Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.Cl[CH2:21]Cl.[OH-].[Na+].S(OC)(OC)(=O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
Dissolve 5.4 g. (0.02 moles) of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (e.g. product of Example 3) in 35 ml. of dichloromethane and add to this solution 1.2 g. of NaOH (1.5 moles) dissolved in 17 ml. of water. Cool the mixture with good agitation to 0° C. and add slowly 3.8 g. (0.03 moles) of dimethyl sulfate with good cooling and stirring. After all the dimethyl sulfate is added remove the cooling bath and continue stirring for an additional 2 hours. Add water and methylene chloride to the reaction mixture. Separate the layers and wash the methylene chloride layers with water. Dry the organic solution over anhydrous sodium sulfate and evaporate. After recrystallization, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one is obtained which after drying under vacuum at 110° C. shows a melting point of 129.5°-130.5° (corr.) and no depression on mixed melt with an authentic sample.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=[N:44][C:39]2[CH:40]=[CH:41][CH:42]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(CN)CC1>CN(C=O)C>[CH:40]1([CH2:39][NH:44][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([B:11]3[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:16])([CH3:17])[O:15]3)[CH:4]=2)[CH2:42][CH2:41]1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (Intermediate 4) (2.0 g) DIPEA (4-ml) and HATU (3.05 g) were dissolved in DMF (20 ml) and stirred at room temp for 15 min. Cyclopropylmethylamine (568 mg) was added and the mixture was stirred at room temp for 18 h. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (250 ml) and water (50 ml). The organic phase was washed with hydrochloric acid (2N, 50 ml) and aqueous sodium bicarbonate (1M, 50 ml) dried (magnesium sulphate) and concentrated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane/ethyl acetate (4:1) to give the title compound (1.73 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CS([C:20]1[N:25]=[CH:24][C:23]2=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])[N:22]2[N:21]=1)=O.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[OH:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20]3[N:25]=[CH:24][C:23]4=[CH:26][CH:27]=[C:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])[N:22]4[N:21]=3)=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: Nc1ccc(N2CCN(CCO)CC2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc(N4CCN(CCO)CC4)cc3)nn12)S(C)(=O)=O
Temperature: 120 °C

Procedure:
Into a 8-dram vial, 2-[4-(4-Amino-phenyl)-piperazin-1-yl]-ethanol (0.134 g, 0.604 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (0.100 g, 0.274 mmol), Cesium fluoride (0.104 g, 0.686 mmol), N,N-Diisopropylethylamine (0.1051 mL, 0.6036 mmol) and tert-Butyl alcohol (1.50 mL) were added. The reaction was heated at 120° C. overnight. LCMS suggested presence of desired product. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-[2-(2-{4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a yellow solid (48 mg, 34%). LCMS (E/I+) 522.16 (M+H). NMR 1H (DMSO-d6)-9.15 (bs, 1H), 9.24 (s, 1H), 8.94 (s, 1H), 8.02 (d, 1H, J=7.91 Hz), 7.66 (d, 1H, J=7.34 Hz), 7.47-7.62 (m, 4H), 6.98 (d, 1H, J=4.52 Hz), 6.93 (d, 1H, J=4.52), 6.87 (d, 1H, J=8.47 Hz), 3.77 (bs, 2H), 3.70 (d, 2H, J=12.98 Hz), 3.58 (d, 2H, J=12.86 Hz), 3.13-3.30 (m, 2H), 3.08 (s, 1H), 2.97 (t, 2H, J=12.42 Hz), 2.89 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]1=[O:25])[C:6]([O:8][CH3:9])=[O:7].C(N(C(C)C)C(C)C)C.[Cl:35][C:36]1[CH:37]=[C:38]([F:43])[C:39](F)=[N:40][CH:41]=1>CN(C=O)C.CCOC(C)=O>[Cl:35][C:36]1[CH:37]=[C:38]([F:43])[C:39]([N:22]2[CH2:23][CH2:24][CH:19]([N:16]3[CH2:17][CH2:18][C@H:14]([O:13][C:12]4[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=4[F:2])[C:15]3=[O:25])[CH2:20][CH2:21]2)=[N:40][CH:41]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: COC(=O)c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)c(F)c1
Temperature: 60 °C
Yield: 54.6 %

Procedure:
To a solution of (S)-methyl 3-fluoro-4-(2-oxo-1-(piperidin-4-yl)pyrrolidin-3-yloxy)benzoate hydrochloride (Example 151, Step B; 2.0 g, 5.9 mmol) in DMF (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (3.8 g, 30 mmol) and 5-chloro-2,3-difluoropyridine (2.7 g, 18 mmol) and the reaction was heated to 60° C. overnight. The reaction was next diluted with EtOAc (30 mL) and washed with water (30 mL), and brine (30 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified on silica using a gradient of DCM to 1:19 EtOAc:DCM as eluent to yield (S)-methyl 4-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoate (1.5 g, 54%)
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1
Reactant: Cn1c(C2CCN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1c(C2CCNC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 165.8 %

