Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][CH2:7][N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])([CH3:3])[CH3:2].Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][CH2:7][N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)/[C:11](=[N:23]\[NH:24][C:25]([NH2:27])=[O:26])/[C:9]1=[O:10])([CH3:3])[CH3:2]
Reactant: NNC(N)=O
Reactant: CC(C)N(CCCN1C(=O)C(=O)c2ccccc21)C(C)C
Agent: Cl
Product: CC(C)N(CCCN1C(=O)/C(=N/NC(N)=O)c2ccccc21)C(C)C
Yield: 66.6 %

Procedure:
By using 1-(3-diisopropylaminopropyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-1-(3-diisopropylaminopropyl)isatin 3-semicarbazone having a melting point of 173°-175° C. (yield: 66.6%, recrystallizing solvent: methanol-benzene).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17]C(OC(C)(C)C)=O)[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11](O)=[O:12])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:52]([O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)(=[O:55])[CH2:53][OH:54].CN1CCOCC1.CC#N.Cl>C(Cl)Cl.O1CCOCC1>[CH2:57]([O:56][C:52]([CH2:53][O:54][C:11](=[O:12])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH2:17])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:2][CH:3]=1)=[O:55])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: O=C(CO)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)OCC(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
(2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (100 mg, 242 μmol), HOBt (98 mg, 726 μmol), and EDCI (128 μL, 726 μmol) were dissolved in DCM (2 mL). After stirring for 15 minutes, benzyl glycolate (274 μL, 1.9 mmol) and 4-methylmorpholine (106 μL, 967 μmol) were added. The resulting mixture was stirred at room temperature overnight, and then the reaction was quenched with water. The DCM layer was separated, concentrated, purified ((Interchim reverse phase chromatography column), and dried under vacuum. The purified material was combined with MeCN (1 mL, 20 mmol) and 4 M HCl in dioxane (240 μL, 970 μmmol) and stirred at room temperature for 1 hour. The solvent was then removed to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid benzyloxycarbonylmethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH:11]([N:12]2[C:16]([CH:17]=O)=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:19])[O:3]1.C([O-])(O)=O.[Na+].Cl.[NH2:27][OH:28]>C(O)C.O>[CH3:1][C:2]1([CH3:20])[CH:11]([N:12]2[C:16]([CH:17]=[N:27][OH:28])=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:19])[O:3]1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1C=NO
Reaction time: 1 h

Procedure:
3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carbaldehyde (0.100 g, 0.363 mmol) (Example 9a) in ethanol (3 mL) is added to NaHCO3 (0.246 g, 2.901 mmol) and hydroxylamine hydrochloride (0.208 g, 2.901 mmol) in water (1 mL). After 1 hr, water is added and the mixture is extracted three times with dichloromethane. The combined organic phase is dried over magnesium sulfate and filtered through a cotton plug. Concentration in vacuo gives a residue, which is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 49:1), resulting in the separation of the two isomers. Each isomer is obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](SC)=[CH:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH3:17][NH2:18]>CCO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8]([NH:18][CH3:17])=[CH:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Reactant: CN
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCc1ccc(Cl)cc1
Temperature: 0 °C
Yield: 68.7 %

Procedure:
In 100 ml of EtOH on reflux was dissolved 2.59 g (0.01 mole) of 1-(4-chlorobenzyl)amino-1-methylthio-2-nitroethylene, and with refluxing continued, a solution of 1.94 g of 40% aqueous methylamine solution in 10 ml of EtOH was added dropwise over a period of 50 minutes. After completion of dropwise addition, the mixture was further refluxed for 15 minutes, at the end of which time it was cooled with ice-water, whereupon crystals separated out. The crystals were collected by filtration, washed with EtOH and ether in that order, and dried. The procedure gave 1.66 g of the title compound as white crystals.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[C:33]1[O:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>O1CCCC1>[O:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[N:13]1[CH2:14][CH2:15][N:10]2[C:9](=[O:16])[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]2[CH2:12]1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: Clc1nc2ccccc2o1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2CN(c3nc4ccccc4o3)CCN12
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (60 mg, 0.2 mmol) in tetrahydrofuran (2 mL) were sequentially added diisopropylethylamine (0.3 mL) and 2-chlorobenzoxazole (45 mg, 0.29 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. Then, the residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) and recrystallized from diisopropyl ether to obtain the title compound (51 mg, yield 62%).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:32]=[C:31](C(O)=O)[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:36])[CH:29]=2)[N:24]=1)([OH:16])=[O:15].[OH-].[Na+]>[Cu]=O.O>[CH3:36][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]([OH:16])=[O:15])[CH:32]=[CH:31]2
Reactant: Cc1ccc2nc(-c3ccccc3C(=O)O)cc(C(=O)O)c2c1
Agent: O=[Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 170 °C
Yield: 46.7 %

