Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[C:12]([CH:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:14][CH:15]=O)=[CH:11][C:10]3[C:6](=[C:7]([C:28]([NH:30][CH3:31])=[O:29])[N:8]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.C1(C2C(C(S(C)(=O)=O)CC(O)O)=CC3C(=C(C(NC)=O)N(C4C=CC(C)=CC=4)N=3)C=2)CC1.C1(P(=[CH:83][C:84]([O:86][CH2:87][CH3:88])=[O:85])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH:1]1([C:4]2[C:12]([CH:13]([S:17]([CH3:20])(=[O:18])=[O:19])[CH2:14][CH:15]=[CH:83][C:84]([O:86][CH2:87][CH3:88])=[O:85])=[CH:11][C:10]3[C:6](=[C:7]([C:28](=[O:29])[NH:30][CH3:31])[N:8]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CNC(=O)c1c2cc(C3CC3)c(C(CC=O)S(C)(=O)=O)cc2nn1-c1ccc(C)cc1
Agent: CNC(=O)c1c2cc(C3CC3)c(C(CC(O)O)S(C)(=O)=O)cc2nn1-c1ccc(C)cc1
Solvent: ClCCl
Product: CCOC(=O)C=CCC(c1cc2nn(-c3ccc(C)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of an approximately 1:1 mixture of racemic 5-cyclopropyl-N-methyl-2-(4-methylphenyl)-6-[1-(methylsulfonyl)-3-oxopropyl]-2H-indazole-3-carboxamide (v) and compound (vi) (16 mg, 0.036 mmol) in DCM (10 mL) under argon was added ethyl (triphenyl-λ5-phosphanylidene)acetate (20 mg, 0.057 mmol), and the reaction was stirred at RT under argon for 1 h. The reaction mixture was evaporated to dryness and purified by flash column chromatography eluting with EtOAc/heptane (50-100%) to give racemic ethyl 5-[5-cyclopropyl-3-(methylcarbamoyl)-2-(4-methylphenyl)-2H-indazol-6-yl]-5-(methylsulfonyl)pent-2-enoate (vii) as a mixture of E and Z isomers (≈4:1) as an oil (18 mg, 99%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=[C:16]2[O:24][C@H:25]3[CH2:51][N:28]([C:29](=[O:50])[C@H:30]([CH:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)[NH:31][C:32](=[O:44])[O:33][C@@H:34]4[CH2:43][CH2:42][CH2:41][C@H:35]4[CH2:36][CH2:37][CH:38]=[CH:39][CH2:40][C:15]=12)[C@H:27]([C:52]([NH:54][C@:55]1([C:60](=[O:68])[NH:61][S:62]([CH:65]2[CH2:67][CH2:66]2)(=[O:64])=[O:63])[CH2:57][C@H:56]1[CH:58]=[CH2:59])=[O:53])[CH2:26]3)(C(C)(C)C)(C)C>C1COCC1>[CH:45]1([C@H:30]2[C:29](=[O:50])[N:28]3[CH2:51][C@@H:25]([CH2:26][C@H:27]3[C:52]([NH:54][C@:55]3([C:60](=[O:68])[NH:61][S:62]([CH:65]4[CH2:66][CH2:67]4)(=[O:63])=[O:64])[CH2:57][C@H:56]3[CH:58]=[CH2:59])=[O:53])[O:24][C:16]3=[N:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])=[C:15]3[CH2:40][CH:39]=[CH:38][CH2:37][CH2:36][C@@H:35]3[CH2:41][CH2:42][CH2:43][C@H:34]3[O:33][C:32](=[O:44])[NH:31]2)[CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OCCCCO[Si](C)(C)C(C)(C)C)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OCCCCO)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OCCCCO[Si](C)(C)C(C)(C)C)O2)C(=O)NS(=O)(=O)C1CC1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OCCCCO)O2)C(=O)NS(=O)(=O)C1CC1
Temperature: 50 °C

Procedure:
To a solution of the product of Step 1 (50 mg) in THF (0.5 mL) was added HF-TEA (0.334 mL) at room temperature. The solution was heated to 50° C. for 30 minutes. The reaction mixture was concentrated to remove THF and then diluted with EtOAc (10 mL) and water was added (10 mL). To that mixture was added Na2CO3 (353 mg) portion wise at 0° C. When the quench was complete, the layers were separated. The organic layer was washed with 10% Na2CO3, water and brine. The aqueous layer was re-extracted with ethyl acetate (2×). The combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (40-100% ACN/water with 0.15% TFA) afforded the desired product (7.2 mg) after workup with NaHCO3 and ethyl acetate. HRMS (ES+) m/z 862.4073 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11](OCC)(=[O:13])[CH3:12]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[N:1]1[CH:2]=[CH:3][CH:4]=[C:5](/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:12][CH2:11][OH:13])[CH:10]=1
