Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1.[CH3:31][O:32]/[C:33](/[O:36][Si](C)(C)C)=[CH:34]\[CH3:35]>CN(C=O)C.[F-].[Zn+2].[F-]>[Cl:8][C:5]1[N:4]=[C:3]([O:9][CH3:10])[C:2]([CH:34]([CH3:35])[C:33]([O:32][CH3:31])=[O:36])=[CH:7][CH:6]=1
Reactant: COc1nc(Cl)ccc1Br
Reactant: C/C=C(\OC)O[Si](C)(C)C
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(C)c1ccc(Cl)nc1OC
Temperature: 85 °C
Yield: 63.8 %

Procedure:
To a dry flask was added 3-bromo-6-chloro-2-methoxypyridine (9.7 g, 43.7 mmol), palladium(0)bis(dibenzylideneacetone) (1.3 g, 2.2 mmol), and zinc fluoride (3.4 g, 32.7 mmol). The mixture was degassed with nitrogen. A solution of tri-tert-butylphoshine/toluene (1.0 M, 4.4 mL, 4.4 mmol) in DMF (146 mL) was then added to the degassed mixture. After stirring, (E)-(1-methoxyprop-1-enyloxy)trimethylsilane (15.2 mL, 65 mmol) was added and the reaction was heated at 85° C. for 18 h. The mixture was partitioned between MTBE and brine. The aqueous layer was extracted with MTBE. The combined organic layers were dried over Na2SO4 and concentrated. Purification by silica gel column chromatography (330 g RediSep Gold column, 30-65% DCM/heptanes) provided methyl 2-(6-chloro-2-methoxypyridin-3-yl)propanoate (6.4 g, 64%); 1H NMR (600 MHz, CDCl3) δ: 1.44 (d, 3H), 3.67 (s, 3H), 3.91 (q, 1H), 3.95 (s, 3H), 6.89 (d, 1H), 7.45 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[C:16](#[N:18])[CH3:17]>Cl.O1CCOCC1>[CH3:17][C:16]1[NH:18][C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)[nH]c(C)nc2c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of dimethyl 2-aminoterephthalate (0.50 g, 2.4 mmol) in 4.0 M hydrochloric acid in 1,4-dioxane (4.8 mL) was added acetonitrile (1.0 mL, 19.0 mmol). The reaction mixture was heated to 50° C. and stirred for 3 h. The mixture was then cooled to rt, concentrated and the residue was twice co-evaporated with toluene. Ether was added and the mixture was extracted with water (2×). The combined aqueous phases were then concentrated to afford methyl 2-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.52 g, quant). LC-MS: (FA) ES+ 219.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]3[CH:11]=[C:10]([CH2:12][OH:13])[N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1>C(Cl)Cl.CN(C=O)C.O=[Mn]=O>[CH:12]([C:10]1[N:9]=[C:7]2[N:6]([CH:11]=1)[C:5]1[CH:14]=[CH:15][C:2]([F:1])=[CH:3][C:4]=1[S:8]2)=[O:13]
Reactant: OCc1cn2c(n1)sc1cc(F)ccc12
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1cn2c(n1)sc1cc(F)ccc12

Procedure:
2-Formyl-7-fluoro-imidazo[2,1-b]-benzthiazole was prepared according to the procedure outlined in Example 1, (Step 3). Starting from 7-fluoro-imidazo[2,1-b]-benzthiazole-2-methanol (1.5 g 6.7 mmol) in methylene chloride/DMF(300 mL: 50 mL) and active MnO2 (12 g, excess), 1.1 g (78% Yield) of the aldehyde derivative was isolated as brown solid. (M+H) 221.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23].C(N(CC)CC)C.C(O)(=O)C>C(#N)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([NH:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:17]1=[O:23])=[O:9]
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Nc1ccc(Br)cc1C(=O)NC1CCC(=O)NC1=O
Temperature: 90 °C
Yield: 71.1 %

