Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:27]=[N:26][C:17]4[NH:18][C:19]5[CH:24]=[N:23][C:22]([NH2:25])=[CH:21][C:20]=5[C:16]=4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:28]([NH:30][NH:31][CH:32]=O)=O.Cl[Si](C)(C)C.C(N(CC)CC)C>N1C=CC=CC=1.O.C(Cl)Cl.CO>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:27]=[N:26][C:17]4[NH:18][C:19]5[CH:24]=[N:23][C:22]([N:25]6[CH:32]=[N:31][N:30]=[CH:28]6)=[CH:21][C:20]=5[C:16]=4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: O=CNNC=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: O
Product: c1cc(-c2cnc3[nH]c4cnc(-n5cnnc5)cc4c3c2)ccc1CN1CCCCC1
Yield: 82.2 %

Procedure:
A mixture of 3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-6-amine (22.3 mg, 62.4 μmol), 1,2-diformylhydrazine (16.5 mg, 0.187 mmol), chloro-trimethylsilane (119 μL, 0.936 mmol) in triethylamine (60.9 μL, 0.437 mmol) and pyridine (340 μL) was heated under reflux for 30 minutes. The cooled reaction mixture was diluted with water, DCM, methanol and water. The layers were separated; the aqueous phase extracted with 20% MeOH in DCM, and the combined organic phase was concentrated in vacuo. The resultant residue was purified by preparative HPLC (0-30% MeCN in water (0.1% formic acid) over 30 min, 35 mL/min) to afford the title compound as a yellow solid (21 mg, 81%). 1H NMR (DMSO-D6, 400 MHz): 12.50 (s, 1H), 9.25 (s, 2H), 8.99 (d, J=2.1 Hz, 1H), 8.94 (d, J=2.2 Hz, 1H), 8.86 (s, 1H), 8.73 (s, 1H), 7.76 (d, J=8.1 Hz, 2H, 7.46 (d, J=8.1 HZ, 2H), 3.50 (s, 2H), 2.35 (m, 4H), 1.58-1.46 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=7.46 min, M+H+=410.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]([OH:24])[CH3:23])[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+].[ClH:49]>ClCCl.CCOCC>[ClH:49].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:22](=[O:24])[CH3:23])[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1csc(Nc2ncc(C(C)O)cc2OCc2ccccc2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.3 %

Procedure:
1-(5-(Benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-yl)ethanol (prepared according to Example 19; 0.128 g, 0.375 mmol) was placed in dichloromethane (5 mL). A solution of Dess-Martin periodinane (0.167 g, 0.394 mmol) in dichloromethane (7 mL) was added and the reaction mixture was stirred at room temperature for 20 minutes. 1M NaOH and ether were added, and the layers were separated. The organic layer was washed with 1M NaOH and water, then dried, filtered, and concentrated. The residue was purified by silica gel to provide the free base, which was dissolved in dichloromethane. 2M HCl was added and the solution was concentrated to afford 1-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-yl)ethanone hydrochloride (0.068 g, 48.3% yield). 1H NMR (DMSO-d6) δ 8.62 (d, 1H), 7.73 (m, 1H), 7.60 (m, 2H), 7.42 (m, 2H), 7.35 (m, 1H), 6.79 (s, 1H), 5.36 (s, 2H), 2.57 (s, 3H), 2.30 (s, 3H). Mass spectrum (apci) m/z=340.1 (M+H-HCl).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:36]/[O:37][CH3:38])/[C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[I-:39].[Na+]>CC(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:36]/[O:37][CH3:38])/[C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:23])=[C:15](/[CH:18]=[CH:19]/[CH2:20][I:39])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(/C=C\CCl)CS[C@H]12)c1nsc(N)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(/C=C/CI)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
To a solution of p-methoxybenzyl 7β[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[(Z)-3-chloro-1-propen-1-yl]3-cephem-4-carboxylate(1.5 g) dissolved in acetone(20 ml), sodium iodide (0.82 g) was added thereto under ice-cooling. The resulting solution was stirred for 15 minutes under ice-cooling and for additional an hour at room temperature. The solvent was distilled off, and the residue was extracted with ethyl acetate. The extract was washed with a 10%-sodium thiosulfate and with a saturated brine, followed by drying with addition of anhydrous magnesium sulfate. The dried extract was concentrated under reduced pressure and the resulting precipitates were collected by filtration to obtain 1.1 g of p-methoxybenzyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[(E)-3-iodo-1-propen-1-yl]3-cephem-4-carboxylate. The powder was dissolved in N,N-dimethylformamide(2.5 ml), and 4-ethylmethylamino-2-butenylamide(0.2 g) was added thereto at -10° C. The resulting solution was stirred for 4 hours at -10° C. 10%-sodium thiosulfate(70 ml) was added to the reaction solution, and the resulting precipitates were collected by filtration to obtain the yellowish brown powder. The powder was stirred in 88%-formic acid(1.3 ml) for 3 hours at room temperature, and acetone(400 ml) was added thereto. The resulting precipitates were collected by filtration and washed with acetone. The precipitates were chromatographed over silicagel[acetonitrile:distilled water 4:1 (v/v)], Sephadex LH-20(or Amberlite XAD-2), and then lyophilized to obtain the target product (180 mg) as white solid.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[S:3]([O:6][C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1(NCCN1CCS(=O)(=O)CC1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=[O:5])=[O:4].C[C@]12[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)[C:62](=[O:71])CC4)CCC1[C@H]1[C@H](C(C)=C)CC[C@]1(C=O)CC2>>[F:48][C:2]([F:47])([F:1])[S:3]([O:6][C:7]1[C:8]([CH3:46])([CH3:45])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:44])([C@@:13]3([CH3:43])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([CH:62]=[O:71])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=[O:4])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)C(CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 71 %

