Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:26]([OH:28])=[O:27])[O:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH3:15])[CH2:4][O:3]1.[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:29]([O:27][C:26]([C:2]1([CH3:1])[O:3][CH2:4][CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH3:15])[CH2:6][O:7]1)=[O:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCBr
Reactant: CC(=NOCCCCC1COC(C)(C(=O)O)OC1)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOC(=O)C1(C)OCC(CCCCON=C(C)c2ccc3ccccc3c2)CO1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of 2-Methyl-5-[4-(1-naphthalen-2-yl-ethylideneaminooxy)-butyl]-[1,3]dioxane-2-carboxylic acid (prepared as per example 63) (0.9 g), n-octyl bromide (0.6 mL) and potassium carbonate (0.64 g) in anhydrous dimethyl formamide (10 mL) was stirred at 60° C. for about 8 hours in an inert atmosphere. The reaction mixture was cooled to ambient temperature, poured into ice cold water and extracted with ethyl acetate. The combined organic extract was washed with water, brine solution, dried over sodium sulphate and evaporated under reduced pressure. Crude product was flash chromatographed over silica gel 8% ethyl acetate in petroleum ether as eluent to obtain 1 g of pure product.
Reaction SMILES: [CH2:1](OC(=O)C)[CH3:2].[CH2:7]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:8]#[CH:9].[CH2:16]([O:18][C:19](=[O:56])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:29]2[CH:34]=[C:33](C#CC3C=CC(CO)=CC=3)[CH:32]=[C:31]([O:45][CH2:46][CH2:47][C:48]3[CH:53]=CC(Cl)=CC=3)[CH:30]=2)=[CH:24][C:23]=1[CH3:55])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:56])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:29]2[CH:34]=[C:33]([C:9]#[C:8][CH2:7][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:32]=[C:31]([O:45][CH2:46][CH:47]([CH2:1][CH3:2])[CH2:48][CH3:53])[CH:30]=2)=[CH:24][C:23]=1[CH3:55])[CH3:17]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Reactant: C#CCN1CCOCC1
Reactant: CCOC(C)=O
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC(CC)CC)c2)cc1C

Procedure:
The title product was prepared from 4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.42 mmol) and 4-prop-2-ynyl-morpholine (156.0 mg; 1.26 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 210 mg (95%). HPLC-MS: m/z: 526.2 (M+H)+; Rt: 2.23 min
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:34]([F:37])([F:36])[F:35])=[C:7]([NH:9][C:10]2[NH:14][C:13]3[CH:15]=[C:16]([O:32][CH3:33])[C:17]([C:19]([NH:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]4)=[O:20])=[CH:18][C:12]=3[N:11]=2)[CH:8]=1.[C:38]([O:42][C:43]([NH:45][CH:46]([C:50]([F:53])([F:52])[F:51])[C:47](O)=[O:48])=[O:44])([CH3:41])([CH3:40])[CH3:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[C:38]([O:42][C:43]([NH:45][CH:46]([C:50]([F:51])([F:52])[F:53])[C:47]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:34]([F:36])([F:37])[F:35])=[C:7]([NH:9][C:10]2[NH:14][C:13]3[CH:15]=[C:16]([O:32][CH3:33])[C:17]([C:19]([NH:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([C:28]([F:29])([F:30])[F:31])[CH2:24][CH2:23]4)=[O:20])=[CH:18][C:12]=3[N:11]=2)[CH:8]=1)=[O:48])=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: COc1cc2[nH]c(Nc3cc(CN)ccc3C(F)(F)F)nc2cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: COc1cc2[nH]c(Nc3cc(CNC(=O)C(NC(=O)OC(C)(C)C)C(F)(F)F)ccc3C(F)(F)F)nc2cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared from 2-(5-aminomethyl-2-trifluoromethyl-phenylamino)-6-methoxy-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzo[d]imidazole-5-carboxamide and 2-tert.butoxycarbonylamino-3,3,3-trifluoro-propionic acid with TBTU, and TEA in THF_in analogy to example 3e.
Reaction SMILES: [F:1][C:2]1[C:3]([F:18])=[C:4]([F:17])[C:5]([F:16])=[C:6]2[C:11]=1[C:10]([F:12])=[C:9](F)[C:8]([F:14])=[C:7]2[F:15].[OH-].[K+].C([OH:25])(C)(C)C>O>[F:1][C:2]1[C:3]([F:18])=[C:4]([F:17])[C:5]([F:16])=[C:6]2[C:11]=1[C:10]([F:12])=[C:9]([OH:25])[C:8]([F:14])=[C:7]2[F:15]
Reactant: Fc1c(F)c(F)c2c(F)c(F)c(F)c(F)c2c1F
Reactant: CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Oc1c(F)c(F)c2c(F)c(F)c(F)c(F)c2c1F
Reaction time: 3.5 h
Yield: 72 %

