Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5])[CH3:2].[CH3:20][O:21][C:22](=[O:29])[C@@H:23]([NH2:28])[CH2:24][CH:25]([CH3:27])[CH3:26].CCN(C(C)C)C(C)C.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([O:3][C:4]([CH:6]1[C:15]([CH2:16][NH:28][C@H:23]([C:22]([O:21][CH3:20])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:18][CH3:19])[O:7]1)=[O:5])[CH3:2]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)C1Oc2cccc(OC)c2C=C1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)C1Oc2cccc(OC)c2C=C1CN[C@@H](CC(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 30.2 %

Procedure:
To a solution of 5-methoxy-3-formyl-2H-chromene-2-carboxylic acid ethyl ester (Example 7, step 1) (1.0 g, 3.81 mmol) in methanol (20 mL) containing molecular sieves (0.7 g) was added commercially available (S)-2-amino-4-methyl-pentanoic acid methyl ester (0.77 g, 6.86 mmol) and N,N′-diisopropylethylamine (0.99 mL, 7.63 mmol). The mixture was stirred at 25° C. for 10 hours. At this time, sodium cyanoborohydride (0.48 g, 7.63 mmol) and acetic acid (0.8 mL, 13.72 mmol) were added simultaneously to the reaction mixture, and the reaction mixture was stirred for additional 16 hours at 25° C. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated in vacuo. Flash column chromatography (eluant-ethyl acetate:petroleum ether 1:9, Rf=0.45) over neutral alumina afforded 5-methoxy-3-[((S)-1-methoxycarbonyl-3-methyl-butylamino)-methyl]-2H-chromene-2-carboxylic acid ethyl ester (0.45 g, 43.3%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>CS(C)=O.CS(C)=O.CO>[Cl:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:20]=[C:19]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)[CH:18]=[C:17]3[C:13]=2[CH:14]=[N:15][NH:16]3)=[O:10])=[N:4][C:5]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(N2CCOCC2)ccc1Cl
Temperature: 160 °C
Yield: 16.1 %

Procedure:
To a microwave vial was added 2 ml of a solution of 3,6-dichloro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (306 mg, 0.71 mmol) in DMSO (6 ml). Morpholine (0.022 ml, 0.25 mmol) and DIPEA (0.129 ml) were added and the mixture was heated at 160° C. for 3 h under microwave irradiation. The crude reaction mixture was dissolved in DMSO/MeOH (1:1) and purified by Mass Directed Automated Preparative HPLC (Method E). The sample was further purified by Mass Directed Automated Preparative HPLC (Method E) and product-containing fractions were dried under a stream of nitrogen to afford the title compound (19 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[O:13])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(Cc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1ccc(Cc2ccccc2)cc1
Yield: 53.3 %

Procedure:
The above alcohol (2.52 g) was oxidised using the conditions of Swern (oxalyl chloride, 1.2 ml; dimethyl sulphoxide, 1.8 ml; triethylamine, 8.8 ml) in dichloromethane to give 4-benzylbenzaldehyde (1.33 g). NMR 1H: 9.93(1H,s), 7.78(2H,d), 7.33(2H,d), 7.20(5H,s), 4.04(2H,s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:21]([NH:17][C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:20][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 81.2 %

