Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:28][OH:29]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])=[N:28][OH:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(C(F)(F)F)ccc2F)CC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C(=NO)c2cc(C(F)(F)F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 4-(2-fluoro-5-trifluromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (5 g, 0.013M) in pyridine (25 mL) was treated with hydroxylamine hydrochloride (1.11 g, 0.015 M -1.2 eq). The reaction was stirred under N2 at room temperature for 14 hours and then poured onto ice water (250 mL). The mixture was stirred at 0° C. for 1 hour, the product was then filtered off, washed with cold water (3×15 mL) and dried in a vacuum oven at 50° C. A white solid was obtained (5.03 g, 97%).
Reaction SMILES: COC1C=CC(C2(C3N4N=C(C5C=CC([N+]([O-])=O)=CC=5)C=NC4=NN=3)CC2)=CC=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2([C:41]3[N:45]4[N:46]=[CH:47][C:48]([C:50]5[CH:55]=[CH:54][C:53]([N+:56]([O-])=O)=[CH:52][CH:51]=5)=[N:49][C:44]4=[N:43][N:42]=3)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.CO>[Pt]>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2([C:41]3[N:45]4[N:46]=[CH:47][C:48]([C:50]5[CH:51]=[CH:52][C:53]([NH2:56])=[CH:54][CH:55]=5)=[N:49][C:44]4=[N:43][N:42]=3)[CH2:40][CH2:39]2)=[CH:36][CH:37]=1
Reactant: COc1ccc(C2(c3nnc4nc(-c5ccc([N+](=O)[O-])cc5)cnn34)CC2)cc1
Agent: [Pt]
Agent: COc1ccc(C2(c3nnc4ncc(-c5ccc([N+](=O)[O-])cc5)nn34)CC2)cc1
Solvent: CO
Product: COc1ccc(C2(c3nnc4nc(-c5ccc(N)cc5)cnn34)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Platinum (5.0 mg) on carbon (5%) was added to a 140 mg mixture of the two regioisomers: 3-[1-(4-methoxyphenyl)cyclopropyl]-6-(4-nitrophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazine and 3-[1-(4-methoxyphenyl)cyclopropyl]-7-(4-nitrophenyl)-[1,2,4]-triazolo[4,3-b][1,2,4]triazine in methanol (5.0 mL, 0.12 mol) under nitrogen. The mixture was stirred at RT under an atmosphere of hydrogen for 3 h, and was filtered. The filtrate was concentrated and subject to preparative RP-HPLC to afford two regioisomers. Analytical LCMS: (M+H)+=359.1. Isomer-I: Rt=1.565 min; Isomer-II: Rt=1.619 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[N:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[C:14]([O:28][CH3:29])[CH:13]=1)[C:5]2=[O:30].[BH4-].[Na+].C(N(C(C)C)CCOC1C=CC(N2C(O)C3C(=CC=CC=3)C2=O)=CC=1OC)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C1COCC1.C(O)(=O)C.ClCCl.C(O)(C)C>[CH:25]([N:21]([CH:22]([CH3:24])[CH3:23])[CH2:20][CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([N:6]2[CH2:7][C:8]3[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=3)[C:5]2=[O:30])=[CH:13][C:14]=1[O:28][CH3:29])([CH3:26])[CH3:27]
Reactant: COc1cc(N2C(=O)c3ccc(Br)cc3C2=O)ccc1OCCN(C(C)C)C(C)C
Agent: CC[SiH](CC)CC
Agent: COc1cc(N2C(=O)c3ccccc3C2O)ccc1OCCN(C(C)C)C(C)C
Agent: [BH4-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2Cc3ccccc3C2=O)ccc1OCCN(C(C)C)C(C)C
Reaction time: 2 h

