Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([O:28][CH2:29][CH3:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH3:27].[Li+].[OH-].Cl>C1COCC1.CO>[CH2:29]([O:28][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH3:27])[C:3]([OH:31])=[O:2])[CH3:30]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3C)oc2C)cc1C)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
To a solution of (S)-2-ethoxy-3-[2-methyl-4-(5-methyl-2-o-tolyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester (100 mg, 0.24 mmol) in THF/methanol 2/1 (1.5 ml) was added a 1 N aqueous LiOH solution (1.4 ml, 1.4 mmol). The reaction mixture was stirred for 1.5 h at ambient temperature, neutralized with 1 N aqueous HCl solution under ice cooling and concentrated under reduced pressure. The residue was dissolved in 1 N HCl/ice water 1/1 and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (88 mg, 0.21 mmol, 91%) as off-white solid, which was crystalized from dichloromethane/hexane to afford colorless crystals. According to chiral HPLC of the corresponding methyl ester (Chiralcel-ODH), the enantiomeric excess amounts to 98.6%.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1([N:12]2[CH2:16][CH2:15][CH:14]([C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]#[N:19])[CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-:32].[NH4+]>C(OCC)(=O)C>[CH:6]1([N:12]2[CH2:16][CH2:15][CH:14]([C:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]([NH2:19])=[O:32])[CH2:13]2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: N#CC(c1ccccc1)(c1ccccc1)C1CCN(C2CCCCC2)C1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(C2CCCCC2)C1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 80 ml. of concentrated sulfuric acid was added 20 g. (0.057 mole) of α-(cyclohexyl-3-pyrrolidinyl)-α,α-diphenylacetonitrile. The mixture was shaken until solution occurred while being cooled in an ice bath until heat was no longer evolved. The solution was heated at 70° C. for 48 hours, poured on ice and made basic with ammonium hydroxide. The resulting white solid precipitate was taken up in ethyl acetate and the solution dried over sodium sulfate. The solution was concentrated and the residual oil taken up in hot ligroin, filtered and allowed to stand overnight at room temperature. The resulting crystals were recrystallized from ligroin. Yield 9.0 g. (42.5%); m.p. 119°-121° C.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:20])[CH3:19].Cl>ClCCl>[C:18]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A dichloromethane (1 L) solution of fluorene (150 g) was cooled down to 0° C., and anhydrous aluminum chloride (126 g) was added thereto little by little. Next, a dichloromethane (400 mL) solution of acetyl chloride (74 g) was dropwise added and stirred for one hour while maintaining 0° C. The reaction mixture was poured into 6M-hydrochloric acid (1 L) containing ice, and the solid matters deposited were obtained by filtering under reduced pressure. They were dried and then recrystallized from toluene to obtain 2-acetylfluorene (165 g) of colorless needle crystal. The melting point of this compound was 129° C.
Reaction SMILES: BrC1C=NC(I)=NC=1.C(OC1C=CC(B(O)O)=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].F[C:33]1[C:38](F)=[C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]C)[CH:36]=[CH:35][C:34]=1[C:49]1[N:54]=[CH:53][C:52]([Br:55])=[CH:51][N:50]=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.COCCOC>[CH2:41]([O:40][C:37]1[CH:38]=[CH:33][C:34]([C:49]2[N:50]=[CH:51][C:52]([Br:55])=[CH:53][N:54]=2)=[CH:35][CH:36]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Brc1cnc(I)nc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Brc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Yield: 79 %

Procedure:
--Quantities: 5-bromo-2-iodopyrimidine 2 (4.33 g, 15.2 mmol), 4-benzyloxyphenylboronic acid 25 (3.81 g, 16.7 mmol), tetrakis(triphenylphosphine)palladium (351 mg, 0.30 mmol), 2M sodium carbonate (50 ml), DME (50 ml). The experimental procedure was as described for compound 4 to yield the benzyloxyphenylpyrimidine 26 (4.12 g, 79%) (from EtOH), m.p. 155° C.; νmax /cm-1 (KBr) 3200, 1600, 1550, 1520, 1410, 1325, 1250, 1165, 1040, 1025, 1010 and 840; δ 5.14 (2H, s, OCH2), 7.06 (2H, d, J 9, 3'- and 5'-H), 7.30-7.48 (5H, m, PhH), 8.35 (2H, d, J 9, 2'-and 6'-H) and 8.77 (2H, s, 4- and 6-H); m/z 342 (M+), 340 (M+), 249, 221, 196, 142, 115 and 91.
