Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:25])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH:10]2O)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:25])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)[C:11]([CH3:22])([CH3:23])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-6-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (24.3 g, 59.5 mmol) and triethylsilane (20 mL) at 25° C. was added trifluoroacetic acid (20 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium bicarbonate solution (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (5% ethyl acetate/hexanes) to afford 2-(3-bromo-phenyl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (10 g, 43%) as a white solid: LC/MS m/e calcd for C19H19BrFNO2 M+: 392.3, observed: 391.9, 393.9.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=1)[CH:12]=O.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.COC(C)(C)C.CCCCCC>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:12]=[CH2:1])[CH:14]=1
Reactant: [Li]CCCC
Reactant: CC(C)Oc1ccc(Br)cc1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C=Cc1cc(Br)ccc1OC(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (41.1 g, 115 mmol) in anhydrous THF (1.2 L) was added n-butyllithium (123 mmol, 2.5 M in hexanes) at −70° C. The mixture was stirred for a further 10 min, and then allowed to warm up to 0° C. and stirred at this temperature for 10 min. The reaction mixture is then cooled again at −50° C., and 5-bromo-2-isopropoxybenzaldehyde (20.0 g, 82.2 mmol) in solution in anhydrous THF (5 mL) was added. The mixture was stirred for 10 min, and then allowed to warm up to room temperature. An ammonium chloride solution was added and the reaction mixture was diluted with a mixture methyl t-butylether/hexane, filtered through celite, and then dried over magnesium sulfate. The solvent was removed in vacuo to afford compound AY (18.9 g) as a pale yellow oil in 95% yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.34 (d, J=6.0 Hz, 6H), 4.50 (sept., J=6.0 Hz, 1H), 5.27 (dd, J=11.0 and 1.1 Hz, 1H), 5.71 (dd, J=17.9 and 1.2 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 6.97 (dd, J=17.7 and 11.2 Hz, 1H), 7.28 (dd, J=8.7 and 2.5 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O.CO>[CH2:26]([O:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[CH:8]=2)[CH:3]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1ccc2cc(O)c(C(=O)OC)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(OCc3ccccc3)c(C(=O)OC)cc2c1
Temperature: 100 °C
Yield: 68.8 %

Procedure:
2-Hydroxy-3,6-di-methoxycarbonylnaphthalene (2.7 g) obtained in Example 26 was dissolved in N,N-dimethylformamide (50 g), followed by heating to 100° C. Potassium carbonate (1.5 g) was slowly added and benzyl chloride (1.4 g) was added dropwise. After heating for about 20 hours, the reaction solution was poured into a mixed solution of water (300 g) and methanol (100 g). The deposit was filtered and then washed with water to obtain 2.5 g of 2-benzyloxy-3,6-di-methoxycarbonylnaphthalene as whitish yellow powder (DSC analysis value: 113.8° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][CH:16]([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.N[C:23]1C=CC(C2CCC(=O)CC2)=C2C=1C(=O)N(C)C2.C(NC)C>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][CH:16]([N:19]([CH2:21][CH3:23])[CH3:20])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(C3CCC(=O)CC3)ccc(N)c2C1=O
Reactant: CN1Cc2c(C3CCC(N(C)C)CC3)ccc(N)c2C1=O
Agent: CCNC
Product: CCN(C)C1CCC(c2ccc(N)c3c2CN(C)C3=O)CC1