Procedure:
A solution of 5-bromo-2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-isoindole-1,3-dione [Example A1] (66 mg, 0.14 mmol) was dissolved in THF (ml) and treated with sodium borohydride (5.2 mg, 0.14 mmol). After stirring for 2 hours, the mixture was treated with isopropanol, stirred for a further 1 h then treated with acetic acid (2 drops) and stirred for 16 h at RT. The solvent was removed and the residue purified by flash chromatography to give an approximately 1:1 mixture of the 5- and 6-bromo substituted isomers of 2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-3-hydroxy-2,3-dihydro-isoindol-1-one (37 mg). This material was dissolved in dichloromethane (2 ml) and treated with triethylsilane (1 ml) and trifluoroacetic acid (0.5 ml). The mixture was stirred at RT for 16 hours, the solvents were removed in vacuo and the residue purified by flash chromatography on silica gel (eluting with methanol-dichloromethane-aq. ammonia) to obtain 2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-isoindol-1-one as an approximately 1:1 mixture of 5- and 6-bromo isomers (33 mg). A solution of this material in benzene (5 ml) was treated with aqueous sodium carbonate (2M, 1 ml), ethanol (1 ml), phenylboronic acid (9 mg, 0.07 mmol) and tetrakis(triphenylphosphine)palladium[0] (10 mg) and the mixture heated to reflux for 16 h. The less dense phase was decanted, filtered through filter-aid (washing with dichloromethane), the filtrate evaporated and purified by flash chromatography on silica gel (eluting with dichloromethane-methanol-aq. ammonia) and reverse phase preparative chromatography (aq. MeCN, TFA) to give the title compounds as an approximately 1:1 mixture of isomers as their TFA salts;
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=2)=[CH:7][CH:6]=[C:5]([C:16]([O:18]C)=[O:17])[N:4]=1.[ClH:20]>O1CCOCC1>[ClH:20].[CH3:15][C:11]1[CH:10]=[C:9]([C:8]2[C:3](=[O:2])[NH:4][C:5]([C:16]([OH:18])=[O:17])=[CH:6][CH:7]=2)[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)c1ccc(-c2ccnc(C)c2)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(C(=O)O)[nH]c2=O)ccn1

Procedure:
Methyl 2-methoxy-2′-methyl-3,4′-bipyridine-6-carboxylate (C32) (1.25 g, 4.84 mmol) was dissolved in dioxane (40 mL) and aqueous hydrochloric acid (37%, 40 mL), and heated to reflux for 18 hours. The reaction was cooled and concentrated to dryness, azeotroped with toluene and methanol and again concentrated to dryness. This process was repeated twice and the resulting solid was triturated three times with a 1:2:0.5 mixture of ethyl acetate/heptane/methanol to give the title compound as a yellow solid. Yield: 1.30 g, 4.87 mmol, quantitative. LCMS m/z 231.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 2.76 (s, 3H), 7.08 (d, J=7.3 Hz, 1H), 8.24 (d, J=7.3 Hz, 1H), 8.31-8.38 (m, 2H), 8.76 (d, J=6.0 Hz, 1H), 12.2 (v br s, 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6]C(=O)CCCCCCCCCCCCC)=[N+:2]=[N-:3].[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([F:32])[CH:31]=1)[C:26](Cl)=[O:27].N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:26](=[O:27])[C:25]1[CH:24]=[C:23]([F:22])[CH:31]=[C:30]([F:32])[CH:29]=1)=[N+:2]=[N-:3]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=NCCNC(=O)c1cc(F)cc(F)c1
Yield: 59 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 3,5-difluorobenzoyl chloride (0.219 g, 1.24 mmol) was reacted with 2-azidoethanamine (0.107 g, 1.24 mmol) and triethylamine (0.251 g, 2.48 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-3,5-difluorobenzamide (0.280 g, 59%). 1H NMR (300 MHz, CDCl3) δ 7.32 (s, 2H), 7.29 (s, 1H), 6.91 (t, 1H), 3.58 (q, 2H), 3.51 (t, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 165.9, 164.7, 161.5, 161.4, 137.6, 110.7, 106.9, 50.7, 39.9 ppm; HRMS (ESI) calcd for C9H8F2N4O2S (M+) 226.0666. found 226.0662.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:19][CH2:20][S:21]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[C:6]2[C:5](=[O:41])[N:4]([CH3:42])[C:3]1=[O:43].CSC1NC(=S)NC(=S)N=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[SH:21][CH2:20][CH2:19][N:9]1[C:10]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[C:6]2[C:7]([N:2]([CH3:1])[C:3](=[O:43])[N:4]([CH3:42])[C:5]2=[O:41])=[CH:8]1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Agent: CC[SiH](CC)CC
Agent: CSc1nc(=S)[nH]c(=S)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCS)cc2n(C)c1=O