Procedure:
A stirred mixture of 5-bromo-isatoic anhydride (6.0 g, 25 mmol), 3-amino-piperidine-2,6-dione hydrogen chloride (4.1 g, 25 mmol), triethylamine (18 mL, 129 mmol), and acetic acid (15 mL, 262 mmol) in acetonitrile (60 mL) was heated at 90° C. for 18 hours. The suspension was filtered and washed with acetonitrile (2×80 mL), water (2×80 mL) and ethyl acetate (2×80 mL) to give 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide as a white solid (5.8 g, 72% yield): LCMS: MH=326, 328. The sample was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:4]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C:5]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:20](=[O:42])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([NH:31][C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])=[NH:30])=[CH:25][CH:24]=3)[CH2:13][C@:14]([CH2:16][C:17](O)=[O:18])([CH3:15])[C:8]2=[N:7][CH:6]=1)[CH:2]=[CH2:3].[NH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1>>[CH2:46]([O:45][C:43](=[O:44])[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:20](=[O:42])[NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([NH:31][C:32]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:33])=[NH:30])=[CH:27][CH:28]=3)[CH2:13][C@@:14]([CH3:15])([CH2:16][C:17](=[O:18])[N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[C:8]2=[N:7][CH:6]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)CC(=O)O
Reactant: C1CCNCC1
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)CC(=O)N1CCCCC1
Yield: 72.5 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 18 g, intermediate 39a (20 mg, 0.028 mmol) was coupled with piperidine (8.1 mg, 0.14 mmol) to provide 15.7 mg (71%) of intermediate 41a. MS (ESI) 774.5 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])=[CH:11][CH:10]=1)(C)(C)C.Cl>ClCCl.O1CCOCC1>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[CH:21][C:20]3=[O:31])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc3c(=O)cc(N4CCOCC4)oc23)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCc1ccc(-c2cccc3c(=O)cc(N4CCOCC4)oc23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[4-(2-Morpholin-4-yl-4-oxo-4H-chromen-8-yl)-benzyl]-carbamic acid tert-butyl ester [F] (230 mg, 0.53 mmol), in dichloromethane (5 ml) was treated with 4M hydrogen chloride in dioxane (2 ml). The reaction was stirred at room temperature for 3 hours during which time a precipitate forms. The solvent was removed in vacuo and the residue triturated with ether. The resulting solid was collected by filtration and dried to give 8-(4-aminomethyl-phenyl)-2-morpholin-4-yl-chromen-4-one [G]. Yield 189 mg, quantitative.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[SH:7].[H-].[Na+].Cl[C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1>CN(C=O)C.C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: Cn1ccnc1S
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cn1ccnc1Sc1nccnc1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to Example 1 by using 1-methyl-1H-imidazole-2-thiol (228 mg, 2.00 mmol), NaH (60% dispersion in mineral oil, 88 mg, 2.20 mmol), and 3-chloropyrazine-2-carbonitrile (280 mg, 2.00 mmol) in DMF and benzene (6 ml, 1/1) by stirring at room temperature under nitrogen atmosphere for 4 hr.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].[C:22]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:23][C:24]([CH3:26])=O>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:13][CH2:12]2)[N:1]=[C:24]([CH3:26])[C:23]=1[C:22]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CC(C)C(=O)N1CCC(Oc2cccc(N)c2C#N)CC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCN(C(=O)C(C)C)CC3)c2c1N

Procedure:
Prepared as in Example Ba from 2-amino-6-((1-isobutyrylpiperidin-4-yl)oxy)benzonitrile (Example 10b) and ethyl acetoacetate as an off-white solid (82%). MS 400 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:5][C@H:4]2[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:18](=[O:20])[O:19][C@@H:3]12>CO.[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:6]1[CH2:7][C@@H:2]([CH3:1])[C@@H:3]2[O:19][C:18](=[O:20])[N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:4]2[CH2:5]1
Reactant: C[C@@H]1CN(c2ccncc2[N+](=O)[O-])C[C@@H]2[C@H]1OC(=O)N2C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CN(c2ccncc2N)C[C@@H]2[C@H]1OC(=O)N2C(=O)OC(C)(C)C
Reaction time: 14 h

Procedure:
To a solution of (3aR,7R,7aS)-tert-butyl 7-methyl-5-(3-nitropyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate (1.0 equiv.) in methanol, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 14 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding (3aR,7R,7aS)-tert-butyl 5-(3-aminopyridin-4-yl)-7-methyl-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate. LCMS (m/z): 349.1 (MH+); LC Rt=2.06 min.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=1>CN(C=O)C>[CH3:8][C:9]1[CH:13]=[C:12]([CH3:14])[N:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:10]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Ic1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(C)n(-c2ccccc2)n1