Procedure:
For about 3.5 hours, a mixture of 25 g octafluoronaphthalene (PCR Inc.; Gainesville, Fla.), 12 g KOH, and 100 mL tertiary butyl alcohol was refluxed. Water was added, and the tertiary butyl alcohol was distilled from the reaction mixture. The residue remaining in the flask was acidified with HCl and the aqueous mixture was extracted three times with 75 mL dichloromethane. The combined extracts were washed twice with 150 mL distilled water, dried over MgSO4, and rotary evaporated to yield a semi-crystalline solid. Recrystallization from hot hexanes gave 18 g heptafluoro-2-naphthol (72% yield) as slightly tan colored crystals.
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=2[O:40][CH3:41])[N:15]=1.[NH2:42][C:43]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:44]=1[C:45](=[O:60])[C:46]([CH3:59])=[CH:47][N:48]2[CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55]>>[CH2:57]([O:56][C:54](=[O:55])[CH2:53][N:48]1[C:49]2[C:44](=[C:43]([NH:42][C:14]3[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:17]=[C:16]([NH:24][C:25]4[CH:39]=[CH:38][C:28]([CH2:29][P:30]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:37])=[CH:27][C:26]=4[O:40][CH3:41])[N:15]=3)[CH:52]=[CH:51][CH:50]=2)[C:45](=[O:60])[C:46]([CH3:59])=[CH:47]1)[CH3:58]
Reactant: CCOC(=O)Cn1cc(C)c(=O)c2c(N)cccc21
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: CNC(=O)c1cc(F)ccc1N
Product: CCOC(=O)Cn1cc(C)c(=O)c2c(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)cccc21

Procedure:
The title compound was prepared according to Compound 102A using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (50.0 mg, 0.110 mmol) and ethyl (5-amino-3-methyl-4-oxoquinolin-1(4H)-yl)acetate (Example 301A, 31.5 mg, 0.121 mmol). 1H NMR (CD3OD, 400 MHz): δ=1.24-1.32 (m, 9H), 2.12 (s, 3H), 3.29 (d, J=21.2 Hz, 2H), 4.05-4.16 (m, 6H), 4.84 (s, 2H), 6.91 (dt, J=2.8, 8.4 Hz, 1H), 7.04 (t, J=2.0 Hz, 1 H), 7.40 (d, J=8.8 Hz, 1H), 7.60 (t, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 8.37 (s, 1H), 8.66 (d, J=7.6 Hz, 1H). MS (ES+): m/z 678.17 [MH+]. HPLC: tR=1.50 min (UPLC TOF, polar—3 min).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][N:11]1[CH:15]=[C:14]([Sn](CCCC)(CCCC)CCCC)[N:13]=[CH:12]1>C1(C)C=CC=CC=1>[CH3:10][N:11]1[CH:15]=[C:14]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)[N:13]=[CH:12]1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Solvent: Cc1ccccc1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1
Temperature: 120 °C
Yield: 62.8 %

Procedure:
To a solution of 2-chloro-4-pyridinenitrile (300 mg, 2.16 mmol) in toluene (10 mL) was added N-methyl-4-(tributylstannyl)imidazole (964 mg, 2.6 mmol), followed by tetrakistriphenylphosphine palladium (0) (150 mg, 0.13 mmol). The reaction mixture was heated at 120° C. in a microwave initiator for 1 hr. The mixture was cooled down to r.t, solid filtered and dried to give 250 mg of 2-(1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile as a white solid. Filtrate was purified by flash column chromatography (CH2Cl2/MeOH=20/1) to give additional 100 mg of the product (total 350 mg, 88%). 1H NMR (400 MHz, DMSO-d6): δ 3.73 (3H, s), 7.59 (1H, d, J=4.8 Hz), 7.82 (1H, s), 8.09 (1H, s), 8.72 (1H, d, J=5 Hz). [M+H] Calc'd for C10H8N4, 185. Found, 185.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[C:12]([O-])(=[O:14])[CH3:13].[Na+].[C:17]([NH:20][CH2:21][C:22]([OH:24])=[O:23])(=O)[CH3:18].C(OC(=O)C)(=O)C>>[CH3:18][C:17]1[O:24][C:22](=[O:23])[C:21](=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([O:1][C:12](=[O:14])[CH3:13])=[C:3]([O:10][CH3:11])[CH:4]=2)[N:20]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(=O)NCC(=O)O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1cc(C=C2N=C(C)OC2=O)ccc1OC(C)=O
Temperature: 0 °C