Reactant: CCOC(C)=O
Reactant: c1ccc2ncccc2c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Product: OCCCC/C=C\c1cccnc1
Yield: 73 %

Procedure:
A solution of 45 ml (0.47 mol) of 3-bromopyridine and 52 g (0.53 mol) of 5-hexyn-l-ol in 150 ml of triethylamine and 500 ml of dichloromethane is degassed for 15 minutes with argon, and 3 g (4,3 mmol) of bis(triphenylphosphine)palladium(II)chloride and 450 mg of cuprous iodide is added. The mixture is heated at reflux for 3 h. The cooled reaction mixture is diluted with 1 liter of dichloromethane and is washed with water and brine, dried (K2CO3), concentrated and bulb-to-bulb distilled (b.p. 120°-130° C./0.05 mbar), to give 63 g of 6-(3-pyridyl)hex-5-ynol as a yellow oil, which is dissolved in 500 ml of ethyl acetate and af ter addition of 15 ml of quinoline is hydrogenated f or 5 h over 6 g Lindlar catalyst (Pb-poisoned Pd catalyst) in a Parrhydrogenator. The crude product is evaporatively distilled (b.p. 120°-130° C./0.05 mbar), yielding 61 g (73%) of (Z)-6-(3-pyridyl)hex-5-enol as a colourless viscous liquid. (C11H15NO; F.W. 177.3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][CH:16]([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18])[CH:5]=[N:6][CH:7]=1
Reactant: Oc1cncc(Cl)c1
Reactant: CCC(Br)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(Oc1cncc(Cl)c1)C(=O)OC
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
5-Chloro-3-pyridinol (10.0 g) was dissolved in anhydrous N,N-dimethyl formamide (150 ml) containing anhydrous potassium carbonate (21.2 g) and methyl 2-bromobutyrate (16.4 ml). The mixture was stirred at 70° C. for 1.5 hours and allowed to cool to ambient temperature. The mixture was poured into water, extracted with diethyl ether (three times) and the combined extracts were washed with water (twice), dried over magnesium sulphate and evaporated under reduced pressure to give the required product as a pale brown oil, 27.4 g.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[CH:21][N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[CH:21][N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)[CH3:5]
Reactant: CC(N=[N+]=[N-])c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a stirred solution of 7-(1-azidoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.295 g, 0.885 mmol) in tetrahydrofuran (5 mL) and water (1 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (1.06 mL, 1.06 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate, and the mixture was extracted with aqueous 1N HCl solution (three times). The combined extract was neutralized with solid NaHCO3 and extracted with dichloromethane (two times). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the desired compound (0.241 g, 88.6%), which was used directly in next step. LCMS calculated for C14H12F2N3OS (M+H)+: m/z=308.1. Found: 308.0.