Procedure:
To 3 ml of diphenyl ether were added 0.5 g of the 2-(2-carboxyphenyl)-6-methyl-4-quinolinecarboxylic acid obtained in Example 2. After adding 6.5 mg of copper oxide, the mixture was heated at 170° C. for 1 hour. Then the reaction mixture was poured into water, made alkaline by adding sodium hydroxide and washed with ethyl acetate. The aqueous layer was neutralized with 3M hydrochloric acid until a precipitate was formed. After extracting with ethyl acetate, 0.2 g of 2-(6-methylquinolin-2-yl)benzoic acid were obtained. NMR (270 MHz, CD3OD): δ 7.58-8.32 (m,9H); 2.58 (s,3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C1(C2C=CC(N)=CC=2)CC1.Br[CH:23]([CH:41]([CH3:43])[CH3:42])[C:24]([O:26]CC1C=CC=C(OC2C=CC=CC=2)C=1)=[O:25]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C@H:23]([C:24]([OH:26])=[O:25])[CH:41]([CH3:43])[CH3:42])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N)cc1
Reactant: CC(C)C(Br)C(=O)OCc1cccc(Oc2ccccc2)c1
Agent: Nc1ccc(C2CC2)cc1
Product: CCCCc1ccc(N[C@H](C(=O)O)C(C)C)cc1

Procedure:
Following the procedure of Example 1, each of 4-n-butylaniline and 4-cyclopropylaniline is reacted with m-phenoxybenzyl α-bromoisovalerate to yield the m-phenoxybenzyl ester of N-(4-n-butylphenyl)valine, MS m/e 431.2 (M+), and the m-phenoxybenzyl ester of N-(4-cyclopropylphenyl)valine, MS m/e 415.1 (M+).
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[OH:6][CH:7]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCc1ccc(C#N)cc1)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: N#Cc1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Yield: 79.8 %

Procedure:
Analogous to the procedure described for Example 1A, Step E, 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzonitrile (257.6 mg, 0.525 mmol) was deprotected with TBAF (1M in THF, 0.79 mL, 0.79 mmol) over 24 h. Purification by medium pressure chromatography (1:1 EtOAc: hexanes to EtOAc to 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2) provided 4-{3-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-propyl}-benzonitrile (157.8 mg). 1H NMR (CDCl3) δ7.56 (m, 2H), 7.26 (m, 7H), 3.80 (m, 1H), 3.67-3.55 (m, 2H), 2.98 (m, 1H), 2.80 (m, 1H), 2.65 (t, 2H), 2.43-2.24 (m, 2H), 2.08 (m, 1H), 1.89-1.33 (m, 9H); MS 375.3 (M−1).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C@H:10]([O:21][C@H:22]([C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:54](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:17]([CH3:54])[N:18]=[N:19][N:20]=3)[CH2:15][C@@:9]1([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C@H:10]([O:21][C@H:22]([C:32]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[C:34]([C:42]([F:44])([F:45])[F:43])[CH:33]=1)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc([C@H](COCc2ccccc2)O[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1nnnc1[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](COCc3ccccc3)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-phenylmethoxyethoxy}1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Example 158; 0.403 g, 0.57 mmol), methyl iodide (0.2427 g, 0.107 ml, 1.71 mmol) and potassium carbonate (0.236 g, 1.71 mmol) in acetonitrile (10 ml) were heated at 60° C. for 2 hours. The mixture was quenched with water and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organics were collected, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 1% methanol/dichloromethane to give the title compounds (isomer A; 60 mg) and (isomer B; 70 mg), together with mixed fractions.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2].[CH2:18]([NH2:21])[CH2:19][CH3:20].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:21][CH2:18][CH2:19][CH3:20])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2]
Reactant: CCCN
Reactant: N#Cc1nc(Cl)c(-c2ccccc2)nc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCNc1nc(C#N)c(C#N)nc1-c1ccccc1
Yield: 91.9 %

