Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]([C:26]([C:28]([C:44](=[O:72])[C@H:45]([CH2:53][C:54]1[CH:61]=[C:59]([I:60])[C:58]([O:62][C:63]2[CH:70]=[C:68]([I:69])[C:67]([OH:71])=[C:65]([I:66])[CH:64]=2)=[C:56]([I:57])[CH:55]=1)[NH:46]C(=O)C(F)(F)F)([CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][C:41]([NH2:43])=[O:42])[C:29]([NH2:31])=[O:30])=[O:27])[CH2:7][C:8]1[CH:15]=[C:13]([I:14])[C:12]([O:16][C:17]2[CH:24]=[C:22]([I:23])[C:21]([OH:25])=[C:19]([I:20])[CH:18]=2)=[C:10]([I:11])[CH:9]=1)=O.[OH-].[Na+].[ClH:77]>CO.C(O)C>[ClH:77].[ClH:77].[NH2:5][C@H:6]([C:26]([C:28]([C:44](=[O:72])[C@H:45]([CH2:53][C:54]1[CH:55]=[C:56]([I:57])[C:58]([O:62][C:63]2[CH:64]=[C:65]([I:66])[C:67]([OH:71])=[C:68]([I:69])[CH:70]=2)=[C:59]([I:60])[CH:61]=1)[NH2:46])([CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][C:41]([NH2:43])=[O:42])[C:29]([NH2:31])=[O:30])=[O:27])[CH2:7][C:8]1[CH:9]=[C:10]([I:11])[C:12]([O:16][C:17]2[CH:18]=[C:19]([I:20])[C:21]([OH:25])=[C:22]([I:23])[CH:24]=2)=[C:13]([I:14])[CH:15]=1
Reactant: NC(=O)CCOCCCCOCC(C(N)=O)(C(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)C(F)(F)F)C(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: NC(=O)CCOCCCCOCC(C(N)=O)(C(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reaction time: 40 h

Procedure:
Bis-(trifluoroacetyl-L-thyroxyl)-4,9-dioxadodecane-1,12-diamide (example 8A), 0.34 g, was dissolved in 3 ml methanol. 1M sodium hydroxide was added with stirring and the reaction was allowed to go at room temperature for 40 hours. The reaction mixture was diluted into 20 ml of cold 1M hydrochloric acid to give a fine suspension of product. The suspension was centrifuged and the pellet was dissolved in ethanol. The ethanol solution was evaporated to a solid residue of crude product. The product was recrystallized from methanol/ether to obtain 0.18 g of bis-(L-thyroxyl)-4,9-dioxa-1,12-dodecanediamide, dihydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6](Cl)[CH:5]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH2:27])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1>>[Cl:10][C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([NH:27][C:17]2[CH:18]=[CH:19][C:20]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:15]([O:14][CH3:13])[CH:16]=2)[N:7]=1)[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COC(=O)c1cc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)c1

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from methyl-2,6-dichloroisonicotinate (64 mg, 0.3 mmol) and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol). The reaction mixture was heated for 16 h to reflux. Obtained as a yellow solid (40 mg, 36%) after column chromatography of the crude product on silica gel using dichloromethane/methanol (19:1 v/v) as eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=O)[CH:10]([CH3:14])[CH2:9][NH:8][C:7]=2[N:15]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[S:25])[CH:10]([CH3:14])[CH2:9][NH:8][C:7]=2[N:15]=1
Reactant: COc1ccc2c(n1)NCC(C)C(=O)N2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(n1)NCC(C)C(=S)N2
Temperature: 80 °C
Reaction time: 12 h
Yield: 61.9 %

Procedure:
To a solution of 7-methoxy-3-methyl-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepin-2(3H)-one (2.7 g, 13.03 mmol) in anhydrous tetrahydrofuran (30 mL) was added Lawesson's Reagent (8.32 g, 20.60 mmol). The mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated in vacuo and washed with brine (20 mL), and then the mixture was filtered through a celite pad. The filtrate was extracted with acetic ester (20 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph silica gel (elute: dichloromethane/Methanol: 80:1→50:1→30:1) to give 7-methoxy-3-methyl-4,5-dihydro-1H-pyrido[2,3-b][1,4]diazepine-2(3H)-thione (1.8 g, 62%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:3]=1[O:25][CH3:26].[CH3:27][C:28]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>>[CH3:27][C:28]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:3]=1[O:25][CH3:26])=[O:31]
Reactant: Cc1cccc(C(=O)Cl)c1C
Reactant: COc1cc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)ccc1N
Product: COc1cc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)ccc1NC(=O)c1cccc(C)c1C

