Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][O:7][CH2:8][C:9]([NH:26][C:27]([CH2:29][CH2:30][O:31][CH2:32][C:33]([NH:98][C:99]([CH2:101][CH2:102][CH2:103][NH:104][C:105](=[O:122])[O:106][CH2:107][C:108]1[C:109]2[C:114]([CH:115]=[C:116]3[C:121]=1[CH:120]=[CH:119][CH:118]=[CH:117]3)=[CH:113][CH:112]=[CH:111][CH:110]=2)=[O:100])([CH2:66][O:67][CH2:68][CH2:69][C:70]([NH:72][C:73]([CH2:90][O:91][CH2:92][CH2:93][C:94]([O:96]C)=[O:95])([CH2:82][O:83][CH2:84][CH2:85][C:86]([O:88]C)=[O:87])[CH2:74][O:75][CH2:76][CH2:77][C:78]([O:80]C)=[O:79])=[O:71])[CH2:34][O:35][CH2:36][CH2:37][C:38]([NH:40][C:41]([CH2:58][O:59][CH2:60][CH2:61][C:62]([O:64]C)=[O:63])([CH2:50][O:51][CH2:52][CH2:53][C:54]([O:56]C)=[O:55])[CH2:42][O:43][CH2:44][CH2:45][C:46]([O:48]C)=[O:47])=[O:39])=[O:28])([CH2:18][O:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[O:4]>CC(C)=O.[OH-].[Na+]>[C:46]([CH2:45][CH2:44][O:43][CH2:42][C:41]([NH:40][C:38]([CH2:37][CH2:36][O:35][CH2:34][C:33]([NH:98][C:99]([CH2:101][CH2:102][CH2:103][NH:104][C:105](=[O:122])[O:106][CH2:107][C:108]1[C:109]2[C:114]([CH:115]=[C:116]3[C:121]=1[CH:120]=[CH:119][CH:118]=[CH:117]3)=[CH:113][CH:112]=[CH:111][CH:110]=2)=[O:100])([CH2:32][O:31][CH2:30][CH2:29][C:27]([NH:26][C:9]([CH2:10][O:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])([CH2:8][O:7][CH2:6][CH2:5][C:3]([OH:4])=[O:2])[CH2:18][O:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:28])[CH2:66][O:67][CH2:68][CH2:69][C:70]([NH:72][C:73]([CH2:82][O:83][CH2:84][CH2:85][C:86]([OH:88])=[O:87])([CH2:74][O:75][CH2:76][CH2:77][C:78]([OH:80])=[O:79])[CH2:90][O:91][CH2:92][CH2:93][C:94]([OH:96])=[O:95])=[O:71])=[O:39])([CH2:58][O:59][CH2:60][CH2:61][C:62]([OH:64])=[O:63])[CH2:50][O:51][CH2:52][CH2:53][C:54]([OH:56])=[O:55])([OH:48])=[O:47]
Reactant: COC(=O)CCOCC(COCCC(=O)OC)(COCCC(=O)OC)NC(=O)CCOCC(COCCC(=O)NC(COCCC(=O)OC)(COCCC(=O)OC)COCCC(=O)OC)(COCCC(=O)NC(COCCC(=O)OC)(COCCC(=O)OC)COCCC(=O)OC)NC(=O)CCCNC(=O)OCc1c2ccccc2cc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(O)CCOCC(COCCC(=O)O)(COCCC(=O)O)NC(=O)CCOCC(COCCC(=O)NC(COCCC(=O)O)(COCCC(=O)O)COCCC(=O)O)(COCCC(=O)NC(COCCC(=O)O)(COCCC(=O)O)COCCC(=O)O)NC(=O)CCCNC(=O)OCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.4 %

