Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:8]2[C:9]([O:11][C:12](=[O:13])[C:7]2=[CH:6][CH:5]=1)=O)([O-])=O.[CH3:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:17]=1[NH2:18].[Sn](Cl)Cl.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[NH2:1][C:4]1[CH:14]=[C:8]2[C:7](=[CH:6][CH:5]=1)[C:12](=[O:13])[N:18]([C:17]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:16]=1[CH3:15])[C:9]2=[O:11]
Reactant: Cc1cccc(C)c1N
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1N1C(=O)c2ccc(N)cc2C1=O
Temperature: 100 °C
Yield: 67.2 %

Procedure:
A mixture of 5-nitrophthalic anhydride (1.0 g, 5.2 mmol) and 2,6-dimethylaniline (0.65 mL, 5.3 mmol) in acetic acid (50 mL) was heated at 100° C. overnight (14 h). The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The product was dissolved in ethanol (50 mL), tin (II) chloride (1.4 g, 6.2 mmol) was added and the mixture was heated to reflux for 5 h. The reaction mixture was cooled and made basic by adding aqueous 2 N sodium hydroxide. Ethyl acetate was added and the layers were separated. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give 5-amino-2-(2,6-dimethylphenyl)isoindoline-1,3-dione (0.93 g, 67%), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:9])=[O:7])([CH3:4])[CH3:3].[CH3:21][S:22][CH2:23][CH2:24][NH2:25]>>[CH3:21][S:22][CH2:23][CH2:24][NH:25][C:18](=[O:20])[C@H:10]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH3:9]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Reactant: CSCCN
Product: CSCCNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C

Procedure:
This was prepared by coupling of BOC Me Phe OH with 2-methylthioethylamine by the method of Example 1(b) The product was obtained as an oil. Rf1G=0.71 Rf32A=0.48
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][NH:16][C:15](=[N:19]N)[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1>C(N)CC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:12][CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=4)[CH:14]=3)=[CH:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN=c1cc(-c2c[nH]nc2-c2cccc(Cl)c2)cc[nH]1
Agent: NCCc1ccccc1
Product: Clc1cccc(-c2n[nH]cc2-c2ccnc(NCCc3ccccc3)c2)c1
Yield: 163.6 %

Procedure:
A solution of the bromopyridine compound prepared in step 3 of Example A-219 (250 mg, 0.75 mmol) in phenethylamine (5 ml) was heated at 175° C. for six hours under a nitrogen atmosphere. The excess amine was distilled off under high vacuum and the residue was dissolved in ethyl acetate and washed with water. After drying over magnesium sulfate and removal of solvent, the residue was chromatographed on silica gel with mixtures of ethyl acetate and toluene to give 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-(phenylethyl)-2-pyridinamine (230 mg, 81%) as a solid, m.p. 185-186° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH2:27][CH3:28])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:29]([N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH2:27][CH3:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(CC)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 59 %

Procedure:
A solution of 4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.5 g), benzyl bromide (0.58 mL) and cesium carbonate (1.6 g) in N,N-dimethylacetamide (15 mL) was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.0 g, 59%) as a colorless liquid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[Cl:27][CH2:28][CH2:29][CH2:30][C:31](=[CH:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)[C:32]([OH:34])=O.[F:50][C:51]1[CH:52]=[C:53]([C:58]([NH2:61])([CH3:60])[CH3:59])[CH:54]=[CH:55][C:56]=1[F:57]>CN(C=O)C.C(OCC)(=O)C.O.C(Cl)CCl>[F:50][C:51]1[CH:52]=[C:53]([C:58]([NH:61][C:32](=[O:34])[C:31](=[CH:35][C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]3)=[C:38]([O:48][CH3:49])[CH:37]=2)[CH2:30][CH2:29][CH2:28][Cl:27])([CH3:59])[CH3:60])[CH:54]=[CH:55][C:56]=1[F:57]
Reactant: CC(C)(N)c1ccc(F)c(F)c1
Reactant: COc1cc(C=C(CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc(C=C(CCCCl)C(=O)NC(C)(C)c2ccc(F)c(F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
IPEA (0.5 mL), EDC (192 mg) and HOBT (135 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (150 mg) and 1-(3,4-difluorophenyl)-1-methylethylamine (114 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(3,4-difluorophenyl)-1-methylethyl)amide. Sodium hydride (containing mineral oil at 40%, 40 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(3,4-fluorophenyl)-1-methylethyl)-amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 20 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 85 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:21])([F:22])[F:23])[CH2:12][CH2:13]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccccc1C1=CCN(Cc2ccccc2)CC1
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCC(c2ccccc2C(F)(F)F)CC1
Yield: 83.4 %

