Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.[CH3:34][C:35]1([CH3:42])[C:39]([CH3:41])([CH3:40])[O:38][BH:37][O:36]1.[C:43]([NH:46][C:47]([C@@H:59]1[CH2:63][CH2:62][N:61]([S:64]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=2[N+:73]([O-:75])=[O:74])(=[O:66])=[O:65])[CH2:60]1)([CH2:55][CH2:56][CH:57]=[CH2:58])[C:48]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])(=[O:45])[CH3:44]>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Ir].[Ir]>[C:43]([NH:46][C:47]([C@@H:59]1[CH2:63][CH2:62][N:61]([S:64]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=2[N+:73]([O-:75])=[O:74])(=[O:66])=[O:65])[CH2:60]1)([CH2:55][CH2:56][CH2:57][CH2:58][B:37]1[O:38][C:39]([CH3:41])([CH3:40])[C:35]([CH3:42])([CH3:34])[O:36]1)[C:48]([NH:50][C:51]([CH3:54])([CH3:52])[CH3:53])=[O:49])(=[O:45])[CH3:44]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CCCC(NC(C)=O)(C(=O)NC(C)(C)C)[C@@H]1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1=CCCC=CCC1
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)[C@@H]1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 50 mL round bottomed flask, a solution of bis(1,5-cyclooctadiene)diiridium(I) dichloride (72 mg, 0.11 mmol) and 1,2-bis(diphenylphosphino)-ethane (84 mg, 0.21 mmol) in tetrahydrofuran (10 mL, 100 mmol) was cooled to 0° C., stirred for 15 min and treated with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (450 uL, 3.1 mmol). After additional stirring for 5 min the cooling bath was removed and the reaction mixture was allowed to warm to room temperature with stirring a period of 15 min. The reaction mixture was then recooled to 0° C. and treated with a solution of 2-acetamido-N-tert-butyl-2-((R)-1-(2-nitrophenylsulfonyl)pyrrolidin-3-yl)hex-5-enamide (1.00 g, 2.08 mmol) in tetrahydrofuran (2 mL, 20 mmol) added in a dropwise manner via syringe. After stirring for 5 min at 0° C. the reaction was warmed to room temperature and stirred until the desired product was obtained in good yield. The reaction mixture was quenched by pouring the crude into a saturated solution of aqueous sodium carbonate (50 mL). The aqueous layer was extracted using ethyl acetate (3×30 mL), and the combined organic layers were washed with saturated aqueous sodium chloride (20 mL), dried over Na2SO4, filtered and concentrated to give 2-acetamido-N-tert-butyl-2-((R)-1-(2-nitrophenylsulfonyl)pyrrolidin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (1.20 g, 94.8%) as a foam. The titled compound was used without further purification. ESI MS found for C28H45N4O8BS m/z 609.5 (M+H)+; 607.5 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:15][O:16]3)=[CH:11][C:10]=2[Cl:24])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].Cl[C:28]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH:31]=[CH:30][N:29]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:24][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[O:8][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[NH:2][C:28]3[N:33]=[C:32]([C:34]4[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:38][CH:39]=4)[CH:31]=[CH:30][N:29]=3)=[CH:26][CH:25]=1)[O:16][CH2:15][CH2:14][CH:13]2[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3)c(Cl)cc21
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)n2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4nccc(-c5ccc(C(F)(F)F)cc5)n4)cc3)c(Cl)cc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
Ethyl 7-(4-carbamoylphenoxy)-6-chlorochroman-4-carboxylate (Example 45, Step A; 75 mg, 0.20 mmol) 2-chloro-4-(4-(trifluoromethyl)phenyl)pyrimidine (52 mg, 0.20 mmol), XPHOS (9.5 mg, 0.020 mmol), Pd2dba3 (9.1 mg, 0.0100 mmol) and Cs2CO3 (130 mg, 0.40 mmol) were diluted with THF (0.6 mL) and purged with Argon for 2 minutes. The reaction was capped, heated to 50° C. and stirred overnight. The reaction was loaded directly onto silica gel and eluted with 50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes to yield the desired compound (50 mg, 0.084 mmol, 42% yield).