Procedure:
3-(1,3-Dimethyl-2,4-dioxo-6-(2-(tritylthio)ethyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (step 1)(573 mg, 0.983 mmol) was dissolved in DCM (20 ml) to form a clear brown solution and passed through 2×500 mg Isolute® Si-TMT (silica bound equivalent of 2,4,6-trimercatotriazine) cartridges to afford a colourless solution. The solution was placed under a nitrogen atmosphere and whilst stirring rapidly, treated dropwise with triethylsilane (1.571 ml, 9.83 mmol) followed TFA (3.79 ml, 49.2 mmol). After stirring at RT for 1 h, the reaction mixture was concentrated under reduced pressure to yield a white solid. The isolated crude product was triturated with diethyl ether and dried in a vacuum oven at 50° C. to afford the title compound;
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([F:61])[C:56]=1[C:62]1[CH:67]=[CH:66][C:65]([C:68](O)=[O:69])=[CH:64][CH:63]=1>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:68]([C:65]1[CH:64]=[CH:63][C:62]([C:56]2[C:57]([F:61])=[CH:58][CH:59]=[CH:60][C:55]=2[F:54])=[CH:67][CH:66]=1)=[O:69]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2c(F)cccc2F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 36 %

Procedure:
DIPEA (198.6 mg, 0.26 mL, 1.5 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (144.1 mg, 0.4 mmol) in DMF (4 mL). HOBT (50.7 mg, 0.37 mmol) and EDCI (163.6 mg, 0.85 mmol) were then added at room temperature. After 2 minutes, 2′,6′-difluoro-biphenyl-4-carboxylic acid (80 mg, 0.34 mmol) (prepared by the method as described above) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 65 mg (35.8% yield) of 2′,6′-difluoro-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 82.25%. 1H NMR (DMSO-d6): δ 8.8-8.7 (t, 1H), 8.0 (d, 2H), 7.9-7.7 (m, 2H), 7.7-7.6 (m, 1H), 7.6-7.5 (m, 4H), 7.3-7.2 (m, 2H), 4.2 (dd, 2H), 3.8-3.7 (m, 2H), 3.7-3.5 (m, 3H), 3.2-3.1 (m, 2H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:31])[CH2:13][CH:14]2[C:19](=[O:20])[NH:18][CH:17]=[CH:16][N:15]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:5][CH:4]=1.O=S(Cl)[Cl:34]>O1CCOCC1>[Cl:34][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=[O:31])[CH2:13][CH:14]2[C:19](=[O:20])[NH:18][CH:17]=[CH:16][N:15]2[S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)NCCc2ccc(CO)cc2)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)C2CC(=O)NCCc2ccc(CCl)cc2)cc1

Procedure:
To a suspension of N-[2-(4-hydroxymethyl-phenyl)-ethyl]-2-[3-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-pyrazin-2-yl]-acetamide (0.376 g, 0.85 mmol) in 1,4-dioxane (10 mL) was added SOCl2 (Aldrich, 0.25 mL, 3.4 mmol) at rt. The reaction mixture was concentrated in vacuo after 30 min. The crude product was used in next step without purification. MS (ESI): 464 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:17])/[C:5](=[CH:8]/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)/[CH2:6][CH3:7])C.[Li+].[OH-].O>C1COCC1.CCOC(C)=O.Cl>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)/[CH:8]=[C:5](\[CH2:6][CH3:7])/[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)/C(=C/c1cccc(OC)c1)CC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC/C(=C\c1cccc(OC)c1)C(=O)O
Temperature: 25 °C
Yield: 72 %

Procedure:
(E)-Ethyl-2-(3-methoxybenzylidene)butanoate (300 mg, 1.28 mmol) was dissolved in THF (30 mL), and LiOH (61 mg, 2.56 mmol), and water (100 μL) were added. The reaction mixture was heated to reflux for 48 h and then cooled to rt. The reaction mixture was diluted with EtOAc and 1N HCl. The aqueous phase was extracted with EtOAc and the combined organic solutions were dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, 0-70% EtOAc with 1% acetic acid in DCM) provided the title compound (190 mg). 1H NMR (400 MHz, d6-DMSO): δ 7.52 (s, 1H), 7.37-7.33 (dd, 1H), 6.99 (d, 1H), 6.95-6.93 (m, 2H), 3.77 (s, 3H), 2.43 (q, 2H), and 1.10 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:15]([OH:17])[CH3:16]>CN(C)C=O>[CH2:15]([O:17][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1)[CH3:16]
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(NC)n1

