Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CC1C=CC(S(O[CH2:38][CH2:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH:43]=[CH:42]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:38][CH2:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH:43]=[CH:42]2)=[CH:24][CH:25]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCCOC2C=CCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOC4C=CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (30 mg) in anhydrous DMF were added 2-(cyclohex-2-enyloxy)ethyl 4-methylbenzenesulfonate (intermediate BV) (1.5 eq) and Cs2CO3 (2 eq). The mixture was stirred at room temperature for 16 h, after which LC-MS showed the reaction was complete. The reaction mixture was poured into water, extracted with EA, washed with water and brine, and then dried with anhydrous Na2SO4 and concentrated to an oil. The crude oil was purified by preparative-HPLC to obtain compound BW (17.1 mg). 1H NMR (CD3OD, 400 MHz): δ 7.32 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.87˜5.76 (s, 2H), 4.59 (s, 1H), 4.11˜3.89 (m, 6H), 3.89˜3.76 (m, 3H), 3.72˜3.68 (m, 1H), 3.49˜3.40 (m, 3H), 2.03˜1.98 (m,2H), 1.89˜1.84 (m, 1H), 1.80˜1.62 (m, 2H), 1.79˜1.51 (m, 1H); MS ESI (m/z) 506 (M+H)+, calc. 505.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:20])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Reactant: C1CCNCC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added piperidine (0.13 ml, 1.29 mmol) and T3P (50 wt % solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (113 mg, 46% yield). Rf=0.80 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C21H29ClN2O2, 376.9, found, 377.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.47 (d, J=2.1 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.34 (dd, J=7.9, 1.7 Hz, 1H), 3.70 (s, 2H), 3.54-3.48 (m, 2H), 3.32-3.26 (m, 2H), 3.02-2.93 (m, 1H), 2.75-2.67 (m, 2H), 2.65-2.51 (m, 6H), 1.78-1.71 (m, 4H), 1.63-1.44 (m, 6H); 100 MHz 13C NMR (CDCl3) δ 173.5, 146.3, 135.4, 133.9, 130.8, 126.5, 123.7, 72.9, 56.7, 54.3, 46.8, 43.5, 41.0, 28.4, 26.8, 25.8, 24.7, 23.7.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3[N:18]([CH2:19][CH3:20])[N:17]=[C:16]([C:21]#[N:22])[CH:15]=3)=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:21]([C:16]1[CH:15]=[C:14]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:3][CH:4]=3)[N:8]([CH:11]([CH3:12])[CH3:13])[CH:7]=2)[N:18]([CH2:19][CH3:20])[N:17]=1)#[N:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1nc(C#N)cc1-c1cn(C(C)C)c2cc(N)ccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCn1nc(C#N)cc1-c1cn(C(C)C)c2cc(NS(C)(=O)=O)ccc12
Yield: 90.4 %

Procedure:
Stir a solution of 5-(6-Amino-1-isopropyl-1H-indol-3-yl)-1-ethyl-1H-pyrazole-3-carbonitrile (0.126 g, 0.393 mmol), pyridine (0.062 g, 0.786 mmol) and methanesulfonyl chloride (0.068 g, 0.590 mmol) in methylene chloride (3 mL) at room temperature for 2.5 h. After this time, Purify the reaction directly by chromatography (silica, methylene chloride to 1:9 ethyl acetate/methylene chloride) then freeze-dried from acetonitrile/water to afford N-[3-(5-Cyano-2-ethyl-2H-pyrazol-3-yl)-1-isopropyl-1H-indol-6-yl]-methanesulfonamide (0.132 g, 90%) as alight purple solid: mp 144-145° C.; 1H NMR (500 MHz, DMSO-d0.6 δ0.60 (s, 1H), 7.84 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.11 (s, 1H), 7.04 (dd, J=8.5, 1.5 Hz, 1H), 4.73 (m, 1H), 4.27 (q, J=7.0 Hz, 21H), 2.96 (s, 3H), 1.52 (d, J=6.5 Hz, 6H), 1.35 (t, J=7.0 Hz, 3H) LCMS (Method 4)>99%, 6.96 min, m/z 372 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:37])[CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].Br[C:39]1[CH:40]=[CH:41][C:42]2[S:46][CH:45]=[CH:44][C:43]=2[CH:47]=1>CC(N(C)C)=O>[S:46]1[C:42]2[CH:41]=[CH:40][C:39]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:37])[CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:28]([CH3:29])[CH3:30])[CH:31]([CH3:33])[CH3:32])[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[CH:47][C:43]=2[CH:44]=[CH:45]1
Reactant: Brc1ccc2sccc2c1
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)[Si](OC[C@H](C)Oc1cc(Oc2ccc3sccc3c2)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Temperature: 200 °C
Yield: 34.5 %

