Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:9])[CH:4]=[C:5]([NH2:8])OC.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:14][NH:15][NH2:16]>O1CCOCC1>[NH2:8][C:5]1[NH:16][N:15]([CH2:14][C:13]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:11]([Cl:10])[CH:12]=2)[C:3](=[O:9])[CH:4]=1
Reactant: NNCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C=C(N)OC
Solvent: C1COCCO1
Product: Nc1cc(=O)n(Cc2ccc(Cl)c(Cl)c2)[nH]1
Reaction time: 2 h

Procedure:
144 g (10% excess) of β-amino-β-methoxyacrylic acid methyl ester are introduced into 500 ml of dioxane. 191 g of 3,4-dichlorobenzylhydrazine are introduced into the reaction mixture while flushing with nitrogen. The mixture is stirred for 2 hours at 60°, the solvent is driven off on a rotary evaporator, the residue is worked with 600 ml of 2 N NaOH and extracted with ether, and the aqueous phase is stirred with animal charcoal for one-half hour. After filtration, the mixture is adjusted to pH 5 with dilute acetic acid. The product which initially is obtained as an oil becomes crystalline on rubbing and is finally purified by recrystallising it again from alcohol. 139 g, corresponding to about 54% of theory, of the compound identified above, as felted colorless needles of melting point 159° are obtained.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH:37]2[CH2:42][CH2:41][N:40]([C:43]3[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=3)[CH2:39][CH2:38]2)[CH2:33][CH2:32]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:49][C:46]3[CH:47]=[CH:48][C:43]([N:40]4[CH2:41][CH2:42][CH:37]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[CH2:38][CH2:39]4)=[CH:44][CH:45]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: CN1CCN(C2CCN(c3ccc(N)cc3)CC2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCC(N5CCN(C)CC5)CC4)cc3)nn12
Yield: 76.2 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 4-[4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamine (0.239 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 164.97 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-{4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine as a lyophilized powder. (M+H)=498.9. 1H NMR (400 MHz, DMSO, d6) δ 9.42 (s, 1H), 8.94 (s, 1H), 7.80 (dd, 1H, J=1.60, 6.00 Hz), 7.69 (d, 2H, J=8.93 Hz), 7.46 (m, 1H), 7.20 (d, 1H, J=8.28 Hz), 7.13 (m, 3H), 6.94 (m, 2H), 3.70 (s, 3H), 3.67 (m, 7H), 3.01 (m, 6H), 2.83 (s, 3H), 2.07 (m, 2H), 1.79 (m, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1([S:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([NH2:71])[CH:66]=2)(=[O:58])=[O:57])[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN(C=O)C>[N:50]1([S:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([NH:71][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:66]=2)(=[O:58])=[O:57])[CH2:51][CH2:52][O:53][CH2:54][CH2:55]1
Reactant: Nc1cccc(-c2ccccc2S(=O)(=O)N2CCOCC2)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccccc4S(=O)(=O)N4CCOCC4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 73.6 %

Procedure:
DIEA (0.009 mL, 0.052 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.010 g, 0.047 mmol) and HATU (0.020 g, 0.052 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-(Morpholine-4-sulfonyl)-biphenyl-3-ylamine (0.015 g, 0.047 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 73% yield: LCMS (ESI) m/z 521 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=4)=[N:15][N:14]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:33](=[O:37])[N:34]([CH3:36])[CH3:35].[N:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[Cl:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:44]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[O:45])=[C:3]([C:33](=[O:37])[N:34]([CH3:36])[CH3:35])[CH:4]=3)[CH:9]=2)[N:14]([CH2:25][O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[N:15]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(Cc2cccc(Cl)c2)nn3COC(=O)C(C)(C)C)ccc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(-c2cnc3c(c2)c(Cc2cccc(Cl)c2)nn3COC(=O)C(C)(C)C)ccc1NC(=O)N1CCOCC1
Reaction time: 48 h
Yield: 49.3 %