Procedure:
By using 5-(4-amino-3-methoxyphenyl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione, and 2,3-dimethylbenzoyl chloride, the title compound was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:15][C:16]1[CH:30]=[CH:29][C:19]([CH2:20][S:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[N:25]2)=[CH:18][CH:17]=1)[CH:13]=[CH2:14]>C(OCC)(=O)C.ClCCl>[CH2:12]([O:15][C:16]1[CH:30]=[CH:29][C:19]([CH2:20][S:21]([CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[N:25]2)=[O:9])=[CH:18][CH:17]=1)[CH:13]=[CH2:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOc1ccc(CSCCn2ccnn2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(CS(=O)CCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
A solution of 1.86 g (8.29 mmol) 77% 3-chloroperbenzoic acid in 40 ml ethyl acetate was added at -30° C. within 20 min. to a solution of 1.90 g (6.90 mmol) 1-[2-(4-allyloxy-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 160 ml dichloromethane and stirred for 1 h. The mixture was allowed to warm to r.t. washed with sat. NaHCO3-solution, water and evaporated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol 5:1) to give 1.25 g of the title compound as white powder.
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][C:23]1[N:27]=[C:26]([CH2:28][NH2:29])[O:25][N:24]=1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:29][CH2:28][C:26]2[O:25][N:24]=[C:23]([CH3:22])[N:27]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1noc(CN)n1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: Cc1noc(CNC(=O)c2cnc(OCC(F)(F)F)c(C3CCCCC3)c2)n1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and 3-methyl-1,2,4-oxadiazole-5-methanamine (CAN 90928-92-0) (37 mg, 0.33 mmol) as starting materials; off white solid (30 mg, 22.9%). MS (ESI): 399 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[N:29]=[CH:28][CH:27]=[CH:26][C:20]=2[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:11][CH2:10]1.[C-]#N.[Na+]>CS(C)=O.O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[N:29]=[CH:28][CH:27]=[CH:26][C:20]=2[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCNc2ncccc2C(=O)N(C)C)CC1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C(=O)c1cccnc1NCCCN1CCN(c2ccccc2O)CC1
Yield: 25.7 %

Procedure:
A mixture of 2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide (0.54 g, 1.36 mmol), prepared as in Example 21, and sodium cyanide (0.33 g, 6.8 mmol) in 12 mL of DMSO was heated at reflux for 14 hours and then diluted with water and extracted twice with diethyl ether. The aqueous layer was extracted twice with methylene chloride and the combined methylene chloride layers were washed with water and brine, dried (MgSO4), filtered and concentrated. The residue was purified on silica gel by column chromatography eluting with 8% methanol/methylene chloride to give 2-{3-[4-(2-hydroxyphenyl)-piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide (0.134 g, 0.35 mmol) as an oil. The free base was recrystallized from a solution of fumaric acid in alcohol to give di(2-{3-[4-(2-hydroxyphenyl)-piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide) fumarate, m.p. 185°-186° C. Anal.: Calcd. for C21H30N5O2.(C4H4O4)0.5 : C, 62.57; H, 7.08; N, 15.86; Found: C, 62.44H, 7.08; N, 15.73%.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[C:17]([O:22][CH2:23]Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>CN(C)C=O>[C:17]([O:22][CH2:23][N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)OCCl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)OCn1cc(F)c(=O)[nH]c1=O
Yield: 86.9 %