Procedure:
Cesium carbonate (163 mg, 0.05 mmol) was added to a solution of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzamide (225 mg, 0.5 mmol), bromotris(triphenylphosphine)copper1 (93 mg, 0.1 mmol) and 5-bromobenzothiophene (107 mg, 0.5 mmol) in dimethylacetamide (2.5 mL) and the stirred mixture heated at 200° C. in a “Biotage Initiator” microwave for 4 hours. The mixture was cooled to ambient temperature and pressure, poured onto water (40 mL) and extracted with ethyl acetate (3×15 mL), the combined organic layers washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 40% ethyl acetate in isohexane, to give the desired compound (100 mg).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:26])=[C:12]([N:16]2[CH2:19][CH:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.C(N(CC)CC)C.[C:34](Cl)(=[O:37])[CH2:35][CH3:36].[OH-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[F:26][C:11]1[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][C:12]=1[N:16]1[CH2:19][CH:18]([CH:20]2[CH2:25][CH2:24][N:23]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:22][CH2:21]2)[CH2:17]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC(C3CCNCC3)C2)c1F
Reactant: CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCC(C2CN(c3cccc(CO)c3F)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
4-{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (120 mg) and triethylamine (145 mg) were mixed with dichloromethane (3 ml), and propanoyl chloride (48 mg) was added thereto, followed by stirring at room temperature for 1 hour. A 1 M aqueous NaOH solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3 ml), and a 1 M TBAF/THF (0.5 ml) solution was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 1-(4-{1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}piperidin-1-yl)propan-1-one (98 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:33])([F:32])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28][CH2:29][CH2:30]O)=[CH:22][CH:21]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:32])[F:33])=[CH:21][CH:22]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: OCCCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)Cn1ccc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2cc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)ccc21

Procedure:
In analogy to the procedure described for example 1 d], (5-hydroxy-indol-1-yl)-acetic acid ethyl ester was reacted with 5-(4-trifluoromethoxy-phenyl)-pent-4-yn-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give the title compound as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[NH2:5].C1C(=O)N([Br:20])C(=O)C1>C(Cl)Cl>[Br:20][C:6]1[CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Solvent: ClCCl
Product: Nc1cc(F)c(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring mixture of 3-fluoro-4-(trifluoromethyl)aniline (1.5 g) in DCM (12 mL) at room temperature was added dropwise a solution of NBS (1.5 g) in DCM (24 mL) over 15 min. The reaction mixture was stirred at rt for 1.5 h. The product mixture was concentrated under reduced pressure to one half of its original volumn. The white solid was filtered off and the crude product mixture was further purified via column chromatography. Retention time (min)=2.490, method [1], MS (ESI) 257.9 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].N1C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CCCCCC.C(OCC)(=O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])=[CH:3][CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 60 °C
Yield: 65 %