Procedure:
2,3-Dicyano-5-chloro-6-phenylpyrazine (12.03 g; 0.05 mole) was dissolved in 1,400 ml of toluene. The solution was cooled to 5° to 10° C., and with stirring, 3.25 g (0.055 mole) of n-propylamine was added dropwise over the period of 10 minutes. Subsequently, 55 ml of a 1 N aqueous solution of sodium hydroxide was added dropwise over the period of 10 minutes. The mixture was then stirred at 5° to 10° C. for 30 minutes. After the reaction, the reaction mixture was separated into two layers. The toluene layer was concentrated under reduced pressure to obtain a solid. The solid was washed twice with 200 ml of water, dried under reduced pressure, and recrystallized successively from toluene and ethanol to afford 12.1 g (yield 92%) of 2,3-dicyano-5-n-propylamino-6-phenylpyrazine.
Reaction SMILES: [CH2:1]([N:5]([C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:23])(=O)=O>C1C=CC=CC=1>[CH2:1]([N:5]([C:14]1[C:18]([Cl:23])=[CH:17][N:16]([CH3:19])[N:15]=1)[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCN(C(=O)C1CCCCC1)c1ccn(C)n1
Solvent: c1ccccc1
Product: CCCCN(C(=O)C1CCCCC1)c1nn(C)cc1Cl
Reaction time: 12 h

Procedure:
N-Butyl-N-(1-methylpyrazol-3-yl) cyclohexane carboxamide (1.3 g, 0.0049 m) in dry benzene (15 cc) was cooled at 0° C. while sulphuryl chloride (0.67 g, 0.0049 m) was added slowly. The cooling bath was then removed and the solution was kept at room temperature for 12 hours. The solvent was then evaporated and the residue crystalled from ether/petrol (40°-60° C.) as white prisms, 1.0 g, m.p. 110°-112° C.
Reaction SMILES: [O:1]=[O+][O-].CSC.[CH3:7][C:8]12[O:22][C@H:9]1[CH2:10][C@@H:11](/[C:14](/C)=[CH:15]\CC=C(C)C)[CH2:12][CH2:13]2>C(Cl)Cl>[CH3:7][C:8]12[O:22][CH:9]1[CH2:10][CH:11]([C:14](=[O:1])[CH3:15])[CH2:12][CH2:13]2
Reactant: CC(C)=CC/C=C(/C)[C@H]1CCC2(C)O[C@H]2C1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)C1CCC2(C)OC2C1

Procedure:
Compounds 8 and 9 were deoxygenated after the procedure of Delay and Ohloff, supra. These compounds dexoygenated (FIG. 1) individually or as a mixture, produced a single new compound that coeluted with 6 and matched the MS of synthetic 6. Isolated components in ca. 100 μl of CH2Cl2 were ozonized by addition of 100 μl of O3 -saturated CH2Cl2 at -78° C. (8341 Matheson Laboratory Ozonator), and ozonides were cleaved with methyl sulfide (30 μl; 40 μl/μl CH2Cl2). Compounds 12 and 13 (1-methyl-4-acetyl-1,2-epoxycyclohexane) were synthesized by standard methods and structurally verified by spectral comparisons to published values for these isomers. Ozonolysis of compounds 8 and 9 together produced ozonides 12 and 13 (FIG. 1) in approximately the same ratio as the ratio of 8:9 in airborne-trapped samples. Thus, compound 8 is trans-(Z)-1-methyl-4-(1,5-dimethyl-1,4-hexadienyl)-1,2-epoxycyclohexane. Deoxygenation of isolated 9 (>80% purity) produced a single compound having a GC-retention time and MS identical to synthetic 6 (FIG. 1). Ozonolysis of isolated 9 produced 13, but did not produce 12. Thus, component 9 is cis-(Z)-1-methyl-4-(1,5-dimethyl-1,4-hexadienyl)-1,2-epoxycyclohexane.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:9]=[CH:10][CH:11]=1.[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23]1>CCO>[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][N:23]1[CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:7]=1
Reactant: c1cc(OC[C@@H]2CO2)cc(-c2cccc3cccnc23)c1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCO
Product: O[C@H](COc1cccc(-c2cccc3cccnc23)c1)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 10.7 %

