Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:25])[C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[C@H:10]([CH2:26][N:27]([CH:44]([CH3:46])[CH3:45])[C:28](=[O:43])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=2)[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[CH:44]([N:27]([CH2:26][C@H:10]1[C@H:11]([CH2:13][NH:14][C:15](=[O:25])[C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:12][NH:8][CH2:9]1)[C:28](=[O:43])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1)([CH3:46])[CH3:45]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC(=O)C(C)(C)c2ccccc2)C(C)C)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CNC(=O)C(C)(C)c2ccccc2)C(C)C)ccc1OC

Procedure:
The title compound is prepared according to Scheme 6 as follows: The solution of (3R,4R)-3-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-4-[(2-methyl-2-phenyl-propionylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (227 mg, 0.319 mmol) in 4N HCl in dioxane (2 mL) is stirred for 6 hrs at room temperature. The volatiles are removed by freeze-drying to give the title compound as white solid. MS [M+H]+=540.2. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 3.91 min.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[C:5](Br)[C:3]=1[NH2:4].C([O-])([O-])=O.[Na+].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:8]=[CH:7][CH:6]=[C:5]([C:21]3[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=3)[C:3]=2[NH2:4])=[CH:20][CH:19]=1
Reactant: Nc1c(Br)cccc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1c(-c2ccc(C(F)(F)F)cc2)cccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 93.5 %

Procedure:
A suspension of tetrakis(triphenylphosphine) palladium(0) (66 mg, 0.06 mmol) in toluene (8 mL) was treated with 2,6-dibromoaniline (500 mg, 2.0 mmol), aqueous Na2CO3 (2M, 3.98 mL), and 4-trifluoromethylphenyl boronic acid (831 mg, 4.4 mmol). The resulting suspension was immersed in a 110° C. oil bath, and stirred under Ar for 22 h. The suspension was cooled to rt, and extracted with ether. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 2.5-5.0% EtOAc/Heptane) to afford 4,4″-Bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-2′-ylamine (713 mg, 93%): 1H NMR (CDCl3, chemical shifts in ppm relative to TMS): 6.93 (t, 1H, J=7.3 Hz), 7.14 (d, 2H, J=7.3 Hz), 7.64 (d, 4H, J=8.0 Hz), 7.74 (d, 4H, J=8.0 Hz).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][N:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.[OH-].[Na+]>CS(C)=O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)Oc1ccc(F)nc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(Oc2ccc(Br)cc2)nc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.9 %

Procedure:
To a mixture of Example 69A (˜53.05 mmol) and 4-bromophenol (13.80 g, 79.76 mmol) in DMSO (50 mL) cooled with an ice-bath was added NaH (60%, 3.20 g, 80.0 mmol) in several portions. After the addition, the mixture was stirred at room temperature for 10 minutes. To this was added 18-crown-6 (16.0 mL, 80.6 mmol). The reaction mixture was heated to 160° C. for 60 hours. The mixture was poured into 1N NaOH, extracted with ethyl acetate (2×). The combined extracts were washed with water (1×), brine (1×), dried over MgSO4 and concentrated. The residue was purified on silica gel eluting with ethyl acetate and hexane to give the desired product as yellow oil (11.1 g).
Reaction SMILES: [CH2:1]([N:8]([CH3:22])[CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]([CH3:22])[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 4-(benzyl(methyl)amino)piperidine-1-carboxylate (1.2 g, 3.947 mmol, 1.0 eq.) was dissolved in DCM (10 ml); TFA (1.2 ml) was added at 0° C. and the mixture was stirred for 2 hours at RT. The reaction mixture was concentrated under reduced pressure, taken up several times in toluene and dried. The crude product was used in the next stage without being purified further.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]=[C:12]1[C:20]2[S:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[N:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[CH:25](OC)=[O:26].Cl>C1COCC1>[CH:25]([CH:13]1[CH2:14][CH2:15][C:16]2[N:17]=[C:18]([NH:21][C:22](=[O:24])[CH3:23])[S:19][C:20]=2[C:12]1=[O:11])=[O:26]
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CCC2
Reactant: COC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2c(s1)C(=O)C(C=O)CC2
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
LiHMDS solution (1 M, 27.7 mL) was added over 10 min to a suspension of N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (Stage A.5, 2.0 g, 9.23 mmol) in dry THF (20 mL) cooled at −78° C. under an argon atm. The RM was then stirred at −78° C. for 2.5 h and methyl formate (2.308 mL, 36.9 mmol) added dropwise over 30 min. The RM was then warmed slowly to rt and was then stirred 18 h at rt. The RM was drown out into aqueous 1 M HCl (70 mL) and extracted 3× with DCM, dried over Na2SO4 and evaporated to give a the title compound as a solid. HPLC: tR 3.65 min (method D). MS: M−H=237. 1H-NMR in DMSO-d6 (400 MHz): 12.50 (s, br, 1H); 7.55 (s, 1H); 2.90-2.60 (m, 4H); 2.15 (s, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:11]3=[O:19])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C1(N)CCCCC1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH:13]([C:15]([F:17])([F:18])[F:16])[N:12]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:11]3=[O:19])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1NC(C(F)(F)F)CN1c1ccc2ncsc2c1
Reactant: Brc1cccnc1
Agent: I[Cu]I
Agent: NC1CCCCC1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3ncsc3c2)CC(C(F)(F)F)N1c1cccnc1
Yield: 23.7 %