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N+:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:11]([CH3:29])([CH2:22][CH2:23][CH2:24][S:25]([OH:28])(=[O:27])=[O:26])[C:10]=1/[CH:30]=[CH:31]/NC1C=CC=CC=1)([OH:3])=[O:2].[CH3:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][N+:46]1[C:54]2[C:49](=[CH:50][C:51]([S:55]([OH:58])(=[O:57])=[O:56])=[CH:52][CH:53]=2)[C:48]([CH3:66])([CH2:59][CH2:60][CH2:61][S:62]([OH:65])(=[O:64])=[O:63])[C:47]=1[CH3:67].C([O-])(=O)C.[Na+:72].C(OCC)C>C(O)(=O)C.C(OC(=O)C)(=O)C>[Na+:72].[Na+:72].[Na+:72].[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:11]([CH3:29])([CH2:22][CH2:23][CH2:24][S:25]([OH:28])(=[O:26])=[O:27])/[C:10]/1=[CH:30]\[CH:31]=[CH:67]\[C:47]1[C:48]([CH3:66])([CH2:59][CH2:60][CH2:61][S:62]([OH:65])(=[O:64])=[O:63])[C:49]2[C:54](=[CH:53][CH:52]=[C:51]([S:55]([OH:58])(=[O:56])=[O:57])[CH:50]=2)[N+:46]=1[CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH3:39])([OH:3])=[O:2]
Reactant: COCCOCC[N+]1=C(C)C(C)(CCCS(=O)(=O)O)c2cc(S(=O)(=O)O)ccc21
Reactant: CC1(CCCS(=O)(=O)O)C(/C=C/Nc2ccccc2)=[N+](CCCCCC(=O)O)c2ccc(S(=O)(=O)O)cc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: COCCOCC[N+]1=C(/C=C/C=C2/N(CCCCCC(=O)O)c3ccc(S(=O)(=O)O)cc3C2(C)CCCS(=O)(=O)O)C(C)(CCCS(=O)(=O)O)c2cc(S(=O)(=O)O)ccc21
Temperature: 25 °C

Procedure:
Both 1 mmol 1-(5-carboxypentyl)-3-methyl-2-((E)-2-phenylamino-vinyl)-5-sulfo-3-(3-sulfopropyl)-3H-indolium and 1 mmol 1-[2-(2-methoxy-ethoxy)-ethyl]-2,3-dimethyl-5-sulfo-3-(3-sulfo-propyl)-3H-indolium were dissolved in 20 ml acetic acid/acetic anhydride (1/1) followed by the addition of 200 mg sodium acetate. The solution was stirred under reflux for 15 min. After cooling to room temperature, 20 ml diethylether was added. The resulting precipitate (mixture of the diastereomers 550-1 compound 2 and 550-2 compound 2) was extracted by suction, washed with ether and dried.
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:33])[CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C@@H:20]([C:22]4[CH:31]=[CH:30][C:25]5[C:26](=[O:29])[O:27][CH2:28][C:24]=5[C:23]=4[CH3:32])[OH:21])[CH2:15][CH2:14]3)=[CH:10][C:5]=2[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[O:34]=[S:2]1(=[O:1])[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([OH:33])[CH2:12][N:13]3[CH2:14][CH2:15][N:16]([CH2:19][C@@H:20]([C:22]4[CH:31]=[CH:30][C:25]5[C:26](=[O:29])[O:27][CH2:28][C:24]=5[C:23]=4[CH3:32])[OH:21])[CH2:17][CH2:18]3)=[CH:10][C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1c([C@@H](O)CN2CCN(CC(=O)c3ccc4c(c3)CCS4(=O)=O)CC2)ccc2c1COC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c([C@@H](O)CN2CCN(CC(O)c3ccc4c(c3)CCS4(=O)=O)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-[(1R)-2-{4-[2-(1,1-dioxido-2,3-dihydro-1-benzothiophen-5-yl)-2-oxoethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one (56 mg, 0.12 mmol) in 3 mL MeOH was added sodium borohydride (4.4 mg, 0.12 mmol) portion wise. The reaction was allowed to stir at ambient temperature for one hour, quenched by the addition of water and then concentrated in vacuo. The crude residue was dissolved in DCM/water mixture. The aqueous layer was extracted three times with DCM (10 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified via MPLC (10% DCM/MeOH) to afford 5-[(1R)-2-{4-[2-(1,1-dioxido-2,3-dihydro-1-benzothiophen-5-yl)-2-hydroxyethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1(3H)-one as a mixture of diastereomers.