Procedure:
The title product was prepared according to the procedure for Compound 233A using 7-amino-2-methyl-4-(4-oxocyclohexyl)-2,3-dihydro-1H-isoindol-1-one and ethyl-methylamine. Used without purification in the next step.
Reaction SMILES: [C:1]([NH:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][C:23]([OH:31])([CH2:24]3)[CH2:22]1)[CH2:28]2)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1.CO>C1COCC1>[C:1]([NH:20][C:21]12[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][C:23]([O:31][CH2:45][C:44]4[CH:47]=[CH:48][C:41]([C:33]5[O:32][C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=6[N:34]=5)=[CH:42][CH:43]=4)([CH2:29]3)[CH2:22]1)[CH2:30]2)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: OC12CC3CC(C1)CC(NC(c1ccccc1)(c1ccccc1)c1ccccc1)(C3)C2
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(C(NC23CC4CC(C2)CC(OCc2ccc(-c5nc6ccccc6o5)cc2)(C4)C3)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
To KH (35%; 0.35 g; 0.003 mole) in THF (8 ml) under N2 and cooled to 0° C. is added N-trityl-3-hydroxytricyclo-[3.3.1.13,7 ]decan-1 -amine (1 g; 0.0025 mole) of all at once. The reaction is stirred for 5 minutes with ice cooling then at room temperature for an hour, developing into a clear yellow solution. Then 4-(benzoxazol-2-yl)benzyl bromide (0.70 g; 0.0025 mole) is added and the reaction cooled in ice for 10 minutes and stirred at room temperature for 4 hours. Methanol is added to quench any KH, then the reaction is filtered and evaporated to dryness. HPLC is used to purify the product (eluting with 10% ethyl acetate/hexane) to obtain N-trityl-3-[4-(benzoxazol-2-yl)benzyloxy]tricyclo[3.3.1.13,7 ]decan-1-amine (m.p. 174°-177° C.) which is used directly in step D.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]1[N:20]=[C:19](SC)[C:18]([F:23])=[CH:17][N:16]=1)=O)(C)(C)C.ClC1N=C(SC)C(F)=CN=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:23][C:18]1[CH:17]=[N:16][C:15]([N:11]2[CH2:10][C@@H:9]3[CH2:14][C@H:12]2[CH2:13][NH:8]3)=[N:20][CH:19]=1
Reactant: CSc1nc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)ncc1F
Agent: CSc1nc(Cl)ncc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cnc(N2C[C@@H]3C[C@H]2CN3)nc1
Yield: 149.5 %

Procedure:
2-(t-butyloxycarbonyl)-5-(5-fluoro-4-methylthio-2-pyrimidinyl)-(1S,4S)-2,5-diazabicyclo[2.2.1]heptane (4.50 g, 22.73 mmol), 2-chloro-5-fluoro-4-methylthiopyrimidine [4.64 g (87.5% pure), 22.73 mmol], micropulverized K2CO3 (9.40 g, 68.19 mmol), and KI (0.57 g, 3.41 mmol) in 65 mL of MeCN was refluxed for 44 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in a minimum amount of H2O. The solution was extracted with CH2Cl2, washed with saturated NaCl solution, dried over K2CO3, filtered and concentrated under reduced pressured. Flash chromatography (Hexane:EtOAc; 4:1) gave the title compound (6.60 g, 85.4%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[C:11]([O:12][CH3:14])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1ncccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccnc1C(=O)N(C)OC
Yield: 28.2 %

Procedure:
3-Hydroxy-pyridine-2-carboxylic acid methoxy-methyl-amide (5.21 g, 28.60 mmol), N,N-dimethylformamide (500 ml), potassium carbonate (15.91 g), and methyl iodide (3.6 ml, 57.70 mmol) were stirred for 18 hours at room temperature. The reaction was concentrated. Water and ethyl acetate was added. The organic layer was separated, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography (0-70% [10% methanol in ethyl acetate] in hexanes) to give 1.58 g (28%) of 3-methoxy-pyridine-2-carboxylic acid methoxy-methyl-amide. 1H NMR (250 MHz, CDCl3) δ 8.20-8.11 (m, 1H), 7.32-7.18 (m, 2H), 3.83 (s, 3H), 3.51 (s, 3H), 3.35 (s, 3H); MS: m/z 310.6+197.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCC(=O)O)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CCCO)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-(3-Methoxyphenyl)propionic acid (see Example 1, Step J) (10.09 g, 0.058 mol) dissolved in anhydrous THF 60 mL) was added dropwise to a solution of LiAlH4 (1M in THF) (60 mL, 0.06 mol) in THF (60 mL) at ambient temperature under Ar. The resulting solution was stirred at reflux for 6 hr, then cooled to 0° C., treated dropwise with H2O (2.2 mL), 20% NaOH (1.7 mL), then H2O (6.62 mL). After stirring for 15 min, MgSO4 was added, stirring was continued for 15 min, the solids were filtered off, washed well with EtOAc, and the filtrate concentrated to dryness to give the title compound. MS (M+1) 167.1
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1.[C-:19]#[N:20].[Na+]>CN(C)C=O>[C:19]([CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[C:7](=[O:16])[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:5]=2[CH:4]=1)#[N:20]
Reactant: [C-]#N
Reactant: O=C1Nc2ccccc2Sc2cc(CBr)ccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc2c(c1)Sc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dissolve 6.4 gm. of the bromide of Step B in 75 cc. of dimethylformamide and add 2.95 gm. of sodium cyanide. Stir the mixture at room temperature for 1.5 hours. Dilute with 600 cc. of water and extract three times with ether. Wash the combined organics with water, dry and strip to a solid residue. Triturate in hexane and recover the solid by filtration.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:18])[C@H:5]([NH:13][C:14]([O:16][CH3:17])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O>ClCCl>[CH3:1][O:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@@H:5]([NH:13][C:14](=[O:15])[O:16][CH3:17])[C:4]1=[O:18]
Reactant: CONC(=O)[C@@H](Cc1ccccc1)NC(=O)OC
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@@H]1Cc2ccccc2N(OC)C1=O
Reaction time: 1 h

