Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([O:14][C:15]([C:17]1([CH2:24][CH2:25]OC)[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1)=O)C.[Cl-].C[Al+]C.O>C1(C)C=CC=CC=1.CCOC(C)=O>[OH:23][CH:20]1[CH2:21][CH2:22][C:17]2([C:15](=[O:14])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[CH2:25][CH2:24]2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Reactant: CC(C)Oc1ccc(N)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(N2CCC3(CCC(O)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Isopropoxy-phenylamine (11.3 g) was added to a solution of 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (11.5 g) in toluene (361 ml). The mixture was stirred for 10 minutes at RT. Then, dimethylaluminiumchloride (0.9 M in hexane, 99 ml) was added dropwise and the reaction mixture was heated to reflux for 4 h. The mixture was then cooled to 0° C., water (50 ml) was added dropwise then AcOEt (300 ml). The mixture was stirred further 30 minutes, more AcOEt was added, the layers were then separated, the organic layer was dried over MgSO4, filtered and the solvent was evaporated off. The crude product was triturated with diethyl ether/heptane to give the title compound as a mixture of cis/trans isomers as brown solid (14.3 g) which was used directly in the next step. MS (m/e): 304.190 [MH+].
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][NH:55][C:56]([NH:58][C:59]([CH3:63])([CH3:62])[CH2:60][OH:61])=[O:57])=[CH:49][CH:48]=2)[C:43]([CH3:64])=[CH:42][C:41]=1[O:65]CC1C=CC=CC=1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].CO>[OH:61][CH2:60][C:59]([NH:58][C:56]([NH:55][CH2:54][CH2:53][C:50]1[CH:51]=[CH:52][C:47]([CH2:46][C:44]2[C:43]([CH3:64])=[CH:42][C:41]([OH:65])=[C:40]([C@@H:10]3[O:11][C@H:12]([CH2:31][OH:32])[C@@H:13]([OH:23])[C@H:14]([OH:15])[C@H:9]3[OH:8])[CH:45]=2)=[CH:48][CH:49]=1)=[O:57])([CH3:62])[CH3:63]
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(CCNC(=O)NC(C)(C)CO)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(O)c([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(CCNC(=O)NC(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a methanol solution (4 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-[4-[2-[[[(2-hydroxy-1,1-dimethylethyl)amino]carbonyl]amino]ethyl]benzyl]-4-methylphenyl]-D-glucitol (0.184 mg, 0.190 mmol) was added 20% palladium hydroxide (0.180 g), and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. The reaction solution was filtered through celite and evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (chloroform:methanol=17:3) to obtain the title compound (57 mg, 58%) as a colorless powder. NMR data and MS data of the compound are shown in Table 1.
Reaction SMILES: CC(O)C.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22].Cl>>[CH3:22][CH:21]([OH:23])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 163.8 %

Procedure:
2-Propanol (1.53 ml, 20 mmol) was added to 9.9 ml (10 mmol) of a toluene solution of DIBAH (1.02 M) at room temperature and the mixture was stirred at room temperature for 1 hour. Thereto was added 0.601 g of acetophenone, and the resultant mixture was stirred at room temperature for 6 hours, followed by hydrolysis with 1 N hydrochloric acid with ice cooling. Extraction with ethyl acetate and concentration gave 1.001 g of α-phenethyl alcohol as an oil. Conversion 55%, yield 47.7%.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH:3]=[C:4]([C:23]1[CH:24]=[C:25]([C:29](=[O:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1)[C:5]1[N:13](S(C2C=CC=CC=2)(=O)=O)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][CH:2]([CH3:32])[CH:3]=[C:4]([C:23]1[CH:24]=[C:25]([C:29](=[O:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1)[C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1
Reactant: CC(=O)c1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)c1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