Reaction SMILES: C(OC(=O)NCC1C=CC2N(CCC(C)C)C(CN3C4C(=CC=CC=4)C(=O)N(C4CC4)C3=O)=NC=2C=1)(C)(C)C.[CH3:40][O:41][C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][C:44](=[O:52])[CH:43]=1.[C:53]([O:57][C:58]([NH:60][CH2:61][C:62]1[CH:83]=[CH:82][C:65]2[N:66]([CH2:71][CH2:72][CH2:73][CH2:74][O:75][C:76](=[O:81])[C:77]([CH3:80])([CH3:79])[CH3:78])[C:67]([CH2:69]Cl)=[N:68][C:64]=2[CH:63]=1)=[O:59])([CH3:56])([CH3:55])[CH3:54].Cl>>[C:53]([O:57][C:58]([NH:60][CH2:61][C:62]1[CH:83]=[CH:82][C:65]2[N:66]([CH2:71][CH2:72][CH2:73][CH2:74][O:75][C:76](=[O:81])[C:77]([CH3:80])([CH3:79])[CH3:78])[C:67]([CH2:69][N:45]3[C:46]4[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:42]([O:41][CH3:40])=[CH:43][C:44]3=[O:52])=[N:68][C:64]=2[CH:63]=1)=[O:59])([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(CCl)n2CCCCOC(=O)C(C)(C)C
Reactant: COc1cc(=O)[nH]c2ccccc12
Agent: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Agent: Cl
Product: COc1cc(=O)n(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCOC(=O)C(C)(C)C)c2ccccc12
Yield: 67 %

Procedure:
The procedure for the preparation of [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester was followed starting from 4-methoxy-1H-quinolin-2-one (106 mg, 0.605 mmol) and 2,2-dimethyl-propionic acid 4-[5-(tert-butoxycarbonylamino-methyl)-2-chloromethyl-benzoimidazol-1-yl]-butyl ester; HCl salt (296 mg, 0.605 mmol). Purification by flash chromatography (eluent hexane-ethyl acetate 1:1, 1:2, 0:1) afforded 2,2-dimethyl-propionic acid 4-[5-(tert-butoxycarbonylamino-methyl)-2-(4-methoxy-2-oxo-2H-quinolin-1-ylmethyl)-benzoimidazol-1-yl]-butyl ester (240 mg, 67%) as a white solid:
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][CH2:10][C:6]=2[CH:5]=1)(=O)[CH3:2].[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14].C(N)C1C=CC=CC=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:19][O:18][C:16](=[O:17])/[C:15](/[C:13]#[N:14])=[C:1](/[C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][CH2:10][C:6]=2[CH:5]=1)\[CH3:2]
Reactant: COC(=O)CC#N
Reactant: CC(=O)c1ccc2c(c1)CCO2
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: NCc1ccccc1
Product: COC(=O)/C(C#N)=C(\C)c1ccc2c(c1)CCO2
Yield: 60.1 %

Procedure:
To a stirred solution of 5-acetyl-2,3-dihydrobenzo[b]furan (Aldrich) (1 g, 6.17 mmol) in toluene (60 ml) was added methyl cyanoacetate (0.60 ml, 6.78 mmol), benzylamine (0.07 ml, 0.61 mmol) and acetic acid (0.3 ml, 5.3 mmol) and the whole refluxed in a Dean-Stark apparatus for 16 h. The reaction mixture was cooled, washed with 2N HCl (30 ml), NaHCO3 (30 ml), brine (30 ml), dried (MgSO4) and evaporated to a yellow residue. This residue was purified by column chromatography using 15-20% EtOAc in pentane as eluant to provide the title product (902 mg, 60%); 1HNMR (400 MHz, CDCl3) δ: 2.65 (s, 3H), 3.25 (t, 2H), 3.9 (s, 3H), 4.6 (t, 2H), 6.8 (d, 1H), 7.25 (d, 1H), 7.8 (s, 1H); LRMS: M+NH4+, 261. (ES+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9](O)=O.BrC1C=CN=CC=1.[NH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]1>CS(C)=O.C(OCC)(=O)C.[Cl-].[Na+].[Cu]I>[N:7]1[CH:9]=[CH:8][C:12]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24][CH2:23]2)=[CH:13][CH:14]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: [Cu]I
Agent: Brc1ccncc1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2ccncc2)CC1
Temperature: 100 °C
Yield: 30 %

Procedure:
Potassium carbonate (3 eq), L-proline (0.4 eq), CuI (0.2 eq) and 4-bromopyridine (1 eq) were added under a protecting gas atmosphere to a solution of tert-butyl piperidin-4-ylmethyl-carbamate (3 g, 15 mmol) in DMSO. The reaction mixture was heated for 20 h at 100° C. After cooling to room temperature, the mixture was diluted with ethyl acetate and sat. sodium chloride solution and filtered over Celite, and the residue was then washed with ethyl acetate. The phases were separated, dried and concentrated under reduced pressure. The crude product was purified by column chromatography. Yield: 30%
