Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12])(=[O:7])=[O:6])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[N-:21]=[C:22]=[S:23].[K+]>ClCCCl>[CH2:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([N:21]=[C:22]=[S:23])=[O:12])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: [N-]=C=S
Reactant: C=CCNS(=O)(=O)c1cccc(C(=O)O)c1
Agent: [K+]
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: C=CCNS(=O)(=O)c1cccc(C(=O)N=C=S)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
To a suspension of 3-(N-allylsulfamoyl)benzoic acid (2 g, 8.29 mmol) in 1,2-dichloroethane (25 mL) was added thionyl chloride (1.271 mL, 17.41 mmol) dropwise. The suspension was stirred for 2 hours at 80° C. After 2 hours, the reaction mixture was concentrated to an off-white solid. The solid was redissolved in 25 mL acetone, and potassium isothiocyanate (0.967 g, 9.95 mmol) was added. A precipitate formed immediately upon addition. The reaction was stirred at 50° C. After 2 hours, the reaction was filtered, concentrated, and adsorbed onto a silca-gel pre column. The residue was purified by column chromatography, eluting with 20-100% EtOAc in hexanes, to provide 3-(N-allylsulfamoyl)benzoyl isothiocyanate as an off-white solid (0.71 g, 30.3% yield). MS, m/z (C11H10N2O3S2): calcd, 282.0. found, 282.9 [M+H].
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[CH2:8]([O:10][C:11]([C:13]1[C:14]([CH2:38]Cl)=[N+:15]([O-:37])[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[CH:20][C:19]([O:33][CH3:34])=[C:18]([O:35][CH3:36])[CH:17]=2)=[O:12])[CH3:9].O>CN(C)C=O>[CH2:8]([O:10][C:11]([C:13]1[C:14]([CH2:38][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[N+:15]([O-:37])[C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[CH:20][C:19]([O:33][CH3:34])=[C:18]([O:35][CH3:36])[CH:17]=2)=[O:12])[CH3:9]
Reactant: c1nc[nH]n1
Reactant: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[n+]([O-])c1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[n+]([O-])c1Cn1cncn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
Oily sodium hydride (60%, 0.156 g) was added to a solution of 1H-1,2,4-triazole (0.27 g) in N,N-dimethylformamide (DMF) (20 ml), followed by stirring at room temperature for 15 minutes. Then 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester 1-oxide (1.5 g) was added, followed by stirring at 80° C. for 45 minutes. The reaction mixture was poured over water and extracted with dichloromethane. The dichloromethane layer was washed with water and then dried (MgSO4), after which the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography and eluted with chloroform-methanol (30:1, v/v) to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester 1-oxide (0.8 g, 50%), which was then recrystallized from dichloromethane-hexane to yield a colorless prismatic crystal having a melting point of 221° to 222° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:5][C@H:6]([NH:20][C:21](C1C=C(C)N=C(N(CCC)CCC)N=1)=[O:22])[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1.[CH2:41]([C:45]1[N:49]2[CH:50]=[C:51](C(O)=O)[CH:52]=[CH:53][C:48]2=[N:47][CH:46]=1)[CH2:42][CH2:43][CH3:44]>>[CH2:41]([C:45]1[N:49]2[CH:50]=[C:51]([C:21]([NH:20][C@@H:6]([CH2:5][C:4]3[CH:3]=[C:2]([F:1])[CH:39]=[C:38]([F:40])[CH:37]=3)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=3)=[O:22])[CH:52]=[CH:53][C:48]2=[N:47][CH:46]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCN(CCC)c1nc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)n1
Reactant: CCCCc1cnc2ccc(C(=O)O)cn12
Product: CCCCc1cnc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cn12