A solution of 1-(3-(3-methyl-1-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)but-1-enyl)phenyl)ethanone (1.5 g, 3.4 mmol) in ethanol (30 mL) and tetrahydrofuran (60 mL) was treated with an aqueous sodium hydroxide solution (10%, 20 mL). The reaction was stirred at 80° C. for 16 h. Most of the solvent was removed in vacuo. The resulting precipitate was removed by filtration and washed with water (50 mL). The filtrate was concentrated in vacuo. Silica gel column chromatography (30 g, 200-300 mesh, 15% ethyl acetate/petroleum ether) afforded 1-(3-(3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)but-1-enyl)phenyl)ethanone (0.85 g, 82.2%) as an off-white solid: 1H NMR (300 MHz, d6-DMSO) δ ppm 11.60 (s, 1H), 8.20 (dd, 1H, J1=4.8 Hz, J2=1.5 Hz), 7.96 (d, 1H, J=8.1 Hz), 7.90-7.87 (m, 1H), 7.78 (s, 1H), 7.48-7.46 (m, 2H), 7.09 (dd, 1H, J1=7.5 Hz, J2=5.1 Hz), 6.44 (d, 1H, J=1.8 Hz), 6.24 (d, 1H, J=9.9 Hz), 2.63-2.56 (m, 1H), 2.57 (s, 3H), 1.08-1.02 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[S:7][C:6]=2[C:13]=1[Cl:14].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:3]([OH:15])=[CH:4][C:5]2[CH:9]=[C:8]([CH:10]([CH3:11])[CH3:12])[S:7][C:6]=2[C:13]=1[Cl:14]
Reactant: COc1cc2cc(C(C)C)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 4.5 h
Yield: 98.5 %

Procedure:
A mixture of 6.00 g of 6,7-dichloro-2-isopropyl-5-methoxybenzo[b]thiophene and 50 g of pyridine hydrochloride, is heated under nitrogen with stirring in a 185° bath for 4.5 hours and at 200° for one hour. The reaction is cooled, triturated with 500 ml of water and extracted with three 150 ml-portions of ether. The combined ether extracts are washed with one 150 ml-portion of 2N hydrochloric acid, two 150 ml-portions of water and one 50 ml-portion of saturated sodium chloride solution and dried over magnesium sulfate to give 5.61 g of 6,7-dichloro-5-hydroxy-2-isopropylbenzo[b]thiophene as an amber oil which crystallized on standing to a product having mp 44.5-46.5. A sample recrystallized twice from hexane melts at 44.5°-46.5°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:24]([S:27](Cl)(=[O:29])=[O:28])([CH3:26])[CH3:25].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:27]([CH:24]([CH3:26])[CH3:25])(=[O:29])=[O:28])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine from General Procedure B-3 (500 mg), isopropylsulfonyl chloride (0.26 mL) and triethylamine (0.57 mL) in dichloromethane (5 mL) was stirred at room temperature. After stirring for 24 hours, standard work-up yielded 2-chloro-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[CH:12]=[CH:13][C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[NH2:27][CH:28]([C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][N:31]=1)[CH3:29].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>CN(C)C=O>[CH3:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([CH:28]([NH:27][C:14](=[O:16])[CH:13]=[CH:12][C:11]2[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[CH3:29])[CH:35]=1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: Cc1ccnc(C(C)N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccnc(C(C)NC(=O)C=Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 3-benzyloxy-4-nitrocinnamic acid (12.9 g) and 2-(1-aminoethyl)-4-methylpyridine acetate (8.5 g) in N,N-dimethylformamide (150 ml) were added 1-hydroxybenzotraizole (7 g), N,N'-dicyclohexylcarbodiimide (10.65 g) and triethylamine (4.36 g), which was stirred at ambient temperature for 24 hours. After filtration, the filtrate was evaporated under reduced pressure. The residue was suspended in ethyl acetate (100 ml), which was filtered, and evaporated. The residue was subjected to column chromatography on silica gel to give 4-methyl-2-[1-(3-benzyloxy-4-nitrocinnamoylamino)ethyl]pyridine.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([O:42]C)=O)[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=C[N:52]([C:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.C1(N)CCCCCC1>>[CH:54]1([NH:52][C:40]([C:35]2[CH:34]=[CH:33][C:32]3[C:37](=[CH:38][CH:39]=[C:30]([C:2]([OH:1])([C:6]4[N:7]=[CH:8][NH:9][CH:10]=4)[CH:3]([CH3:5])[CH3:4])[CH:31]=3)[CH:36]=2)=[O:42])[CH2:67][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1
Reactant: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: NC1CCCCCC1
Product: CC(C)C(O)(c1ccc2cc(C(=O)NC3CCCCCC3)ccc2c1)c1c[nH]cn1

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (490 mg) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with cycloheptylamine (0.20 mL) in a similar manner as described in Example 24-(i) to give the titled compound (560 mg) as a colorless powder.