Procedure:
Using the same reaction conditions and work up as described in example 1, step-3,1-Benzothiazol-6-yl-4-trifluoromethyl-imidazolidin-2-one (I-170b: 50 mg, 0.174 mmol) was refluxed with 3-Bromo-pyridine (33 mg, 0.209 mmol), copper iodide (3.3 mg, 0.0174 mmol), Cyclohexane-1,2-diamine (6 mg, 0.0522 mmol), potassium phosphate (110 mg, 0.522 mmol) and 1,4-Dioxane (2 mL) at 120° C. for 12 hours to afford the crude product. Purification by column chromatography on silica gel (2% methanol in chloroform) followed by n-pentane washing afforded 15 mg of the product (23.8% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[SH:11])(=[O:3])[CH3:2].[OH:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1.[Na]>>[OH:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)/[CH:19]=[CH:20]\[C:10]1[C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10](/[CH:20]=[CH:19]\[C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([OH:12])[CH:14]=3)[C:5]=2[O:4][C:1](=[O:3])[CH3:2])[CH:7]=[CH:8][CH:9]=1
Reactant: C#Cc1cccc(O)c1
Reactant: CC(=O)Oc1ccccc1S
Agent: [Na]
Product: CC(=O)Oc1c(/C=C\c2cccc(O)c2)cccc1Sc1cccc(/C=C\c2cccc(O)c2)c1OC(C)=O
Yield: 78 %

Procedure:
A solution of 2-acetoxythiophenol (10 mmol), 3-hydroxy-phenylacetylene (10 mmol) and sodium (0.01 g atom) was subjected to the General Procedure. The title compound was obtained in 78% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26]CC5C=CC=CC=5)=[CH:23][CH:24]=4)[CH2:19][CH2:18][N:17]3[C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[B-](Br)(Br)(Br)[S+](C)C>ClCCl>[CH3:41][N:2]([CH3:1])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH:16]3[C:25]4[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=4)[CH2:19][CH2:18][N:17]3[C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(-c2ccc(CC3c4ccc(OCc5ccccc5)cc4CCN3c3ccc(F)cc3)cc2)cn1
Agent: C[S+](C)[B-](Br)(Br)Br
Solvent: ClCCl
Product: CN(C)c1ccc(-c2ccc(CC3c4ccc(O)cc4CCN3c3ccc(F)cc3)cc2)cn1
Reaction time: 5 h
Yield: 71.3 %