Procedure:
Tertiarybutyloxycarbonyl-L-valine (25 g) in dichloromethane (200 ml) was treated with 1-hydroxybenzotriazole (15.5 g) hexylamine (11.6 g) and DCC (26 g) at room temperature for 2 days. The solution was filtered and the organic phase washed with aqueous sodium hydrogen carbonate, aqueous citric acid (1M) and water, dried over sodium sulphate and concentrated in vacuo to afford tertiary butyloxycarbonyl-L-valine N-hexylamide (28 g) which crystallised from methanol-water as needles; m.p. 74°-76° C.; (Found: C,63.8; H,10.6; N,9.4. C16H32N2O3 requires C,64.0; H,10.7; N,9.32%); νmax (Nujol): 3280 and 1630 cm-1 ; δ(CDCl3) 0.8-1 (9H,m, 3×CH3); 1.3 (8H,m,(CH2)4); 1.45 (9H,s, (CH3)3C); 2.1 (1H,m,CH(CH3)2); 3.3 (2H,m, NHCH2 ); 3.9 (1H,dd, J=8 Hz and 5 Hz., α-CH); 5.2 (1H,d, J=8Hz, CONH) and 6.26 (1H,m,NH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:32])[CH2:26][S:27][CH2:28][C:29](O)=[O:30])=[C:20]([C:33]([O:35]C)=[O:34])[CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:32])[CH2:26][S:27][CH2:28][C:29](=[O:30])[NH:16][C:11]2[CH:10]=[C:9]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=3)[CH:14]=[CH:13][C:12]=2[CH3:15])=[C:20]([CH:19]=1)[C:33]([OH:35])=[O:34]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CSCC(=O)O
Reactant: Cc1cc(C)cc(-c2ccc(C)c(N)c2)c1
Product: Cc1cc(C)cc(-c2ccc(C)c(NC(=O)CSCC(=O)Nc3ccc(Cl)cc3C(=O)O)c2)c1

Procedure:
Using the same method as in Example 1-(ii), 3′,4,5′-trimethylbiphenyl-3-amine was reacted with the [(2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethyl)sulfanyl]acetic acid obtained in Example 12-(i) to give 5-chloro-2-([((2-oxo-2-[(3′,4,5′-trimethylbiphenyl-3-yl)amino]ethyl)sulfanyl)acetyl]amino)benzoic acid.methyl ester (yield: 87%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23](F)[CH:22]=3)[C:19]=2[CH3:20])[CH2:10][CH2:9]1)=O)(C)(C)C.C(N1C(=O)C(COS(C)(=O)=O)=CC(C2C=CC=CC=2)=N1)C(C)C.CN1CCNCC1>>[CH2:29]([N:16]1[C:15](=[O:33])[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]2)=[C:19]([CH3:20])[C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[N:17]1)[CH:30]([CH3:31])[CH3:32]
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CC(C)Cn1nc(-c2ccccc2)cc(COS(C)(=O)=O)c1=O
Agent: CN1CCNCC1
Product: Cc1c(-c2ccccc2)nn(CC(C)C)c(=O)c1N1CCN(C)CC1
Yield: 77.1 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 77.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][CH:29]([NH2:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)[NH:34][CH:29]([CH3:28])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(NC(SC)=C(C#N)S(=O)(=O)c2ccc(Cl)cc2)cc(OC)c1
Reactant: CC(N)C(C)(C)C
Product: COc1cc(NC(NC(C)C(C)(C)C)=C(C#N)S(=O)(=O)c2ccc(Cl)cc2)cc(OC)c1
Yield: 72 %

Procedure:
2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-methylsulfanyl-2-propenenitrile (0.34 g, 0.8 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 22 h at 75° C. under nitrogen. Work up as described in EXAMPLE 1, 2) gave 264 mg (72%) of the title compound. Mp 177.5-179° C. 1H NMR (200 MHz, CDCl3): δ=0.82 (s, 9H), 0.95 (d, 3H), 3.2 (m, 1H), 6.13 (d, 2H), 6.32 (t, 1H), 7.45 (d, 2H), 7.82 (d, 2H); EI SP/MS: 478 (M+).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][CH2:10][C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[OH:17])[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>C1COCC1>[NH2:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][CH2:10][C@@H:11]2[CH2:16][CH2:15][N:14]([C:40](=[O:43])[CH:41]=[CH2:42])[CH2:13][C@H:12]2[OH:17])[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1
Reactant: Nc1ncnc(NC[C@@H]2CCNC[C@H]2O)c1-c1ccc(Oc2ccccc2)cc1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)N1CC[C@@H](CNc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)[C@H](O)C1
Reaction time: 8 h
Yield: 3.5 %