Procedure:
In a 300 cc 4-necked flask equipped with a stirrer, a thermometer and a dropping funnel were placed 80 ml of dimethylformamide. Then, 10.41 g (0.08 mol) of 5-fluorouracil was dissolved in the dimethylformamide and 24.29 g (0.24 mol) of triethylamine was added to this solution. To the mixture was added dropwise over 15 minutes 10.93 g (0.08 mol) of butyryloxymethyl chloride. The mixture was reacted together for 5 hours at room temperature and the reaction liquid was filtered to remove the precipitated triethylamine hydrochloride. The solvent was then distilled from the filtrate and the residue was subjected to a treatment using a column packed with silica gel and a mixture (1:1 in mixing ratio) of benzene and ethyl acetate whereby crude 1-butyryloxymethyl-5-fluorouracil was isolated. This crude product was recrystallized from benzene whereby 16.0 g of pure white crystals having a melting point of 96°~98° C. were obtained in a yield of 86.9%.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[C:8]([NH2:13])[CH:9]=[CH:10][C:11]=1[CH3:12].C([O:16][C:17]([C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[C@H:20]1[C:34]1[CH:39]=[CH:38][C:37]([NH:40][CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:36][CH:35]=1)=O)C>ClC(Cl)C.C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:17]([C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[C@H:20]2[C:34]2[CH:39]=[CH:38][C:37]([NH:40][CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)=[CH:36][CH:35]=2)=[O:16])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(N)cc1Cl
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2C)[C@H]1c1ccc(NC2CCCC2)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Cc1ccc(NC(=O)[C@H]2CCCN(C(=O)c3ccccc3C)[C@H]2c2ccc(NC3CCCC3)cc2)cc1Cl
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
Me3Al (290 μL, 0.57 mmol, 2M in toluene) was added to a solution of the 3-Chloro-4-methylphenylamine (65 mg, 0.46 mmol) in dry dichloroethane (1 mL) at ambient temperature. Stirred for 20 minutes, then (2R,3S)-2-(4-Cyclopentylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (100 mg, 0.23 mmol) dissolved in dry dichloroethane (1 mL) was added to it. The reaction mixture was then heated to 85° C. for 3 h, cooled to r.t, diluted with CH2Cl2 (20 mL), washed with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 (20 mL) and the combined organic layer was dried (MgSO4) and concentrated. The residue was purified by reverse phase preparative HPLC (20-95% gradient of CH3CN—H2O with 0.1% TFA as additive), the product containing fractions were pooled together and concentrated. The residue was diluted with CH2Cl2 (30 mL), washed with saturated aqueous NaHCO3 solution. The CH2Cl2 layer was dried (MgSO4) and concentrated to get the pure (2R,3S)-2-(4-Cyclopentylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid (3-chloro-4-methylphenyl)amide in 50% yield.
Reaction SMILES: [OH:1][C@H:2]([CH3:7])[CH2:3][C:4]([O-:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:60]=[CH:59][C:58]([N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)=[CH:57][CH:56]=3)[N:49]=2)=[CH:44][CH:43]=1>CN(C=O)C>[OH:1][C@H:2]([CH3:7])[CH2:3][C:4]([NH:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][N:51]=[C:50]([NH:54][C:55]3[CH:56]=[CH:57][C:58]([N:61]4[CH2:62][CH2:63][O:64][CH2:65][CH2:66]4)=[CH:59][CH:60]=3)[N:49]=2)=[CH:44][CH:43]=1)=[O:6]
Reactant: C[C@@H](O)CC(=O)[O-]
Reactant: Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CC(=O)Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of (R)-3-hydroxybutyrate (0.180 g, 1.73 mmol), HATU (0.602 g, 1.58 mmol), DIEA (1.0 mL, 5.4 mmol) in DMF (3.0 mL) was added and a solution of 4-(4-aminophenyl)-N-(4-morpholinophenyl)pyrimidin-2-amine (249(a)) (0.500 g, 1.44 mmol) in DMF (1.0 mL). The reaction mixture was stirred at room temperature for 2 hours, at which time it was quenched with saturated NaHCO3 (10 mL, aq.), extracted into DCM (3×), washed with brine (1×), and the organic layers were dried with sodium sulfate. The solution was concentrated and the product was purified by reverse phase HPLC to afford (R)-3-hydroxy-N-(4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)phenyl)butanamide (364) (0.129 g, 21% yield) as a light brown solid. 1H-NMR (400 MHz, DMSO)-d6: 10.14 (s, 1H), 9.38 (s, 1H), 8.44 (d, 1H), 8.12 (d, 2H), 7.77 (d, 2H), 7.68 (d, 2H), 7.27 (d, 1H), 6.94 (d, 2H), 4.79 (d, 1H), 4.11 (m, 1H), 3.74 (m, 4H), 3.05 (m, 4H), 2.47 (dd, 1H), 2.35 (dd, 1H), 1.15 (d, 3H); MS (EI) m/z for C24H28N5O3: 434.3 (MH+).
Reaction SMILES: [C:1]1([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:17]=[O:18]>CN(C=O)C>[OH:18][CH2:17][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:8]#[N:9]
Reactant: CCCCCC(C#N)c1ccccc1
Reactant: C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(C#N)(CO)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
5.14 g (27.4 mmol) of 2-phenylheptanenitrile are added to a suspension of 1.34 g of 60% NaH in 50 ml of DMF cooled to 0° C. After stirring for 30 minutes, 7.6 g (220 mmol) of paraformaldehyde are added portionwise. The reaction medium is left to stir at ambient temperature for 6 hours and then hydrolysed with ice and extracted with diethyl ether. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulphate, filtered and evaporated under pressure. The crude product obtained is purified by silica gel chromatography (eluent 8/2 heptane/ethyl acetate). 4.24 g in the form of a pale yellow oil are obtained with a yield of 71%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>C(O)(=O)C>[N:15]1[CH:16]=[CH:17][C:12]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:14]=1
Reactant: Clc1ccncc1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(Nc2ccncc2)cc1