Procedure:
p-Bromoanisole(3.74 g, 20 mmol), tetrakis(triphenylphosphine)palladium (1.16 g, 1 mmol) and CuI (0.381 g, 2 mmol) were placed in a 100 mL three neck round bottom flask, equipped with a pressure equalizing addition funnel and a reflux condenser which was connected to a vacuum line. The third neck of the flask was sealed with a rubber septum. The apparatus was purged with nitrogen three times. Pyridine, (30 mL) was added and the mixture was stirred until it became a single clear phase. Trimethylsilyl-acetylene (1.96 g, 20 mmol) and 20 mL of pyridine were placed in the addition funnel and the solution was added dropwise to the reaction mixture at 45° C. The reaction mixture was heated to 60° C. The progress of the reaction was monitored by TLC (silica gel with hexane/ethyl acetate). When the reaction was complete, it was extracted with ether. The organic solution was dried over anhydrous magnesium sulfate, filtered and the volatile solvents removed by evaporation under reduced pressure. The residue was purified by column chromatography (silica gel with hexane/ethyl acetate). In this way, 2.66g, 65% yield, was obtained. 1H NMR δ: 7.39(d, 2H, J=8.75 Hz), 6.80(d, 2H, J=8.75 Hz), 3.78(s, 3H), 0.23(s, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[C:20]12([CH2:30][CH:31]=O)[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>C(Cl)Cl>[C:20]12([CH2:30][CH:31]3[C:12]4[NH:13][C:14]5[C:19]([C:11]=4[CH2:10][CH2:9][NH:8]3)=[CH:18][CH:17]=[CH:16][CH:15]=5)[CH2:21][CH:22]3[CH2:28][CH:26]([CH2:25][CH:24]([CH2:23]3)[CH2:29]1)[CH2:27]2
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=CCC12CC3CC(CC(C3)C1)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2c3c([nH]c2c1)C(CC12CC4CC(CC(C4)C1)C2)NCC3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (443 μl, 5.8 mmol) was added to a solution of tryptamine (5.76 g, 36 mmol) and 1-adamantylacetaldehyde (6.52 g, 36.6 mmol) in dry DCM (450 ml) wth 3A molecular sieves (46.5 g) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours, followed by the addition of trifluoroacetic acid (5.76 ml, 74.8 mmol) then allowed to warm to room temperature and stirring continued for a further 16 hours. The resultant suspension was concentrated in vacuo, taken up in ethyl acetate (200 ml), filtered, washed successively with saturated NaHCO3 solution (200 ml), brine (2×200 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product as an orange foam which was used without further purification. (10.95 g, 95%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[C:9]([CH3:12])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.C(N(CC)CC)C.[CH2:22]([O:24][C:25](=[O:30])[CH2:26][N:27]=[C:28]=[O:29])[CH3:23]>C(Cl)Cl>[CH2:22]([O:24][C:25](=[O:30])[CH2:26][NH:27][C:28]([C:3]1[C:4](=[O:14])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][C:9]([CH3:12])=[C:8]([CH3:13])[CH:7]=2)=[O:29])[CH3:23]
Reactant: CCOC(=O)CN=C=O
Reactant: Cc1cc2oc(=O)cc(O)c2cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(C)c(C)cc2oc1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
4-Hydroxy-6,7-dimethyl-chromen-2-one (500 mg, 2.4 mmol), triethylamine (368 uL, 2.64 mmol) and methylene chloride (4 mL) were placed together in a dry flask. Isocyanato-acetic acid ethyl ester (283 uL, 2.52 mmol) was added and the reaction was stirred overnight (24 h) at room temperature. The crude reaction mixture was purified using silica gel chromatography (SGC) (1% Methanol in Methylene Chloride) to provide the title compound in 85% yield. MS ESI(−) m/e: 318.33 (M−1).
Reaction SMILES: Cl.[N:2]1[N:3]([C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[CH2:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]2)[N:4]=[CH:5][CH:6]=1.[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:25]([CH:29]=1)[C:26](O)=[O:27]>>[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:25]([C:26]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]2[CH2:10][C:9]2[CH:17]=[CH:18][CH:19]=[C:7]([N:3]3[N:4]=[CH:5][CH:6]=[N:2]3)[CH:8]=2)=[O:27])[CH:29]=1
Reactant: c1cc(C[C@@H]2CCCCN2)cc(-n2nccn2)c1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: Cl
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCCC[C@H]2Cc2cccc(-n3nccn3)c2)c1

Procedure:
The title compound was prepared from (S)-2-(3-[1,2,3]triazol-2-yl-benzyl)-piperidine hydrochloride and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid E-3 following the procedure described for B-28. LC-MS D: tR=0.94 min; [M+H]+=427.92.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:31][C:32]([CH3:34])=O.C([BH3-])#N.[Na+]>CO.FC(F)(F)C(O)=O>[F:30][C:2]([F:29])([F:1])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][O:7][CH2:8][C:9]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][N:12]([CH:32]([CH3:34])[CH3:31])[CH2:11][CH2:10]1
Reactant: CC(C)=O
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCNCC2)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
Mixture of isomer A of 4-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-4-phenylazepane (3 mg) and acetone (1.2 mg) in methanol (0.15 mL) was stirred at room temperature for 0.5 hr, then sodium cyanoborohydride (1.0 M solution in THF, 0.02 mL) was added followed by 1 drop of trifluoroacetic acid. The mixture was stirred at 65° C. for overnight and concentrated under vacuum. Then saturated sodium bicarbonate solution and dichloromethane was added to the mixture and the organic layer was separated. The aqueous layer was extracted with dichloromethane 2 times and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under vacuum to give the product as a clear sticky oil (2.5 mg, 76% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:26][C:10]3=[CH:11][C:12]4[C:13]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH2:27]([N:29]([CH2:33][CH3:34])[C:30](Cl)=[O:31])[CH3:28]>>[CH2:24]([C:13]1([CH2:22][CH3:23])[C:12]2[CH:11]=[C:10]3[NH:26][C:7]([C:3]4[C:2]([NH:1][C:30](=[O:31])[N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[CH:6][NH:5][N:4]=4)=[N:8][C:9]3=[CH:17][C:16]=2[N:15]([CH:18]([CH3:20])[CH3:19])[C:14]1=[O:21])[CH3:25]
Reactant: CCC1(CC)C(=O)N(C(C)C)c2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Reactant: CCN(CC)C(=O)Cl
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(CC)(CC)C(=O)N3C(C)C