Procedure:
A suspension of (R)-N-methoxy-2-(methoxycarbonylamino)-3-phenylpropanamide (III, EXAMPLE 2, 11.25 g, 44.6 mmol) in dichloromethane (170 ml) is cooled in an ice bath and trifluoroacetic acid (9.25 ml, 13.7 g, 0.120 mol) is added. Bis(trifluoroacetoxy)iodobenzene (19.78 g, 0.046 mol) is added portion wise over 10 min at 0°, and the mixture is stirred at this temperature for one hour. The mixture is washed with sodium carbonate mixture (10%) and dried over magnesium sulfate. The solvent is removed under reduced pressure to give a concentrate. Purification by flash chromatography (230-400 mesh silica gel, 40-50% ethyl acetate/hexane) gives the desired product. An analytical sample is crystallized from ethyl acetate/hexane to give the title compound, mp=117-119°; NMR (CDCl3) 2.85, 3.44, 3.72, 3.93, 4.42, 5.82, 7.09, 7.33 and 7.22 δ; IR (mineral oil) 1722 and 1703 cm−1; [a]25D=+34.20 (CH3OH, c=0.927).
Reaction SMILES: [Cl:1][C:2]1[C:7](/[C:8](/O)=[CH:9]\[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20].C1C(=O)N(Br)C(=O)C1.[CH:38]1([C:42](=[S:44])[NH2:43])[CH2:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[C:7]([C:8]2[N:43]=[C:42]([CH:38]3[CH2:41][CH2:40][CH2:39]3)[S:44][C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20]
Reactant: NC(=S)C1CCC1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Agent: O=C1CCC(=O)N1Br
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step A using N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (1.2 g, 2.5 mmol), NBS (0.45 g, 2.5 mmol) and cyclobutanecarbothioamide (0.29 g, 2.5 mmol) the title compound was obtained as a white solid (0.75 g, 1.6 mmol, 54% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92-10.69 (m, 1H), 8.32-8.85 (m, 1H), 7.83-7.57 (m, 1H), 7.59-7.31 (m, 3H), 7.33-7.07 (m, 2H), 6.49 (d, J=5.3 Hz, 1H), 3.89 (quin, J=8.5 Hz, 1H), 2.67-2.14 (m, 4H), 2.14-1.79 (m, 2H). MS (ESI): 553 [M+H]+.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:19][CH2:18]1)[CH2:4][O:5][C:6]1[C:14]2[NH:13][CH:12]=[N:11][C:10]=2[C:9]([CH3:15])=[CH:8][CH:7]=1.[C:31](O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1>CN(C)C=O>[ClH:1].[C:31]([O:2][CH:3]([CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:19][CH2:18]1)[CH2:4][O:5][C:6]1[C:14]2[NH:13][CH:12]=[N:11][C:10]=2[C:9]([CH3:15])=[CH:8][CH:7]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccc(OCC(O)CN2CCC(COc3ccccn3)CC2)c2[nH]cnc12
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(CN2CCC(COc3ccccn3)CC2)OC(=O)c2ccccc2)c2[nH]cnc12

