Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:16][CH2:17][C:18]1[N:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[O:25])[C:21]([OH:35])=[C:20]([OH:36])[N:19]=1)[C:9](=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C=O.C([BH3-])#N.[Na+]>ClCCl.FC(F)(F)C(O)=O.C(O)(=O)C>[CH2:1]([N:8]([CH3:9])[CH2:16][CH2:17][C:18]1[N:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[O:25])[C:21]([OH:35])=[C:20]([OH:36])[N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCc1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1)Cc1ccccc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CN(CCc1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Crude tert-butyl benzyl[2-(4-{[(4-fluorobenzyl)amino]carbonyl}-5,6-dihydroxypyrimidin-2-yl)ethyl]carbamate (prepared as described in Step 3) was taken in dichloromethane/trifluoroacetic acid (8/2 v/v) and the mixture was stirred 1 hour at room temperature. After evaporation of volatiles, the crude organic product was taken in methanol and treated with triethyl amine (1 equivalent), formaldehyde (2 equivalents), sodium cyanoborohydride (1.2 equivalents) and acetic acid (pH=5.5). The mixture was stirred at room temperature for 1 hour. Volatiles were evaporated and product was purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant). Lyophilization of appropriate fractions gave the title compound (TFA salt) as a white solid. 1H NMR (400 MHz, d6-DMS) δ 12.78 (bs, 1H), 12.32 (bs, 1H), 9.5-9.4 (m, 2H), 7.48 (s, 5H), 7.42-7.32 (m, 2H), 7.12 (t, J=8.7 Hz, 2H), 4.59-4.45 (m, 3H), 4.23 (bs, 1H), 3.75 (bs, 1H), 3.52 (bs, 1H), 3.08-3.00 (m, 2H), 2.72 (s, 3H); MS (ES) C22H23FN4O3 requires 410. Found: 411 (M+H+).
Reaction SMILES: CN(C1CCCCC1)[CH:3]1CCCC[CH2:4]1.Br[C:16]1[S:20][C:19]([C:21]([CH2:23][C:24]([C:26]([F:29])([F:28])[F:27])=[O:25])=[O:22])=[CH:18][CH:17]=1.C=C.Cl>O.CCOCC.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[CH:3]([C:16]1[S:20][C:19]([C:21]([CH2:23][C:24]([C:26]([F:29])([F:28])[F:27])=[O:25])=[O:22])=[CH:18][CH:17]=1)=[CH2:4]
Reactant: CN(C1CCCCC1)C1CCCCC1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Br)s1
Agent: C=C
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=Cc1ccc(C(=O)CC(=O)C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.2 %

Procedure:
1,4-Dioxane (40 mL), tri-t-butylphosphine (0.182 g, 0.9 mmol), and methyldicyclohexylamine (19.5 g, 100 mmol) were placed into a Schlenk flask and transferred by syringe to a PPI LC series 300 mL reactor containing dipalladium tris(dibenzylidenelacetone) (0.420 g, 0.45 mmol) and 5-bromothenoyltrifluoroacetone (9 g, 30 mmol) The reactor was charged to 300 psi with ethylene and the reaction was allowed to stir for 48 hours at room temperature. Upon completion of the reaction the contents taken up in water (50 mL) and ether (50 mL), the aqueous phase acidified by addition of concentrated hydrochloric acid, and extracted with ether (2×50 mL). The combined organic phase was rinsed with saturated sodium chloride solution, and the organic phase was dried over magnesium sulfate overnight. The solution was filtered, the solvent was removed by vacuum, and the residue dissolved in chloroform (3 mL). The product was isolated by column chromatography from silica gel (Selecto, mesh size 63-200) with 10% ether in chloroform as eluent. The solvent was removed to give a light green solid (2.4 g, 32% yield). The solid was reacted with cupric chloride dehydrate in methanol, precipitated by addition of water, and recrystallized from THF/hexanes to give (VTTFA)2Cu.1.5THF. 1H-NMR (90 MHz, 25° C., CDCl3): δ 14.25 (s, 1H), 7.63 (d, 1H), 7.12 (d, 1H), 6.94 (dd, 1H), 6.36 (s, 1H), 5.86 (s, 1H). Anal.: (found/calc for C26H24CuF6O5.5S2) 81.71 (81.58), H 5.65 (5.59).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][OH:39])[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCO[Si](C)(C)C(C)(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCO)c2)cc1