Procedure:
3-[3-(7,7-Diethyl-5-isopropyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-1,1-diethyl-urea was prepared using 2-(4-amino-1H-pyrazol-3-yl)-7,7-diethyl-5-isopropyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (150 mg, 0.43 mmol) and diethylcarbamoyl chloride (58 mg, 0.43 mmol). 12 mg (6%) %) of the title compound were obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[C:19]1([S:25]([O-:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][S:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:27])=[O:26]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccccc3)c(C)o2)cc1
Yield: 83.7 %

Procedure:
Reaction of chloride 2 (267 mg, 1.0 mmol) and sodium benzenesulfinate (173 mg, 1.1 mmol) gave benzoate 16 (311 mg, 84%) as a white powder: mp (EtOAc) 159-161° C.; 1H NMR (CDCl3) δ 8.07 (ddd, J=8.7, 1.9, 1.5 Hz, 2H, H-2, H-6), 7.91 (ddd, J=8.7, 1.9, 1.5 Hz, 2H, H-3, H-5), 7.82 (ddd, J=8.2, 2.0, 1.2 Hz, 2H, H-2′, H-6′), 7.64 (tt, J=7.5, 1.2 Hz, 1H, H-4′), 7.52 (br dd, J=8.2, 7.5 Hz, 2H, H-3′, H-5′), 4.32 (s, 2H, CH2SO2), 3.94 (s, 3H, OCH3), 2.32 (s, 3H, CH3); MS m/z 372.3 (MH+, 100%). Anal. calcd for C19H17NO5S: C, 61.44; H, 4.61; N, 3.77. Found: C, 61.75; H, 4.62; N, 3.75%.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[C:21](Cl)[N:20]=[CH:19][N:18]=1.C(N(CC)CC)C.O>ClCCl>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:21]1[C:22]([N+:23]([O-:25])=[O:24])=[C:17]([Cl:16])[N:18]=[CH:19][N:20]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1c(Cl)ncnc1N(Cc1ccccc1)Cc1ccccc1
Reaction time: 1 h
Yield: 105 %

Procedure:
A solution of dibenzylamine (10.2 g) in dichloromethane (30 mL) was dripped into a solution of 4,6-dichloro-5-nitropyrimidine (10 g) in dichloromethane (70 mL) on an ice bath. Then triethylamine (14.4 mL) was added, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain the title compound (19.2 g) with the physical property value shown below.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35](C(=O)CCC3C=CC=CC=3)=[CH:34][CH:33]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=2[C:8]2([CH2:14][CH2:13][C:12]3[CH:11]=[CH:5][CH:3]=[CH:2][CH:1]=3)[CH2:5][C:3]([OH:4])=[CH:2][C:1](=[O:6])[O:7]2)[CH2:27][CH2:28]1)=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C(=O)CCc3ccccc3)cc2)CC1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccccc2C2(CCc3ccccc3)CC(O)=CC(=O)O2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound was prepared as described in General Method 6 using 37.2 g (320 mmol) of methyl acetoacetate, 13.2 g (330 mmol) of sodium hydride (60% dispersion in oil), 200 mL of 1.6M n-butyllithium (320 mmol), 70.2 g (160 mmol) of 4-{2-[4-(3-phenyl-propionyl)-phenoxy]-ethyl}-piperazine-1-carboxylic acid tert-butyl ester prepared in Example W, and 400 mL of THF. After addition of the ketone, the reaction mixture was stirred at 1 hour at 0° C. and then quenched with a 50:50 mixture of acetic acid:H2O. Standard work-up gave the crude aldol product which was carried on without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[CH:25]=[CH:24][C:12]([C:13]([N:15]3[CH2:20][CH2:19][C:18]4[CH:21]=[CH:22][O:23][C:17]=4[CH2:16]3)=[O:14])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:28][NH:29][CH3:30].[CH2:31]=O>C(O)(=O)C>[CH3:28][N:29]([CH2:31][C:22]1[O:23][C:17]2[CH2:16][N:15]([C:13](=[O:14])[C:12]3[CH:24]=[CH:25][C:9]([C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:27][CH:26]=4)=[CH:10][CH:11]=3)[CH2:20][CH2:19][C:18]=2[CH:21]=1)[CH3:30]
Reactant: C=O
Reactant: CNC
Reactant: COc1ccc(C(=O)c2ccc(C(=O)N3CCc4ccoc4C3)cc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2ccc(C(=O)N3CCc4cc(CN(C)C)oc4C3)cc2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.280 g (0.775 mmol) of 6-[4-(4-methoxybenzoyl)benzoyl]-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.105 ml (1.16 mmol) of 50% aqueous dimethylamine and 0.094 ml (1.16 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1) to yield the desired product.