Reaction SMILES: C[Si](O[C:6]([O:10][CH3:11])=[C:7](C)[CH3:8])(C)C.ClC1C=[C:15](C=CC=1)[C:16]([O-:18])=[O:17].C([N+](CCCC)(CCCC)CCCC)CCC.C(OC)(=O)C(C)=C.C(OCCN(C)C)(=O)C(C)=C>CO.C(#N)C.O1CCCC1>[C:16]([O:18][CH:7]([CH3:8])[CH2:6][O:10][CH3:11])(=[O:17])[CH3:15]
Reactant: O=C([O-])c1cccc(Cl)c1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: C=C(C)C(=O)OC
Agent: C=C(C)C(=O)OCCN(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: COCC(C)OC(C)=O

Procedure:
A 500 mL four-necked round-bottom separable flask was equipped with a condenser tube, a dropping funnel, a nitrogen inlet, a stirrer and a thermometer. Tetrahydrofuran (THF) of 250 parts by weight and dimethylketene methyl trimethylsilyl acetal of 2.32 parts by weight, which is an initiator, were poured into the flask through the dropping funnel, followed by sufficient nitrogen substitution. Then, 0.2 part by weight of 1 mol/L acetonitrile solution of tetrabutylammonium m-chlorobenzoate, which is a catalyst, was injected with a syringe. Methyl methacrylate (hereinafter may be referred to as MMA) of 93.3 parts by weight was added dropwise with the dropping funnel for 60 minutes. While cooling the separable flask, the temperature was kept below 40° C. One hour later, dimethylaminoethyl methacrylate (hereinafter may be referred to as DMMA) of 40.0 parts by weight was added dropwise for 20 minutes. After one hour reaction, methanol of 0.5 parts by mass was added to terminate the reaction. The thus-obtained copolymer THF solution was reprecipitated in hexane, filtrated, dried in vacuum and then purified, thus obtaining a polymer. To the amine-containing polymer obtained in this manner of 60 parts by weight, propylene glycol monomethyl ether acetate (hereinafter may be referred to as PGMEA) of 40 parts by weight was added and uniformly mixed to obtain a polymer solution B1. For the polymer solution B1, GPC was measured with HLC-8220 equipped with an RI detector (manufactured by Tosoh Corporation), using THF as the developing solvent and a molecular weight standard polymer as the standard polystyrene, thus obtaining the molecular weight distribution and mass average molecular weight. The amine value was 115 mg KOH/g. The mass average molecular weight Mw was 9,900. The number average molecular weight Mn was 8,320. The molecular weight distribution Mw/Mn was 1.19 (MMA/DMMA mass ratio: 7/3).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH:16]=1)[C:13]([OH:15])=O.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=1.C(N(CC)CC)C>ClCCl>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH:16]=1)[C:13]([NH:31][C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(O)ccc1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.08 ml, 12.28 mmol) was added to a mixture of 5-hydroxy-2-[(phenylmethyl)oxy]benzoic acid (1 g, 4.09 mmol) dissolved in dichloromethane. The mixture was stirred for 2 h, and then concentrated. The residue was dissolved in dichloromethane, and then added to a mixture of pyridin-3-amine (0.39 g, 4.09 mmol) and triethylamine (1.14 ml, 8.19 mmol) in dichloromethane. The mixture was stirred at 40° C. for 3 h. The mixture was filtered, and the filtrate was added to water (10 ml) and extracted with ethyl acetate (30 ml). The organic phase was concentrated to yield the title compound as a crude solid product. 0.72 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:24]([O:26]CC)=[O:25])[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.CO.O.O[Li].