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.5 %

Procedure:
A solution of 15 g (90.3 mmol) of methyl 4-hydroxyphenylacetate in 25 mL of dimethylformamide (DMF) was added 32.4 g (99.3 mmol) of cesium carbonate, followed by 13.4 mL (112.9 mmol) of benzyl bromide (BnBr), and the resulting heterogeneous mixture was stirred at rt for 72 h. The reaction mixture was filtered, the solids were washed with ethyl acetate, and the combined organic extracts were concentrated to give a residue which was chromatographed on silica gel (25% hexane in dichloromethane) to afford 19.1 g (83% yield) of desired (4-benzyloxy-phenyl)-acetic acid methyl ester as indicated by 1H NMR; LC-MS—calcd for C16H16O3 [M++H]+: 257.11, found: 257.2.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1.C(OC(=O)C)(=O)C>>[CH3:5][C:6]1([C:10]2[CH:11]=[CH:12][C:13]([N+:1]([O-:4])=[O:2])=[CH:14][CH:15]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: CC1(c2ccccc2)CCC1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC1(c2ccc([N+](=O)[O-])cc2)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
70% Nitric acid (7:3, Nitric acid:Water, 0.375 ml, 5.92 mmol) was added dropwise over 60 minutes to a solution of (1-methylcyclobutyl)benzene (346 mg. 2.37 mmol) in Acetic anhydride (1.4 mL, 15 mmol) cooled at 0° C. The temperature of the solution was maintained below 5° C. during the addition. Upon completion of the addition, the reaction was stirred for 60 minutes with cooling. The reaction mixture was poured into 40 ml ice water and the ice was allowed to melt. The aqueous phase was extracted with three×20 ml portions of Et2O and the combined organic phase was washed with 25 ml H2O followed by two 20 ml portions of sat NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated to yield a light the product as an oil (418 mg) which was used as is in the next step. 1H NMR (400 MHz, CDCl3) d ppm 8.16 (d. J=8.71 Hz, 2H), 7.29 (d, J=8.71 Hz, 2H), 2.41 {m, 2H), 2.15 (m, 3H), 1.88 (m, 1H). 1.48 (s, 3H)
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C@@H:40]1[C:43](=[O:44])[NH:42][C@@H:41]1[CH2:45][N:46]1[N:50]=[C:49]2[CH2:51][N:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:53][C:48]2=[N:47]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23]([NH:39][C@@H:40]2[C:43](=[O:44])[NH:42][C@@H:41]2[CH2:45][N:46]2[N:50]=[C:49]3[CH2:51][N:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:53][C:48]3=[N:47]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1Cc2nn(C[C@H]3NC(=O)[C@H]3N)nc2C1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2nc3c(n2)CN(C(=O)OC(C)(C)C)C3)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a cooled (0° C.) slurry of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)-imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (15.3 mg, 0.028 mmol), tert-butyl 2-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-4,6-dihydropyrrolo[3,4-d][1,2,3]triazole-5(2H)-carboxylate (8.3 mg, 0.027 mmol) and HATU (11.4 mg, 0.029 mmol) in DMF (500 μL) was added DIPEA (9.5 μL, 0.054 mmol). After stirring at rt for 16 h, it was diluted with EtOAc and washed with LiCl (5%, aq). The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound (18.1 mg, 81%) as a white solid. Rt=1.08 min, m/z=828.5 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[F:31])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.[C:32]([O:36][N:37]([CH2:41][C:42](O)=[O:43])[C:38]([CH3:40])=[O:39])([CH3:35])([CH3:34])[CH3:33].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(Cl)Cl.CO>[C:32]([O:36][N:37]([CH2:41][C:42]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=4[F:31])=[CH:20][CH:21]=3)[CH2:13][CH2:14]2)[CH:4]=1)=[O:43])[C:38]([CH3:40])=[O:39])([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1ccc(N)cc1C1CCN(Cc2ccc(Oc3cc(F)c(F)cc3F)cc2)CC1