Procedure:
To a solution of 1-({4-[6-(dimethylamino)(3-pyridyl)]phenyl}mehyl)-2-(4fluorophenyl)-6-(phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline (0.58 g, 1.07 mmol) in anhydrous dichloromethane (10 mL) under nitrogen at room temperature was added 1.0 M solution of boron tribromide-methyl sulfide complex in dichloromethane dropwise. After stirring for 5 hours, the reaction was quenched with ice-water and extracted with ethyl acetate. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 30-50% ethyl acetate/hexane) to provide the title compound (0.346 g, 71% yield): 1H NMR (CDCl3) 8.42 (d, 1H), 7.69 (dd, 1H), 7.38 (m, 2H), 7.05 (d, 2H), 6.93 (m, 2H), 6.79 (m, 2H), 6.53-6.67 (m, 4H), 5.09 (br, 1H), 4.76 (t, 1H), 3.58 (m, 1H), 3.48 (m, 1H), 3.17 (m 1H), 3.13 (s, 6H), 2.92 (m, 2H), 2.07 (dt, 1H); ES-MS m/z 454 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:22]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[Al]>CO>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCCCC1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Agent: [Al]
Solvent: CO
Product: C1=Cc2ccccc2C(C2CCN(C3CCCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.50 gram (1.8 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 6.68 gram (68.1 millimoles) of cyclohexanone, 0.49 gram of finely cut bits of aluminum foil and 15 milliliters of methanol were mixed together. To the mixture, 0.01 gram (0.04 millimole) of mercuric chloride was added and the resulting mixture stirred at ambient temperature for 24 hours at which time a TLC analysis indicated complete consumption of the starting material and formation of a new product. The reaction mixture was filtered successively through celite and silica gel to remove aluminum and mercury salts and the filtrate concentrated in vacuo to obtain a yellow oil which crystallized on trituration with acetonitrile. Recrystallization from acetonitrile produced purified 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-cyclohexylpiperidine product as long, straw-colored needles of melting point 162°-164° C. in a yield of 490 milligrams (75 percent). Elemental analyses were as follows:
Reaction SMILES: ClC(OCC(C)C)=O.[Cl:9][C:10]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13].C(N(CC)CC)C.[C:31]1([CH:37]([NH2:39])[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH3:38][CH:37]([NH:39][C:16](=[O:18])[CH2:15][NH:14][C:12](=[O:13])[C:11]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:10]=1[Cl:9])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(N)c1ccccc1
Reactant: O=C(O)CNC(=O)c1c(Cl)cccc1Cl
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(NC(=O)CNC(=O)c1c(Cl)cccc1Cl)c1ccccc1
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
1.05 g of isobutyl chloroformate was slowly dropped at -20° C. under a nitrogen stream onto a solution of 1.74 g of N-(2,6-dichlorobenzoyl)glycine and 0.71 g of triethylamine in 30 ml of anhydrous tetrahydrofuran, and the reaction solution was stirred for 20 minutes. Then, 0.84 g of α-phenylethylamine was added to the solution, which was subsequently stirred for 30 minutes keeping the reaction temperature within the range from -10° C. to -20° C. The reaction solution was then extracted with 60 ml of ethyl acetate. The extract was washed with a 10% w/v aqueous solution of sodium hydroxide, then with 1N aqueous hydrochloric acid, and finally with a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. The reaction solution was concentrated by evaporation under reduced pressure, and the resulting residue was subjected to silica gel column chromatography for purification to give 1.58 g (yield 67%) of the title product melting at 155° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>O.CCO.C1(C)C=CC=CC=1.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.CCCCCC>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:36]3[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:35]=3[Cl:34])[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Reactant: O=[N+]([O-])c1ccc(Cl)c(B(O)O)c1
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: CCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc([N+](=O)[O-])ccc1Cl