Procedure:
To a round bottom flask containing (3S,4S)-4-{[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methyl}-piperidin-3-ol hydrochloride (591.95 mg; 1.38 mmol; 1.00 eq.) and DIPEA (0.69 ml; 4.15 mmol; 5.00 eq.) in THF (30.00 ml) was slowly added acryloyl chloride (0.11 ml; 1.38 mmol; 1.00 eq.) in 1 mL THF over 1 h. The reaction mixture was concentrated and purified with using preparative HPLC. Fractions containing the desired product were combined and lyophilized overnight to afford 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one as a white solid (21.5 mg, 2.7%). HPLC purity: 99%. MS: m/z=446 [M+H]+. 1H NMR (CD3OD) δ 8.25 (s, 1H), 7.10-7.45 (m, 9H), 6.73 (dd, 1H), 6.34 (d, 1H), 5.77 (d, 1H), 4.5 (m, 1H), 4.03 (m, 1H), 3.62 (m, 1H), 3.50 (m, 1H), 3.25 (m, 1H), 3.01 (m, 1H), 2.57 (m, 1H), 1.71 (m, 2H), 1.19 (m, 1H).
Reaction SMILES: [CH3:1][C:2](C)=[CH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:27])[C:14]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:8][CH2:7]1.Cl.Cl.N[CH:32]1[CH2:37]CN(CC2CCCCCC2)C[CH2:33]1>>[CH:4]1([CH2:5][N:6]2[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:27])[C:14]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)([OH:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:8][CH2:7]2)[CH2:37][CH2:32][CH2:33][CH2:1][CH2:2][CH2:3]1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2ccccn2)C2CCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1ccccn1)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Sept 4 of Example 22 using 2-cyclopentyl-2-hydroxy-2-(2-pyridyl)acetic acid obtained in Example 52 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[F:25][C:26]([F:38])([F:37])[C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[C:13]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11][CH2:10][N:9]([S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:37])[F:38])[CH:28]=3)(=[O:35])=[O:34])[C:8]2=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1NCCC1(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCC1(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 3,3-diphenylpyrrolidin-2-one (Example 1A, 0.237 g, 1.0 mmol) dissolved in tetrahydrofuran (10 mL) was added potassium t-butoxide (1.0 M in tetrahydrofuran, 1.5 mL, 1.5 mmol) under nitrogen. The reaction mixture was stirred for 15 minutes, and then 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.294 g, 1.2 mmol) was added. The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was concentrated and then diluted with ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Analogix®, Burlington, Wis.) eluting with ethyl acetate/hexane (40:60) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.26-8.12 (m, 3H), 7.87 (t, J=7.8, 1H), 7.28-7.16 (m, 6H), 7.08-6.98 (m, 4H), 3.82 (t, J=6.4, 2H), 2.90 (t, J=6.4, 2H); MS (DCI) m/z 446.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([CH:20]=[C:21]([C:23]([NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)=[O:24])[N:22]=2)[CH:19]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Nc1cccc(OC(F)(F)F)c1
Product: O=C(Nc1cccc(OC(F)(F)F)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 3-(trifluoromethoxy)aniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[CH2:3][CH2:2]1.Br[C:12]1[CH:13]=[CH:14][C:15]2[O:19][CH2:18][CH2:17][C:16]=2[CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:12]3[CH:13]=[CH:14][C:15]4[O:19][CH2:18][CH2:17][C:16]=4[CH:20]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)CCO2
Reactant: Brc1ccc2c(c1)CCO2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1cc2c(cc1Nc1ccc3c(c1)CCO3)CCO2
Temperature: 25 °C