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]([CH2:29][C:30]([F:31])([F:32])[F:33])[C:24]([OH:26])=[O:25])[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=2)[C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: CCOC(=O)C(CC(F)(F)F)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CC(F)(F)F)c1cc(Cl)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of ethyl 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoate (0.1 g, 0.404 mmol) in a mixture of THF (10 mL), methanol (10 mL) and water (5 mL) was added LiOH.H2O (85 mg, 2.024 mmol) at room temperature and the mixture was stirred at RT for 2 h. After complete consumption of the starting material as monitored by TLC, the reaction mixture was diluted with water (10 mL) and acidified using 1 N HCl at 0° C. The aqueous layer was extracted with EtOAc (2×20 mL) the combined organic extracts were washed with water (10 mL), brine (20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude material was purified by column chromatography to 2-(5-chloro-6-(cyclopropylmethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4,4,4-trifluorobutanoic acid (38 mg) as sticky syrup. 1HNMR (500 MHz) (CDCl3): δ (ppm) 7.71 (m, 4H), 7.39 (s, 1H), 7.19 (s, 1H), 3.92 (m, 1H), 3.41 (d, 2H), 3.08 (m, 1H), 2.54 (m, 1H), 0.96 (m, 1H), 0.40 (d, 2H), 0.00 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH2:11][OH:12])=[CH:5][CH:4]=1.C(P(CCCC)CCCC)CCC.[CH3:34][O:35][C:36](=[O:50])[CH:37]([CH2:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1)[C:38]([O:40][CH3:41])=[O:39].CCCCCCC>C1C=CC=CC=1>[CH3:41][O:40][C:38](=[O:39])[CH:37]([CH2:42][C:43]1[CH:44]=[CH:45][C:46]([O:12][CH2:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:47][CH:48]=1)[C:36]([O:35][CH3:34])=[O:50]
Reactant: COc1ccc(C(=CCO)c2ccc(OC)cc2)cc1
Reactant: COC(=O)C(Cc1ccc(O)cc1)C(=O)OC
Agent: CCCCP(CCCC)CCCC
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: COC(=O)C(Cc1ccc(OCC=C(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.7 %

Procedure:
Under a nitrogen atmosphere, 3,3-bis-(4-methoxy-phenyl)-prop-2-en-1-ol (500 mg, 1.95 mmol), tributylphosphine (424 (mg, 2.1 mmol) and 2-(4-hydroxy-benzyl)-malonic acid dimethyl ester (464 mg, 1.95 mmol) were successively dissolved in dry benzene (50 mL). Solid azodicarboxylic dipiperidide (ADDP) (530 mg, 2.1 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (10 mL) was added to the reaction mixture and di hydro-ADDP separated out was filtered off. After evaporation of the solvent the product was purified by chromatography eluting with heptane/ethylacetate (4:1) to give 150 mg (16%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:18]([O-:20])=[O:19])[CH:6]=[CH:7][C:8]=2[C:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH:12]=2)[C:3]1=[O:21].[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25].Cl.CCOCC>C(Cl)Cl>[CH2:24]([O:23][P:22]([C:14]1([OH:17])[CH2:15][CH2:16][C:11]([C:8]2[CH:7]=[CH:6][C:5]([N+:18]([O-:20])=[O:19])=[C:4]3[C:9]=2[CH2:10][N:2]([CH3:1])[C:3]3=[O:21])=[CH:12][CH2:13]1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:25]
Reactant: CCOP(OCC)OCC
Reactant: CN1Cc2c(C3=CCC(=O)CC3)ccc([N+](=O)[O-])c2C1=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C1(O)CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
2-methyl-7-nitro-4-(4-oxocyclohex-1-en-1-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 193D) was dissolved in DCM (10 mL), then triethyl phosphite (520 mg, 3.1 mmol) and 1N HCl/Et2O (3.1 mmol, 3.1 mL) were added at 0° C. under nitrogen. The resulting mixture was slowly warmed to rt and stirred at rt overnight. The solvent was evaporated, and the residue was purified by silica gel chromatography (ISCO Combi-flash system, eluting with 0-10% MeOH/DCM) to give the title compound as a yellow solid, 470 mg, 71% yield (over two steps). 1H NMR (CDCl3): 1.39 (t, J=7.1 Hz, 6H), 2.02 (m, 1H), 2.20 (m, 1H), 2.30-2.47 (m, 2H), 2.65-2.83 (m, 2H), 3.20 (s, 3H), 4.21-4.29 (m, 4H), 4.42, 4.48 (AB, JAB=18.0 Hz, 2H), 5.86 (m, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H). MS (ES+): m/z=425.12 [MH+]. HPLC: tR=3.19 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][N:19]=[N+]=[N-])[O:15][C:14]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[N:9]1.C(N(CC)CC)C.[Cl:30][CH:31]([Cl:35])[C:32](Cl)=[O:33]>C1COCC1.[Ni].C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][C@H:16]([CH2:18][NH:19][C:32](=[O:33])[CH:31]([Cl:35])[Cl:30])[O:15][C:14]2=[O:22])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[N:9]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(-n3ccnn3)c(F)c2)C(=O)O1