Procedure:
In the same manner as for N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(dipropylamino)-6-methylpyrimidine-4-carboxamide {EXAMPLE S-SP-235}, Step 3, 3-butylimidazo[1,2-a]pyridine-6-carboxylic acid (0.16 g) was converted to 0.30 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:4]=1C=O.[C:21](O)(=O)[CH2:22][C:23]([OH:25])=[O:24].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([OH:20])([C:12]([F:14])([F:15])[F:13])[C:16]([F:18])([F:17])[F:19])[CH:8]=[CH:7][C:4]=1[CH:21]=[CH:22][C:23]([OH:25])=[O:24]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1C=CC(=O)O
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 15 g (0.05 mole) 2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzaldehyde in 50 ml of pyridine are added 11 g (0.11 mole) of malonic acid and 1 g of piperidine. The solution is stirred and gradually heated to 80°. Heating and stirring are continued for 1 hour at 80°. The solution is then heated at reflux for an additional 3 hours, cooled, and evaporated at reduced pressure to obtain a residual oil which is extracted into ether. The resulting ether solution is washed with water and 1N hydrochloric acid, dried with anhydrous magnesium sulfate, filtered, and evaporated at reduced pressure to obtain a residual solid which is recrystallized from chlorobutane/hexane mixed solvent to give 10.5 g of 3-{2 -methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-2-propenoic acid having a melting point of 138°-140°.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[C:6](I)[C:5]([C:20]2[CH:21]=[C:22]([C:26]([NH:29][S:30]([CH2:33][C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:31])([CH3:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)=[N:4]1)[CH3:2]>[C-]#CC1C=CC=CC=1.[Cu+].N1C=CC=CC=1>[CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[C:6]([C:6]#[C:5][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:5]([C:20]2[CH:21]=[C:22]([C:26]([NH:29][S:30]([CH2:33][C:34]([F:37])([F:36])[F:35])(=[O:32])=[O:31])([CH3:28])[CH3:27])[CH:23]=[CH:24][CH:25]=2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)c(I)c1Oc1ccc(C(F)(F)F)cc1
Agent: [Cu+]
Agent: [C-]#Cc1ccccc1
Solvent: c1ccncc1
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)c(C#Cc2ccccc2)c1Oc1ccc(C(F)(F)F)cc1
Temperature: 100 °C

Procedure:
A solution of N-[2-(3-{1-ethyl-4-iodo-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)propan-2-yl]-2,2,2-trifluoroethanesulfonamide (51.2 mg, 0.077 mmol) and pyridine (387 μL) was treated with copper (I) phenylacetylide (12 mg, 0.085 mmol), degassed with argon, sealed in a microwave vial and heated to 100° C. via a block heater. After 2 days the resulting brown solution was cooled, diluted with EtOAc, washed with 50% sat. aq. NaHCO3 2×, sat. aq NaHCO3, dried (MgSO4) and concentrated to afford a black residue purified via MPLC, 10 g silica, 5-30% EtOAc in heptanes to afford a light yellow solid: MS: cal'd 636 (MH+), exp 636 (MH+).
Reaction SMILES: [NH2:1][C:2]1([CH3:13])[C:7](=[O:8])[N:6]([CH2:9][CH3:10])[C:5](=[O:11])[NH:4][C:3]1=[O:12].[F:14][C:15]1[C:16]([F:28])=[C:17]([F:27])[C:18]([F:26])=[C:19]2[C:24](=O)[O:23][C:21](=[O:22])[C:20]=12>CC(O)=O>[CH2:9]([N:6]1[C:7](=[O:8])[C:2]([CH3:13])([N:1]2[C:21](=[O:22])[C:20]3[C:19](=[C:18]([F:26])[C:17]([F:27])=[C:16]([F:28])[C:15]=3[F:14])[C:24]2=[O:23])[C:3](=[O:12])[NH:4][C:5]1=[O:11])[CH3:10]
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: CCN1C(=O)NC(=O)C(C)(N)C1=O
Solvent: CC(=O)O
Product: CCN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Temperature: 25 °C