Procedure:
A mixture of 9-anthrylmethyl N-[({tris[(2-{[(tris{[2-(methoxycarbonyl)ethoxy]methyl}methyl)amino]carbonyl}ethoxy)methyl]methyl}amino)carbonyl]propylcarbamate (0.60 g, 0.34 mmol) in acetone (30 ml) and 0.20 N NaOH (30 ml) was stirred at room temperature for 1 d, after which acetone was removed. The aqueous solution was washed with EA, stirred in an ice bath, acidified with dilute HCl, and extracted with EA. The organic layer was dried with MgSO4, filtered, and concentrated to yield 0.37 g (68% yield) of a yellow powder.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[CH3:34][S:35]([O:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:20])[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][C:3]=1[O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NC1=Nc2c(ccc(OCCCN3CCOCC3)c2O)C2=NCCN12)c1cccnc1
Product: CS(=O)(=O)Oc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 36 was used to prepare the title compound from N-[7-hydroxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]nicotinamide (Intermediate H) and methanesulfonyl chloride (58 mg, 49%). TLC: Rf=0.38 in 10% MeOH/CH2Cl2, HPLC MS RT=2.05 min, [M+Na]+=551; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.18-2.30 (2H, m), 3.03-3.17 (2H, m), 3.28-3.37 (2H, m), 3.44-3.54 (2H, m), 3.60-3.75 (5H, m), 3.95-4.05 (2H, m), 4.19-4.29 (2H, m), 4.40 (2H, t), 4.56-4.66 (2H, m), 7.63 (1H, d), 7.82 (1H, dd), 8.29 (1H, d), 8.64 (1H, d), 8.93 (1H, dd), 9.35 (1H, s).
Reaction SMILES: [F:1][CH:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]1([CH2:10][O:11][CH3:12])[OH:9].[Li]CCCC.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[F:1][CH:2]1[C:7]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:6]([F:8])[CH:5]=[CH:4][C:3]1([CH2:10][O:11][CH3:12])[OH:9]
Reactant: COCC1(O)C=CC(F)=CC1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCC1(O)C=CC(F)=C([Si](C)(C)C)C1F
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 67.1 %

Procedure:
A flame-dried 3-necked flask was charged with 2,4-difluoro-1-methoxymethylphenol (26, 0.84 g, 4.8 mmol) in 30 mL of freshly distilled THF under argon and this mixture was cooled to -78° C. (FIG. 2E). nBuLi (2.5 M solution in hexane, 2.2 mL, 5.43 mmol) was added to this reaction mixture which was allowed to stir at -78° C. for 2.5 hours under argon. Chlorotrimethyl silane (1.0 M solution in THF, 5.43 mL, 5.43 mmol) was then added to the deep pink colored mixture at -78° C. and then the acetone/dry ice bath was removed and the reaction was allowed to proceed at room temperature for 14 h. Sat. NH4Cl (~20 mL) was added to the mixture which was then stirred for an additional 10 minutes and then extracted with ethyl ether (3×10 mL). The combined organic solution was washed with brine, water and then dried (MgSO4) and filtered. The solvent was removed under vacuo to afford the crude product which was purified by flash chromatography on silica gel (EtOAc:hexanes; 5:95) to yield a yellow oil (0.8 g, 79%). 1H NMR (CDCl3) δ 7.09-7.17 (m, 1H, ArH), 6.68-6.74 (m, 1H, ArH), 5.13 (s, 2H, CH2), 3.52 (s, 3H, CH3), 0.36-0.37 (t, 9H, Si(CH3)3); FAB-MS 247 (MH+, 70), 229 (40), 219 (60), 189 (58), 157 (40), 133 (60), 79 (100).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.N[C:20]1[CH:33]=[CH:32][C:23]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:21]=1>N1C=CC=CC=1.[Cu](F)F>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]2([CH3:11])[CH3:10])=[CH:28][CH:27]=1)(=[O:25])[C:23]1[CH:32]=[CH:33][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)CCCC(C)(C)N1O
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1Oc1ccc(C(=O)c2ccccc2)cc1
Yield: 80.6 %

Procedure:
The procedure of Example 1 is repeated using 1.95 g (12.5 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 3.92 g (38 mmol) of tert-butyl nitrite, 12.5 mg (0.125 mmol) of copper(II) fluoride, 120 mL of pyridine and 4.93 g (25 mmol) of 4-aminobenzophenone in 40 mL of pyridine at 70° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 3.40 g of the title compound as a light yellow oil in 80.6% yield. The structure is confirmed by 1Hnmr, elemental and mass spectrographic analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C1C=CC=CC=1.C(N(CC)C#CC)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[C:39](=[CH:45][C:46]1[CH:51]=[C:50]([O:52][CH3:53])[C:49]([O:54][CH3:55])=[C:48]([O:56][CH3:57])[CH:47]=1)[NH:38][CH2:37][CH2:36]2>N1C=CC=CC=1>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])/[C:39](=[CH:45]/[C:46]1[CH:51]=[C:50]([O:52][CH3:53])[C:49]([O:54][CH3:55])=[C:48]([O:56][CH3:57])[CH:47]=1)/[N:38]([C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:37][CH2:36]2
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Reactant: COc1cc2c(cc1OC)C(=Cc1cc(OC)c(OC)c(OC)c1)NCC2
Agent: CC#CN(CC)CC
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)/C(=C/c1cc(OC)c(OC)c(OC)c1)N(C(=O)Cc1cc(OC)c(OC)c(OC)c1)CC2