Reaction SMILES: [Br:1][CH2:2][C@@H:3]([OH:21])[CH2:4][C@@H:5]([OH:20])[CH2:6][C:7]([O:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8].Cl[CH2:23][C@@H:24](O)[CH2:25][C@@H](O)CC(OC(C)(C)CC1C=CC=CC=1)=O>>[Br:1][CH2:2][C@H:3]1[O:21][C:24]([CH3:25])([CH3:23])[O:20][C@@H:5]([CH2:6][C:7]([O:9][C:10]([CH3:18])([CH3:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:4]1
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H](O)C[C@H](O)CBr
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H](O)C[C@H](O)CCl
Product: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CBr)OC(C)(C)O1

Procedure:
The procedure was carried out in the same manner as in Example 5, except that the crude compound (3R,5S)-2-methyl-1-phenylpropan-2-yl 6-bromo-3,5-dihydroxy-hexanoate (21.0 g) prepared in Example 4 was used in place of the crude compound (3R,5S)-2-methyl-1-phenylpropan-2-yl 6-chloro-3,5-dihydroxy-hexanoate (21.1 g) prepared in Example 3. The crude title compound was obtained (22.5 g).
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C(O)(=O)C(C1C=CC=CC=1)O.[CH:26]([N:29]([CH:48]([CH3:50])[CH3:49])[CH2:30][CH2:31][C@@H:32]([C:39]1[CH:44]=[C:43]([CH2:45][OH:46])[CH:42]=[CH:41][C:40]=1[OH:47])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:28])[CH3:27].P([O-])([O-])([O-])=O.[OH-].[Na+]>C(OCC)C.ClCCl>[CH:48]([N:29]([CH:26]([CH3:28])[CH3:27])[CH2:30][CH2:31][C@@H:32]([C:39]1[CH:44]=[C:43]([CH:45]=[O:46])[CH:42]=[CH:41][C:40]=1[OH:47])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:50])[CH3:49]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1O)C(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C(O)C(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(C=O)ccc1O)C(C)C

Procedure:
DDQ (1.1 eq) was added to a solution of (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine mandelate (prepared as described in WO 94/11337, Example 1) (2.46 g, 5 mmol), dichloromethane (20 mL) and phosphate buffer (pH 7) (0.1 mL). Thereafter, sodium hydroxide solution (20 mL, 1 M) and diethyl ether were added and the phases were separated. The water-phase was extracted twice with dichloromethane-diethyl ether (2:1). The organic phase was dried (MgSO4) and evaporated. The residue was crystallised from ethyl acetate-hexane to yield 1.35 g (80%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C(N(CC)CC)C.[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(#N)C.ClCCl>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[O:18]
Reactant: Nc1cc[nH]n1
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: O=C(Nc1cc[nH]n1)c1ccccc1F
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To a solution of 1H-pyrazol-3-amine (249 mg, 3 mmol, Aldrich) in acetonitrile (10 ml) was added triethylamine (0.836 ml, 6.0 mmol, Aldrich) and the stirred solution cooled in an ice-water bath. A solution of 2-fluorobenzoyl chloride (0.358 ml, 3.0 mmol, Alfa Aesar) in acetonitrile (10 ml) was added dropwise. The mixture was stirred under nitrogen and allowed to warm slowly to ambient temperature overnight. The solvent was concentrated in vacuo. The residue was partitioned between ethyl acetate (˜50 ml) and water approximately 50 ml). The phases were separated and the aqueous phase washed with further ethyl acetate (2×approximately 30 ml). The combined organic layers were filtered through a hydrophobic frit and the filtrate concentrated in vacuo to give the crude material (0.64 g). The sample was loaded in dichloromethane and purified on silica 70 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and concentrated in vacuo to give the title compound as a colourless solid (342 mg); LCMS: (System 4) MH+=206, tRET=1.50 min.