Procedure:
2,2-Dimethyl-propionic acid 5-(4-amino-3-dimethylcarbamoyl-phenyl)-3-(3-chloro-benzyl)-pyrazolo[3,4-b]pyridin-1-ylmethyl ester (300 mg, 0.577 mmol), chloroform (50 ml), 4-morpholinecarbonyl chloride (1.2 ml, 10.45 mmol), and di-iso-propyl ethyl amine (2.4 ml, 13.78 mmol) were combined and stirred for 48 hours at 50 oC. The reaction was quenched with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (0 to 100% [10% methanol in ethyl acetate] in hexanes) to give 180 mg (49%) of 2,2-dimethyl-propionic acid 3-(3-chloro-benzyl)-5-{3-dimethylcarbamoyl-4-[(morpholine-4-carbonyl)-amino]-phenyl}-pyrazolo[3,4-b]pyridin-1-ylmethyl ester. MS: m/z 633.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)[CH:16]=[CH:17]3)=[C:12]([C:31](=[O:37])[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:11]=2[CH2:38][C:39]([CH3:46])([CH3:45])[C:40]([O:42]CC)=[O:41])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[C:15]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)[CH:16]=[CH:17]3)=[C:12]([C:31](=[O:37])[CH2:32][C:33]([CH3:35])([CH3:36])[CH3:34])[C:11]=2[CH2:38][C:39]([CH3:46])([CH3:45])[C:40]([OH:42])=[O:41])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)CC(C)(C)C)c2cc(OCc3ccc4ccccc4n3)ccn2c1C(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)c1c(CC(C)(C)C(=O)O)c(C(=O)c2ccc(Cl)cc2)n2ccc(OCc3ccc4ccccc4n3)cc12
Temperature: 23 °C
Yield: 21.8 %

Procedure:
A solution of ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(3,3-dimethylbutanoyl)-7-(quinolin-2-ylmethoxy)indolizin-2-yl}-2,2-dimethylpropanoate (39 mg, 0.06 mmol) in THF (1 mL), MeOH (1 mL), and 6M aqueous NaOH (1 mL) is heated at 70° C. for 2.5 h then cooled to 23° C. and acidified to pH=1 with 6 M aqueous HCl. The mixture is partitioned between CH2Cl2 and brine then the organics are collected and dried with MgSO4, filtered, and concentrated in vacuo. The crude is purified by flash chromatography (SiO2, CH2Cl2 to 10% MeOH in CH2Cl2) to give the title compound (8 mg, 22%).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29]Cl)[C:24]=1[CH3:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CO.C(OCC)(=O)C>[CH2:14]([O:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:24]=1[CH3:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCCCCCCOc1ccnc(CCl)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 32.2 %

Procedure:
To a liquid prepared by dissolving with stirring 6.7 g (0.045 mol, 0.95 eq.) of 2-mercaptobenzimidazole and 52.5 g (0.273 mol, 5.8 eq.) of a 28% sodium methoxide solution in 350 mL of methanol, a liquid prepared by dissolving the whole amount of 4-octyloxy-2-chloromethyl-3-methylpyridine in 180 mL of methanol was added at 27° C. Subsequently, the mixture was heated to reflux for one hour and cooled, and then methanol was solid dried under reduced pressure. A brown oily residue resulting therefrom was dissolved in 250 mL of ethyl acetate, and then the organic layer was washed with 100 mL of water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated to dryness. The resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 14.9 g of an orange-colored oily matter. The orange-colored oily matter was recrystallized from ethyl acetate (5 vol.), to obtain 5.8 g of colorless crystals (HPLC: 98.8 Area %, yield 32.2%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[SH-:12].[K+].O>C(O)C>[SH:12][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1
Reactant: [SH-]
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc2ccc(S)nn12

Procedure:
A mixture of 6-chloro-2,3-dihydro-s-triazolo[4,3-b]-pyridazin-3-one [P. Francavilla and F. Lauria, J. Het. Chem., 8, 415 (1971) ] (1.70 g., 0.01 mole) and potassium hydrosulfide (1.44 g., 0.02 mole) in ethanol (30 ml.) was heated in a sealed tube for 8 hours at 140°. After cooling, water (50 ml.) was added to the reaction mixture and a small amount of insoluble material was removed by filtration. The filtrate being concentrated under reduced pressure, the concentrate was acidified to pH 2 with dil. HCl to afford yellow precipitate of 6-mercapto-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-one which was collected by filtration, washed with water (10 ml.) and dried in vacuo on P2O5. Yield 1.43 g. (84%). M.p. > 300° C.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.CN(C(O[N:37]1N=N[C:39]2[CH:40]=[CH:41]C=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.ON=C(C1CC1)N>CN(C)C=O>[CH:39]1([C:38]2[N:43]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][S:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:27][N:37]=2)[CH2:41][CH2:40]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(=NO)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N1CCSCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Alternative Synthesis: 600 mg (1.43 mmol) of the compound from Example 25A in dimethylformamide (29.0 ml) were admixed at RT with 654 mg (1.72 mmol) of HATU and 0.55 ml (498 mg, 3.16 mmol) of N,N-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, 158 mg (1.58 mmol) of N′-hydroxycyclopropanecarboximidamide were added and the mixture was stirred at RT overnight. The reaction solution was heated to 120° C. and stirred at this temperature for 1 h. The reaction solution was subsequently purified directly by means of preparative HPLC. Yield: 315 mg (45% of theory)
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.Cl.Cl[CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:1][C:2]1[N:3]([CH2:19][C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Reactant: Cc1cccnc1CCl
Agent: Cl
Product: Cc1cccnc1Cn1cc(C#Cc2cccc(C#N)c2)nc1C

Procedure:
The title compound, MS: m/e=313.2 (M+H30), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-chloromethyl-3-methyl-pyridine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]([OH:20])=[O:19])[CH2:16][CH:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Si](C=[N+]=[N-])(C)C>CO.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([O:20][CH3:22])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2=CC(O)=CCC2CC1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1Cc2ccc(O)cc2CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2-(t-Butyloxycarbonyl)-7-hydroxy-tetrahydro-isoquinoline-3-carboxylic acid (0.5 g, 1.71 mmol) was dissolved in 10% MeOH/CHCl3 (70 mL). The solution was cooled to 0° C. and trimethylsilyldiazomethane (2 M in hexane) (1.88 mL, 3.76 mmol) was added dropwise via syringe. A yellow color persisted after addittion of 1.2 mL of this reagent. The cooling bath was removed and the solution was stirred at 25° C. for 0.75 hr. The reaction was cooled to 0° C. and acetic acid was added dropwise until the yellow color disappeared. The solvent was evaporated in vacuo and the residue was partitioned between EtOAc (50 mL) and saturated NaHCO3 solution (30 mL). The organic layer was washed with saturated NaCl solution (30 mL) and dried (MgSO4). Filtration and evaporation in the title compound which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.[CH2:23]([O:25][CH:26](OCC)[O:27][CH2:28][CH3:29])[CH3:24]>>[CH2:23]([O:25][CH:26]([O:27][CH2:28][CH3:29])[N:5]1[C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]=2[C:2]([CH3:22])([CH3:1])[O:7][C:6]1=[O:8])[CH3:24]
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Reactant: CCOC(OCC)OCC
Product: CCOC(OCC)N1C(=O)OC(C)(C)c2cc(-c3cc(F)cc(C#N)c3)ccc21
Temperature: 160 °C
Yield: 33 %

Procedure:
A mixture of 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6yl)-5-fluoro-benzonitrile (0.25 g, 0.84 mmol) and triethylorthoformate (50 mL) was heated at 160° C. for 12 hours. The excess triethylorthoformate was removed in vacuo and purification via chromatography (silica gel, 20% ethyl acetate/hexane) gave 3-(1-diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile (0.116 g, 33%) as a white solid: mp 123-124° C.; 1H-NMR (DMSO-d6) δ 7.97 (d, 1H, J=8.68 Hz), 7.66 (bs, 1H), 7.53-7.44 (m, 2H), 7.35-7.32 (m, 2H), 6.65 (s, 1H), 3.88-3.78 (m, 2H), 3.73-3.61 (m, 2H), 1.77 (s, 6H), 1.27 (t, 6H), J=7.05 Hz); MS (ESI) m/z 295 ([M−H]−, 100%, lower MW ion consistent with loss of diethyl acetal); Anal. Calc. For C21H23FN2O4: C, 66.32; H, 5.82; N, 7.03. Found: C, 65.89; H, 5.92; N, 6.66.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:13]Br.Cl>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:13][C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][CH:1]2[C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: O=C(O)C1CCc2ccccc21
Reactant: BrBr
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(O)C1CCc2ccc(Br)cc21
Reaction time: 3 h

Procedure:
By following the procedure of Tetsuya, et al. referenced in part A, the 6-bromo compound can be obtained. For example, to a stirred, ice-cooled mixture of 8.1 g (50 mmol) indane-1-carboxylic acid and 8.1 g of FeCl3 in 300 ml of CCl4 is added dropwise a solution of 8.8 g of Br2 in 100 ml methylene chloride over a 1 hour period. The mixture is stirred for 3 hours under cooling and then for 1.5 hours at room temperature. The mixture is poured into 500 ml of dilute HCl and extracted with CHCl3. The extract is washed with water, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue is crystallized from hexane to give 6-bromo-indane-1-carboxylic acid.
Reaction SMILES: N1C=CC=CC=1.[C:7]([OH:16])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[C:7]([OH:16])=[O:15])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccccc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
Pyridine (64 μl, 0.80 mmol) was added to an ice cooled mixture of salicylic acid (10 mg, 0.72 mmol) and methylene chloride (10 mL). After 5 minutes, acetic anhydride (10 μl, 1.09 mmoles) was added. The resulting mixture was stirred at room temperature for 4 hrs. The product was extracted with methylene chloride and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 2-acetoxybenzoic acid in 76% yield.
Reaction SMILES: O.FC1C=CC(C2NN=C(C(N3CCNCC3)=O)C=2C2C=CN=CC=2)=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[NH:39][N:38]=[C:37]([CH2:40][CH:41]3[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]3)[C:36]=2[C:54]2[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:36]([C:54]3[CH:55]=[CH:56][N:57]=[CH:58][CH:59]=3)=[C:37]([CH2:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[NH:38][N:39]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2n[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CC1
Agent: O=C(c1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1)N1CCNCC1
Solvent: O
Product: Fc1ccc(-c2n[nH]c(CC3CCNCC3)c2-c2ccncc2)cc1

Procedure:
4-[3-(4-Fluorophenyl)-5-(4-piperidinylmethyl)-1H-pyrazol-4-yl]pyridine was prepared using the same method as described for Example A-314, step 1 by replacing 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine, monohydrate with the pyrazole of step 5 of the present Example. Anal. Calc'd for C20H21N4F.2TFA.1.25H2O: C, 49.11; H, 4.38; N. 9.54; Found: C, 48.74; H, 4.02; N, 9.57. MS (MH+): 337 (base peak)
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[Br:13]N1C(=O)CCC1=O.O>C(#N)C.[Fe](Cl)(Cl)Cl>[Br:13][C:5]1[CH:4]=[C:3]([C:9]([F:12])([F:10])[F:11])[C:2]([NH2:1])=[C:7]([F:8])[CH:6]=1
Reactant: Nc1c(F)cccc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CC#N
Product: Nc1c(F)cc(Br)cc1C(F)(F)F
Yield: 96.9 %

Procedure:
To a solution of 2-amino-3-fluorobenzotrifluoride (0.7 ml, 5.6 mmol) in acetonitrile (2 ml) was added N-bromosuccinimide (994 mg, 5.6 mmol), followed by iron (III) chloride (90.1 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 90 min, before addition of water (20 ml). The mixture was extracted with tert-butyl methyl ether (2×15 ml) and the combined extracts were washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo to give the title compound (1.4 g), which was used directly.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]([CH3:16])[CH3:15])=[S:13])=[CH:7][CH:6]=1)=[O:2].[C:17](NNC1C=CC(N)=CC=1)(=O)C.CN(C)C(Cl)=S.C(N(CC)C(C)C)(C)C>>[C:1]([NH:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:14]([CH3:16])[CH3:15])=[S:13])=[CH:9][CH:10]=1)(=[O:2])[CH3:17]
Reactant: CN(C)C(=S)Nc1ccc(NNC=O)cc1
Reactant: CC(=O)NNc1ccc(N)cc1
Agent: CN(C)C(=S)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NNc1ccc(NC(=S)N(C)C)cc1

Procedure:
The procedure for the preparation of NA-1 in Example 1 was followed with 1-acetyl-2-(4-aminophenyl)hydrazine (0.82 g, 0.005 mole), dimethylthiocarbamoyl chloride (0.62 g, 0.005 mole) and N,N-diisopropylethylamine (0.65 g, 0.005 mole). Yield 0.30 g (24 percent), m.p. 187°-189° C.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]([CH2:11][NH:12][CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[CH3:13][NH:12][CH2:11][CH:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)[C:10]=2[O:9]1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CNCC1Cc2cccc(Br)c2O1
Product: CNCC1Cc2cccc(-c3ccc(Cl)cc3)c2O1

Procedure:
The title compound was prepared (0.037 g, 16%) following the general procedure of Example 154 as a white solid, hydrochloride salt from (±)-[(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl]methylamine (0.200 g, 0.826 mmol) and 4-chlorophenylboronic acid (0.193 g, 1.24 mmol). mp 227-230° C.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:19]1[S:20][CH:21]=[CH:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>C(OCC)(=O)C.[Cu]>[CH:1](/[C:9]1[N:10]([C:19]2[S:20][CH:21]=[CH:22][N:23]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Brc1nccs1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOC(C)=O
Product: C(=C/c1nc2ccccc2n1-c1nccs1)\c1ccccc1
Yield: 65.6 %

Procedure:
A stirred mixture of 2-styryl-1H-benzimidazole (220 mg, 1 mmol), 2-bromothiazole (328 mg, 2 mmol), potassium carbonate (138 mg, 1 mmol), copper bronze (20 mg) and nitrobenzene (10 ml) was heated to reflux under a nitrogen atmosphere for 7 h. The cooled reaction mixture was diluted with ethyl acetate (150 ml) and filtered through a pad of celite. The filtrate was washed consecutively with water (50 ml), and brine (50 ml), dried (magnesium sulfate) and concentrated to dryness. Column chromatography (silica gel, 100 g; n-hexane/ethyl acetate (9/1 to 3/1)) gave 199 mg of the titled compound as an orange oil, which was solidified on standing at room temperature. Recrystallization from isopropyl ether gave 117 mg (39%) of the titled compound as colorless crystals.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH2:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:30][CH2:31][NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC[C@H](NC(=O)c1c(OCCN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)c2ccccc2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
0.95 g (2.2 mmol) of (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide (compound of Description 4) were dissolved, under nitrogen atmosphere and magnetical stirring, in 12 ml of dry CH2Cl2; 0.37 ml (2.6 mmol) of TEA were added, the solution cooled to 0° C. and 0.3 ml (2.6 mmol) of benzoyl chloride, dissolved in in 3 ml dry CH2Cl2 were added dropwise. The reaction was left 30 minutes at 0° C., then allowed to reach room temperature and left overnight. The mixture was evaporated in-vacuo to dryness, the residue was dissolved in CH2Cl2, and washed with H2O, 20% citric acid, sat. sol. NaHCO3, sat. sol. NaCl; the organic layer was dried over Na2SO4 and evaporated in-vacuo to dryness. The residue was triturated with hot i-Pr2O/i-PrOH to yield 0.8 g of the title compound as a white solid.