Procedure:
The product from Example 72B(0.368 g, 0.558 mmoles) in anhydrous TBF (2 mL) was treated with 1.0 M tetrabutylammonium fluoride (0.67 mL, 0.669 mmoles) and mixed overnight at room temperature. Reaction diluted with ethyl acetate, washed with saturated NH4Cl, H2O, and brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>CN(C)C=O>[CH3:1][C:2]1[C:9]([C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:26]1[C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]2[C:22]1=[O:32]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1c(CBr)cccc1C(F)(F)C(F)(F)c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1c(CN2C(=O)c3ccccc3C2=O)cccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
A mixture of 8.02 g. (0.022 mole) of 2-methyl-3-(α,α,β,β-tetrafluorophenethyl)-benzyl bromide, 4.10 g. (0.022 mole) of potassium phthalimide, and 40 ml. of dimethylformamide is stirred 30 minutes at room temperature, 4 hours at 95°C., and 3 hours at reflux. The cooled mixture is diluted with 100 ml. of chloroform and washed with 150 ml. of water. After re-extraction of the aqueous layer with chloroform, the combined organic extracts are washed with 0.1 N. sodium hydroxide, water, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo. Recrystallization of the residual solid from isopropyl alchol affords the white crystalline product, m.p. 135°-137°C.
Reaction SMILES: OC1(C(C2C=CC=CC=2)C2C=CC=CC=2)CCCCN1CCCC([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:24])([CH3:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)=O.[BH4-].[Na+]>CO>[CH3:24][C:19]([C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)([CH3:23])[C:20]([OH:22])=[O:21]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCN2CCCCC2(O)C(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[4-[4-(hydroxydiphenylmethyl-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetic acid, prepared in accordance with Example 12, and 300 mg of NaBH4 in 25 mL of CH3OH was stirred overnight at room temperature. The mixture was then concentrated in vacuo. The residue was partitioned between EtOAc and H2O. The aqueous portion was treated with concentrated HCl until pH 6, then extracted with EtOAc. The organics were concentrated in vacuo. The residue was dissolved in EtOAc, filtered, and concentrated in vacuo to an oil. The oil was dissolved in CH3OH and concentrated to a solid. The solid was slurried with EtOAc, filtered, and rinsed with EtOAc to afford 4-[4-[4-hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C:10](=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([NH2:18])[C:16]#[CH:17]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][C:10]3[N:18]=[CH:15][CH:16]=[CH:17][C:11]=3[C:12]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2C1
Reactant: C#CCN
Product: O=[N+]([O-])c1ccc2c(c1)-c1cccnc1CC2
Yield: 41 %

Procedure:
The title compound is prepared from 7-nitro-2-tetralone and propargylamine following a procedure analogous to that described in Step 1 of Intermediates 1 and 2. Yield: 41% of theory; LC (method 1): tR=2.20 min; Mass spectrum (ESI+): m/z=227 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[CH:12]=[C:11]([CH3:13])[O:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[F:14][C:15]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:20][C:19]=1B1OC(C)(C)C(C)(C)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:14][C:15]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:16]=1[O:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][S:25]([CH2:28][CH3:29])(=[O:26])=[O:27])=[CH:22][C:23]=1[C:2]1[C:3]2[CH:12]=[C:11]([CH3:13])[O:10][C:4]=2[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc2c(Br)cn(C)c(=O)c2o1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3oc(C)cc23)c1