Procedure:
Using the procedure from Example 14A, Step 14D, 1-benzyl-4-[2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (Example 14A, Step 14C, 150 mg, 0.65 mmol) was reacted with 4-chlorobenzenesulfonyl chloride (165 mg, 0.78 mmol) to afford the title compound (219 mg), a white solid, in 84% yield.
Reaction SMILES: C([NH:8][C:9]([C:11]1[C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[S:14][C:15]=1[OH:16])=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:16][C:15]1[S:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:9]([NH2:8])=[O:10]
Reactant: O=C(NCc1ccccc1)c1c(O)sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1c(O)sc2ccccc12

Procedure:
A mixture of N-benzyl-2-hydroxybenzo(b)thiophene-3-carboxamide (4.3 g, 0.016 m), 10% palladium on carbon (2.0 g), and ethanol are stirred under a hydrogen atmosphere (40 p.s.i.) at 35° C. until hydrogen uptake is completed. The reaction mixture is filtered, the cake washed well with warm ethanol, and the combined filtrates concentrated in vacuo to yield 2-hydroxybenzo(b)thiophene-3-carboxamide.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[O:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31]([NH:35][C:36]([C:38]4[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=4)=[O:37])=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)[CH2:20][CH2:19]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:42]([C:41]3[CH:40]=[CH:39][C:38]([C:36]([NH:35][C:31]4[CH:30]=[C:29]5[C:34](=[CH:33][CH:32]=4)[N:26]([CH2:25][CH2:24][N:21]4[CH2:20][CH2:19][O:18][CH2:23][CH2:22]4)[CH:27]=[CH:28]5)=[O:37])=[CH:45][CH:44]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3c(ccn3CCN3CCOCC3)c2)cc1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc5c(ccn5CCN5CCOCC5)c4)cc3)[nH]c2c1

Procedure:
Compound 676 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(1-(2-morpholinoethyl)-5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C31H33N5O4: 540.26; found: 540.10.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C:6]([C:7]#[N:8])([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:15]
Reactant: N#CCc1cccs1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1cccs1

Procedure:
Prepare by the method of example 1.1.2 using thiophen-2-yl-acetonitrile (0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH:9]=1)[CH:7]=O.C(O)(=O)C.ClC(Cl)C.[CH2:38]([N:40]([CH2:43][CH2:44][NH2:45])[CH2:41][CH3:42])[CH3:39].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([N:14]2[CH2:19][C@H:18]([CH3:20])[N:17]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:16][C@H:15]2[CH3:29])=[O:13])=[C:6]([CH2:7][NH:45][CH2:44][CH2:43][N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])[CH:9]=1
Reactant: CCN(CC)CCN
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(CC)CCNCc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of (2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde (0.100 g, 0.25 mmol) in 10:1 dichloroethane acetic acid (2.2 mL) was added (diethylamino)ethylamine (0.088 mL, 0.625 mmol) and the resulting solution was stirred for 1 hour at ambient temperature. To this was added sodium cyanoborohydride (0.0094 g, 0.15 mmol) and the reaction was stirred overnight at ambient temperature. Upon completion water was added and the mixture was basified with solid sodium bicarbonate (pH>10). The product was extracted with dichloromethane (2×) and diethyl ether (2×). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.039 g, x 30% yield)
Reaction SMILES: C([O:4][CH2:5][C:6]1[NH:7][CH:8]=[C:9]([S:13]C(C)(C)C)[C:10](=[O:12])[CH:11]=1)(=O)C.[ClH:18]>>[ClH:18].[OH:4][CH2:5][CH:6]1[CH:11]=[C:10]([OH:12])[C:9]([SH:13])=[CH:8][NH:7]1
Reactant: CC(=O)OCc1cc(=O)c(SC(C)(C)C)c[nH]1
Agent: Cl
Product: OCC1C=C(O)C(S)=CN1
Temperature: 80 °C