Procedure:
The title compound was prepared following the procedure described in method 1 for the preparation of intermediate 1, Step 5, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbaldehyde as the starting material. (71% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 9.69 (d, J=1.8 Hz, 1H), 5.58 (dd, J=6.7, 2.1 Hz, 1H), 4.89-4.54 (m, 2H), 2.90 (td, J=11.0, 5.8 Hz, 1H), 2.28-2.00 (m, 3H), 2.00-1.64 (m, 7H), 1.60-1.55 (m, 3H), 1.53-1.18 (m, 11H), 1.14 (s, 3H), 1.08 (d, J=7.8 Hz, 1H), 1.03 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H), 0.93 (s, 3H)
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[C:16]([C:17](=[O:19])[CH:18]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(=O)c3ccccc3s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1cc(-c2ccc(O)cc2)sc2ccccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer, 2-(4-methoxyphenyl)-thiochromen-4-one (500 mg, 1.86 mmol) and DCM (20 mL) were taken. The mixture was cooled to 0° C. and BBr3 (933 mg, 3.72 mmol, 1M solution in DCM) was added slowly at 0° C. Then the reaction mixture was stirred for overnight at rt under N2. The unreacted BBr3 was carefully quenched by addition of MeOH under cooling. Solvent was removed under reduced pressure to give crude product, which was purified by column chromatography using 5% MeOH in DCM to afford 2-(4-hydroxy-phenyl)-thiochromen-4-one (380 mg, 80%). MS (ES) m/z: 255.02 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]([CH2:12][CH:13]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH2:28])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].C(O)(=O)C.[CH:34](=O)[C:35]([CH3:38])([CH3:37])[CH3:36].C([BH3-])#N.[Na+]>CO.ClCCl>[CH3:1][O:2][C:3](=[O:29])[CH2:4][N:5]([CH2:12][CH:13]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH:28][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]
Reactant: CC(C)(C)C=O
Reactant: COC(=O)CN(CC(c1cc(Cl)ccc1N)c1ccccc1Cl)C(=O)C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CN(CC(c1ccccc1Cl)c1cc(Cl)ccc1NCC(C)(C)C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of N-[2-(2-amino-5-chlorophenyl)-2-(2-chlorophenyl)ethyl]-N-(trifluoroacetyl)glycine methyl ester (0.39 g) in methanol (5 ml) were added acetic acid (0.05 ml) and pivalaldehyde (78 mg). The mixture was stirred for 30 minutes at room temperature, to which was added sodium cyanoborohydride (57 mg). The mixture was stirred for one hour at room temperature, followed by addition of dichloromethane (50 ml) thereto. This solution was washed with a 1N aqueous solution of sodium hydroxide, then with water, followed by distilling off the solvent. The residue was purified by means of a silica-gel column chromatography (hexane:acetic acid ethyl ester=5:1 v/v as an eluent) to give 0.27 g of an oily compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:48])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:32]1[CH:31]=[C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:48])=[O:18])[CH:27]=2)=[O:29])[CH:35]=[CH:34][CH:33]=1)([OH:38])=[O:37]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1CCCCCCBr
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCCCCc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 32.6 %