Procedure:
A mixture of 5-amino-1-ethyl-5-methylbarbituric acid (0.28 g, 1.50 mmol) and tetrafluorophthalic anhydride (0.40 g, 1.80 mmol) in glacial AcOH (111 mL) was stirred under reflux for 3 hours. The yellow solution was then allowed to cool down to room temperature and evaporated to dryness under reduced pressure. The oily residue was recrystallized from EtOH to give 1-ethyl-5-methyl-5-(tetrafluorophthalimido)barbituric acid (19f) as white crystals.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14](=[O:15])[CH2:13][C:12]2([C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=3)[NH:17][C:16]2=[O:25])[C:11]1=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>O1CCCC1>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][N:17]1[C:18]2[C:23](=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:12]2([CH2:13][C:14](=[O:15])[N:10]([CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:11]2=[O:26])[C:16]1=[O:25])[CH3:33]
Reactant: O=C1CC2(C(=O)Nc3ccc(Cl)cc32)C(=O)N1Cc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CN1C(=O)C2(CC(=O)N(Cc3ccccc3)C2=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A stirred suspension of sodium hydride (60% dispersion in oil [39 mg, 0.969 mmol]) in anhydrous tetrahydrofuran (10 ml) was treated with 1′-benzyl-5-chloro-1H-spiro[indole-3,3′-pyrrolidine]-2,2′,5′-trione, intermediate 14 (300 mg, 0.88 mmol). After stirring at ambient temperature for 30 min, the clear solution was treated with ethyl bromoacetate (0.13 ml, 1.16 mmol). The resultant suspension was stirred for 3 hours and then left to stand overnight. Water (50 ml) was added and the mixture extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (50 ml), dried (MgSO4) and the solvent removed in vacuo to give the crude (1′-benzyl-5-chloro-2,2′,5′-trioxo-spiro[indole-3,3′-pyrrolidin]-1-yl)-acetic acid ethyl ester. Purification by flash chromatography (silica) eluting with petroleum ether (40-60) containing an increasing amount (0 to 50%) of ethyl acetate, followed by trituration with di-isopropyl ether gave a white solid (264 mg, 70%), m.pt. 143-144° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:6]([CH3:16])=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:17][S:18]([O-:21])(=[S:20])=[O:19].[K+]>C(O)C>[CH3:17][S:18]([S:20][CH2:2][CH2:3][O:4][C:5]1[C:6]([CH3:16])=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:21])=[O:19]
Reactant: CS(=O)([O-])=S
Reactant: CCOC(=O)c1cccc(OCCBr)c1C
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cccc(OCCSS(C)(=O)=O)c1C

Procedure:
2 g (7 mmol) of ethyl 3-(2-bromoethoxy)-2-methylbenzoate and 1.1 g (7.3 mmol) of potassium thiomethanesulfonate are dissolved in 10 ml absolute ethanol. The reaction mixture is refluxed for 20 hours. The solvent is then distilled off and the residue taken up in methylene chloride and washed with water. The organic phase is dried over sodium sulfate and the solvent is removed. The product of value is purified by column chromatography.
Reaction SMILES: [Br:1][C@H:2]1[C@H:8]2[C@H:5]([C:6](=[O:9])[O:7]2)[CH2:4][C@H:3]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Li+].CCOC(C)=O.CCCCCC.[NH4+].[Cl-]>C(OCC)C>[Br:1][C@@H:2]1[C@H:3]([NH:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:4][C@@H:5]([CH2:6][OH:9])[C@H:8]1[OH:7]
Reactant: O=C1O[C@H]2[C@H](Br)[C@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@@H]12
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCOCC
Product: OC[C@@H]1C[C@@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](Br)[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
(1R,3R,4R,5R)-4-bromo-3-(tritylamino)-6-oxabicyclo[3.2.0]heptan-7-one (0.6 g, 0.0013382 mol) was dissolved in diethyl ether (20 mL) and the mixture was cooled to 0° C. Lithium tetrahydroborate (0.087 g, 0.004015 mol) was added in one portion and the mixture was stirred at 0° C. for 1 hour, then allowed to warm to ambient temperature and stirred for a further 1 hour. TLC (20% EtOAc/Hexane) showed no starting material. The reaction mixture was cooled to 0° C. at which point saturated NH4Cl aq (20 mL) was added dropwise maintaining a temperature less than 5° C. The mixture was allowed to warm to ambient temperature and extracted with methylene chloride (3×20 mL). The organics were combined and dried over Na2SO4, filtered and concentrated to afford the title compound (0.61 g) as a white solid which was used without further purification. 1H NMR (300 MHz, CD3OD, δ): 7.56 (m, 6H), 7.25 (m, 9H), 4.15 (m, 1H), 3.55 (m, 1H), 3.40 (m, 2H), 2.90 (m, 1H), 2.53 (m, 1H) and 1.63 (m, 2H). LCMS: Rf=13.30 mins, ES+Na=474 (AA).
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:41])[C:5]([N:7]([CH3:40])[CH:8]1[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11][N:10]2[C:22](=[O:39])[C:23]([OH:38])=[C:24]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[CH:31]=3)=[O:27])[N:25]=[C:9]12)=[O:6])[CH3:3]>ClCCl.FC(F)(F)C(O)=O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:26]([C:24]2[N:25]=[C:9]3[CH:8]([N:7]([CH3:40])[C:5](=[O:6])[C:4]([N:2]([CH3:1])[CH3:3])=[O:41])[CH2:14][NH:13][CH2:12][CH2:11][N:10]3[C:22](=[O:39])[C:23]=2[OH:38])=[O:27])=[CH:31][C:32]=1[CH3:37]
Reactant: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CCN(C(=O)OC(C)(C)C)CC3N(C)C(=O)C(=O)N(C)C)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2O)CCNCC3N(C)C(=O)C(=O)N(C)C)ccc1F