Procedure:
4-(4-Pyridinylamino)benzoic acid was prepared from 76.6 g of 4-aminobenzoic acid and 63.5 g of 4-chloropyridine in 240 ml of acetic acid, heated at reflux for 6 hours. With a work-up procedure similar to that of Example 33, there was obtained 50 g of product with the m.p. 322°-324° C.(decompn.).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[CH3:15][C:16]1[CH:17]=[C:18]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:29]=[C:28]([C:36](O)=O)[N:27]=2)[CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23]>>[CH3:15][C:16]1[CH:17]=[C:18]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[N:29]=[C:28]([C:36]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=4)[N:14]=3)[N:27]=2)[CH:19]=[CH:20][C:21]=1[C:22]([F:23])([F:24])[F:25]
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(C(=O)O)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3nc(-c4cccc(S(N)(=O)=O)c4)no3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.14 g, 0.65 mmol) and 4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.9) (0.175 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.15 g, 57%). MS (ISN) 528.3 [(M−H)−]; mp 223.5° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=[O:12].[K+].[K+]>CS(C)=O>[C:8]([OH:10])(=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:12]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)Cc1ccccc1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)C(O)c1ccccc1
Temperature: 60 °C
Yield: 74 %

Procedure:
Phenyl acetic acid (1.82 Kg, 8.89 mol, 1.1 eq) and nitrile (1.62 Kg, 8.08 mol, 1.0 eq) were dissolved in DMSO (8 L) at 25° C. To this solution was added K2CO3 (2.46 Kg, 17.8 mol, 2.2 eq) in portions to control off gassing. The purple slurry was heated to 60° C. and aged overnight. Upon reaction completion the reaction mixture was inversely quenched in to a mixture of (16 L) of MTBE, (12.9 L) DI water and (3.5 L) methane sulfonic acid slowly. After mixing for 30 minutes the aqueous layer was removed and the organic layer was washed with 16 L of DI water and concentrated to dryness. MeOH (4 L) was added and the solution concentrated to dryness twice, until the residual MTBE was <5% by GC. To the product, MeOH (22 L) and 8.3 mL of methane sulfonic acid were charged, and the batch was heated to 63° C. over 15 hours, until 99% conversion. The reaction was cooled by ramping to 20° C. and the resulting suspension was filtered and washed with MeOH (2×3 L). The solid cake was dried under N2 to provide 74% yield with 101.8 wt % potency and 99.5 A % purity. Chloroisomer content was 2.16 A %. A second recrystallization using 23.6 L of MeOH and heating to 68° C. obtained the desired product in 67% with 100 wt % potency, 99.7 A % purity and 0.74 A % chloroisomer content. Recrystallization process was repeated until <0.5 A % of chloroisomer content was achieved.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH3:12][C:13]([CH3:39])([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:14][CH2:15][CH2:16][N:17]1[C:29]2[C:28]3[CH:27]=[CH:26][C:25]([Br:30])=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:19]=[C:18]1[CH2:31][O:32][CH2:33][CH3:34].[OH-].[NH4+:41].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH3:39][C:13]([CH3:12])([S:35]([NH2:38])(=[O:36])=[O:37])[CH2:14][CH2:15][CH2:16][N:17]1[C:29]2[C:28]3[CH:27]=[CH:26][C:25]([Br:30])=[CH:24][C:23]=3[N:22]=[C:21]([NH2:41])[C:20]=2[N:19]=[C:18]1[CH2:31][O:32][CH2:33][CH3:34]