Procedure:
Starting with 0.169 g (0.82 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.425 g (0.82 mmol) of 2-(6-bromohexyl)-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.157 g; 34.7% overall yield) was obtained as a white solid, mp 137°-139° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]2[CH2:9][CH2:10][C@:11]([CH2:14][CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20]/[CH:21]=[C:22](/[CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])\[CH3:23])\[CH3:18])([CH3:13])[O:12][C:4]=2[C:3]=1[CH3:30].[C:31]([O:34]C(=O)C)(=[O:33])[CH3:32].C(O)(=O)C>C(OCC)(=O)C.CCCCCCC>[CH3:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]2[CH2:9][CH2:10][C@:11]([CH2:14][CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20]/[CH:21]=[C:22](/[CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])\[CH3:23])\[CH3:18])([CH3:13])[O:12][C:4]=2[C:3]=1[CH3:30].[C:31]([O-:34])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC[C@]1(C)CCc2cc(O)c(C)c(C)c2O1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(=O)O
Product: CC(=O)[O-]

Procedure:
γ-Tocotrienol (crude product, prepared in accordance with Example 3, 4.8 g) was heated with 10 ml of acetic anhydride for 3.5 h under reflux and then freed from acetic acid and acetic anhydride under reduced pressure. Flash chromatography of the crude product with ethyl acetate/heptane as eluent on silica gel gave 3.7 g of γ-tocotrienol acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+].[C:19]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:24]=[CH:23][C:22]([S:25]([O:28][CH2:29][C:30](Cl)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=1>O.C1COCC1.C(OCC)C>[C:19]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:24]=[CH:23][C:22]([S:25]([O:28][CH2:29][C:30]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:31])(=[O:26])=[O:27])=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)COS(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(COS(=O)(=O)c1ccc(-c2ccccc2)cc1)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of p-aminobenzoic acid (43 mg, 0.31 mmol) and NaOH (12.5 mg, 0.31 mmol) in water (3 ml) was stirred at room temperature for 10 min until all of the solid material had dissolved. Na2CO3 (27 mg, 0.258 mmol) was then added and the mixture cooled to 0° C. A suspension of sulfonyl chloride 18 (106 mg, 0.341 mmol) in THF (1 ml) was injected rapidly and the resulting solution allowed to warm to room temperature and stirred for 2 h. Then reaction mixture was poured into a separating funnel containing diethyl ether. The phases were separated and the aqueous phase washed with a further portion of diethyl ether. The aqueous phase was acidified to pH 1 by addition of 1N HCl solution and the product extracted into ethyl acetate. The ethyl acetate was washed twice with 1N HCl solution and the organic phase was dried (Na2SO4), filtered and the solvent removed in vacuo. The resulting solid was recrystallized from hexane/ethyl acetate affording acid 20 as an off white powder (81 mg, 64%). δH (400 MHz, DMSO) 4.79 (2H, s, CH2), 7.45-7.70 (9H, m, ArH), 7.86-8.03 (4H, m, ArH), 10.43 (1H, NH); δc (100.6 MHz, DMSO) 68.2, 119.4, 126.5, 127.9, 128.6, 129.2, 129.6, 129.8, 131.1, 134.3, 138.7, 142.7, 146.7, 164.4, 167.5; MS (ES+) 411.7 (100%, [M+H]+).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:12]=[C:11](C(Cl)(Cl)Cl)[O:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][NH:18][CH3:19]>>[CH3:17][N:18]([CH3:19])[C:11]1[O:10][N:9]=[C:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: CNC
Reactant: ClC(Cl)(Cl)c1nc(Cc2ccccc2)no1
Product: CN(C)c1nc(Cc2ccccc2)no1