Procedure:
A mixture of (S)-8-(3-(oxiran-2-ylmethoxy)phenyl)quinoline (270 mg, 1 mmol), 1,2,3,4-tetrahydroisoquinoline (133 mg, 1 mmol) in EtOH (5 mL) was stirred at 120° C. under microwave heating for 30 minutes. After evaporation of the solvent, the residue was purified by prep-HPLC to afford the desired title compound (43.9 mg, Yield 14.6%). 1H NMR (400 MHz, MeOD): δ 8.80-8.79 (m, 1H), 8.38 (d, J=8 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.74-7.72 (m, 1H), 7.67-7.63 (m, 1H), 7.54-7.51 (m, 1H), 7.41-7.37 (m, 1H), 7.22-7.16 (m, 2H), 7.10-7.00 (m, 5H), 4.27-4.25 (m, 1H), 4.15-4.03 (m, 2H), 3.74 (s, 2H), 2.88-2.78 (m, 5H), 2.73-2.70 (m, 1H) ppm; ESI-MS (m/z): 411.1 [M+1]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C[C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1>S(=O)(=O)(O)O>[N+:1]([C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[CH:6][S:7][C:8]=2[CH:14]=1)([O-:4])=[O:2]
Reactant: Cc1nc2ccccc2s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2ncsc2c1
Temperature: 25 °C

Procedure:
See FIG. 3A. Nitration of 2-methylbenzothizole was performed following the method of Mizuno, J. Pharm. Soc. Japan, 72, 745 (1952). A mixture of fuming nitric acid (1.6 mL) and concentrated sulfuric acid (1.2 mL) was added to an ice-cooled solution of 2-methylbenzothiazole (2 g) in sulfuric acid (8 mL). The solution was allowed to warm to room temperature for one hour, then poured onto 100 mL of ice. The solid was filtered, washed with water, and recrystallized from ethanol (80 mL) to provide 2.5 g of yellowish needles.
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][OH:24]>>[OH:24][CH2:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[NH:16][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:12]=1)=[O:15]
Reactant: NC1CCCCC1CO
Reactant: O=C(O)c1cccc(C2CCCCC2)n1
Product: O=C(NC1CCCCC1CO)c1cccc(C2CCCCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclohexyl-pyridine-2-carboxylic acid (Example 7 b) and 2-amino-cyclohexanemethanol (CAN 89854-92-2) as starting materials, MS (EI): m/e=317.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:17][O:18][C:19](=[O:44])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[N:28][C:29]([NH2:43])=[C:30](OS(C3C=CC(C)=CC=3)(=O)=O)[CH:31]=2)=[CH:22][CH:21]=1>CN(C=O)C.CCOC(C)=O.O>[CH3:17][O:18][C:19](=[O:44])[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[N:28][C:29]([NH2:43])=[C:30]([O:10][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=3[C:11]([F:12])([F:13])[F:14])[CH3:9])[CH:31]=2)=[CH:24][CH:25]=1
Reactant: CC(O)c1cccc(F)c1C(F)(F)F
Reactant: COC(=O)c1ccc(-c2cnc(N)c(OS(=O)(=O)c3ccc(C)cc3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cnc(N)c(OC(C)c3cccc(F)c3C(F)(F)F)c2)cc1
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
To a stirred solution of 1-(3-fluoro-2-trifluoromethyl-phenyl)-ethanol (2.0 g, 9.6 mmol) in anhydrous DMF (500 mL) at 0° C. under a N2 atmosphere was added NaH (0.38 g, 9.6 mmol). The reaction was allowed to stir for 0.5 hr. A solution of 4-[6-Amino-5-(toluene-4-sulfonyloxy)-pyridin-3-yl]-benzoic acid methyl ester (3.8 g, 9.6 mmol) in anhydrous DMF (30 mL) was added to the reaction mixture which was allowed to come to ambient temperature slowly and stirred for 21 hr at this temperature. The reaction was diluted with EtOAc (500 mL) and H2O (100 mL). The organic layer was separated off and the aqueous was further extracted with EtOAc (1×200 mL). The organic layers were combined and washed with brine (1×100 mL), dried with Na2SO4 and concentrated to dryness under vacuum. The crude mixture was purified by column chromatography (silica gel, 40:60 to 70:30 EtOAc:hexanes) and the fractions containing product were combined and concentrated in vacuo to yield 4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid methyl ester (1.4 g, 3.2 mmol, 34%). 1H NMR (CDCl3, 300 MHz) δ 1.73 (d, 3H, J, 6.2 Hz), 3.91 (s, 3H), 4.87-4.64 (brs, 2H), 5.81 (q, 1H, J, 6.1, 6.3 Hz), 6.92 (d, 1H, J, 1.8 Hz), 7.38 (d, 2H, J, 8.5 Hz), 7.46-7.66 (m, 3H), 7.93 (d, 1H, J, 1.8 Hz), 8.02 (d, 2H, J, 8.5 Hz).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Al](C)(C)C.[C:9]([NH:12][C:13]1[C:22]2[C:17](=[N:18][C:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:21]=2)[N:16]([CH3:38])[C:15](=[O:39])[C:14]=1[C:40](OC)=[O:41])(=[O:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([NH:12][C:13]1[C:22]2[C:17](=[N:18][C:19]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:21]=2)[N:16]([CH3:38])[C:15](=[O:39])[C:14]=1[C:40]([N:3]([CH3:4])[CH3:2])=[O:41])(=[O:11])[CH3:10]
Reactant: COC(=O)c1c(NC(C)=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Reactant: CNC
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)Nc1c(C(=O)N(C)C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reaction time: 0.5 h