Procedure:
To a suspension of 24 parts of 3,4,5-trimethoxybenzeneacetic acid in 25 parts of benzene is added 7 parts of N,N-diethyl-1-propyne-1-amine, followed by a solution of 12 parts of 3,4-dihydro-6,7-dimethoxy-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline [Ber. deut. chem. Ges., 55, 2989 (1922)] in 60 parts of pyridine. The resultant mixture is stirred at room temperatures for 18 hours, whereupon it is consecutively washed with aqueous 5% potassium carbonate, approximately 0.2% hydrochloric acid, and water, then dried over anhydrous sodium sulfate and stripped of solvent by vacuum distillation. The residue, crystallized from methanol, affords (Z)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-(3,4,5-trimethoxybenzeneacetyl)-1-[(3,4,5-trimethoxyphenyl)methylene]isoquinoline melting at 148°-150°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)=[N:5][NH:4][C:3]1=[S:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][Cl:24].[H-].[Na+].C(OCC)(=O)C>CCO>[Cl:24][CH2:23][CH2:22][CH2:21][CH2:20][S:18][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)=[N:5][N:4]=1
Reactant: ClCCCCBr
Reactant: Cc1ccc2c(-c3n[nH]c(=S)n3C)cccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc2c(-c3nnc(SCCCCCl)n3C)cccc2n1
Yield: 79 %

Procedure:
4-Methyl-5-(2-methyl-5-quinolinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (400 mg) was reacted with 1-bromo-4-chloro-butane (0.233 ml) and NaH (60%, 69 mg) in absolute EtOH (6.5 ml) at reflux for 45 min. Ethyl acetate was added, the insoluble salts were filtered off and the solvent was evaporated under reduced pressure. The crude was purified on silica gel (eluent: ethyl acetate to ethyl acetate/acetone, 1/1) affording the desired compound as pale yellow solid (430 mg, 79% yield).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]([CH:14]=O)=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]([CH:14]=[N:17][OH:18])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc(-n2c(Cl)ccc2C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-n2c(Cl)ccc2C=NO)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 115.4 %

Procedure:
A mixture of 5-chloro-1-(4-methylphenyl)pyrrole-2-carbaldehyde (365 mg), hydroxylamine hydrochloride (173 mg), and sodium acetate (204 mg) in 60% aqueous ethanol (6 ml) was stirred at 60° C. for one hour. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate. The mixture was washed with water, dried, and concentrated in vacuo to give a residue (450 mg) of 5-chloro-1-(4-methylphenyl)pyrrole-2-carbaldehyde oxime. A mixture of the residue and sodium acetate (30 mg) in acetic anhydride (5 ml) was stirred at 160° C. for one and half hours under nitrogen atmosphere. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted by ethyl acetate:n-hexane =1/15) to yield 5-chloro-1-(4-methylphenyl)pyrrole-2-carbonitrile (325 mg) as an oil.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]3[C:33]4[C:34]5=[C:35]6[C:30](=[CH:31][CH:32]=4)[CH:29]=[CH:28][CH:27]=[C:26]6[CH:25]=[CH:24][C:23]5=[CH:22][CH:21]=3)[C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10][C:9]=3[C:8]=2[C:36]#[N:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C1C[O:43]CC1>>[O:43]=[C:10]1[C:9]2[C:8]([C:36]#[N:37])=[C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:19]=[C:18]([C:20]3[C:33]4[C:34]5=[C:35]6[C:30](=[CH:31][CH:32]=4)[CH:29]=[CH:28][CH:27]=[C:26]6[CH:25]=[CH:24][C:23]5=[CH:22][CH:21]=3)[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccc4cccc5ccc2c3c45)c2c1Cc1ccccc1-2
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccc4cccc5ccc2c3c45)c2c1C(=O)c1ccccc1-2
Temperature: 2.5 °C

Procedure:
A solution of 2-(piperidin-1-yl)-4-(pyren-1-yl)-9H-fluorene-1-carbonitrile (474 mg) in THF was added sodium hydride (42 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Light red solid; mp 180-182° C.; ESMS 489 (M+1); IR (KBr) 2217 (CN), 1713 cm−1 (CO).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6](/[CH:8]=[C:9](/[C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)\[C:10]#[N:11])[CH:7]=1.[BH4-].[Na+]>C1COCC1.CO.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([CH2:8][CH:9]([C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:10]#[N:11])[CH:7]=1
Reactant: Cc1ccc([N+](=O)[O-])c(/C=C(\C#N)c2ccc(C)nc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc([N+](=O)[O-])c(CC(C#N)c2ccc(C)nc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a cooled solution of (Z)-3-(5-methyl-2-nitrophenyl)-2-(6-methylpyridin-3-yl)acrylonitrile (6.5 g, 0.0232 mol) in THF (44 mL) and MeOH (135 mL) was added sodium borohydride (1.7 g, 0.0465 mol) at 0° C. under nitrogen atmosphere. After the addition, the reaction mixture was stirred for 2 h at 0° C. After completion of reaction (monitored by TLC), the reaction mixture was diluted with water (100 mL), and extracted with EtOAc (3×150 mL). The organic layer was dried over anhydrous sodium sulfate, and solvent was removed under reduced pressure to obtain product as a yellow colored solid (6 g, 91.7% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([Si:28]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)Cl)([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1.CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([O:21][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(O)ccc2F)C(=O)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2F)C(=O)C1

