Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6]C)=[O:5].CO[CH:14](OC)[N:15](C)C.O.Cl.NO>CO>[CH2:8]([C:2]1[O:1][N:15]=[CH:14][C:3]=1[C:4]([OH:6])=[O:5])[CH2:9][CH2:10][CH3:11]
Reactant: COC(OC)N(C)C
Reactant: CCCCC(=O)CC(=O)OC
Agent: Cl
Agent: NO
Solvent: CO
Solvent: O
Product: CCCCc1oncc1C(=O)O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Methyl 3-oxoheptanoate (0.16 g, 1 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.12 g, 1 mmol) was mixed and heated for 1 h at 60° C. The bright yellow oil was dissolved in methanol (2 mL) and water (1 mL) whereby and hydroxylamine hydrochloride (0.07 g, 1 mmol) was added, resulting in a pH of ca 5. The reaction was heated at 60° C. for 3 days. The solvents were evaporated and the residue refluxed in acetic acid: conc. HCL (1+1 mL) for 4 h. The solvents were evaporated to dryness and the residue dissolved in water at ca pH 10, filtered and acidified with HCl and extracted to DCM, dried (Na2SO4) and evaporated to yield the title compound as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.93 (t, J=7.32 Hz, 3 H) 1.33-1.45 (m, 2 H) 1.69-1.78 (m, 2 H) 3.12 (t, J=7.57 Hz, 2 H) 8.50 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)[N:14]([CH2:28][C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])[C:13]2=[O:35].[CH3:36][NH:37][CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH3:36][N:37]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[N:14]([CH2:28][C:29]([NH:31][CH:32]([CH3:33])[CH3:34])=[O:30])[C:13]3=[O:35])[CH:4]=1)[CH3:38]
Reactant: CNC
Reactant: COc1cccc(-c2nc3ccc(-c4cc(C=O)ccc4F)cc3c(=O)n2CC(=O)NC(C)C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cccc(-c2nc3ccc(-c4cc(CN(C)C)ccc4F)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 2-[6-(2-fluoro-5-formylphenyl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (19 mg, 0.04 mmol) in dichloroethane (2 mL) and acetic acid (0.05 mL) was added dimethylamine (2M in acetonitrile, 0.50 mL, 1.0 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (70 mg, 0.33 mmol) was then added as a solid with stirring at room temperature for 24 h. The solvent was removed in vacuo, the residue partitioned between ethyl acetate and a 1 N NaOH (aq.), the organic layer was washed with brine, dried (MgSO4) and the solvent evaporated. The resulting residue was subjected to preparative HPLC purification to provide 2-[6-(5-dimethylaminomethyl-2-fluorophenyl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 6a) (10 mg, 0.02 mmol, 50%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1.[CH2:18](Br)[CH:19]=[CH2:20].CO>CN(C=O)C>[CH2:20]([N:9]1[C:10]2[CH:11]=[CH:12][C:4]([Cl:3])=[CH:5][C:6]=2[C:7]2[CH2:16][N:15]([CH3:17])[CH2:14][CH2:13][C:8]1=2)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: C=CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (60% dispersion in oil, 240 mg, 6 mmol) in DMF (15 mL) at 0° C. was added 8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.1 g, 5 mmol) and the reaction mixture was stirred at 0° C. for 30 min, followed by addition of allyl bromide (0.51 mL, 6 mmol). The reaction mixture was allowed to warm to and was stirred at 25° C. for 3 h. MeOH was added and the reaction mixture was evaporated to dryness. The residue was purified by flash chromatography on silica gel using MeOH-DCM gradient. 1H NMR (DMSO-d6) δ (ppm): 7.53 (s, 1H), 7.47 (d, 1H), 7.15 (d, 1H), 5.94 (m, 1H), 5.1 (m, 1H), 4.83 (m, 1H), 4.78 (s, 2H), 4.25 (s, 2H), 3.44 (s, 2H), 3.02 (s, 2H), 2.86 (s, 3H).
Reaction SMILES: [OH-:1].[K+].[C:3]([NH:6][C:7]1[C:8]([I:31])=[C:9]([C:23]([NH:25][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:24])[C:10]([I:22])=[C:11]([C:20]=1[I:21])[C:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13])(=[O:5])[CH3:4].B(O)(O)O.Cl>O.CC(O)(C)C>[C:3]([N:6]([CH2:11][CH:20]([OH:1])[CH2:7][NH2:6])[C:7]1[C:20]([I:21])=[C:11]([C:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13])[C:10]([I:22])=[C:9]([C:8]=1[I:31])[C:23]([NH:25][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:24])(=[O:5])[CH3:4]
Reactant: [OH-]
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: Cl
Agent: OB(O)O
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)N(CC(O)CN)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Yield: 19 %

Procedure:
To a stirred solution of Water/tBuOH (2:1, 8 mL:10 mL) and KOH (0.73 g, 13 mmol, 1.2 eq was added at 40° C. 5-Acetylamino-N,N′-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-isophthalamide (8.1 g, 11 mmol). To the clear solution was then added boric acid (0.47 g, 8 mmol, 0.7 eq). The mixture was cooled to room temperature and the pH adjusted to pH 12.6-13.0 with KOH. t-Butyl n-(2-oxiranyl-methyl)carbamate (0.996 g, 8 mmol, 0.7 eq) was added, and the pH was measured several times and adjusted to 12.6-13.0. The mixture was stirred over the weekend. An aqueous solution of HCl was then added until pH 4. The reaction mixture was evaporated to dryness. The product was purified by C18 column chromatography eluting with MeOH/Water to give 5-[Acetyl-(3-amino-2-hydroxy-propyl)-amino]-N,N′-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-isophthalamide (2.09 mmol, Yield=19%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[CH2:12]=[O:13]>C(O)(C)(C)C.CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: Cc1c(F)cccc1[N+](=O)[O-]
Reactant: C=O
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(F)c1CCO
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A solution of potassium tertiary-butylate (90 mg, 0.8 mmol) in tert.-butanol (1 ml, synthesis quality, 99%) was added to 2-fluoro-6-nitrotoluene (776 mg, 5 mmol) and paraformaldehyde (150 mg, 5 mmol) in DMSO (2.5 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After the addition of the potassium tertiary-butylate solution, a color change from yellow to deep violet occurred. The solution was stirred for 5 min at room temperature and for 30 min at 70° C. (oil bath temperature). It was then left to cool down to room temperature and neutralized with a few drops of conc. HCl. The mixture was diluted with EtOAc (30 ml) and washed with H2O (20 ml). The aqueous phase was post-extracted with EtOAc (2×20 ml). Drying the organic phases over Na2SO4, filtering and evaporating the solvent under reduced pressure yielded the crude product (1.11 g) which was purified by column chromatography (20 g SiO2, 12×2 cm, solvent: PE 40 ml, PE/EtOAc 10:1 110 ml, 8:1 270 ml, 6:1 210 ml, 5:1 60 ml, 4:1 50 ml). 2-(2-fluoro-6-nitrophenyl)ethanol (653 mg, 71%) was obtained as a yellow solid.
Reaction SMILES: [C:1]1(=[CH:6][C:7](=[O:9])[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CC(=O)C)CCCC=1.[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21]([CH3:23])=O>CCCCCCC.C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:23][C:21]1[CH:20]([C:19]([O:25][CH2:26][CH3:27])=[O:24])[C:1]2([CH2:6][C:7](=[O:9])[CH:8]=1)[CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: CC(=O)C=C1CCCC1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)CC1=CCCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CCCCCCC
Product: CCOC(=O)C1C(C)=CC(=O)CC12CCCC2
Yield: 12.1 %

Procedure:
A mixture of 1-cyclopentylidenepropan-2-one/1-cyclopentenylpropan-2-one (25:75, 100 g, 0.805 mol), ethyl acetoacetate (105 g, 0.805 mol), and zinc chloride (16.5 g, 0.12 mol) in heptane (100 ml) and benzene (100 ml) was refluxed for 6 days using a Dean-Stark apparatus. The resulting mixture was cooled, washed with water (250 ml), with a 5% aqueous solution of NaHCO3 (250 ml), with water, dried (MgSO4) and concentrated. Vigreux-Distillation (0.1 mbar, bath temperature 150° C., head temp. 106-130° C.) of the crude product (174 g) followed by FC (SiO2, hexane/MTBE 10:1 to 5:1) gave ethyl 7-methyl-9-oxospiro[4.5]dec-7-ene-6-carboxylate (23 g, 12%).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16](O)[CH2:17][OH:18].[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22]>CC(C)=O>[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22].[CH:10]1([N:9]2[CH2:16][CH2:17][O:18][C:8]2=[N:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: OCCO
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Product: C1CCC(N=C2OCCN2C2CCCCC2)CC1
Yield: 102.9 %

Procedure:
A mixture of 41.2 g of dicyclohexylcarbodiimide and 7 g of ethylene glycol was heated on a water bath for 2 hours. After removing the precipitate of dicyclohexyl urea formed, the resulting oily product was dissolved in acetone and to the acetone solution was added an acetone solution containing 9 g of oxalic acid to obtain 35 g of Compound (1) with a melting point of 130° - 133°C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([CH3:15])[CH2:13][NH:14][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=3)=[CH:8][CH:7]=2)=[CH:2]1
Reactant: CC(CN)c1ccc(-c2ccsc2)cc1
Reactant: O=C(Cl)c1cccnc1
Product: CC(CNC(=O)c1cccnc1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propylamine (see example 14) and nicotinoyl chloride in a manner analogous to the procedure described in example 14. The NMR spectrum was, consistent with the proposed title structure.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[CH3:10][O-:11].[Na+]>CO.[Cl-].[Na+].O>[F:8][C:7]1[C:2]([O:11][CH3:10])=[N:3][C:4]([F:9])=[CH:5][CH:6]=1
Reactant: Fc1ccc(F)c(F)n1
Reactant: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(F)ccc1F
Temperature: 65 °C
Yield: 78.8 %

Procedure:
2,3,6-Trifluoropyridine (17.91 ml, 188 mmol) was dissolved in anhydrous MeOH (300 ml) and the resulting mixture was placed under argon. This mixture then was treated with a 25 wt % methanolic solution of sodium methoxide (43.0 ml, 188 mmol). The resulting mixture was then heated at about 65° C. for 2 hr. The reaction mixture was cooled to ambient temperature, and concentrated in vacuo to yield a residue which then was mixed with brine (200 mL), and extracted with Et2O (3×200 ml). The combined extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give 21.5 g (79% yield) of crude 3,6-difluoro-2-methoxypyridine as a white solid which was carried on to the next step without purification.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10](=[CH:15][CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:12][CH2:13][NH2:14])[CH3:9].[C:19](OC(=O)C)(=[O:21])[CH3:20]>ClCCl>[C:19]([NH:14][CH2:13][CH:12]=[CH:11][C:10]([CH2:8][CH3:9])=[CH:15][CH:16]([CH3:17])[CH3:18])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C=CCN)=CC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C=CCNC(C)=O)=CC(C)C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of triethylamine (2.22 g) and 4-ethyl-6-methyl-2,4-heptadiene-1-ylamine (3.07 g) in dichloromethane (50 ml) at 0° C. was added dropwise acetic anhydride (4.08 g). After one hour, the reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10% methanol-chloroform) to give 1-acetylamino-4-ethyl-6-methyl-2,4-heptadiene (3.86 g) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28]>>[CH2:26]([S:29]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:31])=[O:30])[CH2:27][CH3:28]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 9.0 μL (0.11 mmol) 1-propanesulfonyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:90][C:91]1([CH2:94][OH:95])[CH2:93][CH2:92]1>C(Cl)Cl>[C:43]([O:42][CH2:41][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH:20][C:21]([O:22][CH2:23][CH:24]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=2[C:31]2[C:36]1=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:37])[C:38]([NH:90][C:91]1([CH2:94][OH:95])[CH2:93][CH2:92]1)=[O:39])(=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Reactant: NC1(CO)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NC1(CO)CC1)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (3.5 eq), followed by (1-aminocyclopropyl) methanol hydrochloride (1.2 eq). The reaction was stirred at room temperature for 2 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 30-50% EtOAc/Hex to give (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1-(hydroxymethyl)cyclopropylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)=[O:4].C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[Cl:14][C:8]([C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH2:6]1)=[O:10]
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)Cl)CC1

Procedure:
To solution of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (144 mg, 1 mmol) was added 2M oxalyl dichloride (1.0 mL, 2.0 mmol) in DCM followed by a few drops of DMF. The reaction mixture was stirred until gas evolution ceased (˜1 h). Excess oxalyl chloride and DCM were evaporated to afford methyl 1-(chlorocarbonyl)cyclopropanecarboxylate. To a solution of methyl 1-(chlorocarbonyl)cyclopropanecarboxylate in DCM (2 mL) was added 4,4-difluoropiperidine/HCl (173 mg) and DIPEA (0.384 mL) at 0° C., and then the reaction mixture was allowed to warm to rt. The reaction mixture was purified by silica gel FCC to yield Cap P-20. 1H NMR (500 MHz, CDCl3) δ ppm 3.77-3.82 (2H, m), 3.75 (3H, s), 3.64 (2H, t, J=5.42 Hz), 1.96-2.09 (4H, m), 1.51-1.57 (2H, m), 1.33-1.39 (2H, m). Hydrolysis of methyl 1-(4,4-difluoropiperidine-1-carbonyl)cyclopropanecarboxylate (by 2 mL of 1N NaOH, 1 mL of THF and 1 mL of MeOH) to afford Cap P-20 as a white solid (194 mg). 1H NMR (500 MHz, CDCl3) δ ppm 3.78-3.73 (4H, m), 1.97-2.10 (4H, m), 1.59-1.65 (2H, m), 1.42-1.48 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:17])[C:12](Br)=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH3:17])[C:12]([B:29]([OH:34])[OH:30])=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)cc(C)c1B(O)O
Temperature: -78 °C
Yield: 60.1 %

Procedure:
To a solution (100 mL) of 5-(benzyloxy)-2-bromo-1,3-dimethylbenzene (8.78 g, 30.2 mmol) in tetrahydrofuran was added n-butyllithium hexane solution (1.6 M, 22.6 mL, 36.2 mmol) under stirring at −78° C. The reaction mixture was stirred at the same temperature for 1.5 hr, and triisopropyl borate (20.9 mL, 90.6 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. To the reaction mixture was added 2 M hydrochloric acid (150 mL) and the mixture was stirred for 2.5 hr. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Cold hexane was added to the residue to allow crystallization. The precipitated crystals were collected by filtration, washed with cold hexane and dried to give the title compound (4.65 g, yield 60%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:7]=[CH:6]S[CH:4]=[CH:3]1.Br[C:25]1C=C2C(=CC=1)NC=C2CCN1CCCC1>>[OH:1][C:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:7][CH2:6][CH2:25][CH2:4][CH2:3]1
Reactant: Brc1ccc2[nH]cc(CCN3CCCC3)c2c1
Reactant: OC1(c2ccc3[nH]cc(CCN4CCCC4)c3c2)C=CSC=C1
Product: OC1(c2ccc3[nH]cc(CCN4CCCC4)c3c2)CCCCC1

Procedure:
5-(4-Hydroxythiapyran-4-yl)-3-(2-pyrrolidinylethyl)-1H-indole: (56%) from 5-bromo-3-(2-pyrrolidinylethyl)-1H-indole (Example 3b); mp 66-78° C.; HRMS-FAB+ for C19H27N2OS: calculated MH+ :331.18442; found MH+ :331.18568.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]1.C(N(CC)CC)C>C(#N)C>[C:29]([O:28][C:27]([NH:26][CH:23]1[CH2:24][CH2:25][N:21]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:22]1)=[O:33])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 95.4 %

Procedure:
A suspension of 49.5 g (0.175 mole) of 1-cyclopropyl-1,4-dihydro-4-oxo-6,7,8-trifluoroquinoline-3-carboxylic acid, 37.3 g (0.2 mole) of 1,1dimethylethyl (3-pyrrolidinyl)carbamate, 40.4 g (0.4 mole) of triethylamine in 1.5 1 of acetonitrile was refluxed for three hours. The precipitate was removed by filtration, washed with acetonitrile, then ethyl ether, and dried in vacuo to give 75.0 g of the title compound, mp 239°-240° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and benzyl bromide.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][NH:24][C@@H:25]([CH2:36][CH2:37][C:38]2[NH:39][CH:40]=[C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:42]=2)[C:26](OCC2C=CC=CC=2)=[O:27])=[CH:15]1.C(N(CC)CC)C>C1COCC1>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][N:24]2[C@@H:25]([CH2:36][CH2:37][C:38]3[NH:39][CH:40]=[C:41]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:42]=3)[C:26](=[O:27])[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=3)[C:10]2=[O:11])=[CH:15]1
Reactant: O=C(OCc1ccccc1)[C@H](CCc1nc(-c2ccccc2)c[nH]1)NCc1c[nH]c2ccccc12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1[C@H](CCc2nc(-c3ccccc3)c[nH]2)N(Cc2c[nH]c3ccccc23)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
3-trifluoromethyl-phenylisocyanate (11 mg, 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butanoate (23 mg, 1 eq.) in 2 ml of THF. The mixture is stirred for 2 hours at approximately 20° C. then diluted with 2 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is then concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine) in order to produce the expected compound (25 mg, 92% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH:24]=[N+:25]([CH3:27])[CH3:26].COC1C=C(C=CC=1OC)C=O.CNC>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:24]([N:25]([CH3:27])[CH3:26])[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Reactant: COc1ccc(C=[N+](C)C)cc1OC
Agent: CNC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2ccc(OC)c(OC)c2)N(C)C)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenyl-1H-indole and (3,4-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3,4-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[C:10]([Cl:16])[CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].CN(C)[CH:19]=[O:20].P(Cl)(Cl)(Cl)=O.C([O-])(=O)C.[Na+]>ClC(Cl)C>[CH:19]([C:14]1[C:13]2[C:8](=[CH:9][C:10]([Cl:16])=[CH:11][C:12]=2[Cl:15])[NH:7][C:6]=1[C:1]([O:3][CH2:4][CH3:5])=[O:2])=[O:20]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Combine 2-carboethoxy-4,6-dichloroindole (10.0 g, 0.039 mol), and dimethylformamide (4.5 mL, 0.057 mol) in dichloroethane (20 mL). Add phosphoryl chloride (8.9 g, 0.058 mmol). Heat to 80° C. After 18 hours, cool the reaction mixture to ambient temperature and combine with aqueous 1 M sodium acetate solution and stir. After 18 hours, filter, rinse with water, and dry to give 3-formyl-2-carboethoxy-4,6-dichloroindole.