Procedure:
tert-Butyl 3-(1-methyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (93 mg) was dissolved in CH2Cl2 (3 mL) and 4 M HCl in dioxane (1 mL) was added. The mixture was stirred at rt for 3 h and concentrated to leave 1-methyl-2-(pyrrolidin-3-yl)-1H-benzo[d]imidazole (103 mg) as a red solid. LC-MS Method 1 tR=0.40 min, m/z=202.
Reaction SMILES: [CH:1]([C:3]1[CH:20]=[CH:19][C:6]2/[C:7](=[CH:16]/[C:17]#[N:18])/[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1)=[O:2].[CH3:21][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[OH:2][CH:1]([C:3]1[CH:20]=[CH:19][C:6]2/[C:7](=[CH:16]/[C:17]#[N:18])/[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1)[CH3:21]
Reactant: C[Mg]Cl
Reactant: N#C/C=C1\c2ccccc2CCc2cc(C=O)ccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: -10 °C
Yield: 91.7 %

Procedure:
[step 2] (E)-(2-Formyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)acetonitrile (218 mg, 0.84 mmol) obtained in step 1 was dissolved in THF (4 mL), methylmagnesium chloride (3 mol/L THF solution; 0.42 mL, 1.26 mmol) was added at −78° C., and the mixture was warmed to −10° C. over 40 min. Saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 50/50) to give (E)-[2-(1-hydroxyethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (212 mg, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([S:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([N+:21]([O-])=O)[CH:14]=2)(=[O:11])=[O:10])[CH:6]=[C:5]([O:24][CH3:25])[C:4]=1[O:26][CH3:27].O.O.Cl[Sn]Cl>CO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][S:9]([C:7]2[CH:6]=[C:5]([O:24][CH3:25])[C:4]([O:26][CH3:27])=[C:3]([O:2][CH3:1])[CH:8]=2)(=[O:11])=[O:10])=[CH:14][C:15]=1[NH2:21]
Reactant: COc1ccc(CS(=O)(=O)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: COc1ccc(CS(=O)(=O)c2cc(OC)c(OC)c(OC)c2)cc1N

Procedure:
A solution of Example 91A (490 mg, 1.23 mmol) in methanol (10 mL) was treated with SnCl2.2H2O (1.39 g; 6.17 mmol), heated to reflux for 1 hour, and concentrated. The concentrate was partitioned between saturated NaHCO3 and ethyl acetate, and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/dichloromethane to provide the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:16])([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:9]=[CH2:10])[CH:5]=[C:4](F)[CH:3]=1.FC1C=C(C(O)(C(F)(F)F)C(F)(F)F)C=C([S:25]CC[Si](C)(C)C)C=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:16])([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[CH:9]=[CH2:10])[CH:5]=[C:4]([SH:25])[CH:3]=1
Reactant: C=CC(O)(c1cc(F)cc(F)c1)c1nccs1
Reactant: C[Si](C)(C)CCSc1cc(F)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Product: C=CC(O)(c1cc(F)cc(S)c1)c1nccs1

Procedure:
Following the procedure described for Thiophenol 1, Step 3, but substituting the 5-fluoro-3-[3-hydroxy-3-(thiazol-2-yl)propen-3-yl]-1-(2-trimethylsilylethylthio)benzene from Step 4 for 5-fluoro-3-(hexafluoro-2-hydroxyprop-2-yl)-1-(2-trimethylsilylethylthio)benzene as starting material, the title compound was obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([F:18])[CH2:4]1)[CH3:2].ClCCl.[H][H]>CO>[CH2:1]([N:3]1[CH2:8][CH2:7][C@@H:6]([NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:5]([F:18])[CH2:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCC(NC(=O)c2ccccc2)=C(F)C1
Solvent: CO
Solvent: ClCCl
Product: CCN1CC[C@@H](NC(=O)c2ccccc2)[C@@H](F)C1
Temperature: 40 °C
Reaction time: 20 h
Yield: 108.8 %

