Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[CH:26]=2)=[CH:18][CH:17]=1.[CH3:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([CH3:41])[CH:40]=1)[C:35](Cl)=[O:36]>O>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[C:26]=2[C:35](=[O:36])[C:34]2[CH:38]=[C:39]([CH3:41])[CH:40]=[C:32]([CH3:31])[CH:33]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: COc1ccc(-c2oc3ccccc3c2C(=O)c2cc(C)cc(C)c2)cc1
Reaction time: 0.2 h

Procedure:
To a cooled (0°) solution of 14.0 g. (0.105 mol.) of aluminum chloride in 100 ml. of nitrobenzene was added 11.2 g. (0.05 mol.) of 2-p-methoxyphenylbenzofuran followed immediately by 10.0 g. (0.06 mol.) of 3,5-dimethylbenzoyl chloride. The reaction mixture was stirred at 0° for 12 minutes (until the red color began to turn reddish-brown) then poured into water. The aqueous mixture was steam distilled to remove nitrobenzene and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with aqueous sodium carbonate and saturated sodium chloride solution, dried (MgSO4) and concentrated at reduced pressure to give a residue which was purified by column chromatography to give 2-p-methoxyphenyl-3-(3',5'-dimethylbenzoyl)benzofuran which was then crystallized from ethanol.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1.[F:30][C:31]([F:37])([F:36])[CH:32]=[CH:33][C:34]#[N:35]>>[C:34]([CH2:33][CH:32]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][N:9]3[C:12]([C:15]4[CH:16]=[C:17]([NH:21][C:22]([NH:24][CH2:25][C:26]([F:28])([F:27])[F:29])=[O:23])[CH:18]=[CH:19][CH:20]=4)=[CH:13][N:14]=[C:8]3[CH:7]=2)[CH:3]=[N:2]1)[C:31]([F:37])([F:36])[F:30])#[N:35]
Reactant: N#CC=CC(F)(F)F
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cn[nH]c4)cnn23)c1
Product: N#CCC(n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1)C(F)(F)F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 89, Step 2 starting from N-{3-[7-(1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 4,4,4-trifluorobut-2-enenitrile. LCMS (M+H)+: m/z=523.1.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5].[CH3:20][Mg]Br.Cl>O1CCCC1>[C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)(=[O:5])[CH3:20]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 77.9 %

Procedure:
To a solution of tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (4.0 g, 14.69 mmol) in tetrahydrofuran (50 mL) was added methylmagnesium bromide solution (5.25 g, 44.06 mmol, 3M) at −70° C. over 0.5 hour. The resultant mixture was stirred at room temperature for 6 hours. The reaction solution was adjusted pH to 6.0 by 1.0M hydrochloride solution. The aqueous phase was extracted with ethyl acetate (100 ml*3). The combined organic layers was washed with brine, dried over sodium sulfate and concentrated under vacuum to give tert-butyl 4-acetylpiperidine-1-carboxylate as a yellow liquid (2.6 g, yield 77.8%). LRMS (M+H+) m/z: calcd 227.15. found 228.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][C:5]=1[CH2:21][CH2:22][OH:23])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[CH2:21][CH2:22][O:23][C:33](=[O:34])[NH:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(OCC)c(CCO)c1)OC(C)C
Reactant: COc1ccc(N=C=O)cc1
Product: CCOc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccc(OC)cc1

Procedure:
Using ethyl 3-[4-ethoxy-3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[N:3]=[C:2]1[NH2:9].[CH3:10][C:11]1([CH3:19])[C:13]([CH3:15])([CH3:14])[CH:12]1[C:16](O)=[O:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1>[S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[N:3]=[C:2]1[NH:9][C:16]([CH:12]1[C:13]([CH3:15])([CH3:14])[C:11]1([CH3:19])[CH3:10])=[O:17]
Reactant: Nc1nc2c(s1)CCC2
Reactant: CC1(C)C(C(=O)O)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)C(C(=O)Nc2nc3c(s2)CCC3)C1(C)C

Procedure:
A mixture of 5,6-dihydro-4H-cyclopentathiazole-2-ylamine (177 mg, 1.26 mmol), 2,2,3,3-tetramethylcyclopropanecarboxylic acid (244 mg, 1.52 mmol), 4-dimethylaminopyridine (50.0 mg, 0.41 mmol) and triethylamine (351 μL, 2.52 mmol) in 20 mL of THF was processed according to the method of Example 118A to provide the title compound: MS (DCI/NH3) m/z 265 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[O:20][CH3:21]>>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[O:5])[C:16]([CH3:19])=[CH:15][C:14]=1[O:20][CH3:21]
Reactant: Cc1ccccc1C(=O)O
Reactant: COc1ccc(C)cc1OC
Product: COc1cc(C)c(C(=O)c2ccccc2C)cc1OC