Procedure:
The compound of Step 6 was stirred in dichloromethane/trifluoroacetic acid (8/2 v/v) for 1 hour, then concentrated under reduced pressure and purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording desired compound as trifluoroacetic salt. 1H NMR (300 MHz, CD3CN) δ 12.68 (bs, 1H), 9.96 (bs, 1H), 7.50 (d, J=7.51 Hz, 1H), 7.45-7.41 (m, 1H), 7.21 (t, J=8.62 Hz, 1H), 5.55-5.46 (m, 2H), 4.75 (dd, J=14.6 Hz, J=6.8 Hz, 1H), 4.67 (dd, J=14.6 Hz, J=6.3 Hz, 1H), 4.24-4.05 (m, 3H), 3.96-3.92 (m, 1H), 3.39-3.36 (m, 1H), 3.24 (s, 3H), 3.19 (s, 3H), 3.18 (s, 3H), 2.46 (s, 3H); MS (ES) C22H27FN6O5 requires 474. Found: 475 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH2:19][CH2:18][CH:17]([O:20][CH2:21][C:22]4[C:23]([C:30]5[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])=[N:24][O:25][C:26]=4[CH:27]4[CH2:29][CH2:28]4)[CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[N:7]([CH3:38])[CH:6]=1)=[O:4].[OH-].[K+]>CO.C1COCC1.O1CCOCC1>[CH:27]1([C:26]2[O:25][N:24]=[C:23]([C:30]3[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=3[Cl:36])[C:22]=2[CH2:21][O:20][CH:17]2[CH2:18][CH2:19][N:14]([C:10]3[CH:9]=[C:8]4[C:13]([C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]4[CH3:38])=[CH:12][CH:11]=3)[CH2:15][CH2:16]2)[CH2:28][CH2:29]1
Reactant: COC(=O)c1cn(C)c2cc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: Cn1cc(C(=O)O)c2ccc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
In a 500 mL round bottom flask under nitrogen, containing a solution of 9 g (16.23 mmol) of 6-{4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidin-1-yl}-1-methyl-1H-indole-3-carboxylic acid methyl ester in 80 mL of methanol, 80 mL of THF and 30 mL dioxane, is added 2N KOH (40 mL, 81.16 mmol). The reaction mixture is stirred at 70° C. overnight. The reaction mixture is then cooled to room temperature, and the solvent removed under vacuum. The residue is diluted with 100 mL of water, and washed with MTBE. The aqueous layer is acidified (pH 5) by addition of 2N HCl, then, it is extracted with CH2Cl2 (3×150 mL). The organics are dried over MgSO4, filtered, and evaporated to yield a light green solid that is recrystallized from MeOH/CH3CN (6.05 g (70%)). MS (m/e): 540 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[C:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH2:25]([O:24][C:23]1[C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=[CH:21][CH:22]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: Nc1ncccc1OCc1ccccc1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cccc(OCc3ccccc3)c2n1
Yield: 50 %