Procedure:
A procedure similar to that described in Preparation 88 was repeated, except that 6.00 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66), 1.54 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.1 ml of ethanol and 150 ml of dimethylformamide were used. After working up the product as described in Preparation 88, the resulting crude product was crystallized by trituration with ethanol, to give 5.10 g of the title compound, melting at 101° C.
Reaction SMILES: [C:1]([N:4]1[C@@H:8]([C:9]([OH:11])=[O:10])[C:7]([CH3:13])([CH3:12])[S:6][C@H:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:3])[CH3:2].[C:20]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[S:25][CH:24]1[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1O)(=[O:22])[CH3:21].N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C>[C:20]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=2[S:25][CH:24]1[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[O:10][C:9]([C@H:8]1[C:7]([CH3:13])([CH3:12])[S:6][C@@H:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:4]1[C:1](=[O:3])[CH3:2])=[O:11])(=[O:22])[CH3:21]
Reactant: COc1ccc(O)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Reactant: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CN(C)C=O
Product: COc1ccc(OC(=O)[C@@H]2N(C(C)=O)[C@H](c3ccccc3)SC2(C)C)c(C2Sc3cc(Cl)ccc3N2C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
A solution of (2S,4S)-3-acetyl-5,5-dimethyl-2-phenyl-4-thiazolidinecarboxylic acid [compound described in Reference Example 4 (b)] (102 g, 0.38 mol) in anhydrous DMF (500 ml) was added to a solution of 3-acetyl-6-chloro-2-(2-hydroxy-5-methoxyphenyl)-benzothiazoline (127 g, 0.38 mol) in anhydrous DMF (500 ml) at room temperature. N,N-Dimethylaminopyridine (5.58 g, 45.7 mmol) was added thereto under a nitrogen-atmosphere at room temperature with stirring. After ice-cooling, diethyl azodicarboxylate (87 g, 0.50 mol) was added thereto. The mixture was stirred under ice-cooling for 15 minutes, at room temperature for one hour and further at an internal temperature of about 40° C. for three days. The reaction mixture was concentrated under reduced pressure, a 10% aqueous citric acid solution (1,000 ml) was added to the residue, and the whole was extracted with ethyl acetate (1,000 ml). The organic layer was washed with water (1,000 ml) and saturated brine (1,000 ml) successively and dehydrated with magnesium sulfate, and ethyl acetate was evaporated under reduced pressure. A mixed solvent (ethanol/diisopropyl ether=200 ml/1000 ml) was added to the residue, the residue was dissolved by heating, and then the solution was allowed to stand at room temperature overnight. The precipitated crystals were filtered off and dried to give 34.7 g of the target compound. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase:hexane/ethyl acetate=1/1) to give further 43.8 g of the target compound (total 43%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C@@H:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@H:6]2[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:21][CH:20]=1.Cl.N1C=CC=CC=1>CO.O.ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C@@H:7]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@H:6]2[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1)[C@H](c1ccc(OCCN3CCCC3)cc1)[C@H](c1ccccc1)CO2
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: Oc1ccc2c(c1)[C@H](c1ccc(OCCN3CCCC3)cc1)[C@H](c1ccccc1)CO2
Temperature: 135 °C
Reaction time: 18 h

Procedure:
A mixture of (±)-cis-6-methoxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane (0.34 g, 0.79 mmol) and pyridine hydrochloride (0.91 g, 7.9 mmol) was stirred at 135° C. for 18 h, cooled to room temperature and the resulting dark solid dissolved in a mixture of methanol (10 ml), water (50 ml) and dichloromethane (50 ml). The aqueous layer was separated and further extracted with 4:1 dichloromethane /methanol (50 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate, and evaporated. The product was purified by column chromatography on silica gel 60, with 5% methanol in di-chloromethane as eluent. The resulting gum was dissolved in approximately 1 ml ethanol and then diethylether added. This resulted in the precipitation of the title compound as a partial hydrochloride salt. The solid was dissolved in dichloromethane, washed with sodium hydrogen carbonate solution, brine, dried over magnesium sulfate and evaporated to give the title compound as a pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11]CC=C)[CH:6]=[O:7].[OH-].[Na+].[C:17]1(C)[CH:22]=C(C)C=C(C)[CH:18]=1>>[CH2:22]([C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[OH:11])[CH:6]=[O:7])[CH:17]=[CH2:18]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1ccc(C=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(C=O)cc(OC)c1O