Temperature: 70 °C
Yield: 10.4 %

Procedure:
A mixture of 4-bromo-2,6-dimethylfuro[2,3-c]pyridin-7-one (200 mg, 0.83 mol), N-[4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanesulfonamide (364 mg, 0.99 mmol), Pd(dppf)Cl2 (66 mg, 0.09 mmol), K3PO4 (527 mg, 2.49 mmol) in dioxane/water (4 mL/1 mL) was bubbled with argon for 5 min. The mixture was heated to 70° C. for 18 h. After cooling to rt, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (49 mg, 12%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.35-7.33 (m, 2H) 7.12 (m, 1H) 6.95-6.89 (m, 2H) 6.81 (m, 2H) 6.43 (s, 1H) 6.38 (s, 1H) 3.71 (s, 3H) 3.16 (q, J=7.2 Hz, 2H) 2.47 (s, 3H) 1.43 (t, J=7.2 Hz, 3H). LCMS (M+H)+=475.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:11]([OH:24])[CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(N(CC)CC)C>ClCCl>[CH3:25][S:26]([O:24][C@@H:11]([CH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C@@H:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:10])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](OCc1ccccc1)[C@@H](O)CCc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](OCc1ccccc1)[C@H](CCc1cccc2ccccc12)OS(C)(=O)=O
Temperature: 4 °C
Reaction time: 0.67 h
Yield: 107.4 %

Procedure:
To an ice-cooled solution of (2S,3S)-2-benzyloxy-5-(1-naphthyl)pentan-3-ol (obtained in Preparation 26) (7.43 g) in dichloromethane (100 ml) was added methanesulfonyl chloride (2.15 ml) followed by triethylamine (3.88 ml). The mixture was stirred at 4° C. for 40 min. After being diluted with dichloromethane, the mixture was washed with water and brine, dried and concentrated in vacuo to give (2S,3S)-2-benzyloxy-5-(1-naphthyl)-3-pentyl methanesulfonate (9.92 g, 107.4%) as an oil. The product was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:42])([F:41])[CH2:38][CH2:39][NH2:40]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22]([NH:40][CH2:39][CH2:38][C:37]([F:42])([F:41])[F:36])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCC(F)(F)F
Reactant: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: C[C@@](F)(C(=O)NCCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)—N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 3,3,3-trifluoropropylamine, the title compound was prepared in the same manner as described for example 1c. Colorless, viscous oil (72%). MS: m/e=572(M+H+).
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[NH:12][N:11]=1.[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[C@@H:27]([CH3:28])[CH2:26][N:25]([C:29]3[S:30][C:31]([C:35](O)=[O:36])=[C:32]([CH3:34])[N:33]=3)[C:24]2=[O:38])=[CH:20][CH:19]=1.FC1C=CC(CN2[C@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1>>[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[C@H:27]([CH3:28])[CH2:26][N:25]([C:29]3[S:30][C:31]([C:35]([NH:16][CH2:15][C:13]4[NH:12][N:11]=[C:10]([CH3:9])[CH:14]=4)=[O:36])=[C:32]([CH3:34])[N:33]=3)[C:24]2=[O:38])=[CH:20][CH:19]=1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1cc(CN)[nH]n1
Agent: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cc(CNC(=O)c2sc(N3C[C@@H](C)N(Cc4ccc(F)cc4)C3=O)nc2C)[nH]n1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (3-methyl-1H-pyrazol-5-yl)-methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid the title compound was obtained as a white solid: mp 215-216° C. (ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.31 (br, 1H), 7.40-7.35 (m, 2H), 7.22-7.16 (m, 2H), 5.89 (s, 1H), 4.59 (d, J=15.5 Hz, 1H), 4.33-4.16 (m, 4H), 3.78-3.71 (m, 1H), 3.55 (dd, J=10.1, 6.8 Hz, 1H), 2.46 (s, 3H), 2.17 (s, 3H), 1.22 (d, J=6.1 Hz, 3H); MS (ES+) m/z 442.9 (M+1).