Reaction SMILES: O[C:2]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]2=[O:10].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.CCOC(C)=O>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:2]2[CH:3]3[CH2:9][CH2:8][CH:6]([CH:7]=2)[C:5](=[O:10])[CH2:4]3)=[CH:16][CH:15]=1
Reactant: COc1ccc(C2(O)CC3CCC2CC3=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(C2=CC3CCC2CC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
3.03 g of crude 5-hydroxy-5-(4-methoxy-phenyl)-bicyclo[2.2.2]octan-2-one (intermediate K2A.1) was dissolved in 100 mL of acetone, 2.90 g of TsOH were added and the mixture was stirred at rt overnight. Then the reaction mixture was diluted with EtOAc, the organic phase washed with sat. aq. NaHCO3 and evaporated. The crude material was purified by CC with Hep-EtOAc (20:1) to yield 2.36 g of rac-(1R*,4R*)-5-(4-methoxy-phenyl)-bicyclo[2.2.2]oct-5-en-2-one.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@H:23]([N:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:31](=[O:34])[CH2:32][CH3:33])[CH2:22][C@@H:21]3[CH3:41])=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=O)C.I[Si](C)(C)C>C(#N)C>[CH3:41][C@H:21]1[CH2:22][C@@H:23]([N:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:31](=[O:34])[CH2:32][CH3:33])[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]1[C:18](=[O:19])[C:15]1[CH:14]=[CH:13][C:12]([CH:9]2[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)N1CCC(c2ccc(C(=O)N3c4ccccc4[C@H](N(C(=O)CC)c4ccccc4)C[C@@H]3C)cc2)CC1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C3CCNCC3)cc2)c2ccccc21
Temperature: 25 °C

Procedure:
(±)-Cis-N-[2-methyl-1-(4-piperidin-4-yl-benzoyl)-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide was prepared from (±)-cis-4-{4-[2-methyl-4-(phenyl-propionyl-amino)-3,4-dihydro-2H-quinoline-1-carbonyl]-phenyl}-piperidine-1-carboxylic acid ethyl ester. (±)-Cis-4-{4-[2-methyl-4-(phenyl-propionyl-amino)-3,4-dihydro-2H-quinoline-1-carbonyl]-phenyl}-piperidine-1-carboxylic acid ethyl ester (96 mg, 0.17 mmol) was dissolved in acetonitrile (2 mL). Iodotrimetylsilane (74 uL, 0.51 mmol) was added and the reaction was allowed to stir at room temperature over night. Excess reagent was quenched by the addition of methanol (1 mL) and the mixture was concentrated under reduced pressure. The crude residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The extracts were washed with 1 M sodium hydroxide, saturated aqueous sodium thiosulfate and brine, dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (3:1 methylene chloride/methanol) (77 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][Cl:30])[CH:24]=1>>[ClH:30].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: ClCc1cccnc1
Agent: Cl
Product: COc1ccc(C2=NN(Cc3cccnc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from compound 1 and 3-picolylchloride hydrochloride as described for compound 105. Purified by chromatography (dichloromethane). Crystallized from diethyl ether as the hydrochloride. M.p. 192°-195° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:15]=2)[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:19]=2)[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCOc1ccc(C2CN(Cc3ccccc3)C(=O)CO2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCOc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a solution of 4-benzyl-6-(4-octyloxy-phenyl)-morpholin-3-one (22.22 g; 56.2 mmol) in THF (400 mL) was added borane-THF complex (1M, 140.4 mL; 140.4 mmol) dropwise, at 0° C. After 1 hour the mixture was allowed to warm to RT and stirred for another 2 hours. To the reaction mixture was added MeOH (30 mL), at 0° C., and the resulting mixture was stirred at RT for 30 minutes, and subsequently concentrated in vacuo. The residue was suspended in MeOH (300 mL.) and 1 M aqueous NaOH (112 mL) was added and heated under reflux for 1 hour. The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 5% aqueous NaHCO3-solution. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford 4-benzyl-2-(4-octyloxy-phenyl)-morpholine (20.33 g), which was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]1C=CC=C[CH:13]=1)[C:8](=[O:18])[N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:6]=[CH:5]2.BrC1C=C2C(C=CN(CC3C=CC(OC)=CC=3)C2=O)=CC=1F.C(B(O)O)C>>[CH2:12]([C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][N:7]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:8]2=[O:18])=[CH:3][C:2]=1[F:1])[CH3:13]
Reactant: COc1ccc(Cn2ccc3cc(F)c(-c4ccccc4)cc3c2=O)cc1
Agent: CCB(O)O
Agent: COc1ccc(Cn2ccc3cc(F)c(Br)cc3c2=O)cc1
Product: CCc1cc2c(=O)n(Cc3ccc(OC)cc3)ccc2cc1F

Procedure:
The title compound was synthesized following the method described for 6-fluoro-2-(4-methoxy-benzyl)-7-phenyl-2H-isoquinolin-1-one (315) starting from 7-bromo-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (313) and ethylboronic acid. Rt=1.69 min (Method C). Detected mass: 312.4 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].OS([O-])(=O)=O.[Na+]>CO>[OH:17][CH:14]1[CH2:15][CH2:16][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)c1csc(N2CCC(O)CC2)n1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1csc(N2CCC(O)CC2)n1
Reaction time: 8 h
Yield: 90 %

Procedure:
The 2-(4-hydroxy-piperidin-1-yl)-thiazole-4-carboxylic acid ethyl ester mixture from step a was dissolved in MeOH (10 mL). To this was added NaOH (2 M, 5.00 mL). The reaction mixture was stirred overnight, then diluted 1M NaHSO4 (30 mL). This solution was extracted with EtOAc (3×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give the product (433 mg, 1.90 mmol, 90%) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].Cl.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C.Cl>ClCCl>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([C:1](=[O:4])[CH:2]=[CH2:3])[CH2:17][CH2:16]1
Reactant: C=CC(=O)Cl
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
Acryloyl chloride (10.6 mL, 11.8 g, 0.13 mol) was added dropwise to a stirred, cooled (0° C.) mixture of 1-(2-methoxyphenyl)piperazine hydrochloride (15 g, 66 mmol) and triethylamine (27.3 g, 19.8 g, 0.20 mol) in dichloromethane and the mixture was stirred at room temperature for 2 h. The mixture was poured into hydrochloric acid (1M) and extracted with dichloromethane. The combined organic fractions were washed with aqueous sodium hydrogen carbonate (saturated), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (40:60 increasing to 20:80), to give the title compound as a pale yellow oil (3.6 g, 22%). 1H NMR (360 MHz, CDCl3) δ 7.04 (1H, m), 6.95-6.84 (3H, m), 6.61 (1H, dd, J 16.8, 10.6 Hz), 6.32 (1H, dd, J 16.8, 1.8 Hz), 5.72 (1H, dd, J 10.6, 1.8 Hz), 3.94-3.84 (2H, m), 3.89 (3H, s), 3.74 (2H, m), and 3.06 (4H, m). m/z (ES+) 247 (M+1).