Procedure:
By the reaction of 13.6 g (0.1 mol) of 2-methylbenzoic acid with 15.2 g (0.1 mol) of 1,2-dimethoxy-4-methylbenzene, analogously to Example 3(a), there is obtained (3,4-dimethoxy-6-methylphenyl)-(2-methylphenyl)-methanone as a brown resin-like product.
Reaction SMILES: CO.O=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>CCCCCCC>[C:15]1([C@@H:21]([NH:23][C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)C1CCCCC1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CO
Solvent: CCCCCCC
Product: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1

Procedure:
In an additional embodiment, (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) is produced from a starting material comprising ethyl 2-oxocyclohexane carboxylate (6). This embodiment comprises reacting ethyl 2-oxocyclohexane carboxylate (6) with (S)-(−)-1-phenylethylamine (7) in the presence of a catalyst, ytterbium trifluoromethanesulfonate, and heptane to produce (S)-Ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8). The next step is reduction of the amine (8) with sodium acetoxyborohydride in the presence of a acetonitrile produce (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (9), as illustrated in FIG. 1. The production of the cis-cyclohexane derivative (9) is followed by epimerization of the chiral center adjacent to the ethyl ester functionality using sodium t-butoxide to afford trans-cyclohexane derivative (10) as a major diastereomer. Reduction of the ester functionality in compound (10), using lithium borohydride yields (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) in good overall yield, which is subsequently purified by chromatography.
Reaction SMILES: O.[NH:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([C:10]([OH:12])=O)=[N:3]1.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:4]3[NH:3][N:2]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=3)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(=O)O)n[nH]1
Yield: 1.9 %

Procedure:
The title compound was prepared using the method of Example 54 but starting from 3,5-pyrazoledicarboxylic acid monohydrate (0.60 g; 3.84 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.0 g; 3.84 mmol). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-100% MeOH/DCM) to obtain 29 mg (36%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.14 (s, 3H), 4.30-4.50 (m, 3H), 6.93 (d, 1H), 7.83 (s, 1H), 7.85-8.05 (m, 2H), 8.04 (s, 1H), 8.35-8.65 (m, 1H), 14.06 (s, 1H), 14.24 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[S:9][CH2:10][C:11](=[O:13])[N:12]=1.[N:14]1[C:23]2[C:18](=[N:19][C:20]([CH:24]=O)=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[N:19]1[C:18]2[C:23](=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:22]=[CH:21][C:20]=1[CH:24]=[C:10]1[S:9][C:8]([NH:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:12][C:11]1=[O:13]
Reactant: O=Cc1ccc2ncccc2n1
Reactant: O=C1CSC(NCc2cccs2)=N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1N=C(NCc2cccs2)SC1=Cc1ccc2ncccc2n1
Temperature: 120 °C
Yield: 34.9 %

Procedure:
To a suspension of 2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one (34.0 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 120° C. with microwave for 5 min, then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 5-[1,5]naphthyridin-2-ylmethylene-2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one as a light brown solid (19.7 mg, 34.9%). HR-ES (+) m/e calcd. for C17H12N4OS2: (M+H)+ 353.0526. Found: 353.0526.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[O:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=2[N:3]=1.[ClH:40]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:40].[ClH:40].[ClH:40].[CH3:1][C:2]1[N:6]([CH:7]2[CH2:8][C@H:9]3[N:14]([CH2:15][CH2:16][C:17]4([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)[C@H:12]([CH2:11][CH2:10]3)[CH2:13]2)[C:5]2[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CN(C(=O)OC(C)(C)C)CCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CNCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 2-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholine-4-carboxylate (330 mg, 0.62 mmol) in 5 mL CHCl3 was added 0.8 mL of a solution of 4N HCl in dioxane. After stirring at room temperature for 2 h, another 3 mL 4N HCl in dioxane was added and the mixture was heated at 40° C. for 90 min. The solution was then evaporated and dried in vacuo to provide 2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole trihydrochloride, which was used without further purification. ESI-MS 431 (M+H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1.[Cl:14][C:15]1[N:16]=[N:17][C:18](Cl)=[C:19]([CH3:22])[C:20]=1[CH3:21]>CN(C=O)C>[Cl:14][C:15]1[N:16]=[N:17][C:18]([N:12]2[CH2:11][CH2:10][NH:9][C@H:8]([CH3:7])[CH2:13]2)=[C:19]([CH3:22])[C:20]=1[CH3:21]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)nnc(N2CCN[C@H](C)C2)c1C
Temperature: 60 °C
Reaction time: 48 h
Yield: 48.8 %