Procedure:
4.87 g. 4-{2-Hydroxy-3-[4-(2-pyridyloxymethyl)-piperidino]-propoxy}-7-methylbenzimidazole (preparation see Example 13), 19.5 g. benzoic acid and 2.12 g. benzoic anhydride are heated under reflux for 2 hours in 100 ml. benzene and 25 ml. dimethylformamide. After removing the solvent, the residue is taken up in 100 ml. water, rendered alkaline with concentrated aqueous ammonia solution and extracted with chloroform. The chloroform phase is washed with water, dried over anhydrous sodium sulphate and evaporated. The residue is taken up in ethanol and mixed with ethereal hydrochloric acid. After adding isopropanol and diethyl ether, there crystallize out 2.1 g. (41% of theory) 4-{2-benzoyloxy-3-[4-(2-pyridyloxymethyl)-piperidino]-propoxy}-7-methylbenzimidazole hydrochloride; m.p. 178°-181° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C@H:19]([CH2:21]OS(C)(=O)=O)[O:18][C:17]2=[O:27])=[CH:12][CH:11]=1>CN(C)C=O.O>[CH3:8][S:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:20][C@H:19]([CH2:21][N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[O:18][C:17]2=[O:27])=[CH:14][CH:15]=1
Reactant: c1c[nH]cn1
Reactant: CSc1ccc(N2C[C@H](COS(C)(=O)=O)OC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(N2C[C@H](Cn3ccnc3)OC2=O)cc1
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
Sodium hydride (80% in oil, 23 mg, 0.77 mM) was stirred under nitrogen in N,N-dimethylformamide (5 ml), imidazole (52 mg, 0.77 mM) added, and stirring continued for 10 minutes. (5R)-3-(4-Methylthiophenyl)-5-methanesulfonyloxymethyloxazolidin-2-one (200 mg, 0.63 mM) was dissolved in N,N-dimethylformamide (5 ml), added to the above, and the mixture stirred 18 hours at ambient temperature. After diluting with water (30 ml), the mixture was extracted with ethyl acetate (30 ml), the extract washed with brine (25 ml), dried (magnesium sulfate) and evaporated. The residue was triturated with diethyl ether, and filtered to give the desired product (129 mg, mp 129–131°).
Reaction SMILES: N.[CH3:2][CH:3]([OH:9])/[CH:4]=[CH:5]/[CH:6]([OH:8])[CH3:7].[C:10]([Cl:21])(=[O:20])[C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([Cl:16])=[O:15])[CH:12]=1.C([O:25][C:26]1[CH:27]=[C:28]([C:35]([Cl:37])=[O:36])[CH:29]=[C:30]([CH:34]=1)[C:31]([Cl:33])=[O:32])(=O)C>O1CCCC1>[CH3:2][CH:3]([OH:9])/[CH:4]=[CH:5]/[CH:6]([OH:8])[CH3:7].[C:14]([Cl:16])(=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([C:10]([Cl:21])=[O:20])[CH:12]=1.[OH:25][C:26]1[CH:34]=[C:30]([C:31]([Cl:33])=[O:32])[CH:29]=[C:28]([CH:27]=1)[C:35]([Cl:37])=[O:36]
Reactant: CC(=O)Oc1cc(C(=O)Cl)cc(C(=O)Cl)c1
Agent: CC(O)/C=C/C(C)O
Agent: N
Agent: O=C(Cl)c1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Product: O=C(Cl)c1cc(O)cc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
To a solution of methanolic ammonia (20 mL, 1 N), polymer (124) dissolved in 5 mL tetrahydrofuran is added and the solution is stirred for two hours. The polymer was then precipitated in 100 mL of cold 1 N hydrochloric acid and collected by filtration. The polymer was then dried under high vacuum and was found to have a molecular weight of ˜5,000 g/mol by GPC.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17]([OH:19])=[O:18])=[O:14])[CH:10]=[CH:11][C:5]=2[N:4]=1.N[C:25]1C=CC2N=C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)N(C(OC(C)(C)C)=O)C=2C=1.C12CC(C=C1)C1C(OC(=O)C21)=O>>[ClH:1].[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:12][C:13]([C@@H:15]3[CH:23]4[CH2:25][CH:20]([CH:21]=[CH:22]4)[C@@H:16]3[C:17]([OH:19])=[O:18])=[O:14])[CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Reactant: Nc1nc2ccc(NC(=O)c3ccccc3C(=O)O)cc2[nH]1
Agent: Cl
Agent: O=C1OC(=O)C2C3C=CC(C3)C12
Product: Nc1nc2ccc(NC(=O)[C@@H]3C4C=CC(C4)[C@@H]3C(=O)O)cc2[nH]1
Yield: 94 %