Reactant: CC(=O)N(CC(=O)O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N(CC(=O)Nc1ccc(C)c(C2CCN(Cc3ccc(Oc4cc(F)c(F)cc4F)cc3)CC2)c1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 90.6 %

Procedure:
To a stirred solution of 4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))phenylamine (271 mg, 0.64 mmol) in dimethylformamide (15 mL) was added 2-[(tert-butoxy)-N-methylcarbonylamino]acetic acid (361 mg, 1.91 mmol) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 728 mg, 1.91 mmol) and diisopropylethylamine (328 mg, 2.54 mmol). After stirring at room temperature for 21 h, the reaction mixture was partitioned between CH2Cl2 (30 mL) and saturated aqueous NaHCO3 (30 mL). The organic layer was washed with water (3×30 mL) and brine (30 mL), dried over MgSO4 and concentrated in vacuo provided the crude product. Purification on silica gel (silica gel 60, 40 mL) eluting with CH2Cl2 then 3% methanol in CH2Cl2 to give 2-[(tert-butoxy)-N-methylcarbonylamino]-N-[4-methyl-3-(1-{[4-(2,4,5-trifluorophenoxy)phenyl]methyl}(4-piperidyl))phenyl]acetamide (345 mg, 0.58 mmol, 90% yield) as a white solid. LCMS (method B): 2.81 min, 598.3 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].Cl.[CH3:15][O:16][C:17](=[O:23])[C@H:18]([CH:20]([CH3:22])[CH3:21])[NH2:19].CN1CCOCC1>C(Cl)Cl>[CH3:15][O:16][C:17](=[O:23])[C@H:18]([CH:20]([CH3:22])[CH3:21])[NH:19][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 66.1 g (0.328 mol) of 4-nitrophenyl chloroformate in 1.2 liters of CH2Cl2 was cooled to 0° C. and treated with L-valine methyl ester hydrochloride. The resulting mixture was treated slowly, with stirring, with 68.9 ml (0.626 mol) of 4-methylmorpholine. The resulting solution was allowed to slowly warm to ambient temperature and was stirred overnight. After washing with 3 portions of 10% aqueous NaHCO3, the solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography by eluting with chloroform to provide the desired compound. 1H NMR (DMSO-d6) δ 0.94 (d, J=7 Hz, 3H), 0.95 (d, J=7 Hz, 3H), 2.12 (octet, J=7 Hz, 1H), 3.69 (s, 3H), 4.01 (dd, J=8, 6 Hz, 1H), 7.41 (dt, J=9, 3 Hz, 2H), 8.27 (dt, J=9, 3 Hz, 2H), 8.53 (d, J=8 Hz, 1H). Mass spectrum: (M+NH4)+ =314.
Reaction SMILES: N1(CCS(N2CCC(C3[C:25]4[C:20](=[C:21]([C:31](N)=[O:32])[CH:22]=[C:23](C5C=CSC=5)[CH:24]=4)NC=3)CC2)(=O)=O)CCCC1.Br[C:35]1[CH:36]=[C:37]2[C:41](=[C:42]([C:44]([NH2:46])=[O:45])[CH:43]=1)[NH:40][CH:39]=[C:38]2[CH:47]1[CH2:52][CH2:51][N:50]([S:53]([CH2:56][CH2:57][CH2:58][N:59]2[CH2:63][CH2:62][CH2:61][CH2:60]2)(=[O:55])=[O:54])[CH2:49][CH2:48]1.OCC1C=C(B(O)O)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[OH:32][CH2:31][C:21]1[CH:20]=[C:25]([C:35]2[CH:36]=[C:37]3[C:41](=[C:42]([C:44]([NH2:46])=[O:45])[CH:43]=2)[NH:40][CH:39]=[C:38]3[CH:47]2[CH2:52][CH2:51][N:50]([S:53]([CH2:56][CH2:57][CH2:58][N:59]3[CH2:63][CH2:62][CH2:61][CH2:60]3)(=[O:55])=[O:54])[CH2:49][CH2:48]2)[CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCN4CCCC4)CC3)c[nH]c12
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: OCc1cccc(B(O)O)c1
Product: NC(=O)c1cc(-c2cccc(CO)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12

Procedure:
The title compound was prepared following the general procedure for intermediate 16. Thus, 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (150 mg, 0.30 mmol), [3-(hydroxymethyl)phenyl]boronic acid (188 mg, 1.20 mmol), Pd(PPh3)4 (30 mg, 10%) and cesium carbonate (200 mg, 0.60 mmol) were reacted to form the desired product which was purified by reverse phase HPLC eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to yield the desired product (280 mg, 44%).
Reaction SMILES: C(Cl)(=O)OC(Cl)C.C([N:15]1[CH2:38][CH:37]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)[O:36][C:17]2([CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([CH3:35])[CH:26]=3)=[O:24])[CH2:19][CH2:18]2)[CH2:16]1)C1C=CC=CC=1>ClCCCl>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([CH:37]2[O:36][C:17]3([CH2:18][CH2:19][N:20]([C:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:33])[CH3:34])=[C:27]([CH3:35])[CH:26]=4)=[O:24])[CH2:21][CH2:22]3)[CH2:16][NH:15][CH2:38]2)=[CH:40][CH:41]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2ccc(Cl)cc2)O3)ccc1OC(C)C
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cc1cc(C(=O)N2CCC3(CC2)CNCC(c2ccc(Cl)cc2)O3)ccc1OC(C)C
Temperature: 25 °C
Yield: 62.1 %

Procedure:
1-Chloroethyl carbonochloridate (142 mg, 108 μL, 0.99 mmol) was added to a solution of [8-benzyl-10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (44 mg, 0.08 mmol) in DCE (508 μL) at room temperature and then the reaction mixture was heated at reflux for 1 hour. The excess solvent was removed in vacuo and the carbamate intermediate was dissolved in MeOH (2 mL) and heated at reflux for 20 minutes. The reaction mixture was cooled to room temperature, filtered and purified by Waters mass directed LC/MS-HPLC: (1-99% ACN/H2O (5 mM HCl)). The desired fractions were concentrated to dryness, dissolved in EtOAc and washed with 1M NaOH. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to yield [10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (22 mg, 60%). ESI-MS m/z calc. 442.2. Found 443.5 (M+1)+; Retention time: 1.51 minutes (3 min run)
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].Cl.[CH3:15][C:16]1[N:17]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=2)[CH:18]=[CH:19][N:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:3]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:25][C:24]3[CH:23]=[CH:22][C:21]([N:17]4[CH:18]=[CH:19][N:20]=[C:16]4[CH3:15])=[CH:28][CH:27]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(c2cccc(O)c2)CCC1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1-c1ccc(COc2cccc(C3(C#N)CCC3)c2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
A mixture of 1-cyano-1-(3-hydroxyphenyl)cyclobutane (1.76 g, 10 mmol), 4-(2-methylimidazol-1-yl)benzylchloride hydrochloride (2.10 g, 10 mmol) and potassium carbonate (6.90 g, 50 mmol) in DMF (80 ml) were stirred together at 80° C. for 3 hrs. Water (200 ml) was added and the mixture extracted with ethyl acetate/benzene (2/1, 100 ml×2), washed with water (100 ml×2), brine (100 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 150 g; dichloromethane/methanol (20/1)) to afford 2.90 g (84%) of the titled compound as a clear yellow oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[CH2:16]=[O:17]>C(N(CC)CC)C.CC(C)=O>[F:15][C:2]([F:1])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:16][OH:17])[CH:6]=1)=[O:4]
Reactant: C=O
Reactant: O=C(c1c[nH]c2ccccc12)C(F)(F)F
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1cn(CO)c2ccccc12)C(F)(F)F
Temperature: 130 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
The mixture of 4.80 g of 3-(trifluoroacetyl)-1H-indole, 1.35 g of paraformaldehyde and 0.10 g of triethylamine was stirred at 130° C. for 2 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered, and then the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and hexane was added to the residue, as a result, a crystal was formed. The crystal was collected to obtain 5.36 g of 3-(trifluoroacetyl)-1H-indole-1-ylmethanol.