Procedure:
As described for Example 2, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-3-benzyloxypyridine instead of 2-amino-3-methylpyridine, to the title compound (96 mg, 50%) which was obtained as a light yellow solid. MS: m/e=382.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:12]=[N:11][C:10]2=[C:13]3[N:3]1[CH2:4][C@@H:5]([CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1)[N:6]3[C:7](=[O:14])[CH:8]=[CH:9]2.[ClH:30]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:30].[ClH:30].[NH2:22][CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][C@H:5]2[N:6]3[C:13]4[N:3]([C:2](=[O:1])[CH:12]=[N:11][C:10]=4[CH:9]=[CH:8][C:7]3=[O:14])[CH2:4]2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 1,1-dimethylethyl (1-{[(1R)-3,8-dioxo-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylen-1-yl]methyl}-4-piperidinyl)carbamate (0.57 g, 1.420 mmol) in chloroform (7 ml) at room temperature was treated with 4M HCl in 1,4-dioxane (7 ml). A solid precipitated out and the mixture was stirred at room temperature. After 0.5 h some methanol was added to dissolve most of the solid, followed by toluene and all the solvents were removed to afford the product as a yellow solid (0.53 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][CH:42]=[CH:41][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32](=[O:40])[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:13][CH:12]=1.Cl[CH2:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51]>>[CH3:1][O:2][C:3]1[CH:44]=[CH:43][CH:42]=[CH:41][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32](=[O:40])[N:33]([CH2:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:15][CH:16]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC(=O)Nc2ccccc2)cc1
Reactant: COCCCCCl
Product: COCCCCN(C(=O)COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1)c1ccccc1

Procedure:
Analogously to Example 2c, 0.49 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-phenylcarbamoylmethoxypiperidine-1-carboxylate (Example 62b) and 0.37 g of 1-chloro-4-methoxybutane are reacted. The title compound is obtained as a yellow oil. Rf=0.20 (1:1 EtOAc-heptane); Rt=5.89.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2C(OCC)=O)(=O)=O)C=CC=CC=1.[Br:24]Br.O>CN(C=O)C>[Br:24][C:11]1[NH:10][C:18]2[C:13]([CH:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Reactant: BrBr
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of ethyl 1-phenylsulfonylindole-2-carboxylate (1 eq.) in DMF (2.5 ml/mmol) under N2, was added a solution of bromine (4 eq.) in DMF (0.5 ml/mmol). This reaction mixture was stirred at room temperature for about 4 hours, following which water was added and the mixture was extracted with dichloromethane (×3). The organic layer was washed with a saturated solution of Na2SO5, dried and evaporated to give a crude yellow oil. Purification by chromatography on silica gel (eluent:C6H12/EtOAc 9/1) afforded 3-brominated indole 11.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[C:9]1([CH2:15][OH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I.C(OCC)C.C1(C)C=CC=CC=1>[CH2:15]([O:16][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: Brc1ccccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Brc1ccccc1OCc1ccccc1
Temperature: 110 °C

Procedure:
A vial was charged with 1-bromo-2-iodobenzene (0.642 mL, 5 mmol), phenylmethanol (1.036 mL, 10.00 mmol), copper(I) iodide (95 mg, 0.500 mmol), 1,10-phenanthroline (180 mg, 1.000 mmol), cesium carbonate (2281 mg, 7.00 mmol) and toluene (2.5 mL). The vial was sealed under air atmosphere and heated to 110° C. for 36 h. The reaction mixture was cooled to RT and diethyl ether was added. The suspension was filtered through a pad of silica gel. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (13% EtOAc/hexanes). 1-(Benzyloxy)-2-bromobenzene was obtained as a yellow oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:14](=S)=[S:15].C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:14]([SH:15])=[N:13][N:12]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: S=C=S
Reactant: NNC(=O)c1ccc2c(c1)CCO2
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Yield: 80.1 %

Procedure:
A solution of 2,3-dihydro-1-benzofuran-5-carbohydrazide (535 mg, 3.00 mmol), carbon disulfide (0.397 mL, 6.60 mmol) and triethylamine (0.460 mL, 3.30 mmol) in ethanol (5 mL) was heated under reflux for 24 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 0.1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/tetrahydrofuran to give the title compound (529 mg, yield 80%) as pale-yellow crystals.
Reaction SMILES: C1(N2C(=O)C3SC=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.C1(N)CCCCCCC1>C(O)(=O)C>[CH:10]1([N:9]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[C:24]=3[N:23]=[CH:8]2)[CH2:16][CH2:17][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Agent: NC1CCCCCCC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3F)c2ncn1C1CCCCCCC1
Yield: 63.4 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1.0 ml), cyclooctylamine (0.128 ml, 0.92 mmol), and acetic acid (0.1 ml) were used to give 90.4 mg (0.25 mmol, 63.4% yield) of the title compound.