Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:27]1([CH:33]([NH2:41])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:41][CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: NC(Cc1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NC(Cc3ccccc3)c3ccccc3)ncc2[N+](=O)[O-])CC1
Reaction time: 18 h
Yield: 77.4 %

Procedure:
trans-{4-[(2-Chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (100 mg, 0.26 mmol) was dissolved in DCM (5 mL). 1,2-Diphenylethylamine (154 mg, 0.78 mmol) was added in one portion. After 18 h, the solution was partitioned between DCM (15 mL) and 2% AcOH (aq; 10 mL). The layers were separated and the aqueous layer was extracted with DCM (20 mL). The combined organic fraction were washed with saturated sodium carbonate (10 mL) and water, dried over MgSO4, filtered and concentrated to yield a pale yellow solid. Chromatography (silica, 10%-50% Hex/EtOAc) yielded 110 mg of (4-{[2-(1,2-diphenyl-ethylamino)-5-nitro-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester as a pale yellow solid, m/z 547.4 [M+1]+.
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C:12]([NH:31][C:32]1[S:33][CH:34]=[C:35]([C:37](=[N:41][O:42][CH3:43])[C:38]([OH:40])=O)[N:36]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[S:45]([CH2:48][C@H:49]1[NH:52][C:51](=[O:53])[C@H:50]1[NH2:54])[C:46]#[N:47]>C(Cl)Cl.C(N(CC)CC)C>[S:45]([CH2:48][C@H:49]1[NH:52][C:51](=[O:53])[C@H:50]1[NH:54][C:38](=[O:40])[C:37]([C:35]1[N:36]=[C:32]([NH:31][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:33][CH:34]=1)=[N:41][O:42][CH3:43])[C:46]#[N:47]
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N#CSC[C@H]1NC(=O)[C@H]1N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1CSC#N)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1 ml of triethylamine and then 1.38 g of tosyl chloride were added to a suspension of 3.19 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetic acid in 50 ml of methylene chloride and the mixture was stirred at room temperature for 40 minutes. A solution of 1.162 g of the product of Step C in 40 ml of methylene chloride and 2 ml of trietylamine were added to the mixture over 5 minutes and the mixture was stirred for 4 hours, was washed with water, then with water containing 4 ml of N hydrochloric acid, dried and evaporated to dryness. The residue was dissolved in ethyl acetate and the solution was iced and vacuum filtered. The product was washed with methanol and dried to obtain 0.709 g of racemate of syn isomer of cis 4-thiocyanatomethyl-3-[2-(2-tritylamino-4-thiazolyl)-2-methoxyimino-acetamido]-2-oxo-azetidine. The mother liquors were evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 93-7 chloroform-methanol mixture yielded another 1.069 g of the said product.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([OH:20])(=O)[C:17]#[CH:18].[C:21]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)#[C:22][CH3:23]>ClCCl>[C:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:16](=[O:20])[C:17]#[CH:18])=[CH:26][CH:25]=1)#[C:22][CH3:23]
Reactant: CC#Cc1ccc(N)cc1
Reactant: C#CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C#CC(=O)Nc1ccc(C#CC)cc1
Reaction time: 0.5 h

Procedure:
1.2 g (5.86 mmol) of DCC is added to a solution of 375 mg (5.35 mmol) of propynoic acid in 10 mL of dichloromethane at 0° C. and the mixture is stirred for 30 minutes. Then 0.7 g (5.35 mmol) of 4-prop-1-ynylphenylamine dissolved in dichloromethane is slowly added dropwise and the mixture is stirred for 2 hours again at 0° C. The reaction mixture is then filtered through CELITE® filter aid and the filtrate is evaporated down. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol (40:1)). Yield: 0.7 g (71.4% of theory); C12H9NO (M=183.21); calc.: molecular ion peak (M+H)+: 184; found: molecular ion peak (M+H)+: 184; Rf value: 0.65 (silica gel, dichloromethane/ethanol/acetic acid 20:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH:6]=[CH:7][CH:8]=1.Br[CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:39]([CH2:38][CH2:37][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:10]([NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[C:11]1=[O:19])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: BrCCOc1ccccc1
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)[nH]c3ncccc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCOc3ccccc3)c3ncccc23)c1
Reaction time: 10 h
Yield: 72.6 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (500 mg, 1.06 mmol) in DMF (10 ml) were added β-bromophenetole (256 mg, 1.28 mmol) and potassium carbonate (441 mg, 3.19 mmol), and the mixture was stirred at 40°-50° C. for 10 hours. The mixture was allowed to stand for cooling, and then poured into water. The mixture was extracted with ethyl acetate, and the extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1-3% methanol in chloroform), and crystallized from ether to give the title compound (446 mg, 0.77 mmol) as a colorless crystal.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:14]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:10]([C:9]1[CH:12]=[CH:13][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1)=[CH2:14]
Reactant: O=Cc1ccc(-n2cncn2)cc1
Reactant: O=C([O-])[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(-n2cncn2)cc1
Temperature: 70 °C
Yield: 62.9 %