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser, and nitrogen inlet was added 2,3-dihydro-1-benzofuran-5-amine (4.53 grams, 33.3 mmoles, prepared as in Example 23 of U.S. Pat. No. 20040029932), 5-bromo-2,3-dihydrobenzofuran (6.63 grams, 32.9 mmoles), tris(dibenzylideneacetone)dipalladium (0) (0.61 grams, 0.67 mmoles), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (0.83 grams, 1.33 mmoles), sodium tert-butoxide (6.44 grams, 66.6 mmoles) and anhydrous toluene (60 mL). The contents of the flask were refluxed for three days; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with dichloromethane (200 mL). The combined organic layers were concentrated in vacuo to yield a dark yellow oil. The solid was chromatographed on silica gel, eluting with a hexane/ethyl acetate gradient. The resulting solid was recrystallized from ethanol to afford 1.8 grams of the desired product as a white solid. 1H NMR (CDCl3/D2O) δ 6.55-6.95 (m, 6H), 4.5 (t, 4H), 3.15 (t, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][C:4]=1[F:18].[NH:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:18][C:4]1[CH:5]=[C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:7]=[CH:8][C:3]=1[CH2:2][N:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1
Reactant: OC1CCNC1
Reactant: CC1(C)OB(c2ccc(CBr)c(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)OB(c2ccc(CN3CCC(O)C3)c(F)c2)OC1(C)C
Yield: 91.8 %

Procedure:
A solution of 2-[4-(bromomethyl)-3-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 0.95 mmol), pyrrolidin-3-ol (99 mg, 1.1 mmol), and potassium carbonate (160 mg, 1.1 mmol) in acetonitrile (5 mL) was heated to 50° C. for 3 h. The reaction mixture was cooled, filtered and the filtrate was concentrated to afford the desired product (280 mg, 92%) as a red oil: ESI MS m/z 322 [C17H25BFNO3+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CC#N>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:18]1[CH:19]=[CH:20][C:21]([CH:24]2[CH2:25][CH2:26][N:27]([CH2:30][C:31]([F:34])([F:32])[F:33])[CH2:28][CH2:29]2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(I)c(Br)c1
Reactant: CC1(C)OB(c2ccc(C3CCN(CC(F)(F)F)CC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(-c2ccc(C3CCN(CC(F)(F)F)CC3)cc2)c(Br)c1

Procedure:
A mixture of 2-bromo-1-iodo-4-methylbenzene (0.764 g, 2.57 mmol), the title compound from Example 60 Step B (1.00 g, 2.71 mmol), dichloro bis(triphenylphosphine)palladium(II) (0.095 g, 0.135 mmol), sodium carbonate (5.42 mL of 1 M solution, 5.42 mmol) and MeCN (5.42 mL) was heated at 110° C. overnight. Organic layer was separated. Aqueous layer was extracted with hexanes-EtOAc. The organic layers were combined and concentrated. Silica gel flash chromatography eluting with hexanes:EtOAc (20:1 to 9:1 v/v) gave the title compound: LCMS m/z 414.0 [M+H+]; 1H NMR (500 MHz, CDCl3) δ 7.54 (s, 1 H),7.40 (d, J=8.1 Hz, 2 H), 7.31 (d, J=8.1 Hz, 2 H),7.26 (d, J=7.8 Hz, 1 H),7.20 (d, J=7.8 Hz, 1 H),3.16 (m, 2 H), 3.08 (q, J=9.8 Hz, 2 H),2.57 (m, 3 H),2.42 (s, 3 H).1.95-1.88 (m, 4 H).
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]2[CH2:11][CH2:12][CH2:13][C:2]1=2.C1C[O:17]CC1.O>C1COCC1>[O:17]=[C:13]1[C:2]2[NH:1][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[CH2:11][CH2:12]1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cc2c([nH]1)CCC2
Solvent: O
Product: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Reaction time: 1.5 h