Procedure:
152 g (1 mol) of 4-hydroxy-3-methoxy-benzaldehyde, 41 g of sodium acetate, 80 g of N-acetylglycine and 242 g of acetic anhydride are heated together for 30 minutes to 100° C and then for 21/2 hours to the refluxing temperature. The resulting solution is cooled to 0° C and the crystals which have separated out are filtered off and washed with water. The crude 2-methyl-4-(3-methoxy-4-acetoxy-benzylidene)-5(4H)-oxazolone thus obtained is heated to the boil with 1,400 ml of acetone and 545 ml of water for 15 hours under a reflux condenser. Thereafter, the acetone is largely distilled off, whereupon the product crystallises out. After filtration, and washing with acetone, 4-acetoxy-α-acetylamino-3-methoxy-cinnamic acid of melting point 205°-206° C is obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]CC)=O)[C:3]1=[O:13].[NH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([CH2:16][CH2:15][NH:14][C:8](=[O:10])[CH2:7][N:4]2[CH2:5][CH2:6][CH:2]([OH:1])[C:3]2=[O:13])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CN1CCC(O)C1=O
Reactant: NCCN1CCCCC1
Product: O=C(CN1CCC(O)C1=O)NCCN1CCCCC1

Procedure:
3.0 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate and 2.87 g of N-(2-aminoethyl)piperidine are heated to 100° for 4 hours under nitrogen. The excess N-(2-aminoethyl)piperidine is distilled in a high vacuum. The (R/S)-N-[2-(1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide remaining as the residue has a melting point of 110°-111° after crystallization from ethyl acetate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH2:15]([O:22][C:23](OC1CC(=O)NC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[C:23]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: O=C1CC(OC(=O)OCc2ccccc2)C(=O)N1
Reactant: NCCOCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCOCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To 2-(2-aminoethoxyl)ethanol (20 g) dissolved in dichloromethane (200 ml) was added stepwise triethylamine (26.5 ml) and benzyloxy(carbonyloxy)succinimide (47.47 g). The reaction mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in deionized water (500 ml). The insoluble layer was separated, and the aqueous layer was mixed with 50 g of NaCl and the pH adjusted to 5.0 with 5% H3PO4. The product was extracted with dichloromethane (100 ml, 50 ml, and 50 ml) and the extract was dried with MgSO4, filtered, and evaporated to dryness under reduced pressure. The residue was dried under vacuum overnight, then combined with the previously separated insoluble layer and dissolved in dichloromethane (300 ml). The solution was washed with 5-% aqueous NaCl solution (3×50 ml) and dried with MgSO4. The solvent was distilled under reduced pressure, and the residue was dried overnight under vacuum, giving 40 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>C(O)(=O)C>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:21]/[N+:18]([O-:20])=[O:19])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(/C=C/[N+](=O)[O-])cc1OC

Procedure:
207.0 g of 3,4-dimethoxybenzaidehyde, 100.0 g of ammonium acetate and 125 ml of nitromethane are heated to boiling for 3-4 h in 1.0 l of glacial acetic acid. After cooling in an ice bath, the precipitate is filtered off with suction, rinsed with glacial acetic acid and petroleum ether and dried. M.p.: 140-141° C.
Reaction SMILES: CS(C)=O.[OH:5][CH2:6][C@@H:7]1[CH2:11][C@H:10]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23].C(N(CC)CC)C.Cl>C(Cl)Cl.C(Cl)(=O)C(Cl)=O>[CH:6]([C@@H:7]1[CH2:11][C@H:10]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:9][N:8]1[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)=[O:23])=[O:5]
Reactant: COc1ccc(CS[C@H]2C[C@@H](CO)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2C[C@@H](C=O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
In methylene chloride (24 ml), oxalyl chloride (0.40 ml) was dissolved. To the resulting solution, a solution of dimethyl sulfoxide (0.44 ml) in methylene chloride (1.6 ml) was added at -78° C., followed by stirring for 10 minutes. To the resulting solution, a solution of (2S,4S)-2-hydroxymethyl-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1 g) in methylene chloride (8 ml) was added dropwise at the same temperature, followed by stirring at -78° C. for 15 minutes and -50 to -60° C. for one hour. To the reaction mixture, triethylamine (2.4 ml) was added, followed by stirring at -14 to -15° C. for 20 minutes. To the reaction mixture, 1N hydrochloric acid was added to make the resulting solution acidic, followed by extraction with methylene chloride. The methylene chloride layer was washed with water and saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, whereby (2S,4S)-2-formyl-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1 g) was obtained.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)([C:14]#[N:15])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[O-2].[Al+3].[O-2].[O-2].[Al+3].CS(O)(=O)=[O:29]>>[N+:1]([C:4]1[C:9]2[NH:10][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)([C:14]([NH2:15])=[O:29])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)O
Reactant: N#CC1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Agent: [Al+3]
Agent: [O-2]
Product: NC(=O)C1(c2ccccn2)COc2cccc([N+](=O)[O-])c2N1
Temperature: 120 °C