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:16]([C:17]2[CH:22]([CH3:23])[CH2:21][CH2:20][CH2:19][C:18]=2[CH3:24])=[C:15]([CH3:25])[S:14][C:13]=1[CH3:26])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(OC(C1C(C2CCC(C)(C)CC=2)=C(C)SC=1C)C(O)=O)(C)(C)C>>[C:1]([O:5][CH:6]([C:12]1[C:16]([C:17]2[CH:22]([CH3:23])[CH2:21][CH2:20][CH2:19][C:18]=2[CH3:24])=[C:15]([CH3:25])[S:14][C:13]=1[CH3:26])[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1C1=C(C)CCCC1C
Agent: Cc1sc(C)c(C(OC(C)(C)C)C(=O)O)c1C1=CCC(C)(C)CC1
Product: CC1=C(c2c(C)sc(C)c2C(OC(C)(C)C)C(=O)O)C(C)CCC1

Procedure:
Using the procedure described in example 29, step 3, ethyl tert-butoxy-[4-(2,6-dimethyl-cyclohex-1-enyl)-2,5-dimethyl-thiophen-3-yl]-acetate (53b) (90 mg, 0.24 mmol) is converted, after purification by flash chromatography on silica gel (dichloromethane/methanol 95/5), to tert-butoxy-[4-(4,4-dimethyl-cyclohex-1-enyl)-2,5-dimethyl-thiophen-3-yl]-acetic acid (example 53) (21 mg, 0.06 mmol, 25%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:13]3)=[O:9])=[C:6]([F:26])[C:5]([F:27])=[CH:4][C:3]=1[NH:28]C(=O)C(C)(C)C.Cl.[OH-].[Na+]>CC(O)=O>[NH2:28][C:3]1[C:2]([F:1])=[C:7]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:13]3)=[O:9])[C:6]([F:26])=[C:5]([F:27])[CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(N4CCOCC4)nc3c2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(N4CCOCC4)nc3c2)c1F
Temperature: 110 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a solution of N-(2,4,5-trifluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)pivalamide (560 mg, 1.2 mmol, 1.0 eq.) in HOAc (10 mL) was added conc. HCl (50 mL). The mixture was stirred at 110° C. for 4 h, then poured onto ice. The mixture was adjusted to pH 10 by the addition of 1N NaOH solution, then extracted with DCM (100 mL×3). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=1/4, v/v) to afford (3-amino-2,5,6-trifluorophenyl)(3-morpholinoquinoxalin-6-yl)methanone as brown solid (410 mg, 88% yield).
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][N:11]=1.O>CCOCC>[F:9][C:10]1[N:11]=[CH:12][C:13]([C:14]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:15])=[CH:17][CH:18]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: O=C(Cl)c1ccc(F)nc1
Solvent: O
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccc(F)nc1

Procedure:
A 3M etheral solution of phenyl magnesium chloride (4.67 ml, 14 mmol) was slowly added at −30° C. to a solution of 6-fluoronicotinoyl chloride (3.35 g, 21 mmol) in ether (25 ml). After complete addition, the cooling bath was removed and the reaction was allowed to reach 10° C. Hydrolysis was performed by addition of water, and the mixture is then diluted with ether. After separation of the layers, the ether solution was washed with brine, dried over Na2SO4 and evaporated in vacuum to yield a yellowish oil. After purification by chromatography on silica gel (CH2Cl2/Hexane 85/15), the (6-fluoro-3-pyridinyl)(phenyl)methanone 39 was obtained as a yellow oil (980 mg, 35%).