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo -5-(trifluoromethyl)-benzyl]-4-methyl-1,3-oxazolidin-2-one (1.0 g, 1.68 mmol), 2-chloro-5-nitro phenyl boronic acid (0.67 g, 3 3 mmol), tetrakis(triphenylphosphine)palladium (97 mg, 5% mol) and sodium carbonate (0.39 g, 3.68 mmol) in 50 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 4 h. TLC (CH2Cl2:hexane/1:1) showed that the reaction was complete. The solvents were removed. Water (30 ml) was added. The organic was extracted with methylene chloride (3×40 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using CH2Cl2:hexane/6:4 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 1:1 mixture of roamers 8.16-8.31 (m, 1H), 8.21(d, J=2.5 Hz, ½H), 8.16(d, J=2.5 Hz, ½H), 7.90 (s, 1H), 7.71-7.78 (m, 5H), 7.42-7.46 (m, 1H), 5.66 (d, J=4.5 Hz, ½H), 5.64 (d, J=4.5 Hz, ½H), 4.93 (d, J=15.5 Hz, ½H), 4.79 (d, J=16 Hz, ½H), 4.03 (d, J=16 Hz, ½H), 3.94 (m, 1H), 3.91 (d, J=15.5 Hz, ½H), 0.70 (d, J=6.5 Hz, 1.5H), 0.64 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10](OCC)=[O:11])[CH:3]=[N:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][OH:11])[CH:3]=[N:2]1
Reactant: CCOC(=O)c1cccc2cn[nH]c12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccc2cn[nH]c12
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
In a round-bottomed flask, ethyl 1H-indazole-7-carboxylate (600 mg, 3.15 mmol) was dissolved in THF (16 ml). The light yellow solution was cooled to 0° C. and lithium aluminum hydride (1.0 M in THF, 3.8 ml, 3.8 mmol) was added dropwise. The bright yellow reaction mixture was stirred at 0° C. for 1.25 h then sodium sulfate decahydrate was carefully added. When gas evolution had stopped, the ice bath was removed, sodium sulfate was added and the mixture was stirred for 30 min at room temperature. The suspension was filtered over Celite and rinsed with ethyl acetate/methanol. The filtrate was concentrated to afford (1H-indazol-7-yl)-methanol as a light yellow solid which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:15][CH3:16])=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:15]([C:7]1[C:6]([CH2:4][OH:3])=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1)[CH3:16]
Reactant: CCOC(=O)c1c(CC)nn2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nn2ccccc2c1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.9 %

Procedure:
A solution of 2-ethyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester (15 g, 68.7 mmol) in tetrahydrofuran (300 mL) was cooled in an ice bath and lithium aluminum hydride (2.6 g, 68.7 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. Water was added until bubbling stopped. Silica gel was added and the solvent was evaporated in vacuo. The resulting residue was purified via silica chromatography (20-100% ethyl acetate/heptane) to yield the title compound as a yellow/brown oil (9.67 g, 80% yield).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH2:13][C:14]([C:32]([O:34]CC)=O)([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:11]([O:37][CH3:38])[C:10]([O:39][CH3:40])=[C:9]([O:41][CH3:42])[C:8]=1[O:43][CH3:44].C(O)(=O)C.[BH4-].[Na+]>O.C1COCC1.CCCCCC>[CH2:30]([O:29][C:27]([C:14]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][C:12]2[C:7](=[C:8]([O:43][CH3:44])[C:9]([O:41][CH3:42])=[C:10]([O:39][CH3:40])[C:11]=2[O:37][CH3:38])[CH:32]1[OH:34])=[O:28])[CH3:31]
Reactant: CCOC(=O)CCCCCCCC(Cc1c(Br)c(OC)c(OC)c(OC)c1OC)(C(=O)OCC)C(=O)OCC
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: O
Product: CCOC(=O)CCCCCCCC1(C(=O)OCC)Cc2c(OC)c(OC)c(OC)c(OC)c2C1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
A hexane solution of n-butyl lithium (1.68 M, 13.1 ml, 22.0 mmols) was dropwise added to a THF (80 ml) solution of ethyl 10-(6-bromo-2,3,4,5-tetramethoxyphenyl)-9,9-diethoxycarbonyldecanoate (7.54 g, 12.2 mmols) under a nitrogen stream at −70° C. or lower The reaction mixture was stirred for 15 minutes, and then a THF (10 ml) solution of acetic acid (1.71 g, 28.5 mmols) was dropwise added thereto at −70° C. or lower. After having been allowed to warm to room temperature, the reaction mixture was concentrated in vacuo. A saturated aqueous sodium bicarbonate solution was added to the resulting residue, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and distilled in vacuo. The resulting crude product was dissolved in ethanol (80 ml), to which was added sodium borohydride (923 mg, 24.4 mmols) with cooling with ice. The reaction mixture was allowed to warm to room temperature, and then stirred for 6 hours. Water was added thereto, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was isolated through silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to obtain ethyl 8-(2-ethoxycarbonyl-1-hydroxy-4,5,6,7-tetramethoxyindan-2-yl)octanoate (3.77 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:4]([CH:5]=[C:6]([Cl:18])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:3]1[C:19](O)=[O:20].S(Cl)([Cl:25])=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:22])[CH:4]([CH:5]=[C:6]([Cl:18])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:3]1[C:19]([Cl:25])=[O:20]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(C=C(Cl)c2ccc(OC(F)(F)F)cc2)C1C(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(C=C(Cl)c2ccc(OC(F)(F)F)cc2)C1C(=O)Cl
Yield: 94.7 %