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCC(C)(C)S(N)(=O)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCC(C)(C)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Chloroperoxybenzoic acid (0.126 g of 70% pure material, 0.73 mmol) was added in one portion to a stirred solution of dimethyl 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.30 g, 0.63 mmol) in chloroform (7 mL), and the solution was stirred for two hours at ambient temperature. Ammonium hydroxide (2 mL) and p-toluenesulfonyl chloride (0.15 g, 0.76 mmol) were sequentially added, and the mixture was stirred at ambient temperature for one hour. Dichloromethane (100 mL) was added, and the mixture was washed sequentially with 2 M aqueous sodium hydroxide (2×30 mL), saturated aqueous sodium bicarbonate (2×30 mL), and brine (30 mL); dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with ethyl acetate:ethanol in a gradient from 100:0 to 80:20) followed by recrystallization from dichloromethane:heptane. The crystals were dried for two hours under vacuum at 40° C. to provide 0.185 g of dimethyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide as a white solid, mp 193° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([O:23][CH2:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[C@@H:36]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37]1>>[CH2:24]([O:23][C:19]1[C:17]2[O:18][C@@H:13]([CH2:12][NH:41][C@H:38]3[CH2:39][CH2:40][C@@H:36]([C:30]4[C:29]5[C:33](=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=5)[NH:32][CH:31]=4)[CH2:37]3)[CH2:14][O:15][C:16]=2[CH:22]=[CH:21][CH:20]=1)[CH3:25]
Reactant: N[C@H]1CC[C@@H](c2c[nH]c3ccc(F)cc23)C1
Reactant: CCOc1cccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Product: CCOc1cccc2c1O[C@@H](CN[C@H]1CC[C@@H](c3c[nH]c4ccc(F)cc34)C1)CO2
Yield: 57.3 %

Procedure:
This compound was prepared in the same manner as for Example 1, using [(2R)-8-ethoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl]methyl 4-methylbenzenesulfonate (0.25 g, 0.68 mmol) and cis-3-(5-fluoro-1H-indol-3-yl)-cyclopentylamine (0.3 g, 1.38 mmol), to afford 0.16 g (64%) of the title compound as its hydrochloride salt: MS (ESI) m/z 411 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[CH2:11]=O>O.[Pd]>[CH3:11][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCNCC1
Reactant: C=O
Agent: [Pd]
Solvent: O
Product: CN1CCC(CC(=O)O)CC1

Procedure:
4-Piperidinylacetic acid (4 grams) (28.0 mmoles) from Preparative Example 17A was dissolved in water (50 ml) and 37% formalin (2.72 ml) (33.6 mmoles) was added. The mixture was hydrogenated over 10% Pd—C at 55 psi at 25° C. for 68 hours. The catalyst was filtered off and washed with water. The combined filtrates were evaporated to dryness to give the title compound (MH+158).
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])[CH3:5])=[N+]=[N-].[H][H]>CO.[C].[Pd]>[C:7]1([CH3:12])[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH:4]([NH2:1])[CH3:5]
Reactant: [H][H]
Reactant: Cc1ccccc1C(C)N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccccc1C(C)N
Yield: 77.2 %

Procedure:
10% palladium-carbon (water content: 50%, 50 mg) was added to a solution of 1-(1-azidoethyl)-2-methylbenzene (744 mg) in methanol (5 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure to obtain 482 mg of the title compound. The physical properties of the compound are as follows.