Reaction SMILES: [CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]4[NH:20][N:19]=[N:18][N:16]=4)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc2c(=O)n3cc(-c4nnn[nH]4)ccc3nc2s1
Temperature: 0 °C
Yield: 5.7 %

Procedure:
A mixture of 1.5 g (0.0062 mol) of 2-methyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 27), 1.36 g (0.021 mol) of sodium azide and 1.24 g (0.023 mol) of ammonium chloride in 280 ml of dimethylformamide is heated at 110°-120° C. for twelve hours. The reaction mixture is cooled, poured into 11 of ice water and acidified with concentrated hydrochloric acid. The resulting precipitate is filtered and dissolved in hot glacial acetic acid, activated charcoal (Darco-G60, Matheson, Coleman and Bell) is added and the hot suspension is filtered through Supercell Hyflo® (Johns-Manville). The filtrate is cooled to give 0.1 g of 2-methyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one; mp 330°-340° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[O:6][Si](C(C)(C)C)(C)C)=[N+]=[N-].CC1CC=CCC=1.[ClH:40].O1CCOCC1>C(O)C.[Pd]>[ClH:40].[NH2:1][CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[OH:6]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Agent: CC1=CCC=CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of (R)-5-(2-azido-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one (4.50 g, 10.0 mmol) in ethanol (50 mL) was added 10% palladium on charcoal (4.50 g) followed by 1-methyl-1,4-cyclohexadiene (11.0 mL, 97.9 mmol). The reaction was warmed to 60° C. and then stirred at 60° C. for 2 hours. The reaction mixture was allowed to cool and filtered through a pad of celite. The filtercake was washed with further ethanol and the filtrate was evaporated at reduced pressure. The residue was evaporated from iso-propanol (×2) and dissolved in iso-propanol (30 mL). HCl-dioxane (4 M, 50 mL, 200 mmol) was added and the reaction mixture stirred at RT for 18 hours. The resultant suspension was filtered, the filtercake washed with ether and the solid dried under vacuum in the presence of P2O5 to afford the title compound (1.65 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](/[CH:13]=[CH:14]/[C:15]2[N:16]=[C:17]3[C:22]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:21][CH:20]=[N:19][N:18]3[C:29]=2[C:30]2[CH:42]=[CH:41][C:33]([C:34]([O:36]C(C)(C)C)=[O:35])=[CH:32][CH:31]=2)=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](/[CH:13]=[CH:14]/[C:15]2[N:16]=[C:17]3[C:22]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:21][CH:20]=[N:19][N:18]3[C:29]=2[C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:41][CH:42]=2)=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1cc2ccccc2nc1/C=C/c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2ccccc2nc1/C=C/c1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound 63a (212 mg, 1.22 mmol) in 3 mL of DCM at rt was added TFA (1.00 mL, 13.1 mmol). After stirring at rt for 0.5 h, the mixture was concentrated in vacuo and the residue was triturated with DCM to give a red solid. Recrystallization of the solid in 1:1 MeOH/DCM afforded the title compound 119 as a red solid. 1H NMR (DMSO-d6, 400 MHz): δ=8.09-8.22 (m, 2H), 8.00 (s, 1H), 7.77-7.93 (m, 3H), 7.44-7.59 (m, 2H), 6.43 (d, J=5.6 Hz, 1H), 5.99 (d, J=6.1 Hz, 2H), 5.81 (s, 1H), 5.71 (s, 1H), 4.06 (br. s., 4H), 3.99 (s, 3H), 3.86 ppm (br. s., 4H). Mass spectrum (ESI, m/z): Calcd. for C29H25N5O4, 508.2 (M+H). found 508.5.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O.S(=O)(=O)(O)O>>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: O=C(CCl)CCl
Agent: O=S(=O)(O)O
Product: ClCc1coc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1 g (6.43 mmol) of 4-chlorobenzamide is heated together with 816 mg of 1,3-dichloroacetone (6.43 mmol) at 135° C. for 1 h. The mixture is allowed to cool to RT, 1 ml of conc. sulphuric acid is added and the mixture is stirred for 5 min. The mixture is then poured onto ice, and the precipitate is filtered off with suction (946 mg). This precipitate is purified on 100 g of silica gel by column chromatography using a gradient of cyclohexane/ethyl acetate 20:1 to 5:1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].N1C2[C:25](=[CH:26]C=CC=2)[C:24]2(CO[C:32]3C=C4C(=C[C:31]2=3)CCO4)C1=O.BrCCCCC.ClCC1C=NC(OC)=NC=1>>[CH2:26]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21])[CH2:25][CH2:24][CH2:31][CH3:32]
Reactant: O=C1Nc2ccccc2[C@@]12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: COc1ncc(CCl)cn1
Solvent: CCCCCBr
