Na+].C(=O)=O>ClCCl>[F:38][CH2:23][C:21]1[N:22]=[C:16]2[N:17]([CH:18]=[N:19][C:14]([CH2:13][N:9]3[CH:10]=[CH:11][N:12]=[C:8]3[C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[C:15]2[CH2:25][CH2:26][CH3:27])[N:20]=1
Reactant: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(CO)nc12
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncn2nc(CF)nc12
Reaction time: 2 h

Procedure:
To a solution {7-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-8-propyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}-methanol (compound 223, below) (31 mg, 0.08 mmol) in dichloromethane (5 mL) is added bis(2-methoxyethyl)aminosulfur trifluoride (0.2 ml, 50% in THF) at room temperature under N2. The mixture is stirred for two hours, and is poured into saturated NaHCO3 (10 mL), and after CO2 evolution ceases it is extracted into dichloromethane, dried (MgSO4), filtered and evaporated in vacuo. PTLC by 5% MeOH/dichloromethane gives the pure product (157). 1H NMR: 0.98 (3H, t, J=5.4 Hz), 1.67 (2H, m), 2.99 (2H, m), 5.69 (2H, d, J=35.1 Hz), 5.88 (2H, s), 7.22 (1H, s), 7.22–7.31 (2H, m), 7.54 (1H, t, J=6.0 Hz), 8.39 (1H, s), 9.13 (1H, s). LCMS (M+1) 370.20.
Reaction SMILES: CC1O[C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.CCOCC>[NH2:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=1[C:6]([C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)=[O:8]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: COc1ccc2nc(C)oc(=O)c2c1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(N)c(C(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-6-(methyloxy)-4H-3,1-benzoxazin-4-one (for a preparation see Reference compound A) (40.0 g, 0.21 mol) in a toluene/ether (2/1) mixture (760 mL) at 0° C. was added dropwise a solution of 4-chlorophenylmagnesium bromide (170 mL, 1M in Et2O, 0.17 mol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h before being quenched with 1N HCl (200 mL). The aqueous layer was extracted with EtOAc (3×150 mL) and the combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was then dissolved in EtOH (400 mL) and 6N HCl (160 mL) was added. The reaction mixture was refluxed for 2 h before being concentrated to one-third in volume. The resulting solid was filtered and washed twice with ether before being suspended in EtOAc and neutralised with 1N NaOH. The aqueous layer was extracted with EtOAc (3×150 mL) and the combined organics were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound was obtained as a yellow solid (39 g, 88% yield);
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=1)[C:2]1C=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CCCCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a three-neck flask flushed with argon and fitted with a magnetic stir bar was added 30 ml of dry THF, 1.379 gm (6.9 mmol) of p-benzyloxyphenol (the compound of Formula IV), 0.8 gm (6.9 mmol) of (2S,3S)-3-prophloxiranemethanol (the compound of Formula V), and 1.98 gm (7.59 mmol) of triphenylphosophine. The resulting solution was heated to reflux and 1.2 ml (1.32 gm, 7.59 mmol) of diethyl azodicarboxylate was added over a period of 7 hr. After the addition was complete the reaction mixture was allowed to cool to room temperature and stir for an additional two days under argon. The solvent was then removed, and the residue purified by flash chromatography on silica gel using 85:15 hexanes/ethyl acetate as eluent. In this manner 1.6 gm (78%) of 4-benzyloxy-1-[2S,3S)-epoxy]-hexyloxybenzene (the compound of Formula VI) was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][C:12]([S:15][CH3:16])=[N:13][N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[I:19]I>CN(C=O)C>[I:19][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]3[S:11][C:12]([S:15][CH3:16])=[N:13][N:14]=3)[CH:5]=2)[NH:1][CH:2]=1
Reactant: CSc1nnc(-c2ccc3[nH]ccc3c2)s1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1nnc(-c2ccc3[nH]cc(I)c3c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 2-(1H-indol-5-yl)-5-(methylthio)-1,3,4-thiadiazole (18.5 g, 74.8 mmol) in DMF (190 mL) was added KOH (16.2 g, 299 mmol) followed by I2 (38 g, 149.7 mmol). The reaction was stirred at RT for 2 h, and was quenched with 10% aq sodium bisulphate solution. The resulting precipitate was filtered and washed with H2O to give 2-(3-iodo-1H-indol-5-yl)-5-(methylthio)-1,3,4-thiadiazole (21 g, 75%). MS (ESI, pos. ion) m/z: 373.8 (M+1). 1HNMR (DMSO-d6, 300 MHz): 2.8 (s, 3H), 7.5 (d, 1H), 7.7 (m, 2H), 12.0 (s, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[NH:11][CH2:12][C:6]=2[CH:5]=1.[CH2:17]([O:19][CH2:20][C:21](Cl)=[O:22])[CH3:18]>CN(C)C=O>[Cl:3][C:4]1[CH:16]=[CH:15][C:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([C:21](=[O:22])[CH2:20][O:19][CH2:17][CH3:18])[CH2:12][C:6]=2[CH:5]=1
Reactant: CCOCC(=O)Cl
Reactant: CC1Cc2ccc(Cl)cc2CNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCC(=O)N1Cc2cc(Cl)ccc2CC(C)C1=O
Temperature: 80 °C
Yield: 52 %