Procedure:
Following the same procedure to synthesize 2-(2-amino-1H-benzo[d]imidazol-6-ylcarbamoyl)benzoic acid hydrochloride (8), tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.114 g, 0.254 mmol) was reacted with Bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride (0.042 g, 0.254 mmol) to make the title product (0.084 g, 94% yield) as a white solid. 1H NMR (300 MHz, CD3OD) δ 7.35 (d, 1H), δ 7.13 (s, 1H), δ 6.99 (d, 1H), δ 6.23 (s, 2H), δ 3.51 (s, 2H), δ 3.37 (s, 2H), δ 1.68 (dd, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 178.1, 151.7, 134.8, 134.6, 130.6, 129.8, 129.6, 128.1, 122.8, 111.5, 110.7, 52.0, 46.8, 45.9, 45.5, 45.4 ppm; HRMS (ESI) Calcd for C16H16N4O3 (M+) 312.1222. Found 312.1226.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][CH2:4][C@H:3]([NH:12][C:13](=O)[C@H:14]([CH3:25])[CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:2]1.B.C1COCC1>C1COCC1>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[S:16][CH2:15][C@@H:14]([CH3:25])[CH2:13][NH:12][C@H:3]1[CH2:4][S:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2]1
Reactant: COc1ccccc1SC[C@@H](C)C(=O)N[C@@H]1COc2ccccc2SC1
Agent: B
Solvent: C1CCOC1
Product: COc1ccccc1SC[C@@H](C)CN[C@@H]1COc2ccccc2SC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
In a round-bottom flask maintained under an inert atmosphere, 250 mg (0.642 mmole) of (2S)-N-[(3R)-3,4-dihydro-2H-1,5-benzoxathiepin-3-yl]-3-[(2-methoxyphenyl)sulfanyl]-2-methylpropanamide (9a-1) and 7.5 mL of anhydrous THF are introduced. Next, 3.21 mL (3.21 mmoles) of 1 M BH3.THF is added dropwise, then the solution is heated to reflux for 1 h 30 min. The mixture is cooled, concentrated under reduced pressure, taken up with 20 mL of methanol, then acidified with 36% hydrochloric acid. The mixture is brought to reflux for 4 hours then stirred for 12 hours at ambient temperature. The reaction mixture is concentrated under reduced pressure then made basic (pH=10) by adding concentrated soda. The aqueous phase is extracted with dichloromethane, the combined organic phases are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The title compound is obtained in the form of a colorless oil (232 mg, 0.618 mmole).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:18]=[CH:19][C:20]2[C:24]([CH3:25])=[CH:23][S:22][C:21]=2[CH:26]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH3:25])=[CH:23][S:22][C:21]=4[CH:26]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Reactant: Cc1csc2cc(Br)ccc12
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1csc2cc(N3CCN(c4cnccc4C4CC4)C3=O)ccc12
Yield: 26.2 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 6-bromo-3-methylbenzo[b]thiophene (112 mg, 0.492 mmol), 1,4-dioxane (5 mL), copper iodide (9.3 mg, 0.049 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (7.0 mg, 0.049 mmol) and potassium phosphate (313.6 mg, 1.447 mmol) to afford the crude product. Purification by column chromatography on silica gel (2.0% methanol in CHCl3) afforded 45 mg of the product (26% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:31][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[S:26][C:19]3[C:18]([NH:17][C:13]4[CH:12]=[C:11]5[C:16](=[CH:15][CH:14]=4)[NH:8][CH:9]=[CH:10]5)=[N:23][CH:22]=[N:21][C:20]=3[CH:24]=2)=[CH:34][CH:33]=1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: NCc1ccco1
Product: c1coc(CNCc2ccc(-c3cc4ncnc(Nc5ccc6[nH]ccc6c5)c4s3)cc2)c1

Procedure:
The title compound was prepared from C-furan-2-yl-methylamine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 125-134° C.; LC-MS: 452 (MH+); HPLC RT: 4.51 minutes.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH2:11][NH:12][CH:13]1[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)[C:6]#[N:7].[Cl:23][C:24]1[CH:25]=[C:26]([CH3:32])[C:27]([CH:30]=O)=[N:28][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([CH3:32])[C:27]([CH2:30][N:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:2][OH:1])[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[N:28][CH:29]=1
Reactant: Cc1cc(Cl)cnc1C=O
Reactant: N#Cc1ccc(CNC2CCCc3cccnc32)c(CO)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(Cc1ccc(C#N)cc1CO)C1CCCc2cccnc21

Procedure:
Using General Procedure B: Reaction of 3-hydroxymethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzonitrile in CH2Cl2 with 5-chloro-3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave 4-{[(5-chloro-3-methyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzonitrile as a colorless oil. 1H NMR (CDCl3) δ 1.59 (m, 1H), 2.03 (m, 2H), 2.14 (m, 1H), 2.19 (s, 3H), 2.63 (m, 1H), 2.77 (m, 1H), 3.65 (d, 1H, J=12.0 Hz), 3.73-3.83 (m, 3H), 4.20 (d, 2H, J=12.0 Hz), 4.37 (d, 1H, J=12.0 Hz), 7.03 (dd, 1H, J=7.5, 3.0 Hz), 7.15-7.46 (m, 4H), 7.65 (s, 1H), 8.28 (s, 1H), 8.34 (s, 1H).