Product: CCCCCN1C(=O)[C@]2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 5 and making non-critical variations using (3R)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-bromopentane to replace 5-(chloromethyl)-2-methoxypyrimidine, (3R)-1′-pentyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (78%) as a colorless solid: mp 128-129° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.33-7.26 (m, 1H), 7.17 (d, J=7.1 Hz, 1H), 7.07-7.02 (m, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.49 (s, 1H), 6.41 (s, 1H), 4.92 (d, J=8.9 Hz, 1H), 4.67 (d, J=8.9 Hz, 1H), 8.64 (t, J=4.5 Hz, 2H), 3.87-3.63 (m, 2H), 2.99 (t, J=4.5 Hz, 2H), 1.79-1.69 (m, 2H), 1.40-1.35 (m, 4H), 0.94-0.89 (m, 3H); 13C NMR (75 MHz, CDCl3) δ177.5, 161.6, 161.2, 142.4, 133.0, 128.6, 123.8, 123.0, 120.3, 119.7, 118.7, 108.4, 93.1, 80.5, 72.3, 57.6, 40.3, 29.0, 27.1, 22.3, 13.9; MS (ES+) m/z 349.9 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:3]([OH:17])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(CC1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To title A compound, 3-cyclopentyl-2-phenylpropionic methyl ester (13.0 g, 56 mmol) in 100 mL of methanol is added a solution of 5.6 g (140 mmol) of NaOH in 8 mL of water. The reaction mixture is stirred at ambient temperature overnight. The methanol is evaporated and the residue is dissolved in 200 mL of water and extracted with ethyl ether. The aqueous phase is separated and adjusted to pH 2-3 with 1 N HCl and extracted with MTBE twice. The combined extracts are washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. The material is evaporated to a yellow oil that crystallizes to provide 3-cyclopentyl-2-phenylpropionic acid as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 1.7 (m, 2H), 2.1 (m, 2H), 2.2 (m, 3H), 2.4(m, 3H), 2.4 (m, 1H), 4.2 (t, J=7.7 Hz, 1H), 7.9 (m, 5H); LC/MS 236 (M+NH4+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:20]#[N:21])=[N:16][NH:17]2)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:20]#[N:21])=[N:16][N:17]2[CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])=[CH:13][CH:12]=1
Reactant: N#Cc1n[nH]c2cc(Cl)ccc12
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nn(Cc2ccccc2F)c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
Under argon, 2.45 ml (14.2 mmol) of 2-fluorobenzyl bromide, dissolved in 10 ml DMF, were added to a mixture of 2.3 g (12.9 mmol) of 6-chloro-1H-indazole-3-carbonitrile (WO 2011/149921, Expl. 58C) and 2.15 g (15.5 mmol) of potassium carbonate in 40 ml of DMF, and the mixture was stirred at RT overnight. Then the mixture was poured onto 90 ml of water and the mixture was stirred at room temperature for 30 min. The precipitated solids were filtered off, washed with water and dried under high vacuum overnight. 3.77 g of the title compound were obtained as a crude product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][C:3]1([CH3:19])[C:15]([O:17][CH3:18])=[O:16].[ClH:20].O1CCOCC1>O1CCOCC1>[ClH:20].[OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1([CH3:19])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)CCC1O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1(C)CNCCC1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of O1-tert-butyl O3-methyl 4-hydroxy-3-methyl-piperidine-1,3-dicarboxylate (0.5 g, 1.83 mmol) in 1,4-dioxane (10 mL) was added HCl-dioxane (4 M, 5 mL) solution. The resulting mixture was stirred at rt for 30 min. After reaction completion (by TLC), solvent was evaporated to obtain the desired product as a solid (0.4 g). MS: 174.13 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1

Procedure:
Ethyl bromoacetate is reacted with para-nitrophenol under standard conditions to afford ethyl 2-(4-nitrophenoxy)acetate, which is elaborated to ethyl 2-(4-hydrazinophenoxy)acetate using the reduction/oxidation sequence described for Example Y.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=O.Cl.O>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: COCC(=O)N1CCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COCCN1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-methoxyacetyl)-7-nitro-1,2,3,4-tetrahydroquinoline (D6) (212 mg, 0.85 mmol) in dry THF (9 ml) at 0° C. under an argon atmosphere, was added borane/THF complex (4.5 ml, 4.5 mmol). The reaction was stirred at 0° C. for 0.5 h then ambient temperature for 3 h. 2M Hydrochloric acid (3 ml) was added cautiously followed by water (10 ml). The mixture was extracted with EtOAc (2×10 ml) which was dried over MgSO4 and concentrated in vacuo to give the desired product as an orange solid in quantitative yield. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.39 (m, 2H), 7.00 (m, 1H), 3.61 (dd, 2H), 3.52 (dd. 2H), 3.41 (m, 2H), 3.37 (s, 3H), 2.80 (t, 2H), 1.95 (m, 2H).