Procedure:
3-Methoxy-4-(2-propenyloxy)benzaldehyde (19.7 g, 0.100 mol) was heated under reflux in 75 ml mesitylene (1,3,5-trimethylbenzene) for 20 hours. After cooling, 250 ml 2N sodium hydroxide were added to the reaction mixture. The aqueous phase was washed two times with diethyl ether. The aqueous phase was subsequently acidified with concentrated hydrochloric acid under ice cooling and then extracted with ethyl acetate. After drying and concentrating the organic phase, there remained a light orange-colored oil that crystallized on cooling.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:10])[C:5]([CH2:11][S:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][N:3]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH:9]=[O:10])[C:5]([CH2:11][S:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][N:3]=1
Reactant: Cc1ncc(CSC(=O)c2ccccc2)c(CO)c1O
Solvent: ClC(Cl)Cl
Product: Cc1ncc(CSC(=O)c2ccccc2)c(C=O)c1O
Reaction time: 0.5 h

Procedure:
A solution of the 10 g. of the product from Step B in 300 ml. of hot chloroform was treated with 100 g. of maganese dioxide. After 1/2 hour of stirring, the mixture was filtered and the filtrate was evaporated to dryness to give 9.2 g. of 2-methyl-3-hydroxy-4-formyl-5-benzoylthiomethylpyrididne, m.p. 127°-130° C.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][CH:11]([C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([F:6])[CH3:5]>CCOCC.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]([C:7]1[CH:8]=[C:9]([CH:26]=[CH:27][CH:28]=1)[CH2:10][CH:11]([CH:17]([C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[OH:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([F:6])[CH3:5]
Reactant: CCOC(=O)C(Cc1cccc(C(C)(F)F)c1)C(=O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(C(C)(F)F)c1)C(O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a suspension (40 ml) of zinc chloride (5.35 g, 39.2 mmol) in ether was added sodium borohydride (2.97 g, 78.4 mmol) at room temperature, and the mixture was stirred as it was for 2 hrs. Insoluble material was filtered off. To the filtrate was added a solution of ethyl 2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-oxopropionate (7.16 g, 19.6 mmol) in ether (40 ml), and the mixture was stirred at room temperature for 1.5 hrs. The reaction was quenched with 1N hydrochloric acid, and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The mixture was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1, 4:1) to give ethyl (2RS,3RS)-2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionate (6.24 g, 87%) as a colorless transparent oil.
Reaction SMILES: O=[C:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH2:19][Mg]Br.ClC1C=C(C=CC=1Cl)/C=C1\CCC2NC(C(OC)=O)=CC\1=2>[Pd]>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH2:19][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: COc1cccc(C[Mg]Br)c1
Agent: [Pd]
Agent: COC(=O)c1cc2c([nH]1)CC/C2=C\c1ccc(Cl)c(Cl)c1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(OC)c1

Procedure:
The title compound was synthesized in two steps. First, methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (447 mg, 2.5 mmol) was reacted with 3-methoxybenzylmagnesium bromide (0.25 M in hexanes, (25 mL, 6.3 mmol) according to General Procedure 3. The resulting exo-olefin ((E)-methyl 4-(3-methoxybenzylidene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) was then converted to the title compound by hydrogenation according to General Procedure 6 (with 5% Pd/C). The crude product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 40% EtOAc to afford the title compound. 155 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.04-2.21 (m, 1H) 2.50-2.63 (m, 1H) 2.62-2.71 (m, 2H) 2.72-2.86 (m, 2H) 3.23-3.36 (m, 1H) 3.81 (s, 6H) 6.44 (d, J=1.56 Hz, 1H) 6.72-6.85 (m, 3H) 7.22 (t, J=7.78 Hz, 1H) 8.76 (br. s, 1H).