Procedure:
0.018 moles of sodium hydride is added slowly, with stirring, to a solution of 3.4 g. (0.016 moles) of 8-chloro-4-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one in 60 ml. of dimethylformamide. The reaction mixture is heated to 80° C. for 15 minutes and then cooled in an ice bath. While cooling, 2.2 g. (0.018 moles) of ethoxyacetyl chloride are added dropwise and then the reaction mixture is gradually brought to a temperature of 80° C. and maintained at this temperature for 3 hours. The reaction mixture is then cooled, evaporated to dryness in vacuo and the residue extracted with chloroform. The organic solution is washed twice with water, dried over anhydrous sodium sulfate, filtered and then evaporated to dryness in vacuo. The residual solid is purified by chromatography on a silica column, using a mixture of benzene/ethanol (9:1 v/v) as eluent, and it is then recrystallized from 2-propanol. 2.5 g. (52% of theory) of 8-chloro-2-(ethoxyacetyl)-4-methyl-1,2,4,5-tetrahydro- 3H-2-benzazepin-3-one are obtained. M.P. 123°-124° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH2:20]Br)[CH:11]=1.Cl>CN(C=O)C>[Br:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH2:20][O:8][CH2:3][C:4]([F:7])([F:6])[F:5])[CH:11]=1
Reactant: OCC(F)(F)F
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1COCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (0.5 g of 60% dispersion in oil) in DMF (10 ml) was added trifluoroethanol (0.92 ml) and the mixture stirred for 30 minutes. After this time the mixture was cooled to 0° C. and a solution of methyl 4-bromo-2-bromomethylbenzoate (3.52 g) in DMF was added, and the resultant mixture stirred at room temperature for 1 hour. 0.5M HCl was added and the mixture extracted with ether. The organic extract was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to yield methyl 4-bromo-2-trifluoroethoxymethylbenzoate (3.89 g) as a yellow oil, NMR (CDCl3) 3.9(s,3H), 4.0(q,2H), 5.1(s,2H), 7.5(dd,1H), 7.85(d,1H), 7.9(s,1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
In methanol (25 ml) and THF (30 ml) was dissolved methyl 7-(4-ethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.24 g). To the solution was added 1N sodium hydroxide solution (5 ml) and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-(4-ethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.23 g) as pale yellow crystals.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH2:14]([O:21][C:22]([NH:24][CH:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=O)[CH2:26]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>COCCOC.O>[CH2:14]([O:21][C:22]([NH:24][CH:25]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[CH:3][C:1]#[N:2])[CH2:26]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C(NC1CC(=O)c2ccccc2C1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#CC=C1CC(NC(=O)OCc2ccccc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl (cyanomethyl)phosphonate (0.189 mL) in 1,2-dimethoxyethane (1 mL) at room temperature under nitrogen was added 60% sodium hydride oil dispersion (46 mg). Upon completion of addition, the mixture was stirred for 1 h. After this time, a solution of 3-benzyloxycarbonylamino-1-oxo-1,2,3,4-tetrahydronaphthalene (69 mg) in 1,2-dimethoxyethane was added (1 mL). The reaction mixture was stirred at room temperature for 1 h, and then heated to reflux for 4 h. At the conclusion of this period, the reaction mixture was cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated under vacuum to yield a residue. The residue was purified by reverse phase preparative HPLC (trifluoroacetic acid containing solvents were used) to obtain the title compound (38 mg) as a mixture of olefin isomers.
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>CCOCC>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:7]1[S:6][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (1.6M, 10 mL, 15.98 mmol) was added to a solution of benzothiazole (1.80 g, 13.3 mmol) in anhydrous ether (30 ml) stirred at −78° C. under nitrogen. After 10 min, tri-n-butylstannyl chloride (4.33 g, 13.31 mmol) was added, then the solution was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched and washed with 1N sodium hydroxide, dried through MgSO4, filtered, and evaporated to give the sub-title compound as a brown oily residue (5.0 g), which was used without further purification in the next step.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][C:8]3([C:10]([OH:12])=O)[CH2:9][CH:2]1[CH2:3][CH:4]3[CH2:5]2.S(Cl)([Cl:15])=O>>[CH2:5]1[CH:4]2[C:8]3([C:10]([Cl:15])=[O:12])[CH2:9][CH:2]([CH2:1][CH:6]1[CH2:7]3)[CH2:3]2
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C12CC3CC(CC1C3)C2
Temperature: 25 °C

Procedure:
A solution of 3-noradamantanecarboxylic acid (Aldrich, 12 g, 70 mmol) in 100 mL of thionyl chloride was warmed to reflux for 1 hour. The mixture was then cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 100 mL benzene and concentrated under reduced pressure (3×) to afford hexahydro-2,5-methano-pentalene-3a-carbonyl chloride.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:10]=[CH:11][C:12]=1[CH2:13]Br)(C)(C)C.[C-:26]#[N:27].[Na+]>CN(C=O)C.CCOC(C)=O>[O:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:26]#[N:27])=[C:7]([OH:6])[CH:8]=1
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The mixture of 2-(3-{[tert-butyl-(dimethyl)silyl]oxy}-4-bromomethylphenyl)-1,3-benzoxazole (1.6 g, 3.8 mmol) and sodium cyanide (560 mg, 11.4 mmol) in DMF (10 mL) was stirred at 90° C. overnight. After cooling to rt, the mixture was diluted with EtOAc (100 mL), washed with H2O (2×50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford the desired [4-(1,3-benzoxazol-2-yl)-2-hydroxyphenyl]acetonitrile as yellow solid. 1H NMR(CD3OD, 300 MHz), δ10.6(s, 1H), 7.8(m, 2H), 7.7(m, 2H), 7.5(d, 1H), 7.4(m, 2H). MS (ESI) 251 (M+H)+.