Procedure:
To a stirred solution of 4-[1,2,4]-triazol-1-yl-benzaldehyde (9.0 g, 52 mmol) in 1,4-dioxane (100 mL), were added K2CO3 (10.76 g, 78 mmol) and methyl triphenyl phosphonium bromide (22.2 g, 62.4 mmol) at room temperature. The resultant reaction mixture was heated to 70° C. for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afforded the title compound as a white solid (5.6 g, 63%): ESIMS m/z 172.09 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[C:33]([F:36])([F:35])[F:34])[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].Br[CH2:38][C:39](=O)[C:40]([CH3:43])([CH3:42])[CH3:41]>>[F:35][C:33]([F:34])([F:36])[C:24]1[CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=[CH:28][C:23]=1[CH2:22][N:4]([C:2]1[S:3][CH:38]=[C:39]([C:40]([CH3:43])([CH3:42])[CH3:41])[N:1]=1)[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(N)=S)cc1
Reactant: CC(C)(C)C(=O)CBr
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2nc(C(C)(C)C)cs2)cc1)C(=O)O

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 1-bromopinacolone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[C@@H:15]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]=2)=[N:6][C:7]=1[O:8][CH3:9].Cl.O1CCOCC1>CO>[C:17]([O:16][C@@H:15]1[C:10]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([O:8][CH3:9])[N:6]=2)=[CH:11][CH2:12][NH:13][CH2:14]1)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1nc(C2=CCN(C(=O)OC(C)(C)C)C[C@@H]2OC(=O)C(C)(C)C)ccc1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1nc(C2=CCNC[C@@H]2OC(=O)C(C)(C)C)ccc1Cl
Yield: 127.8 %

Procedure:
To a methanol solution (1.0 mL) of tert-butyl (R)-5-chloro-6-methoxy-5′-(pivaloyloxy)-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate (1.35 g, 3.18 mmol) synthesized in Reference Synthesis Example 142, 4 M hydrogen chloride/1,4-dioxane (15 mL) was added and the resultant mixture was stirred at room temperature for 5 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure and saturated sodium bicarbonate aqueous solution and water were added to the concentrated solution, followed by extraction from the resultant mixture with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a crude product of the title compound (1.32 g).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][OH:5].[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:9]([Si:6]([O:5][CH2:4][CH2:3][C:2]#[CH:1])([CH3:8])[CH3:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: C#CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred, 0° C. solution of homopropargyl alcohol (10 g, 0.14 mol) and tert-butyldimethylsilyl chloride (21.5 g, 0.14 mol) in dichloromethane (50 mL) was treated with triethylamine (22.8 mL, 0.168 mol). The mixture was then stirred overnight at room temperature. The mixture was washed with water and the organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography (95:5 hexane/ethyl acetate) to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 0.08 (s, 6H), 0.90 (s, 9H), 1.96 (t, J=3 Hz, 1H), 2.41 (dt, J=6 Hz, J=3 Hz, 2H), 3.75 (d, J=6 Hz, 2H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[CH:27]O>>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[CH:27][NH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: O=C1Nc2ccc(F)cc2C1=CO
Product: O=C1Nc2ccc(F)cc2C1=CNc1ccc(OCCN2CCCC2)cc1
Yield: 68.8 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine (690 mg, 1.2 equiv.) and 5-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (705 mg, 69%).
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1(/[CH:15]=[CH:16]/[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.C(OCC)(=O)C>C1COCC1>[OH:18][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(/[CH:16]=[CH:15]/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C(/C=C/c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(/C=C/c1ccccc1)c1ccccc1
Yield: 97 %

Procedure:
Under nitrogen atmosphere, 15 mL of THF was added to 3.05 g (5 mmol, 1.0 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 1.04 g (5 mmol) of (E)-chalcone in 2.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 0˜5° C. for 3 hours. 7.5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of an aqueous saturated sodium chloride solution, 10 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.44 g of the desired product (yield 97%). 1H NMR (CDCl3), (ppm): δ 1.17 (3H, t, J=7.1 Hz), 3.04 (2H, dd, J=22.8, 15.7 Hz), 4.11 (2H, q, J=7.1 Hz), 4.81 (1H, s), 6.42 (1H, d, J=16.0 Hz), 6.66 (1H, d J=16.0 Hz), 7.25-7.53 (10H, m).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][OH:9].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1.O>CN(C)C=O>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][O:9][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccsc1Br
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccsc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.2 %