Procedure:
A 50 L autoclave was purged with nitrogen. N-(1-ethyl-3-fluoro-1,2,5,6-tetrahydro-pyridin-4-yl)benzamide (6.00 kg, 24.16 mol) was dissolved in methanol (19 L) and dichloromethane (1 L) and transferred to the inert autoclave. After four high vacuum—nitrogen fill cycles the prepared catalyst solution (6.5 L) was added to the autoclave. The reaction was pressurized with hydrogen gas to 20 bar and left to stand at 1000 rpm for 20 h at room temperature, was heated to 40° C. for 7 h, and then cooled to 25° C. Following a nitrogen purge the contents of autoclave were transferred into a 60 L reactor with methanol (2.0 L). Deloxan THPII (2.4 kg, 40 mass %) was added, and stirred at 500 rpm for 3 days at room temperature. The suspension was filtered over Arbocel (0.7 kg) applying high vacuum, the filter cake was washed with methanol (5.0 L), and solvent evaporated at 20 mbar and 45° C. Obtained 6.58 kg of N-((3S,4R)-1-ethyl-3-fluoropiperidin-4-yl)benzamide which was used without further purification. 1H NMR (400 MHz, MeOD) δ 7.83 (2H, t, J=9.1 Hz), 7.53 (1H, t, J=7.3 Hz), 7.45 (2H, t, J=7.6 Hz), 4.84 (1H, d, J=49.28 Hz), 4.25-3.91 (1H, m), 3.37-3.22 (2H, m), 3.10-2.95 (1H, m), 2.60-2.39 (2H, m), 2.32-2.02 (3H, m), 1.79 (1H, d, J=12.3 Hz), 1.11 (3H, t, J=7.2 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH3:15])[C:11]1=[O:16].C(N(CC)CC)C>ClCCl.CS(C)=O>[CH3:15][N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][CH:8]=[O:7])[C:11]1=[O:16]
Reactant: CN1CCC(CCO)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCC(CC=O)C1=O
Reaction time: 0.25 h
Yield: 58 %

Procedure:
A solution of dimethylsulphoxide (1.7 ml) in dichloromethane (10 ml) was added dropwise over 5 min to a stirred solution of oxalyl chloride (1.0 ml) in dichloromethane (20 ml) at - 72° under nitrogen. The resultant solution was stirred at - 72° for 5 min then a suspension of 3-(2-hydroxyethyl)-1-methyl-2-pyrrolidinone (1.30 g) in dichloromethane (10 ml) and dimethylsulphoxide (1 ml; added to improve dissolution of the alcohol) was added dropwise over 8 min. The resultant cloudy solution was stirred at - 72° for 15 min then treated with triethylamine (7.0 ml). The resultant suspension was warmed to room temperature and stirred at room temperature for 1 h. The suspension was filtered. The residue was washed with ethyl acetate. The combined filtrate and washings were evaporated to give a semi-solid which was chromatographed using a mixture of ethyl acetate and methanol (5:1) as the eluent, to give the title compound (743 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:26])[CH:24]=[O:25])[CH3:2].[BH4-].[Li+]>CO.CO.O.C1COCC1>[CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6](=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:26])[CH2:24][OH:25])[C:7](=[O:13])[O:8][CH2:9]2)[CH3:2]
Reactant: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)C=O)C(=O)OC2
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CO)C(=O)OC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal (77.6 mg, 0.207 mmol) was dissolved in MeOH (4 mL). A solution of CeCl3 (51.1 mg, 0.207 mmol) in MeOH/water (9/1, 0.66 mL) was added and the solution was cooled to 0° C. A solution of lithium borohydride in THF (2M, 0.105 mL) was added dropwise. After 15 minutes, the reaction was quenched with 1N HCl (0.5 mL). The MeOH was removed in vacuo and the crude material was partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organic layers were washed with sodium bicarbonate solution and dried over sodium sulfate. Filtration and evaporation of solvents yielded a crude oil, which was purified by silica gel chromatography to provide 57.2 mg (73%) of the desired product. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz, 3H), 1.26 (m, 2H), 1.86 (s, 3H), 2.19 (s, 3H), 2.72 (q, J=7.8 Hz, 2H), 3.52 (d, J=6.3 Hz, 2H), 3.99 (s, 2H), 4.34 (m, 2H), 5.14 (s, 2H), 5.32 (m, 1H) ppm.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]([CH3:19])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])[CH2:7][N:6]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO.O>[CH2:20]([N:6]1[CH2:7][CH:8]([N:10]([CH3:19])[C:11]([O:13][CH2:14][C:15]([Cl:18])([Cl:16])[Cl:17])=[O:12])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(=O)OCC(Cl)(Cl)Cl)CN1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(C(=O)OCC(Cl)(Cl)Cl)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
To a solution of (2S,4S)-1-benzyl-4-[methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester in THF and methanol is added NaOH in water, and the reaction mixture is stirred overnight, and extracted with EA. The aqueous solution is acidified to ph 5-6 and extracted with EA. The organic phase is washed, dried and concentrated to give 1-benzyl-4-[methyl-(2,2,2-trichloro-ethoxycarbonyl)-amino]-pyrrolidine-2-carboxylic acid (28).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:21][CH:20]=3)[C@H:8]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1ccccc1)[C@H]2c1ccc(OCCCN2CCCCC2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-3-phenyl-4-(4-(3-piperidinopropoxy)phenyl)chromane (0.114 g, 0.25 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white foam.
Reaction SMILES: [Si:1]([C:8]1[S:9][CH:10]=[C:11]([CH2:13][C@H:14]2[C@@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[O:17][C:16]([CH3:29])([CH3:28])[N:15]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:38][CH2:39][CH2:40][CH2-].ICCC>C1COCC1>[Si:1]([C:8]1[S:9][C:10]([CH2:38][CH2:39][CH3:40])=[C:11]([CH2:13][C@H:14]2[C@@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:23])[CH3:22])[O:17][C:16]([CH3:29])([CH3:28])[N:15]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:12]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2csc([Si](C)(C)C(C)(C)C)n2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: [CH2-]CCC
Agent: [Li+]
Solvent: CCCI
Solvent: C1CCOC1
Product: CCCc1sc([Si](C)(C)C(C)(C)C)nc1C[C@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N1C(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 1 h