Procedure:
A solution of the ethyl 1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (1.0 g, 5.58 mmol) in THF/Water (10:1, 11 mL) at 0° C. was deoxygenated by passing a stream of dry nitrogen gas for 10 min. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzochinone (DDQ) in THF (4 mL) was added dropwise over 5 min. After stirring for 1.5 h, the cooling bath was removed and stirring was continued at rt. Silica gel was added, the solvent stripped off and the silica gel-imbedded material was purified by flash chromatography (0-60% EtOAc/Heptane) to afford ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate as a taupe solid (270 mg, 25%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 (t, J=7.13 Hz, 3H), 2.87-2.95 (m, 4H), 4.39 (q, J=7.13 Hz, 2H), 6.78 (d, J=1.66 Hz, 1H), 9.86 (s, 1H); LCMS-MS (ESI+) 193.9 (M+H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: ClCCCCCOCCc1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOCCc2ccccc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (2.0 g) as starting compound and 5-(2-phenylethyloxy)-pentyl chloride were reacted and treated in the same manner as in Example 168 to give 0.69 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(2-phenylethyloxy)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: COC(=O)C1C=C(N2CCCC2=O)C=C(Br)C=1.C1CCCCC=1.[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:32]=[C:31]([N:33]2[CH2:37][CH2:36][CH2:35][C:34]2=[O:38])[CH:30]=[C:29]([CH:39]2[CH2:44][CH2:43][CH:42]=[CH:41][CH2:40]2)[CH:28]=1.COC(=O)C1C=C(N2CCCC2=O)C=C(C2CCCCC=2)C=1>>[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:32]=[C:31]([N:33]2[CH2:37][CH2:36][CH2:35][C:34]2=[O:38])[CH:30]=[C:29]([CH:39]2[CH2:44][CH2:43][CH2:42][CH:41]=[CH:40]2)[CH:28]=1
Reactant: COC(=O)c1cc(C2CC=CCC2)cc(N2CCCC2=O)c1
Agent: COC(=O)c1cc(Br)cc(N2CCCC2=O)c1
Agent: COC(=O)c1cc(C2=CCCCC2)cc(N2CCCC2=O)c1
Solvent: C1=CCCCC1
Product: COC(=O)c1cc(C2C=CCCC2)cc(N2CCCC2=O)c1
Yield: 30 %

Procedure:
Description 74 was prepared in an analogous manner to that described for Description 73 from 686 mg (mmol) of 3-bromo-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D9a) and cyclohexene which yielded 207 mg (30%) of 3-cyclohex-2-enyl-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester, 3-cyclohex-3-enyl-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester and 3-cyclohex-1-enyl-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D74) after purification by flash chromatography on silica gel (iso-hexane/EtOAc: 5/1)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]=1[OH:19])([O-:9])=[O:8].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.O>[CH2:20]([O:19][C:11]1[C:10]([N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH2:13][C:12]1[CH:16]=[CH:17][CH:18]=[CH:10][CH:11]=1)=[O:14])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cccc([N+](=O)[O-])c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 162.3 %

Procedure:
Potassium carbonate (16.6 g, 120.1 mmol) was added to a solution of 3-nitrosalicylic acid (10 g, 54.6 mmol) in DMF (100 ml) and benzyl bromide (14.3 ml, 120.1 mmol) was dropped thereinto. The mixture was stirred at 80° C. for 12 hours and the reaction solution was diluted with water and extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and the solvent was evaporated therefrom to provide 16.1 g (yield 81%) of benzyl 2-benzyloxy-3-nitrobenzoate as brown oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=4[Cl:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:26]([OH:30])[CH2:27][CH2:28][CH3:29])=[CH:6][CH:5]=1.[CH3:31]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=4[Cl:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:26]([O:30][CH3:31])[CH2:27][CH2:28][CH3:29])=[CH:6][CH:5]=1
Reactant: CCCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 60.6 %

Procedure:
Sodium hydride (60% in oil, 7.6 mg, 0.190 mmol) was added to a stirred solution of 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]butan-1-ol (69.5 mg, 0.158 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature. After stirring 5 min, methyl iodide (33.6 mg, 0.237 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (43.4 mg, 0.0958 mmol, 61%).