Procedure:
A mixture of 2-(2-bromothiophen-3-yl)ethanol (4.5 g, 21.8 mmol), tert-butylchloro-dimethylsilane (3.16 g, 24.0 mmol) and imidazole (1.63 g, 24.0 mmol) in N,N-dimethylformamide (40 mL) was stirred at rt for 24 h. 100 mL of water was added and the mixture was extracted with diethyl ether (3×00 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the product purified by flash chromatography eluting with ethyl acetate/hexane (1:20) to give the title compound as an oil (5.9 g, 84%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[C:20]([Cu])#[N:21].[C-]#N.[Na+]>CN(C=O)C>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:20]#[N:21])[S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1
Reactant: N#C[Cu]
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Yield: 48.3 %

Procedure:
A mixture of 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A; 0.50 g, 1.3 mmol) and CuCN (0.14 g, 1.6 mmol) was refluxed for 90 minutes in DMF (5 mL). The residue was poured into 25% aq. NaCN (30 mL), extracted with CHCl3, dried over MgSO4, and concentrated. The crude was purified by silica gel flash column chromatography (0.5% MeOH in CH2Cl2) to afford 0.179 g (49%) of the desired product. LRMS (APCI pos) m/e 286.2 (M+1). 1H-NMR (400 MHz, CDCl3) δ 8.62 (d, 1H), 8.08 (s, 1H), 7.05 (t, 1H), 6.67 (d, 1H), 6.53 (m, 2H), 3.87 (s, 2H); 19F-NMR (376 MHz, CDCl3) δ −128.4.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:15][C:16]([F:25])([F:24])[C@H:17]1[CH2:22][CH2:21][C@H:20](O)[CH2:19][CH2:18]1>>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]([O:14][C@H:20]2[CH2:21][CH2:22][C@H:17]([C:16]([F:25])([F:24])[F:15])[CH2:18][CH2:19]2)=[O:13])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O[C@H]1CC[C@H](C(F)(F)F)CC1
Product: CCCCC[C@H]1CC[C@H](C(=O)O[C@H]2CC[C@H](C(F)(F)F)CC2)CC1

Procedure:
0.005 mol of trans-4-pentylcyclohexanecarboxylic acid are esterified analogously to Example 4 using 0.005 mol of trans-4-trifluoromethylcyclohexanol (prepared as in Example 2). The product is obtained as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)[C:9]2[N:10]([CH:17]3[CH2:19][CH2:18]3)[CH:11]=[CH:12][C:13]=2[C:14](O)=[O:15])=[CH:4][CH:3]=1>C(Cl)Cl.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[N:10]([CH:17]4[CH2:19][CH2:18]4)[CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[N:20]2[C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2c(C(=O)O)ccn2C2CC2)cn(C)c1=O
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3ccn(C4CC4)c3C2c2ccc(Cl)cc2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
1-Chloro-N,N-2-trimethyl-1-propenylamine (0.899 mL, 6.80 mmol) was added to a solution of 2-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-cyclopropyl-1H-pyrrole-3-carboxylic acid (Step 240.3) (2 g, 4.86 mmol) in CH2Cl2 (40 mL) at 5° C. The reaction mixture was stirred at RT for 30 min, diluted in CH2Cl2 and a saturated aqueous solution of sodium bicarbonate, and extracted twice with CH2Cl2. The combined organic extracts were washed with water and brine, dried (Na2SO4), and concentrated. The crude product was purified by silica gel column chromatography (CH2Cl2/MeOH 95:5) to afford a red foam. This foam was refluxed in Et2O for 3 hrs. The title compound (1.35 g, 70.6% yield) was collected by filtration and obtained as an off-white solid. tR: 0.95 min (LC-MS 6); ESI-MS: 394.2 [M+H]+ (LC-MS 6); TLC (CH2Cl2/MeOH 95:5): Rf=0.30.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([NH2:34])[CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2].Cl[C:41](=[CH2:44])[C:42]#[N:43].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]4[O:33][CH:41]([C:42]#[N:43])[CH2:44][NH:34][C:29]=4[CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:35][O:36][C:37](=[O:39])[CH3:38])(=[O:3])[CH3:2]
Reactant: C=C(Cl)C#N
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)c(N)c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)NCC(C#N)O4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 22.4 %