Procedure:
5-Nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carbonitrile (100 mg, 0.4 mmol) was added to a vigorously stirring mixture of aluminum oxide (100 mg, 1 mmol) and methanesulfonic acid (2 mL, 30 mmol) at room temperature. The reaction mixture was then heated to 120° C. for 20 min, allowed to cool to room temperature, and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude product. The product was purified by FCC on silica gel eluting a hexane:ethyl acetate gradient to give 5-nitro-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxamide as clear oil (0.040 g. 40%). LCMS calculated for C14H13N4O4 (M+H)+: m/z=301.1. found: 301.1.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:17])[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9](=[O:12])[C:10]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[CH3:20][OH:21].Cl>C(Cl)Cl>[C:1]([C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:20]2[CH2:10][CH2:5][CH2:1][CH2:2][O:21]2)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1=C(C(C)(C)C)C(=O)C(C(C)(C)C)=CC1=O
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(OC2CCCCO2)cc(C(C)(C)C)c(O)c1C(C)(C)C
Reaction time: 3 h
Yield: 81 %

Procedure:
2,6-di-tert-butyl-3-methyl-1,4-benzoquinone (49 g) was dissolved in methylene chloride (300 ml) and sodium borohydride (15 g) was added to the solution under a nitrogen atmosphere. After adding methanol (30 ml) dropwise, the mixture was stirred for 3 h, poured into 5% HCl under ice cooling, And subjected to extraction with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was dissolved in methylene chloride (200 ml) and, after adding 3,4-2H-dihydropyran (26 ml) and a catalytic amount of paratoluenesulfonic acid, the mixture was stirred overnight at room temperature. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 2,6-di-tert-butyl-3-methyl-4-tetrahydropyranyloxyphenol [54.4 g (yield, 81%)] as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].F[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1>CC#N.CCOC(C)=O>[OH:7][CH:4]1[CH2:5][CH2:6][N:1]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=2)[CH2:2][CH2:3]1
Reactant: OC1CCNCC1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCC(O)CC2)cc1
Temperature: 95 °C
Yield: 19.7 %