Procedure:
A solution of product from Step D (2.75 g, 8.48 mmol), tert-butyldiphenylchlorosilane (2.2 mL, 8.48 mmol), and imidazole (860 mg, 12.7 mmol) in DMF (50 mL) was stirred at 60° C. for 15 hours. The reaction was poured into EtOAc (200 mL), and washed with H2O (300×100 mL). The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (25-30% ethyl acetate/hexane) to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[CH:17]1(B(O)O)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH:17]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)[CH2:19][CH2:18]1
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2ccncc2C2CC2)CC1
Yield: 19 %

Procedure:
General procedure D was followed using 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (25 mg, 0.088 mmol), cyclopropyl boronic acid (9.4 mg, 0.44 mmol), tetrakis (triphenylphosphine)palladium(0) (5 mg, 5 mol %), 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) and acetonitrile (1 mL) for 50 min. The crude product was purified by preparative tlc on silica (CH2Cl2, MeOH 10:1) to furnish the title compound as a white solid (4 mg, 19%), LC-MS (ESI, 3.5 min) Rt 0.97 min, m/z 246 (100%, [M+H]+); m/z (ESI) C14H19N3O requires 246.1601 found [M+H]+ 246.1596.
Reaction SMILES: [NH2:1][CH:2]([CH:15]([CH3:17])[CH3:16])[C:3]([N:5]([CH3:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[N+:18]([C:21]1[C:22]([CH:34]=O)=[CH:23][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:25][CH:26]=1)([O-:20])=[O:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.ClCCl>[CH3:16][CH:15]([CH3:17])[CH:2]([NH:1][CH2:34][C:22]1[C:21]([N+:18]([O-:20])=[O:19])=[CH:26][N:25]=[C:24]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=1)[C:3]([N:5]([CH3:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reactant: CC(C)C(N)C(=O)N(C)CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C(=O)N(C)CCc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of 2-amino-3,N-dimethyl-N-phenethyl-butyramide (1.5 g, 6.48 mmol), 5-nitro-2-phenoxy-pyridine-4-carbaldehyde (1.5 g, 6.1 mmol), dichloromethane (75 mL), and THF (75 mL) was stirred for 5 hrs. Sodium triacetoxyborohydride (3.0 g, 14.25 mmol) was then added and the resulting mixture was stirred 16 hrs. Sodium hydroxide solution ([0.1 N], 100 mL) was added, the organic layer was separated, treated with MgSO4, filtered and the solvent evaporated to yield an oil. The oil was purified by column chromatography (10%-40% ethyl acetate/heptane) to yield a residue.
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=CC(Cl)=CC=2)[C:6](=[O:15])[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.[CH2:22]([NH:29]CCN)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCCO)C>>[CH2:22]([N:29]1[C:2]2=[CH:3][C:4]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:5][C:6](=[O:15])[N:7]2[CH2:8][CH2:13]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1cc(-c2ccccc2)cc(Cl)n1-c1ccc(Cl)cc1
Reactant: NCCNCc1ccccc1
Solvent: CCOCCO
Product: O=c1cc(-c2ccccc2)cc2n1CCN2Cc1ccccc1