Agent: [Ni]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC[C@H]1CN(c2ccc(-n3ccnn3)c(F)c2)C(=O)O1)C(Cl)Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 51.5 %

Procedure:
A solution of 275 mg (0.91 mmol) of (R)-[3-[3-Fluoro-4-(1H-1,2,3-triazol-1-yl)phenyl]-2-oxo-5-oxazolidinyl]methylazide (from Example 6) in 15 mL THF was treated with 1.5 g of W-2 Raney nickel, and hydrogenated at atmospheric pressure. After 18 h, the mixture was filtered through celite, washing the filter cake with methanol. The filtrate was concentrated in vacuo and the resulting oil was slurried in 15 mL methylene chloride, cooled to 0° C. and treated with 138 mg (0.19 mL, 1.36 mmol) triethylamine, and 161 mg (0.11 mL, 1.09 mmol) dichloroacetyl chloride. After stirring at ambient temperature for 24 h, the mixture was diluted with methylene chloride and extracted with water (3×20 mL) and saturated aqueous sodium chloride (1×20 mL). Drying (Na2SO4) and concentration in vacuo afforded an off-white solid. The crude material was subjected to radial chromatography on a 4 mm chromatotron plate eluting with dichloromethane and 2% (v/v) methanol-dichloromethane. These procedures afforded 182 mg (52%) of the title compound as a white solid, mp 195-198° C. dec.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[H][H]>C(O)C.[C].[Pd]>[CH2:10]([C:9]1[C:4]([NH2:1])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:11]
Reactant: [H][H]
Reactant: C=Cc1cccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCc1cccnc1N
Yield: 83.9 %

Procedure:
130 mg of the 2-nitro-vinylpyridine [120-1] was dissolved in 5 mL of ethanol, 65 mg of 10% palladiumcarbon catalyst was added thereto, and stirred overnight at room temperature in a hydrogen atmosphere. The insolubles were filtered through celite, the filtrate was concentrated under reduced pressure, and 88.7 mg of 3-ethylpyridin-2-amine [120-2] was obtained as a yellow oily product.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:13].ClC1C=NC=C(Cl)C=1NC(C1C=CC(OC)=C2OC(C)=CC=12)=O.[CH3:37][O:38][C:39]1[CH:40]=[CH:41][C:42]([C:51](O)=[O:52])=[C:43]2[C:47]=1[O:46][C:45]([CH:48]([CH3:50])[CH3:49])=[CH:44]2.S(Cl)(Cl)=O.Cl>O1CCCC1.C1(C)C=CC=CC=1.C(N(CC)CC)C>[Cl:13][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[C:11]([Cl:12])[C:2]=1[NH:1][C:51]([C:42]1[CH:41]=[CH:40][C:39]([O:38][CH3:37])=[C:47]2[O:46][C:45]([CH:48]([CH3:50])[CH3:49])=[CH:44][C:43]=12)=[O:52]
Reactant: COc1ccc(C(=O)O)c2cc(C(C)C)oc12
Reactant: COC(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2cc(C)oc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)c(NC(=O)c2ccc(OC)c3oc(C(C)C)cc23)c(Cl)c1
Temperature: 0 °C

Procedure:
2.0 g of triethylamine were added to a solution of 4.4 g of methyl 4-amino-3,5-dichlorobenzoate in 50 ml of tetrahydrofuran and the mixture was stirred (solution 1). In parallel to this, 4.7 g of 7-methoxy-2-(1-methylethyl)benzofuran-4-carboxylic acid were stirred at 80° C. for 3 h with 10.0 ml of thionyl chloride in 40 ml of toluene and the mixture was then evaporated in vacuo. About 20 ml of toluene were added to the residue and the solution was evaporated again in vacuo. The residue was then taken up in 50 ml of tetrahydrofuran and this solution was added dropwise at RT to the prepared solution 1. After reaction was complete, the mixture was stirred into about 200 ml of ice water, treated with 30 ml of 2 N hydrochloric acid and extracted with ethyl acetate. This extract was dried over calcined sodium sulfate and evaporated in vacuo. The residue was crystallized from toluene: m.p. 175° C.