Procedure:
To a stirred solution of acetic acid (2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[3-(3-amino-4-hydroxy-benzyl)-4-chloro-phenyl]-tetrahydro-pyran-2-ylmethyl ester (1.8 g, 3.2 mmol) in acetonitrile (15 mL) was added 2-chloroacrylonitrile (0.35 mL, 4.5 mmol) and potassium carbonate (882 mg, 6.4 mmol). After the reaction was refluxed overnight, the mixture was filtered through a celite bed. The filtrate was concentrated and purified by silica gel column chromatography to furnish acetic acid (2R,3R,4R,5S,6S)-3,4,5-triacetoxy-6-[4-chloro-3-(2-cyano-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (440 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=3)[CH:10]=2)[C:5]([Cl:26])=[CH:4][N:3]=1>CO.[Pd]>[NH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6]2[C:5]([Cl:26])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:10]=1
Reactant: O=[N+]([O-])c1cccc(CNc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(CNc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Yield: 93.3 %

Procedure:
To a solution of N-(2,5-dichloropyrimidin-4-yl)-N′-(3-nitrobenzyl)benzene-1,3-diamine (2.00 g, 5.12 mmol) in methanol (30 mL) was added 10% palladium on carbon (200 mg, 0.2 mmol). The resultant mixture was hydrogenated at 25 psi for 18 h. The reaction mixture was filtered, washed with MeOH and concentrated to give the desired product (1.72 g, 93%) as a light yellow powder. LCMS for C17H16Cl2N5 (M+H)+: m/z=360.2.
Reaction SMILES: [OH:1][N:2]=[C:3]([Br:5])Br.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8].O>CN(C=O)C>[Br:5][C:3]1[CH2:8][CH:7]([C:6]([O:10][CH2:11][CH3:12])=[O:9])[O:1][N:2]=1
Reactant: C=CC(=O)OCC
Reactant: ON=C(Br)Br
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CC(Br)=NO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a vigorously stirred mixture of hydroxycarbonimidic dibromide (15.5 g, 76.4 mmol) and ethyl acrylate (15.3 g, 153 mmol) in DMF (200 mL) was added a solution of 15 wt % aqueous KHCO3 (102 mL, 153 mmol). The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted twice with methyl tert-butyl ether. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: Brc1ccccn1
Product: OC1(c2ccccn2)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 66 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and 2-bromopyridine, the title compound was formed in 66% yield as a white solid, mp 194°-196° C. free base: 1H NMR (CDCl3, 250 HHz) 8.53 (d, J=5.0 Hz, 1H), 7.70 (ddd, J=1.5, 7.7, 7.7 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.22 (m, 5H), 6.94 (m, 4H), 5.23 (s, 1H), 4.30 (s, 1H), 3.52 (s, 2H), 2.99 (m, 2H), 2.81 (dt, J=2.0, 12.0 Hz, 2H), 2.65 (d, J=2.0 Hz, 2H), 2.07 (dt, J=5.0, 13.0 Hz, 2H), 1.60 (m, 2H) MS (CI, CH4) m/z 383 (M+1,100), 411 (M+29,20), 365 (18), 364 (17) hydrochloride salt: Analysis for C26H26N2 O.2HCl.0.1H2O: Calculated: C, 68.30; H, 6.22; N, 6.13 Found: C, 68.17; H, 6.21; N, 6.09
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:12][C:13](=[O:42])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([C:29]4([C:32]5[CH:33]=[C:34]6[C:39](=[CH:40][CH:41]=5)[N:38]=[CH:37][CH:36]=[CH:35]6)[CH2:31][CH2:30]4)=[N:27][N:28]=3)[N:25]=2)=[CH:16][CH:15]=1)[C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:9][C:8]([CH3:11])([CH3:10])[C@H:7]([NH:12][C:13](=[O:42])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([C:29]4([C:32]5[CH:33]=[C:34]6[C:39](=[CH:40][CH:41]=5)[N:38]=[CH:37][CH:36]=[CH:35]6)[CH2:30][CH2:31]4)=[N:27][N:28]=3)[N:25]=2)=[CH:18][CH:19]=1)[C:6]([OH:43])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1)C(=O)O
Reaction time: 1.5 h

Procedure:
Tert-butyl-(2S)-3,3-dimethyl-2-({4-[3-(1-quinolin-6-ylcyclopropyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoyl}amino)butanoate was dissolved in methylene chloride (0.7 ml). To the solution was added TFA (0.7 ml). The mixture was stirred for 1.5 h. The volatiles were removed under reduced pressure to yield the desired product. Analytical LCMS: (M+H)+=522.2.