Procedure:
To dimethylamine hydrochloride (26.1 mg) in toluene (2 mL) was added Al(CH3)3 (0.16 mL) at 0° C. The reaction stirred for about 30 minutes before adding the product of EXAMPLE 91 (85 mg) in toluene (1 mL). The reaction stirred for 3.5 hours at 50° C. and was quenched with aqueous 1 M HCl. The reaction was diluted with EtOAc washed with aqueous 1 M HCl. The solution was dried (Na2SO4) and concentrated. The concentrated residue was purified by preparative TLC on silica gel eluted with 6% methanol in CH2Cl2 affording the title compound. HPLC/MS: 543.0 (M+1), 545.0 (M+3); Rt=3.51 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:13])=[C:7]([CH:12]=1)[CH:8]=[CH:9][CH:10]=[O:11])#[N:2].[CH3:14][O:15][CH2:16]Cl.C(N(CC)CC)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:13][CH2:14][O:15][CH3:16])=[C:7]([CH:12]=1)[CH:8]=[CH:9][CH:10]=[O:11])#[N:2]
Reactant: COCCl
Reactant: N#Cc1ccc(O)c(C=CC=O)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCOc1ccc(C#N)cc1C=CC=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of 5-cyano-2-hydroxycinnamaldehyde (2.3 g) in N,N-dimethylformamide (25 ml) were added methoxymethyl chloride (1.5 ml) and triethylamine (2.8 ml) in an ice bath and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to give the desired compound (2.8 g, yield 98%) as a colorless solid.
Reaction SMILES: CS(O[CH:6]([C:19]1[CH:20]=[N:21][C:22]([NH:51][C:52]2[CH:53]=[N:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=2)=[C:23]([C:25]2[N:30]=[C:29]([N:31]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[N:28]=[C:27]([CH3:50])[N:26]=2)[CH:24]=1)[C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:18])(=[O:17])[N:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)(=O)=O.[NH3:60]>C(Cl)Cl.O1CCOCC1>[NH2:60][CH:6]([C:19]1[CH:20]=[N:21][C:22]([NH:51][C:52]2[CH:53]=[N:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=2)=[C:23]([C:25]2[N:30]=[C:29]([N:31]([CH2:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)[CH2:41][C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[N:28]=[C:27]([CH3:50])[N:26]=2)[CH:24]=1)[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:14]([CH3:15])[CH3:16])(=[O:18])=[O:17])=[CH:9][CH:8]=1
Reactant: N
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(OS(C)(=O)=O)c4ccc(S(=O)(=O)N(C)C)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(N)c4ccc(S(=O)(=O)N(C)C)cc4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of (5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(4-(N,N-dimethylsulfamoyl)phenyl)methyl methanesulfonate (14.22 mg, 0.017 mmol) in DCM (0.1 mL) was treated with 0.5 M NH3 in dioxane (2 mL). The mixture was allowed to stand overnight, after which time partial conversion to the amine was observed by LCMS. The mixture was then sealed and heated and 80° C. for 2 h, after which time the starting material was consumed. The mixture was concentrated and taken on directly to the next step.