Procedure:
In a 200 mL round bottom flask, piperidin-4-ol (2.165 g, 21.41 mmol) and K2CO3 (2.96 g, 21.41 mmol) were suspended in MeCN (51.0 mL). Ethyl 4-fluorobenzoate (2.62 mL, 17.84 mmol) was added and the reaction mixture was stirred under reflux (95° C.) for 96 hr. The reaction was cooled to RT, diluted with EtOAc (100 mL) and washed with water (50 mL). Dried organic layer with MgSO4, filtered, and concentrated in vacuo. The product was purified by re-crystallization using EtOAc/hexanes, affording the title compound as a white solid (0.878 g, 19.74% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (t, J=7.07 Hz, 3H) 1.34-1.47 (m, 2H) 1.73-1.85 (m, 2H) 3.03 (ddd, J=13.14, 9.98, 3.16 Hz, 2H) 3.63-3.77 (m, 3H) 4.23 (q, J=7.07 Hz, 2H) 4.72 (d, J=4.04 Hz, 1H) 6.86-7.05 (m, 2H) 7.66-7.85 (m, 2H). ESI-MS: m/z 250.2 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH:11]([N:14]1[CH2:19][CH2:18][N:17]([C:8]([C@H:5]2[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]2)=[O:10])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)N1CCNCC1
Reactant: O=C(O)[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](O)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1 g (6.9 mmol) of trans-4-hydroxycyclohexanecarboxylic acid (commercially available), 1.07 mg (8.3 mmol) of 1-(isopropyl)-piperazine (commercially available), 2.67 g (8.3 mmol) of TBTU and 1.54 g (15.2 mmol) of triethylamine in 7 ml DMF was stirred for 12 h at room temperature. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO4, and evaporated. The mixture was purified by column chromatography on NH2-silicagel eluting with CH2Cl2 and methanol=from 100:0 to 98:2. Evaporation of the combined product fractions yielded 0.9 g (51%) of the title compound as brown oil. MS (m/e): 255.2 (MH+).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]([O:9][CH:10]([O:20][CH2:21][CH3:22])[CH2:11][O:12][CH:13]([CH:17]1[CH2:19][CH2:18]1)[CH2:14]C=C)[CH3:8]>ClCCl>[CH:17]1([CH:13]([O:12][CH2:11][CH:10]([O:9][CH2:7][CH3:8])[O:20][CH2:21][CH3:22])[CH2:14]/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4])[CH2:19][CH2:18]1
Reactant: C=CCC(OCC(OCC)OCC)C1CC1
Reactant: C=CC(=O)OC
Solvent: ClCCl
Product: CCOC(COC(C/C=C/C(=O)OC)C1CC1)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of methyl prop-2-enoate (69.5 mL, 767 mmol) and benzylidene[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]dichloro(tricyclohexylphosphine)ruthenium (Grubbs catalyst, second generation) (1.30 g, 1.53 mmol) in dichloromethane (102 mL) was added to a solution of [1-(2,2-diethoxyethoxyl)but-3-en-1-yl]cyclopropane (C15) (7.00 g, 30.7 mmol) in dichloromethane (102 mL), and the reaction mixture was stirred at room temperature for 3 hours. After removal of solvent under reduced pressure, the residue was mixed with diethyl ether and filtered through Celite. The filter pad was washed with additional diethyl ether, and the combined filtrates were concentrated in vacuo. Purification using silica gel chromatography (Gradient: 0% to 30% ethyl acetate in heptane) afforded the product as an oil. Yield: 6.0 g, 21 mmol, 68%. 1H NMR (400 MHz, CDCl3) δ 7.04 (dt, J=15.7, 7.4 Hz, 1H), 5.85-5.91 (m, 1H), 4.59 (dd, J=5.4, 5.2 Hz, 1H), 3.64-3.74 (m, 6H), 3.52-3.61 (m, 2H), 3.44 (dd, J=10.3, 5.5 Hz, 1H), 2.76 (dt, J=8.5, 5.9 Hz, 1H), 2.51 (ddd, J=7.3, 5.9, 1.4 Hz, 2H), 1.19-1.24 (m, 6H), 0.78-0.89 (m, 1H), 0.57-0.66 (m, 1H), 0.37-0.52 (m, 2H), 0.03-0.11 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:24][C:25]([OH:27])=O)[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)OC(C)(C)C)(C)(C)C.C(=O)([O-])O.[NH4+:44].Cl>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:24][C:25]([NH2:44])=[O:27])[CH:12]=[CH:13][C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CCc1ccc(Cc2ccc(CC(=O)O)cc2OCc2ccccc2)cc1
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCc1ccc(Cc2ccc(CC(N)=O)cc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a mixture of [3-benzyloxy-4-(4-ethylbenzyl)-phenyl]acetonitrile (0.41 g) in ethanol (5 mL) and water (10 mL) was added potassium hydroxide (0.68 g), and the mixture was heated under reflux for 4 hours. To the reaction mixture was added 2 mol/L hydrochloric acid to acidify, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give [3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetic acid (0.41 g). To a solution of the obtained [3-benzyloxy-4-(4-ethylbenzyl)phenyl]acetic acid (0.41 g) in tetrahydrofuran (10 mL) were added pyridine (0.19 mL), di-tert-butylcarbonate (0.50 g) and ammonium hydrogen carbonate (0.18 g), and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-[3-benzyloxy-4-(4-ethylbenzyl)phenyl]-acetoamide (0.38 g).
Reaction SMILES: C(C1C=C2C(=CC=1)N(C)C=C2C1CCC(=O)CC1)#N.O1[C:24]2([CH2:29][CH2:28][CH:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:39]#[N:40])[CH:37]=4)[N:32]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH:31]=3)[CH2:26][CH2:25]2)[O:23]CC1>>[C:39]([C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:31]=[C:30]2[CH:27]1[CH2:28][CH2:29][C:24](=[O:23])[CH2:25][CH2:26]1)#[N:40]
Reactant: N#Cc1ccc2c(c1)c(C1CCC3(CC1)OCCO3)cn2Cc1ccccc1
Agent: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Product: N#Cc1ccc2c(c1)c(C1CCC(=O)CC1)cn2Cc1ccccc1
Yield: 53.1 %

Procedure:
This compound was prepared in the manner described above for intermediate 6a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-cyano-1-methyl-indole with 3-(1,4-dioxa-spiro[4,5]-dec-8-yl)-5-cyano-1-benzyl-indole (6.43 g, 20 mmol) to afford 3.49 g (63%) of the title compound as a white solid: mp 115-126° C.