Procedure:
(4S,5S)-Tert-butyl 4-((2-(tert-butyldimethylsilyl)thiazol-4-yl)methyl)-5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.150 g, 0.269 mmol) in THF (3 mL) was cooled to −78° C. when N-BUTYLLITHIUM (2.5 M in hexanes) (0.1 19 ml, 0.296 mmol) was added dropwise. The solution was warmed to −50° C. for 40 minutes and then cooled to −78° C. 1-Iodopropane (0.0549 g, 0.323 mmol) was added dropwise and the solution was allowed to slowly warm to −50° C. and stirred for 1 hr. The reaction was quenched with saturated ammonium chloride. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate to afford the title compound, which was used without further purification for the next step.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([O:26][CH2:27][CH3:28])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH3:25].[Li+].[OH-]>>[C:21]([C:17]1[O:18][C:19]([CH3:20])=[C:15]([CH2:14][O:13][C:9]2[CH:10]=[C:11]([CH3:12])[C:6]([CH2:5][C@H:4]([O:26][CH2:27][CH3:28])[C:3]([OH:29])=[O:2])=[C:7]([CH3:25])[CH:8]=2)[N:16]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: CCO[C@@H](Cc1c(C)cc(OCc2nc(C(C)(C)C)oc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2nc(C(C)(C)C)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 46 d], (S)-3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-2,6-dimethyl-phenyl]-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-[4-(2-tert-butyl-5-methyl-oxazol-4-ylmethoxy)-2,6-dimethyl-phenyl]-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=1)[C:5]#[N:6].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=2[O:21]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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:21]1[C:22]2[CH:23]=[CH:24][C:25]([C:2]3[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[CH:9]=3)[C:5]#[N:6])=[CH:26][C:27]=2[O:28][CH2:20]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: COc1ccc(COc2cc(Br)cc(C#N)c2)cc1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(COc2cc(C#N)cc(-c3ccc4c(c3)OCO4)c2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a solution of 3-bromo-5-(4-methoxy-benzyloxy)-benzonitrile (1.1 g) in 1,2-dimethoxyethane (10 mL) were added 3,4-methylenedioxyphenylboronic acid (860 mg), 2 M aq. sodium carbonate solution (3.5 mL) and Pd(PPh3)4 (40 mg) and the resulting mixture was stirred at 90° C. for 4 h. Then the reaction mixture was diluted with ethyl acetate, filtered through Celite and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, filtered through a silica pad, concentrated and triturated with diethyl ether to yield 1.0 g of the title compound (89% yield). HRMS calcd for C22H17O4N M+ 359.1158, observed 359.1158.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.[CH2:15]([NH:17][CH3:18])[CH3:16].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:15]([N:17]([CH3:18])[C:12]([C:4]1[CH:3]=[C:2]([OH:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[O:14])[CH3:16]
Reactant: CCNC
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C)C(=O)c1cc(O)c2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.5 %

Procedure:
4-Hydroxyquinoline-2-carboxylic acid (1.00 g, 5.29 mmol) was dissolved in DMF (10 mL), and N-ethylmethylamine (91 μL, 10.6 mmol), WSC.HCl (2.03 g, 10.6 mmol), and HOBt.H2O (1.62 g, 10.6 mmol), were added thereto, and the mixture was stirred at room temperature for 3 hours. To the mixture, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=95/5) to give N-ethyl-4-hydroxy-N-methyl-quinoline-2-carboxamide (615 mg, 2.67 mmol, yield: 50%). Mass (m/e): 231 (M+H)+.