Procedure:
A mixture of {5-[(1,1-dimethylethyl)thio]-4-oxo-1,4-dihydro-2-pyridinyl}methyl acetate (240 mg, 0.94 mmol) and concentrated hydrochloric acid (2 ml) was heated to 80° C. overnight. The solvent was evaporated affording a pale yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8](I)[O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:5])C.[NH2:31][C:32]1[CH:33]=[N:34][N:35](C(OC(C)(C)C)=O)[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>CC(O)(C)C.O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH:34]1[CH:33]=[C:32]([NH:31][C:8]2[O:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[C:6]([C:4]([OH:3])=[O:5])[N:7]=2)[CH:36]=[N:35]1
Reactant: CCOC(=O)c1nc(I)oc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(Nc4cn[nH]c4)nc3C(=O)O)cc2)CC1
Yield: 26.1 %

Procedure:
A mixture of tert-butyl 4-(4-(4-(ethoxycarbonyl)-2-iodooxazol-5-yl)phenyl)piperazine-1-carboxylate (0.150 g, 0.28 mmol), tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.261 g, 1.42 mmol), cesium carbonate (0.462 g, 2.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 0.013 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.0165 g, 0.029 mmol) in tBuOH (4.5 ml) and dioxane (4.5 ml) was degassed, placed under a nitrogen atmosphere and then stirred under reflux overnight. The reaction mixture was passed through a MP-SH cartridge and the solvent removed in vacuo. The residue was partitioned between water and EtOAc and the aqueous phase extracted with EtOAc and DCM. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(1H-pyrazol-4-ylamino)-5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)oxazole-4-carboxylic acid (0.033 g, 0.073 mmol, 26%). LCMS (2) Rt: 1.68 min; m/z (ES+) 455.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2>CS(C)=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:12]3[CH2:13][CH2:14][N:15]([CH2:20][C@H:19]([OH:18])[CH2:21][O:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)[CH2:16][CH:17]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1Cl
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3c(Cl)c(Cl)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6,7-dichloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 3.7 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole(0.71 g, 3.7 mmol). The product was isolated as a white foam. Yield 1.17 g (69%). mp 140°-145° C. FDMS m/e=455 (M+ of free base). α[D]589 =+4.59 (c=1.00, dimethylsulfoxide).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[C:11](=O)([O-])[O-].[Ca+2].C(O)C>C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]=[CH:11][NH:10][C:5]=2[CH:4]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O=CO
Solvent: CCO
Product: COc1ccc2nc[nH]c2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
4-Methoxy-1,2-phenylenediamine (5.00 g, 36 mmol) was dissolved in formic acid (10 ml) and heated at reflux for 2 hours. The solution was allowed to cool to room temperature overnight then treated with calcium carbonate (5.0 g). After dilution with ethanol (150 ml) the mixture was heated at reflux for 1 h then filtered, the residue being washed with hot ethanol (50 ml). The combined filtrates were evaporated at reduced pressure to give an oil from which a solid crystallised. The material was slurried with diethyl ether (50 ml) then filtered to give an orange solid which was recrystallised from ethyl acetate to give 5-methoxybenzimidazole (5.33 g, 99%) as a yellow crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]=[CH:5][N:6]([CH3:12])[C:7]=2[NH:8][C:9](=[S:11])[N:10]=1.Cl[CH2:14][C:15]([NH2:17])=[O:16].C(=O)([O-])O.[Na+]>O>[C:15]([CH2:14][S:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[CH3:12])=[C:2]([CH3:1])[N:10]=1)(=[O:16])[NH2:17]
Reactant: NC(=O)CCl
Reactant: Cc1nc(=S)[nH]c2c1ncn2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1nc(SCC(N)=O)nc2c1ncn2C
Yield: 67.5 %

Procedure:
6,9-Dimethylpurine-2-(3H)-thione (0.45 g), chloroacetamide (0.3 g), sodium hydrogen carbonate (0.25 g), and water (10 ml) were heated under reflux for 1 hr. Refrigeration gave a solid which recrystallised from water to give the carbamoylmethylthiopurine (0.40 g), m.p. 163°-164° (Found: C, 45.3; H, 4.9; N, 29.2. C9H11N5OS requires C, 45.6; H, 4.7; N, 29.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[C:13]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Cl)c([N+](=O)[O-])cc1O)c1ccccc1