Reaction SMILES: II.C([O-])([O-])=O.[Ca+2].[C:8]([O:11][C@@H:12]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C:22](=[O:24])[CH3:23])[CH2:13]1)(=[O:10])[CH3:9].[C:34]([O:37][C@@H:38]1[CH2:59][CH2:58][C@@:57]2([CH3:60])[C@@H:40]([CH2:41][CH2:42][C@@H:43]3[C@@H:56]2[CH2:55][CH2:54][C@@:53]2([CH3:61])[C@H:44]3[CH2:45][CH2:46][C@@H:47]2[C:48]([OH:52])([C:50]#[N:51])[CH3:49])[CH2:39]1)(=[O:36])[CH3:35]>C1CCCCC1>[C:8]([O:11][C@@H:12]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH2:33][C:50]#[N:51])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C:22](=[O:24])[CH3:23])[CH2:13]1)(=[O:10])[CH3:9].[C:34]([O:37][C@@H:38]1[CH2:59][CH2:58][C@@:57]2([CH3:60])[C@@H:40]([CH2:41][CH2:42][C@@H:43]3[C@@H:56]2[CH2:55][CH2:54][C@@:53]2([CH3:61])[C@H:44]3[CH2:45][CH2:46][C@@H:47]2[C:48](=[O:52])[CH3:49])[CH2:39]1)(=[O:36])[CH3:35]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)(O)C#N)CC[C@@H]32)C1
Agent: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Agent: II
Agent: O=C([O-])[O-]
Solvent: C1CCCCC1
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(CC#N)[C@@H](C(C)=O)CC[C@@H]32)C1

Procedure:
Compound 8a was prepared using a reported procedure. (See, Kalvoda, J., et al., Reactions of Steroid Hypoiodites. VII. 1,4-Shift of the Nitrile Group (18-Cyanopregnanes), Helv. Chim. Acta 1966, 49: 424-436) I2 (1.6 g, 6.30 mmol) was added to a refluxing mixture of Pb(OAc)4 (6.0 g, 13.5 mmol) and CaCO3 (2 g, 20.0 mmol) in cyclohexane (200 mL). The purple solution was refluxed for 1 h and the mixture of compound 6a and 7a obtained in last step [prepared from 6a (1.0 g, 2.77 mmol)] was added. The reaction mixture was refluxed while irradiated with a 300 W tungsten lamp for 3 h and then cooled to room temperature. After filtration, the precipitate was washed thoroughly with ether. The combined filtrate was washed successively with 10% Na2S2O3 and brine, and dried over Na2SO4. Removal of solvent under reduced pressure gave a residue which was purified by column chromatography (silica gel; hexanes/EtOAc, 4:1) to give compound 8a (400 mg, 40% from 6a) and recovered compound 6a (400 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>O1CCCC1>[CH2:16]([NH:20][C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:17][CH2:18][CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CCCCN
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
5.0 g of succinimide ester of N-(tert-butoxycarbonyl)-L-proline (0.016 mmol), marketed by Novabiochem, are dissolved in tetrahydrofuran (50 ml). 1.533 ml of n-butylamine (0.015 mmol) are then added thereto, at 0° C. over 10 minutes, and the mixture is stirred for one hour. The solvent is removed and the resulting crude material is purified by chromatography on silica, using ethyl acetate as eluent. An oil is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[CH3:1][C:2]1[C:3]([C:4]2[NH:20][C:19]3[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]=3[N:10]=2)=[CH:6][CH:7]=[CH:8][N:9]=1
Reactant: Cc1ncccc1C=O
Reactant: Nc1cccc(C(=O)O)c1N
Product: Cc1ncccc1-c1nc2c(C(=O)O)cccc2[nH]1

Procedure:
2-Methylnicotinaldehyde (149; 2.18 g, 18 mmol) was subjected to the standard conditions used to prepare substituted benzimidazoles by reaction with 2,3-diaminobenzoic acid 1. The desired product, 2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylic acid 150, was obtained by purification using chromatography, followed by crystallization from EtOAc (0.43 g, 11%).