Reaction SMILES: CS(O)(=O)=O.[O:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]([NH:10][CH2:11][C:12]#[CH:13])=[O:9]>O1CCOCC1>[CH3:13][C:12]1[O:9][C:8]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6])=[N:10][CH:11]=1
Reactant: C#CCNC(=O)C(=O)c1ccccc1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: Cc1cnc(C(=O)c2ccccc2)o1

Procedure:
Methane sulfonic acid (10 g, 104 mmol) was added drop wise to a solution of 2-oxo-2-phenyl-N-prop-2-ynyl-acetamide (Intermediate 1) (2.4 g, 12.83 mmol) in 1,4-dioxane (20 mL). The resultant solution was heated at 90° C. for 66 h. The reaction mixture was cooled and the solvent was removed. The dark residue was partitioned between DCM and water. The DCM fraction was washed with 1 M HCl (2×), satd. sodium hydrogencarbonate solution (aq., 2×), then brine. The solution was dried (Na2SO4) and the solvent was removed to give the crude product. Purification was achieved via column chromatography, eluting with cyclohexane/EtOAc (4:1). This afforded the product as an off-white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:9][C:10]([N:12]([CH3:17])[CH2:13][C:14]([OH:16])=O)=[O:11])[CH:7]=[CH2:8].C(OC([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]=[C:30]([CH3:34])[C:31](=[O:33])[CH3:32])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1.Cl>O1CCCC1.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.O.C(OCC)(=O)C.C(O)(=O)C.CN(C)C=O>[CH2:6]([O:9][C:10]([N:12]([CH2:13][C:14]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]=[C:30]([CH3:34])[C:31](=[O:33])[CH3:32])=[O:16])[CH3:17])=[O:11])[CH:7]=[CH2:8]
Reactant: C=CCOC(=O)N1CCC[C@H]1C=C(C)C(C)=O
Reactant: C=CCOC(=O)N(C)CC(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N(C)CC(=O)N1CCC[C@H]1C=C(C)C(C)=O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a mixture of dimethylformamide (4.2 ml) and tetrahydrofuran (10 ml) was added phosphorus oxychloride (4.2 ml) at 5° C. After stirring at 5° C. for 30 minutes, to the mixture were added successively tetrahydrofuran (60 ml) and N-allyloxycarbonyl-N-methylglycine (8.7 g). The mixture was stirred for 30 minutes at 5° C. (solution A). To a solution of (2S)-1-allyloxycarbonyl-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (10.0 g) in tetrahydrofuran (160 ml) were added successively triphenylphosphine (5.5 g), 5,5-dimethyl-1,3-cyclohexanedione (dimedone) (5.8 g), acetic acid (4.8 ml) and tetrakis(triphenylphosphine)palladium(0) (2.4 g). After stirring at ambient temperature for 30 minutes, the mixture was taken up into a mixture of ethyl acetate (100 ml) and water (100 ml). After adjusting to around pH 2 with 1N hydrochloric acid, the aqueous layer was separated, washed with ethyl acetate and tetrahydrofuran (200 ml) was added thereto. After adjusting to around pH 8.5 with 20% aqueous sodium hydroxide, to the mixture was added dropwise the solution A. After stirring at 5° C. for 1 hour, the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. Removal of the solvent gave a residue, which was chromatographed on silica gel (300 ml) eluting with a mixture of n-hexane and ethyl acetate (5.5-3.7 V/V) to give (2S)-1-(N-allyloxycarbonyl-N-methylaminoacetyl)-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (3.4 g).
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:20]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:21]=4[S:22][CH:23]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[F:30][C:28]([F:29])([F:31])[C:25]1[CH:26]=[CH:27][C:20]2[C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:8]4([C:6]([OH:7])=[O:5])[CH2:10][CH2:9]4)[CH2:14][CH2:15]3)=[CH:23][S:22][C:21]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)C1(CCN2CCN(c3csc4cc(C(F)(F)F)ccc34)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1(CCN2CCN(c3csc4cc(C(F)(F)F)ccc34)CC2)CC1

Procedure:
1-{2-[4-(6-Trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-yl]-ethyl}-cyclopropanecarboxylic acid tert-butyl ester, 0.7 g (1.54 mmol), was stirred in 10 mL of trifluoroacetic acid. After 2 hours the reaction mixture was concentrated to an oil. This was taken up in methanolic hydrogen chloride. The salt thus obtained was recrystallized from ethyl acetate/methanol to deliver 0.4 g (60%) of white powder as the desired carboxylic acid mp=255-7° C.