Procedure:
In 100 ml of ethyl acetate was dissolved 40 g (210×10-3 mole) of 2-amino-4-chloro-5-nitrophenol, and 33 g of benzoyl chloride was added at room temperature and then the mixture was refluxed under heating for 2 hours. After the reaction, a solvent was distilled off under reduced pressure and the residue was recrystallized from hexane to obtain products. Yield: 60 g.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].CC1C=CC(S(O)(=O)=O)=CC=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[C:26]([CH:28]3[CH2:31][C:30](=O)[CH2:29]3)[O:25][N:24]=2)=[CH:19][C:18]=1[NH:33][C:34]([C:36]1[N:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]2=[N:38][CH:37]=1)=[O:35]>C1(C)C=CC=CC=1>[CH2:29]1[C:30]2([O:4][CH2:1][CH2:2][O:3]2)[CH2:31][CH:28]1[C:26]1[O:25][N:24]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[C:18]([NH:33][C:34]([C:36]3[N:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]4=[N:38][CH:37]=3)=[O:35])[CH:19]=2)[N:27]=1
Reactant: OCCO
Reactant: Cc1ccc(-c2noc(C3CC(=O)C3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2noc(C3CC4(C3)OCCO4)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 100 °C

Procedure:
Ethylene glycol (10 mg), TsOH (5 mg) and N-(2-methyl-5-(5-(3-oxocyclobutyl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (10) (50 mg) were combined in toluene (3 mL) and heated at 100° C. for 5 hours. The reaction was filtered and purified by preparative reverse phase HPLC to afford N-(5-(5-(5,8-dioxaspiro[3.4]octan-2-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F8). 1H NMR (400 MHz, d4-MeOH) δ 9.53 (d, J=7.2 Hz, 1H), 8.50 (s, 1H), 8.13-8.12 (m, 1H), 7.90 (dd, J=8.2, 2.0 Hz, 1H), 7.75 (d, J=9.6 Hz, 1H), 7.60-7.55 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.18 (ddd, J=7.2, 7.2, 1.2 Hz, 1H), 4.45-4.43 (m, 1H), 3.98-3.81 (m, 4H), 3.32-3.31 (m, 4H), 2.43 (s, 3H). MS m/z 432.1 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][C:60]([S:64](Cl)(=[O:66])=[O:65])=[C:61]([CH3:63])[N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:64]([C:60]1[S:59][C:58]([NH:57][C:54](=[O:56])[CH3:55])=[N:62][C:61]=1[CH3:63])(=[O:65])=[O:66])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexa hydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dim ethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (60 mg) was reacted with 2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride to give (S)-2-({(3S,8S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester according to General Procedure E. This ester (12 mg) was hydrolyzed according to General Procedure B to give the title compound (10 mg). LCMS (m/z): 959.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[C:20]([NH:22][C:23]([CH:25]5[CH2:27][CH2:26]5)=[O:24])[N:21]=4)[N:18]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1.N([C:30]1C=CC(C)=CN=1)N>>[CH3:30][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[C:20]([NH:22][C:23]([CH:25]5[CH2:26][CH2:27]5)=[O:24])[N:21]=4)[N:18]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(c1ccc2nc(NC(=O)C3CC3)cn2n1)c1nnc2ccc(Br)cn12
Reactant: Cc1ccc(NN)nc1
Product: Cc1ccc2nnc(C(C)c3ccc4nc(NC(=O)C5CC5)cn4n3)n2c1

Procedure:
The title compound was synthesized using an analogous procedure to that described in the preparation of Compound 48 (Method A) using 2-hydrazinyl-5-methylpyridine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.76-0.86 (m, 4 H) 1.85 (d, J=7.07 Hz, 3 H) 1.92 (m, 1 H) 3.56 (s, 3 H) 5.02 (d, J=7.07 Hz, 1 H) 7.18 (d, J=9.35 Hz, 1 H) 7.23-7.31 (m, 1 H) 7.70 (d, J=8.84 Hz, 1H) 7.93 (d, J=9.85 Hz, 1 H) 8.10 (s, 1 H) 8.20 (s, 1 H) 11.13 (s, 1 H). MS:m/z 362.2 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([N:23]([CH2:26][CH:27]1[O:32][CH2:31][CH2:30][NH:29][CH2:28]1)[CH2:24][CH3:25])[CH3:22]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][CH2:31][O:32][CH:27]([CH2:26][N:23]([CH2:24][CH3:25])[CH2:21][CH3:22])[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCN(CC)CC1CNCCO1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Product: CCN(CC)CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(diethylaminomethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-7-[2-(diethylaminomethyl)morpholino]-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 155°-157° C.