Procedure:
A mixture of 2 g. of 6-chloro-1-(4-chlorophenyl)-4-phenyl-2-pyridone, 2 g. of N-benzylethylenediamine, and 5 ml. of 2-ethoxyethanol was refluxed for 50 hours. Then, by treating the reaction mixture obtained as in Example 5, 0.5 g. of 1-benzyl-5-oxo-7-phenyl-1,2,3,5-tetrahydroimidazo[1,2-a]pyridine was obtained.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]=[N:39][N:38]=[N:37]2)=[CH:32][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][C:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH2:19][CH2:20]OS(C)(=O)=O)[CH2:15]1)=[O:13])([O:3][CH2:4][CH3:5])=[O:2].[CH2:41]([O:43][CH2:44][CH2:45][N:46]1[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[N:48]=[C:47]1[NH:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1)[CH3:42]>>[C:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]=[N:39][N:38]=[N:37]2)=[CH:32][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][C:16]([CH2:19][CH2:20][N:59]2[CH2:58][CH2:57][CH:56]([NH:55][C:47]3[N:46]([CH2:45][CH2:44][O:43][CH2:41][CH3:42])[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=4[N:48]=3)[CH2:61][CH2:60]2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:15]1)=[O:13])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCOc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OCCCC(=O)OCC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:9])[CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Brc1ccc([C@@H]2CO2)cc1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: O[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
(2R)-2-(4-Bromophenyl)oxirane crude (250 g) was added to morpholine (8 mL, 1 mol) in 100 mL CH2Cl2 solution at 0° C. with magnetic stirring. Montmorillonite K10 clay (20 g) was added portionwise to the brown mixture and the resulting dark brown mixture was maintained under argon for 60 h at room temperature with magnetic stirring. The clay was filtered off and the filtrate was concentrated to a brown oil. The oil was loaded onto a 3 inch plug of silica gel. 12 L of 30% EtOAc/Hexane was used to elute off less polar impurities and then 40 L of 30%-40% EtOAc/Hexane with 1% ammonia was used to elute off the desired product. The fractions were combined, concentrated, and then crystallized from Et2O. The white crystals were filtered and dried to yield the title compound (109 g, 41.6%). MS (ES) m/e 287 [M+H]+. Chiral HPLC analysis (Chiralpak AD-RH, 5 micron, 150×4.6 mm, mobile phase: 50% CH3CN/50% aqueous borate buffer (pH 9.0), 0.50 mL/min, UV 220 nm, 5 uL inj in MeOH) confirmed the product is a single enantiomer (>99% ee).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].O.N([O-])=O.[Na+].C(Cl)Cl.[BrH:20]>>[Br:20][C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7]
Reactant: N#Cc1ccc(N)cc1C#N
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(Br)cc1C#N
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Compound 4 (24 g, 0.17 mol) was suspended in a stirring solution of 100 ml HBr (48%) and 100 ml of H2O cooled to −10° C. Sodium nitrite (14 g, 0.20 mol) was dissolved in ice water and added dropwise to the solution of 4-aminophthalonitrile. The exothermic reaction was carefully monitored and kept under 0° C. After 2 hours of stirring, the solution was added dropwise to a solution of Cu(I)Br (27 g, 0.18 mol) in 100 ml of HBr (48%) at −3° C. and stirred at 0° C. for 2 hours. To minimize foaming as well as increase the yield, methylene chloride was added to the solution and the reaction was allowed to proceed overnight for at least 24 hours. The organic layer was removed, and the aqueous layer was also extracted with toluene. The combined organic layers were washed with water, Na2S2O3 (saturated aqueous solution), water, brine, water, dried over MgSO4 and evaporated under reduced pressure. 25 g of an orange product were collected (73%). 1H NMR (CDCl3) δ: 7.99 (d, 1H), 7.94-7.91 (dd, 1H), 7.72-7.70 (d, 1H).6 13C{1H}NMR (CDCl3) 136.68, 136.42, 134.44, 128.19, 117.39, 114.76, 114.65, 114.04 ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15](O)[CH:14]([C:20]([OH:22])=[O:21])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16]([CH:15]=[C:14]([C:20]([OH:22])=[O:21])[CH2:13][CH2:12]2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCc2cc(OCc3ccccc3)ccc2C1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1=Cc2ccc(OCc3ccccc3)cc2CC1
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
Methyl ester of 6-benzyloxy-1-hydroxy-1,2,3,4-tetrahydro-2-naphthoic acid (0.6 g) is dissolved in methanol (50 ml). To the solution is added an aqueous solution (10 ml) of sodium hydroxide (2 g), and the mixture is left standing for 30 minutes at room temperature. The resultant is concentrated under reduced pressure. The concentrate is diluted with water (50 ml). The precipitating crystals are collected by filtration. This product is dissolved in a mixture of dioxane (50 ml) and concentrated hydrochloric acid (2 ml). The mixture is left standing for 5 minutes at 80° C. and then for 30 minutes at room temperature. The resultant is concentrated under reduced pressure. Water (50 ml) is added to the concentrate. The precipitating crystals are collected by filtration to give 7-benzyloxy-1,2-dihydro-3-naphthoic acid (0.45 g) as colorless crystals, followed by recrystallization from a mixture of methanol and acetone to afford colorless needles, m.p. 202°-205° C.