Procedure:
Solid K2CO3 (10 g, 72.4 mmol, 1.8 eq) is added to a solution of (R)-2-methyl-piperazine (4.00 g, 40 mmol, 1 eq) and 3,6-dichloro-4,5-dimethyl-pyridazine (8 g, 45.2 mml, 1.1 eq) in DMF (50 mL), and the resulting solution is stirred at 60° C. for 48 h. The reaction mixture is concentrated to ½ volume under reduced pressure and the minimum water (ca. 15 mL) required to dissolve the solid salts is added, followed by the addition of dichloromethane (100 mL). The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure, then purified by silica gel column chromatography (2%-20% MeOH/CH2Cl2) to yield the desired compound as a white solid (4.7 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[I:13]Cl.O>C(O)(=O)C.II>[I:13][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: COc1cccc(CC(=O)O)c1
Reactant: ClI
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(I)c(CC(=O)O)c1
Yield: 64.7 %

Procedure:
A solution of 45 g (0.27 mole) of 3-methoxybenzeneacetic acid, 52.6 g (0.32 mole) of iodine monochloride and 1 g of iodine was allowed to stand in 500 ml of glacial acetic acid for six days at room temperature. The reaction was poured into water and the solid collected. It was recrystallized from toluene to give 51 g of crystalline 2-iodo-5-methoxybenzeneacetic acid, mp 133.5°-134.5° C. (65% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13]([C:15]3([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O.CO>[Zn].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13]([C:15]3([OH:21])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[N:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1
Temperature: 50 °C

Procedure:
To a solution of Example 7A (0.106 g, 0.344 mmol) in a solvent mixture of methanol (2 mL) and acetic acid (2 mL) was added Zn powder (0.067 g, 1.03 mmol). The reaction was heated to 50° C. for 5 h, and was then cooled to room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3 (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×5 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound which was used without further purification. MS (ESI) m/z 278 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[N:2]1.[F:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])=[CH:19][CH:18]=[C:17]([F:28])[C:13]=1[C:14](O)=[O:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[F:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:23])=[O:24])=[CH:19][CH:18]=[C:17]([F:28])[C:13]=1[C:14]([NH:10][C:8]1[CH:9]=[C:4]2[CH:3]=[N:2][NH:1][C:5]2=[N:6][CH:7]=1)=[O:15]
Reactant: Nc1cnc2[nH]ncc2c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ncc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 599.5 %

Procedure:
1H-Pyrazolo[3,4-b]pyridin-5-amine (0.036 g, 0.027 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.075 g, 0.27 mmol), EDCI (0.056 g, 0.30 mmol) and HOBt (0.040 g, 0.30 mmol) were dissolved in DMF (8 mL) and stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (200 mL), and the organic layers were washed with water (3×30 mL). The organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (1:1) to give 2,6-difluoro-3-(propylsulfonamido)-N-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (0.064 g, 60%) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.7 (s, 1H), 8.6 (s, 1H), 8.1 (s, 1H), 7.7 (m, 1H), 7.1 (m, 1H), 3.1 (m, 2H), 1.9 (m, 2H), 1.1 (t, J=7.6 Hz, 3H); m/z (APCI-neg) M−1=394.2.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([C:7]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13][CH2:12]2)([C:9]#N)[CH3:8])=[CH:3][CH:2]=1.C[Mg]Br.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:2]=[CH:3][C:4]([C:7]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13][CH2:12]2)([CH3:8])[CH3:9])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(C(C)(C#N)c2ccc(-c3ccccc3)cc2)CC1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CCN(C(C)(C)c2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
To a solution of the compound prepared in Example 363 (0.112 g) in tetrahydrofuran (3 mL) at 0° C. was added a 3.0 M solution of methylmagnesium bromide in diethyl ether (0.27 mL), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured onto cold saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexanes:triethylamine=80:20:1) to obtain the title compound (0.035 g) having the following physical data.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=1.C(N(CC)CC)C.[NH2:29][C:30]1[C:38]([CH3:39])=[CH:37][C:36]([Cl:40])=[CH:35][C:31]=1[C:32](O)=[O:33]>C(#N)C>[Cl:40][C:36]1[CH:37]=[C:38]([CH3:39])[C:30]2[N:29]=[C:12]([C:10]3[N:9]([C:15]4[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=4)[N:8]=[C:7]([Cl:6])[CH:11]=3)[O:14][C:32](=[O:33])[C:31]=2[CH:35]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
To a solution of methanesulfonyl chloride (6.96 g, 61.06 mmol) in acetonitrile (150 mL) was added dropwise a mixture of the carboxylic acid product from Step D (15.0 g, 58.16 mmol) and triethylamine (5.88 g, 58.16 mmol) in acetonitrile (150 mL) at −5° C. The reaction mixture was then stirred for 30 minutes at 0° C. Then, 2-amino-3-methyl-5-chlorobenzoic acid from Example 6, Step A (10.79 g, 58.16 mmol) was added, and stirring was continued for an additional 10 minutes. A solution of triethylamine (11.77 g, 116.5 mmol) in acetonitrile was then added dropwise while keeping the temperature below 10° C. The reaction mixture was stirred 60 minutes at 0° C., and then methanesulfonyl chloride (6.96 g, 61.06 mmol) was added. The reaction mixture was then warmed to room temperature and stirred for an additional 2 hours. The reaction mixture was then concentrated, and the crude product was chromatographed on silica gel using methylene chloride as eluent to afford the title product as a yellow solid (9.1 g).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].[Br:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:27]>C(O)CCC.ClCCl>[Br:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[N:27]1[CH2:8][CH2:7][N:5]([CH3:6])[CH2:4][CH2:3]1
Reactant: Nc1cccc2cc(Br)cnc12
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Solvent: ClCCl
Product: CN1CCN(c2cccc3cc(Br)cnc23)CC1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
bis-(2-Chloro-ethyl)-methyl-amine hydrochloride (3.7 g, 19.2 mmol) and sodium carbonate (9.0 g, 85 mmol) were added to a suspension of 3-bromo-quinolin-8-ylamine (3.9 g, 17.5 mmol) (for synthesis see Gershon et al., Monatsh. Chem., 1991, 122, 935) in n-butanol (70 ml). The stirred suspension was heated at reflux for 72 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (300 ml) and the solution washed with water (300 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane to afford the title compound (Dl) as an oil (2.6 g, 8.5 mmol, 49%);
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH:16]([C:18]1[CH:19]=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH2:17].[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:17][CH2:16][C:18]3[CH:19]=[N:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cnc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cnc3ccccc3c2)C1

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, 3-vinylquinoline and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:12]([C:22](=[O:30])[NH:23][C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH:16]([O:19]C=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:13][CH:14]2[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]2)[C:22]([NH:23][C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[O:30])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(OC=O)C2)C(=O)Nc2cnccn2)cc1Cl
Agent: N
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(O)C2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.9 %

Procedure:
To a solution of formic acid 3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-2-(pyrazin-2-ylcarbamoyl)-ethyl]-cyclopentyl ester (375 mg, 0.83 mmol) in methanol (50 mL) at 0° C. was bubbled ammonia gas for 15 min. The resulting reaction solution was stirred at 0° C. for 15 min. The solvent was removed in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 1–5% methanol/methylene chloride) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-hydroxy-cyclopentyl)-N-pyrazin-2-yl-propionamide (260 mg, 62.5%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(OC(=O)C)(=O)C>[C:8]([N:6]1[C:2]([CH3:1])=[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:4]([C:11](=[O:10])[CH3:12])[C:5]1=[O:7])(=[O:9])[CH3:3]
Reactant: CCOC(=O)c1[nH]c(=O)[nH]c1C
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(C)n(C(C)=O)c(=O)n1C(C)=O

Procedure:
A mixture of 54.5 g of ethyl 2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate and 240 ml of acetic anhydride is refluxed for 13 hours. The mixture is distilled to remove 150 ml of acetic anhydride and acetic acid; this is replaced by fresh acetic anhydride and refluxing is resumed. After a total of 22 hours of reflux, excess acetic anhydride is evaporated under reduced pressure and the resulting residue is triturated with cyclohexane and then recrystallized from cyclohexane to give ethyl 1,3-diacetyl-2,3-dihydro-5-methyl-2-oxo-1H-imidazole-4-carboxylate melting at about 56°-58° C.