Procedure:
19.4 g (0.058 mol) of 2,2-dimethyl-3-(2-chloro-2-(4-trifluoromethoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid were dissolved in 150 ml of carbon tetrachloride, and 15 g of thionyl chloride were slowly added dropwise at 25° C., while stirring. The mixture was then heated to the reflux temperature for 4 hours. After this reaction time, excess thionyl chloride and carbon tetrachloride were distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation under 2 mm Hg at a bath temperature of 60° C. 19.4 g (95% of theory) of 2,2-dimethyl-3-(2-chloro-2-(4-trifluoromethoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid chloride were obtained as an oily liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:20])[N:17]([CH3:19])[CH3:18])[CH:6]=[CH:7][C:8]=1[S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])#[N:2]>C1COCC1.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:20])[N:17]([CH3:18])[CH3:19])[CH:6]=[CH:7][C:8]=1[S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10]
Reactant: CC(C)S(=O)(=O)c1ccc(NC(=O)N(C)C)cc1C#N
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(NC(=O)N(C)C)cc1CN
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To 16A (45 mg, 0.15 mmol) in THF (10 mL) was added Raney Ni (cat.) and the mixture was hydrogenated at 60 psi for 4 h. The reaction was filtered and concentrated to provide 16B (41 mg, 91%). LC-MS: 300.37 (M+H)+
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[N+:5](/[CH:8]=[CH:9]/[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)([O-:7])=[O:6].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C@H:9]([CH2:8][N+:5]([O-:7])=[O:6])[C@H:2]([CH3:3])[CH:1]=[O:4]
Reactant: O=[N+]([O-])/C=C/c1ccco1
Reactant: CCC=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: C[C@H](C=O)[C@@H](C[N+](=O)[O-])c1ccco1

Procedure:
The title compound was prepared from propionaldehyde and (E)-2-(2-nitro-vinyl)furan according to the general procedure. Both enantiomeric excess and diastereomeric ratio were determined by HPLC with an AD-H column at 220 nm (2-propanol:hexane=0.8:99.2), 1.0 mL/min; major enantiomer tmajor=30.44 min, minor enantiomer tminor=26.29 min. [α]D20=−20 (c=2.0, CHCl3).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:16]1([C:3]2[C:2]([N:31]3[CH2:32][CH2:33][N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:29][CH2:30]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccccc4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 109.9 %

Procedure:
To a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (50 mg, 0.15 mmol, 1.00 equiv) in DMF (10 mL) was added 1-phenylpiperazine (50 mg, 0.31 mmol, 2.00 equiv) and DIEA (100 mg, 0.78 mmol, 5.3 equiv). The resulting solution was placed in a 20-mL sealed tube, stirred overnight at 100° C. in an oil bath, then concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:10)) yielded 70 mg (crude) of methyl 2-phenyl-3-(4-phenylpiperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid.