Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:34])=[C:24]([NH:27][C:28]([NH:30][CH:31]3[CH2:33][CH2:32]3)=[O:29])[CH:25]=2)[NH:20][C:19](=[O:35])[C:18]=1[C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([CH3:43])[CH:37]=1)=O)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[Cl:34][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][C@@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:36]3[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([CH3:43])[CH:37]=3)[C:19](=[O:35])[NH:20]2)=[CH:25][C:24]=1[NH:27][C:28]([NH:30][CH:31]1[CH2:32][CH2:33]1)=[O:29]
Reactant: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)c3cc(NC(=O)NC4CC4)c(Cl)cc3[nH]c2=O)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3)c3cc(NC(=O)NC4CC4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
To a solution of (S)-2-{2-[7-chloro-6-(3-cyclopropylureido)-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (615 mg in 10 mL dry methylene chloride) was added 10 drops of anisole followed by 10 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 1 hour the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (chloroform:10% ammonium hydroxide in methanol, 90:10) to give the title compound (451 mg).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C(N(CC)CC)C.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>ClCCl.CN(C)C1C=CN=CC=1>[O:7]([CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])[Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCCCCO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 89.5 %

Procedure:
To a solution of 5-hexyn-1-ol (9.81 g) in dichloromethane (50 ml) was added, at 0° C., triethylamine (10 ml), t-butyldimethylsilylchloride (17 g) and 4-dimethylaminopyridine (100 mg) and the mixture was stirred 16 hrs. while warming to room temperature. Dichloromethane (100 ml) was added and the organic layer was washed with 1N HCl (2×50 ml), brine and dried with Na2SO4. Solvents were removed and residue distilled under vacuum to yield the title compound as an oil (19 g, 89%).
Reaction SMILES: Cl.[CH:2]1([C:5](=[NH:8])[O:6][CH3:7])[CH2:4][CH2:3]1.Cl.N[CH:11](CO)[C:12]([O:14][CH3:15])=[O:13].C(=O)(O)[O-].[Na+]>ClCCl>[CH:2]1([C:5]2[O:6][CH2:7][CH:11]([C:12]([O:14][CH3:15])=[O:13])[N:8]=2)[CH2:4][CH2:3]1
Reactant: COC(=N)C1CC1
Reactant: COC(=O)C(N)CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1COC(C2CC2)=N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.3 %

Procedure:
Into a 500-mL 3-necked round-bottom flask were placed methyl cyclopropanecarbimidate hydrochloride (13.6 g, 100.00 mmol, 1.00 equiv.), methyl 2-amino-3-hydroxypropanoate hydrochloride (17.6 g, 112.82 mmol, 1.10 equiv.) and dichloromethane (150 mL). The resulting solution was stirred for 24 hours at room temperature, then added sodium bicarbonate (16.8 g, 200.00 mmol, 2.00 equiv.). The resulting solution was stirred for 24 hours at room temperature. The solid was filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). This resulted in 8 g (47% yield) of methyl 2-cyclopropyl-4,5-dihydrooxazole-4-carboxylate as a colorless oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][OH:9].N1C=CN=C1.C(N(CC)CC)C.[S:22](Cl)(Cl)=[O:23]>ClCCl>[S@@:22]1(=[O:23])[N:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[CH2:8][O:9]1
Reactant: O=S(Cl)Cl
Reactant: OC[C@@H]1CCCCN1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[S@@]1OCC2CCCCN21
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
To a solution of (S)-1-Piperidin-2-yl-methanol hydrochloride (3.43 g, 22.63 mmol), imidazole (6.1 g, 88.72 mmol) and triethylamine (7.33 g, 72.42 mmol) in anhydrous dichloromethane (120 mL) at 0-5° C. was added a solution of thionyl chloride (3.2 g, 25.86 mmol) in anhydrous dichloromethane (10 mL) over a period of 45 min. The reaction mixture was stirred at 0-5° C. for 45 min, partitioned with H2O and the aqueous layer was extracted with dichloromethane (2×150 mL). The combined organic layer was washed with H2O dried over Na2SO4, and concentrated in vacuo to give an orange liquid. Flash column chromatography purification (silica gel, 2% EtOAc in dichloromethane) afforded the title product as a clear, colorless liquid (1.31 g, 36%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][C@H:15]([OH:18])[CH2:16][CH3:17].[H-].[Na+]>C1COCC1>[F:11][C:10]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:18][C@H:15]([CH2:16][CH3:17])[CH3:14])[C:6]#[N:7]
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: CC[C@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](C)Oc1ccc(C#N)cc1C(F)(F)F
Reaction time: 2 h
Yield: 38.3 %

Procedure:
A solution of 1.1 g (5.9 mmol) of 4-fluoro-3-trifluoromethylbenzonitrile and 485 mg (6.5 mmol) of (S)-(+)-2-butanol in 10 mL of THF at −10° C. was treated with 235 mg (5.9 mmol) of sodium hydride. The resulting mixture was stirred cold for 2 h, then quenched with 10 mL of H2O. The quenched solution was extracted with 30 mL of Et2O, dried over MgSO4 and concentrated. Chromatography on a Biotage 40M cartridge using 4:1 v/v hexanes/EtOAc as the eluant afforded 550 mg of the title compound: 1H NMR (500 Mhz) δ 0.99 (t, J=7.6, 3H), 1.35 (d, J=6.2, 3H), 1.58–1.83 (m, 2H), 4.51 (septet, 1H), 7.04 (d, J=8.7, 1H), 7.75 (d, J=8.7, 1H), 7.85 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=1.C[C:15]1[CH:16]=[C:17]([N:22]2CC[NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][C:20]3[CH:19]=[C:18]4[C:17](=[CH:16][CH:15]=3)[NH:22][CH2:23][CH2:24][NH:25]4)[CH2:10][CH2:9]2)[CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: Cc1ccnc(N2CCNCC2)c1
Product: Cc1ccnc(N2CCN(Cc3ccc4c(c3)NCCN4)CC2)c1

Procedure:
Example 10 was prepared according to Example 2 except that in Step A 1-(4-methylpyridin-2-yl)piperazine is substituted for 1-(3,4-dimethylphenyl)piperazine; mp 179°-180° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][F:9])[N:3]=1.[NH2:10][C:11]1[S:12][C:13]([C:19]2[C:24]([F:25])=[CH:23][C:22]([C:26]([OH:29])([CH3:28])[CH3:27])=[CH:21][C:20]=2[F:30])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17]>>[F:30][C:20]1[CH:21]=[C:22]([C:26]([OH:29])([CH3:28])[CH3:27])[CH:23]=[C:24]([F:25])[C:19]=1[C:13]1[S:12][C:11]([NH:10][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][F:9])[N:3]=2)=[C:15]([C:16]([NH2:18])=[O:17])[CH:14]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: FCc1nccc(Cl)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccnc(CF)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 4-chloro-2-(fluoromethyl)pyrimidine (19.71 mg, 0.13 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (42 mg, 0.13 mmol) as the starting materials.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=[CH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C>[N:28]1[CH:29]=[CH:30][C:25]([CH:23]=[CH:24][C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=2[Cl:8])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=Cc1ccncc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Yield: 68.3 %

Procedure:
A mixture of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinyimethoxy)pyridine from Example 69a (1.18 g, 3 mmol), 4-ethenylpyridine (0.39 mL, 3.6 mmol), Pd(OAc)4 (62.5 mg), tris(o-tolyl)phosphine (312.5 mg), and triethylamine (6.25 mL) in acetonitrile (15 mL) was heated at reflux for 16 hours. The solution was then concentrated, and the residue was washed with water and aqueous NaHCO3 solution. The organic layer was dried and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:Et2O 100:5-100:15 to afford the title compound (852 mg, 69% yield). MS (CI/NH3) m/z 416 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.48 (s, 9H), 1.92 (m, 2H), 2.02 (m, 2H), 3.42 (m, 2H), 3.97 (m, 1H), 4.13 (m, 2H), 7.43 (m, 2H), 7.56 (m, 1H), 8.05 (m, 1H), 8.62 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)=[CH:11][CH:12]=2)[N:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CC#N>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:5]1[C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:20])=[O:21])[CH:14]=3)=[CH:11][CH:12]=2)=[CH:7][C:3]([CH2:2][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[N:4]1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CBr)nn3-c3ccccc3Cl)s2)c1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(CN4CCOCC4)nn3-c3ccccc3Cl)s2)c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 97.3 %

Procedure:
A mixture of 3-bromomethyl-1-(2-chlorophenyl)-5-{5-[3-(methylsulfonyl)phenyl]-thiophen-2-yl]-1H-pyrazole (51 mg, 0.1 mmol), K2CO3 (42 mg, 0.3 mmol), KI (10 mg), and morpholine (0.3 mmol) in anhydrous MeCN (5 mL) was stirred at 90° C. for 6 h under N2. The solid was filtered off, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (0-80% EtOAc/hexanes) to give the title compound as a pale-yellow solid (50 mg, 96%). 1HNMR (CDCl3): δ 8.04 (m, 1H), 7.82 (m, 1H), 7.72 (m, 1H), 7.57-7.43 (m, 5H), 7.20 (d, 1H), 6.75 (d, 1H), 6.66 (s, 1H), 3.77 (m, 4H), 3.66 (s, 2H), 3.07 (s, 3H), 2.60 (m, 4H). MS(ES): 514 [M+H]+.
Reaction SMILES: [O:1]([C:3]#[N:4])[K].[N:5]1([CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:8][N:7]=[CH:6]1.[OH-].[Na+]>O.C(O)(=O)C>[N:5]1([CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:3]([NH2:4])=[O:1])=[CH:18][CH:19]=2)[CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CC(C)C(c1ccc(N)cc1)n1ccnc1
Reactant: N#CO[K]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(c1ccc(NC(N)=O)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
A solution of KOCN (2.25 g) in water was added dropwise at RT to a mixture of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.0278 mol) in acetic acid (4 ml) and water (50 ml) and the mixture was stirred at RT for 1 hour. The mixture was neutralized with NaOH 3N and extracted with CH2Cl2 and CH3OH. The organic layer was washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3O/NH4OH 96/4/0.3). The pure fractions were collected and evaporated. The residue was recrystallized from 2-propanone, yielding 2.7 g (51.4%) (±)-4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenylurea (compound 266).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)[CH2:14][CH2:13][C@H:12]2[C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CCCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C@H:15]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:14][CH2:13][C@H:12]2[C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2[C@H](c3ccc([N+](=O)[O-])cc3)CC[C@H]2c2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCCCCCC
Product: CC(C)(C)c1ccc(N2[C@H](c3ccc(N)cc3)CC[C@H]2c2ccc(N)cc2)cc1

Procedure:
To a 160 ml Parr stirrer hydrogenation vessel was added the product from Example 37D (2 g, 4.49 mmol), followed by 60 ml of THF, and Raney Nickel Grace 2800 (1 g, 50 wt % (dry basis)) under a stream of nitrogen. The reactor was assembled and purged with nitrogen (8×20 psig) followed by purging with hydrogen (8×30 psig). The reactor was then pressurized to 30 psig with hydrogen and agitation (700 rpm) began and continued for a total of 16 h at room temperature. The slurry was filtered by vacuum filtration using a GF/F Whatman glass fiber filter. Evaporation of the filtrate to afford a slurry followed by the addition heptane and filtration gave the crude title compound, which was dried and used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Li]CCCC.Cl[Si:15]([CH3:27])([CH3:26])[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[CH2:23][C:22]([CH3:25])=[CH:21]2>C1COCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][Si:15]([CH3:26])([CH3:27])[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:24]=2[CH2:23][C:22]([CH3:25])=[CH:21]3)=[CH:3][CH:4]=1
Reactant: Cc1ccc(N)cc1
Reactant: CC1=Cc2cccc([Si](C)(C)Cl)c2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=Cc2cccc([Si](C)(C)Nc3ccc(C)cc3)c2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.44 g (60.0 mmol) of p-toluidine in 180 mL of THF 24.0 mL (60.0 mmol) of 2.5 M nBuLi in hexanes was added at 0° C. This mixture was additionally stirred for 4 hours at room temperature, then cooled to −40° C., and a solution of 13.4 g (60.0 mmol) of chloro(dimethyl)(2-methyl-1H-inden-7-yl)silane in 50 mL of THF was added in one portion. The resulting mixture was stirred for 12 hours at room temperature and then evaporated to dryness. To the residue 100 mL of ether was added, and the obtained suspension was stirred for 20 minutes, and then filtered through glass frit (G3). The precipitate was additionally washed with 2×100 mL of ether. The combined filtrate was evaporated to dryness, and the residue was washed with 2×15 mL of cold hexanes and then dried in vacuum. Yield 11.3 g (64%) of white solid. 1H NMR (CD2Cl2): δ 7.40 (dd, J=7.3 Hz, J=1.3 Hz, 1H, 6-H in indenyl), 7.32 (dd, J=7.3 Hz, J=1.3 Hz, 1H, 4-H in indenyl), 7.26 (t, J=7.3 Hz, 1H, 5-H in indenyl), 6.88-6.91 (m, 2H, 2,6-H in p-tolyl), 6.53-6.57 (m, 2H, 3,5-H in p-tolyl), 6.52 (m, 1H, 3-H in indenyl), 3.68 (br.s, 1H, NH), 3.40 (s, 2H, 1,1′-H in indenyl), 2.20 (s, 3H, 4-Me in p-tolyl), 2.16 (m, 3H, 2-Me in indenyl), 0.57 (s, 6H, SiMe2). Anal. Calc. for C19H23NSi: C, 77.76; H, 7.90; N, 4.77%. Found: C, 77.94; H, 8.05; N, 4.94%.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18]>C(O)C>[CH3:12][O:11][C:4]1[N:3]=[C:2]([CH2:13][NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CNCC(O)CO
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(CNCC(O)CO)n1
Temperature: 0 °C
Yield: 87.1 %

Procedure:
4 g (0.0219 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 50 ml of ethanol and 4.15 ml (0.0438 mol) of 3-methylamino-1,2-dihydroxypropane are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 4.74 g of yellow powder are obtained, ie a yield of 87.1%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([O:22][CH3:23])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[C:24]1(=O)[C:27]2([CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:26](=[O:33])[CH2:25]1>C(Cl)Cl>[O:33]=[C:26]1[C:27]2([CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:24]([NH:1][C@@H:2]([CH2:7][C:8]2[CH:9]=[C:10]([O:22][CH3:23])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([O:14][CH3:15])[CH:13]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:25]1
Reactant: O=C1CC(=O)C12CCOCC2
Reactant: COC(=O)[C@@H](N)Cc1cc(OC)c(-c2ccccc2)c(OC)c1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cc(OC)c(-c2ccccc2)c(OC)c1)NC1=CC(=O)C12CCOCC2
Yield: 84.4 %

Procedure:
Using a similar procedure to that for the preparation the compound of Example 38 from methyl (2S)-2-amino-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoate (2.0 g, 6.3 mmol) and 7-oxaspiro[3.5]nonane-1,3-dione (1.1 g, 1.1 eq) in DCM (30 ml) was prepared the title compound as a white foam (2.4 g, 86%). δH (300 MHz, DMSO d6) 8.53 (1H, d, J 8.7 Hz), 7.20-7.30 (3H, m), 7.08 (2H, d, J 8.1 Hz), 6.70 (2H, d, J 8.5 Hz), 4.44 (1H, s), 4.30 (1H, m), 3.72 (3H, s), 3.61 (6H, s), 3.22 (1H, dd, J 13.7, 5.0 Hz), 2.98 (1H, dd, J 13.8, 10.1 Hz), 1.74-1.99 (2H, m), 1.48 (1H, d, J 13.6 Hz), 1.31 (1H, d, J 13.0 Hz); m/z (ES+, 70V) 439 (MH+).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1)=O)[CH:2]=[CH2:3].[O-:30][C:31]#[N:32].[Na+].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]2[C:5]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1)=[N:32][C:31](=[O:30])[N:11]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]=[CH2:3]
Reactant: N#C[O-]
Reactant: C=CCc1c(O)ccc(NCc2ccccc2)c1C(=O)c1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C=CCc1c(O)ccc2c1c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1

Procedure:
A solution of 15 mg (39 μmol) (2-allyl-6-benzylamino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanone and 2.5 mg sodium cyanate in 0.2 ml acetic acid is stirred at r.t. for 16 h. Aqueous sodium hydroxide solution is added and the product is extracted with dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH2:14]OC)=[C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:7]([CH3:27])=[CH:6]2.Cl.O1CCOCC1.FC1[CH:43]=[CH:42][C:39]([CH:40]=[O:41])=[CH:38][CH:37]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:43]=[CH:42][C:39]([CH:40]=[O:41])=[CH:38][CH:37]=1)=[C:8]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[C:7]([CH3:27])=[CH:6]2
Reactant: O=Cc1ccc(F)cc1
Reactant: COCOc1c(-c2cccc(C(F)(F)F)c2)c(C)cc2cc(OC)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3cccc(C(F)(F)F)c3)c(C)cc2c1
Yield: 34.5 %

Procedure:
6-Methoxy-1-methoxymethoxy-3-methyl-2-(3-trifluoromethyl-phenyl)-naphthalene (208) (0.35 g, 0.93 mmol), 4 N HCl/Dioxane (5 mL), 4-fluorobenzaldehyde (0.11 mL, 1.02 mmol), Cs2CO3 (0.364 g, 1.12 mmol) and DMF (3 mL) were reacted as described above to give 0.140 g (35%) of the title compound (209) as oil. 1H NMR (400 MHz, d-CDCl3): δ 2.26 (s, 3H), 3.95 (s, 3H), 6.68 (d, J=8.8 Hz, 2H), 7.09 (dd, J1=2.6 Hz, J2=9.2 Hz, 1H), 7.17-7.17 (m, 1H), 7.31-7.39 (m, 2H), 7.44 (s, 1H), 7.48-7.50 (m, 1H), 7.61-7.64 (m, 3H), 7.73 (d, J=9.1 Hz, 1H), 9.80 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:25])=[C:8](C(OC(C)(C)C)=O)[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:25][C:29]([NH:28][CH2:26][CH3:27])=[O:30])=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cccc(F)c2)c(C(=O)OC(C)(C)C)c1N
Reactant: CCN=C=O
Product: CCNC(=O)Nc1cn(-c2cccc(F)c2)cc1C(=O)OCC
Yield: 73 %

Procedure:
Following general method 4, employing 3-amino-1-(3-fluorophenyl)-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester and ethyl isocyanate, afforded the title compound as a cream solid (0.192 g, 73%); LCMS (method B): RT=3.61 min, M+H+=320; 1H NMR (CDCl3, 300 MHz): 8.41 (s, 1H), 7.62 (d, J=2.7 Hz, 1H), 7.44 (d, J=2.7 Hz, 1H), 7.38 (dt, J=8.2, 6.2 Hz, 1H), 7.21 (dd, J=8.2, 2.4 Hz, 1H), 7.14 (dt, J=9.9, 2.4 Hz, 1H), 6.98 (td, J=8.2, 2.4 Hz, 1H), 4.73 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.35-3.26 (m, 2H), 1.37 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:21])[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[Cl-].[NH4+].O1CC[CH2:26][CH2:25]1>>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH:11]=[C:12]([CH3:21])[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[C:25]#[CH:26]
Reactant: C1CCOC1
Reactant: CC(=O)CCC=C(C)CCC=C(C)COC1CCCCO1
Agent: [Cl-]
Agent: [NH4+]
Product: C#CC(C)(O)CCC=C(C)CCC=C(C)COC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution of 6,10-dimethyl-11-(2-tetrahydropyranyl) oxy-5,9-undecadien-2-one (90 mg, 0.31 mmol) in tetrahydrofuran (5 ml) was stirred on an ice bath under argon atmosphere. To the solution was added lithium acetylide ethylenediamine complex (180 mg, 1.95 mmol), and the mixture was warmed to room temperature and stirred for 3 hours. After addition of saturated aqueous ammonium chloride (2 ml), the reaction mixture was extracted with ether. The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a crude product, which was purified with silica gel column chromatography to obtain 3,7,11-trimethyl-12-(2-tetrahydropyranyl)oxy-6,10-dodecadien-1-in-3-ol (75 mg, 75%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:7]2)([O-])=O>Cl.CO>[NH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[C:8]1[NH:9][C:10]2[C:6]([CH:7]=1)=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2
Reactant: O=[N+]([O-])c1ccc2[nH]c(-c3ccccn3)cc2c1
Agent: Cl
Solvent: CO
Product: Nc1ccc2[nH]c(C3CCCCN3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.6 %

Procedure:
5-Nitro-2-(pyridin-2-yl)-1H-indole (1.0 g, 4.2 mmol) was added to HCl/MeOH (2 M, 50 mL). The reaction mixture was stirred at room temperature for 1 h and the solvent was evaporated under vacuum. PtO2 (200 mg) was added to a solution of the residue in MeOH (50 mL) and the reaction mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 2 h. The catalyst was filtered through a celite pad and the solvent was evaporated under vacuum to afford 2-(piperidin-2-yl)-1H-indol-5-amine (1.0 g), which was directly used in the next step.
Reaction SMILES: [C:1]([C:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([CH3:6])[CH2:4][OH:5])#[N:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:14][S:15]([O:5][CH2:4][C:3]([C:1]#[N:2])([C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH3:6])(=[O:17])=[O:16]
Reactant: CC(C#N)(CO)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C#N)(COS(C)(=O)=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-cyano-2-(4-chlorophenyl)propan-1-ol (68 g., 0.3 mole) and methane sulfonyl chloride (37.5 g., 0.33 mole) in 2 liters of benzene is added dropwise at 10° C., 36 g., (0.36 mole) of triethylamine. The reaction mixture is stirred at room temperature for 30 minutes and then heated on a steam bath for another 30 minutes. The precipitate formed is filtered and the filtrate is washed with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 63 g. of product.