Procedure:
3-(Phenylmethyl)-5-(trichloromethyl)-1,2,4-oxadiazole is reacted with dimethylamine to yield 5-(dimethylamino)-3-(phenylmethyl)-1,2,4-oxadiazole.
Reaction SMILES: C([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][O:20]CC2C=CC=CC=2)[C@H:10]1[O:28]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.C(Cl)Cl>C(Cl)Cl>[OH:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH2:19][OH:20])[C@H:10]1[OH:28]
Reactant: O=C1N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)C[C@@H]2O1
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C1N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)C[C@@H]2O1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a solution of (3aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)hexahydrobenzo[d]oxazol-2(3H)-one (7.35 g, 15.5 mmol) in DCM (80 mL) at −78° C. was added a solution of BCl3 in DCM (1.0 M, 53 mL, 53 mmol). The mixture was slowly warmed up to 0° C. and stirred at this temperature for 4 h. The reaction was cooled to −78° C. again and a 1:1 mixture of MeOH-DCM (50 mL) was added dropwise to quench the reaction. Solvents were evaporated and the residue was treated with MeOH for three more times. The crude product was purified by silica gel column chromatography, eluted with 5%-15% MeOH in DCM to give the product of (3aR,4R,5R,6R,7aS)-4,5-dihydroxy-6-(hydroxymethyl)hexahydrobenzo[d]oxazol-2(3H)-one (2.99 g, 95%) as a white solid. 1H NMR (400 MHz, MeOD) δ 4.68-4.71 (m, 1H), 3.72 (dd, J=10.8 Hz, 3.4 Hz, 1H), 3.64 (dd, J=10.8 Hz, 5.2 Hz, 1H), 3.46 (t, J=7.2 Hz, 1H), 3.32 (t, J=8.7 Hz, 1H), 3.19 (t, J=9.4 Hz, 1H), 2.17-2.25 (m, 1H), 1.64-1.75 (m, 2H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Mg]Br.CN(C)[C:16]1[S:20][C:19]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:18]=2[C:17]=1[C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:31][CH:30]=1)=[O:28]>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:16]1[S:20][C:19]2[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:18]=2[C:17]=1[C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:31][CH:30]=1)=[O:28]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Reactant: Br[Mg]c1ccccc1C1OCCO1
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3C3OCCO3)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add a solution of 2-(1,3-dioxolan-2-yl)phenylmagnesium bromide (15 mL of 0.5 M/THF, 7.5 mmol) to a stirred solution of (2-dimethylamino-6-methoxy-benzo[b]thiophen-3-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (650 mg, 1.48 mmol) in THF (5 mL) at r.t. Stir the reaction mixture at r.t. for 2 h and quench with aq. NaHCO3. Dilute with CH2Cl2 and wash with water and brine, dry over MgSO4, filter and concentrate to afford [2-(2-[1,3]dioxolan-2-yl-phenyl)-6-methoxy-benzo[b]thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone. Use the product without further purification.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:26]=[C:27](C(F)(F)F)[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O.[H-].C([Al+]CC(C)C)C(C)C.CO.O>C1(C)C=CC=CC=1>[CH2:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[NH:14][CH:13]([OH:17])[CH:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:24][CH2:25]1)[C:5]1[CH:4]=[CH:3][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1NC(O)C(c2ccccc2)C12CCN(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(rac)-8-Benzyl-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3-dion (10.0 g, 30 mmol synthesis described in example 156) was dissolved in toluene (200 mL). Diisobutyl aluminium hydride (220 mL, 1M in THF, 220 mmol) was slowly added while cooling with an ice bath so that the reaction temperature did not exceed 10° C. The reaction mixture was stirred at room temperature for 2 days. A mixture of methanol (6 mL) and water (6 mL) was added at room temperature. The resulting gel was filtered through dicalit and washed with methylene chloride. The filtrate was evaporated to give 8-benzyl-3-hydroxy-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one as a mixture of diastereomers (8.0 g, 80%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][C:20](=[O:47])[CH:21]([NH:34][C:35](=[O:46])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br)[CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])([CH3:18])([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].N#N>C(#N)C>[C:15]([O:19][C:20](=[O:47])[CH:21]([NH:34][C:35](=[O:46])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:14])=[CH:12][CH:11]=1)[CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)C(CCC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCBr
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(OCCCCCCCCCC(=O)NC(CCC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Yield: 110.6 %

Procedure:
4-Hydroxy-benzoic acid tert-butyl ester (0.65 g, 3.08 mmol) was dissolved in acetonitrile (7.5 ml) and added to 2-(10-Bromodecanoylamino)pentanedioic acid 5-benzyl ester 1-tert-butyl ester (1.62 g, 3.08 mmol). Acetonitrile (90 ml) and K2CO3 (0.64 g, 4.62 mmol) was added and the mixture was refluxed for 16 h under a flow of N2. The solvent was removed under vacuum. AcOEt (100 ml) was added and the solution was washed with water (2×50 ml) using sat. NaCl and methanol to aid phase separation, dried over MgSO4, and concentrated to yield a light brown oil (2.18 g). The oil was purified by flash chromatography (silica, 95:5 DCM/AcOEt) to yield an oil (160 mg, 8%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C1COCC1>[CH2:10]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][N:23]([S:36]([C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=2)(=[O:37])=[O:38])[CH2:22][CH2:21]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Diisopropylethylamine (1.04 ml, 7.0 mmol) was added in one portion to a stirred solution of piperidin-4-yl-carbamic acid benzyl ester (0.74 g, 3.1 mmol) in THF (10 ml) at room temperature. To this mixture was added 4-nitrophenyl sulfonyl chloride (0.77 g, 3.5 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time the solvent was removed under vacuum and the resulting residue was partitioned between ethyl acetate (50 ml) and HCl (50 ml, 1M solution), the organic layer was separated and washed with brine (50 ml) before being dried (MgSO4), filtered and concentrated under vacuum. The resulting white solid was suspended in heptane and collected by filtration, washed with water (50 ml), heptane (50 ml) and TBME (50 ml) before being dried under vacuum to afford the title compound (1.3 g, 100% yield) as a white solid. Tr=2.09 min m/z (ES+) (M+H+) 420.