Reaction SMILES: Cl[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][C:6]([C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>C(O)(C)C>[Cl:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH:39][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:10](=[O:19])[C:9]3[C:4](=[CH:5][C:6]([C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:8]=3)[N:3]=2)=[CH:36][CH:35]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(NCc3ccc(Cl)cc3)nc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a suspension of methyl 2-chloro-3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.10 g, 0.23 mmol) in isopropyl alcohol (2.5 mL) was added N,N-diisopropylethylamine (84 μL, 0.48 mmol) and p-chlorobenzylamine (70 μL, 0.57 mmol). The reaction mixture was heated to 100° C. and stirred for 1 h. The mixture was then cooled to rt and concentrated. The residue was purified by flash silica gel chromatography (0% to 50% EtOAc/hexanes) to afford methyl 2-[(4-chlorobenzyl)amino]-3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (46 mg, 44%). LC-MS: (FA) ES+ 456.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)[CH:2]=[CH2:3].[CH:13]([C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1)=[CH2:14].C(N(CC)CC)C>CO>[CH2:1]([O:4][C:5]1[C:6](=[O:12])[C:7]2[C:8](=[CH:14][CH:13]=[C:15]3[C:16]=2[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:9](=[O:11])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC1=CC(=O)C=CC1=O
Reactant: C=CC1=CCCCC1
Solvent: CCN(CC)CC
Solvent: CO
Product: C=CCOC1=CC(=O)c2ccc3c(c2C1=O)CCCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
2-Allyloxy-1,4-benzoquinone (10.0 g, 60.9 mM) and 1-Vinylcyclohexene (19.8 g, 183 mM) were dissolved in 100 ml of MeOH, and refluxed for 3 hours. The reaction solution was cooled to room temperature, and then Triethylamine (5 ml) and NaIO4 (13.0 g, 61.0 mM) were added thereto, and stirred vigorously for another 1 hours. Reaction solution therein was filtered and the filtrate was concentrated by distillation under reduced pressure and was then purified by chromatography on silica gel to give 7.6 g (28.4 mM) of 3-Allyloxy-5,6,7,8-tetrahydro-1,4-phenanthrenequinone.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:35]2[N:39]([CH3:40])[C:38]3[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=3[N:36]=2)[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][CH2:34][N:28]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Cn1c(N2CCCNCC2)nc2ccccc21
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: Cn1c(N2CCCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4Oc4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[1.4]diazepan-1-yl-1-methyl-1H-benzimidazole.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH:10]([C:12]([CH3:14])=[O:13])=[CH2:11].C(N(CC)CC)C.O>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.CN(C=O)C>[CH3:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:8])[CH2:11][CH2:10][C:12](=[O:13])[CH3:14]
Reactant: Cc1ccccc1C=O
Reactant: C=CC(C)=O
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)CCC(=O)c1ccccc1C
Temperature: 80 °C
Reaction time: 12 h

Procedure:
25 g (208 mmol) of o-tolualdehyde, 14.58 g (208 mmol) of methyl vinyl ketone, 21.05 g (208 mmol) of triethylamine, 5.4 g (21.4 mmol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide were dissolved in this order in 100 ml of DMF and stirred at 80° C. for 12 hours. The reaction mixture was subsequently admixed with 400 ml of water and extracted twice with methylene chloride. The combined methylene chloride phases were washed with 10% strength sulfuric acid and saturated sodium hydrogencarbonate solution and dried over sodium sulfate. After taking off the solvent on a rotary evaporator, the product was purified by fractional distillation.