Procedure:
Operating protocol A (110° C., 54 hours) was followed using 117 mg of Chxn-Py-Al (0.4 mmoles), 336 μl of iodobenzene (3 mmoles), 192 mg of 3,5-dimethylpyrazole (2 mmoles) and 1.2 ml of DMF. The degree of transformation and selectivity for 5-dimethyl-1-phenyl-1H-pyrazole were 100%.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1.[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Br:26])[CH:20]=1)=O.O>O1CCCC1>[Br:26][C:21]1[C:22]([F:25])=[CH:23][CH:24]=[C:19]([C:17]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=2)=[CH2:16])[CH:20]=1
Reactant: CC(=O)c1ccc(F)c(Br)c1
Reactant: COc1ccc(Br)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1ccc(OC)c(Cl)c1)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
A solution of n-butyllithium (1.6 M solution in hexane, 20 mL, 1.1 eq) was added dropwise to a solution of 4-bromo-2-chloro-1-methoxy-benzene (6 g, 27 mmol, 1 eq) in tetrahydrofuran (25 mL) at −78° C. After stirring 30 min 3-bromo-4-fluoroacetophenone (5.8 g, 27 mmol, 1 eq) in tetrahydrofuran (25 mL) was added dropwise. The mixture was allowed to warm up to room temperature and stirred for 2 h, then treated with water (10 mL), extracted with ethyl acetate, dried (sodium sulfate) and concentrated in vacuo. The crude was dissolved in acetic acid (80 mL) and concentrated sulfuric acid (17 mL) was added. The mixture was warmed to 75° C. for 30 min, cooled at room temperature and neutralized with 1 N NaOH. The aqueous phase was extracted with dichloromethane (3×100 mL), dried (sodium sulfate) the solvent was removed under reduced pressure. The residue was purified by column chromatography (cyclohexane) to afford the title compound as a colourless oil (3.2 g, 36%);
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].N1C=CC=CC=1.Cl[C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:22]>ClCCl>[OH:13][C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:10][CH:11]=[CH:12][C:2]=1[NH:1][C:21]([CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])=[O:22]
Reactant: CCOC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)C1CCCN1C(=O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)C2CCCN2C(=O)OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a stirred solution of ethyl 3-amino-2-hydroxybenzoate (0.601 g, 3.6 mmol) and pyridine (0.633 g, 8 mmol) in anhydrous dichloromethane (20 mL) was added dropwise a solution of benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate (1.12 g, 4 mmol) in anhydrous dichloromethane (5 mL). After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane, washed with water (30 mL×3), 1N hydrochloric acid (30 mL×3), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give benzyl 2-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)pyrrolidine-1-carboxylate (1.43 g). LC-MS (ESI) m/z: 399 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:21]([CH3:22])=[CH:20][C:19]3[C:18]([CH3:24])([CH3:23])[CH2:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1.CO>[CH3:22][C:21]1[C:12]([C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=2)=[O:11])=[CH:13][C:14]2[C:15]([CH3:26])([CH3:25])[CH2:16][CH2:17][C:18]([CH3:23])([CH3:24])[C:19]=2[CH:20]=1
Reactant: COC(=O)c1ccc(C(=O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2c(cc1C(=O)c1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-naphthalene-2carbonyl)-benzoic acid methyl ester (820 mg, 2.25 mmol) in 10 mL of THF and 10 mL of MeOH was added NaOH (22 mL of 1N solution, 22 mmol). The mixture was stirred at room temperature overnight. The mixture was acidified with HCl (23 mL of 1N solution, 23 mmol). The product was extracted with CH2Cl2 twice and EtOAc twice. The combined organic fraction was dried over Na2SO4, filtered and was used in the next step without purification.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:10]=3[N:9]=[C:8]2[NH:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][O:35][CH3:36])[CH:29]=4)[CH:26]=3)[N:21](COCC[Si](C)(C)C)[N:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C(O)C>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:10]=3[N:9]=[C:8]2[NH:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][O:35][CH3:36])[CH:29]=4)[CH:26]=3)[NH:21][N:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCc1cccc(-c2ccc3c(c2)c(Nc2nc4cc(CO)ccc4n2C2CCCCC2)nn3COCC[Si](C)(C)C)c1
Agent: Cl
Solvent: CCO
Product: COCc1cccc(-c2ccc3[nH]nc(Nc4nc5cc(CO)ccc5n4C4CCCCC4)c3c2)c1
Reaction time: 8 h
Yield: 26 %

Procedure:
In a 20 mL vial with septum cover was added {1-cyclohexyl-2-[5-(3-methoxymethyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-ylamino]-1H-benzoimidazol-5-yl}-methanol (58 mg, 0.000095 mol), ethanol (6.0 mL) and HCl (2.0 mL, 0.065 M). The mixture was refluxed for 1.5 hr. The mixture was concentrated and the residue dissolved in approx 1.5 mL of DMSO and purified by HPLC. The product fractions were lyopholized overnight to give 11.9 mg of the title compound as an off white solid.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=CC=2)[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:15][CH2:14]C(C3SC(C(OC)=O)=CN=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:31]O.O1CCOCC1.[OH-].[Na+]>O>[CH:3]1[C:2]2[C:1](=[CH:25][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]=1[S:7]([N:10]1[CH2:11][CH2:12][NH:31][CH2:14][CH2:15]1)(=[O:8])=[O:9]
Reactant: COC(=O)c1cnc(C2CCN(S(=O)(=O)c3ccc(-c4ccccc4)cc3)CC2)s1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-[1-(1,1′-biphenyl-4-ylsulfonyl)piperidin-4-yl]-1,3-thiazole-5-carboxylate 25.3 (9 mg), 50% hydroxylamine in water (0.05 mL), and dioxane (1 mL) were cooled in ice-water. To the reaction was added 1N sodium hydroxide (0.053 mL) followed by removal of the cooling bath. After stirring overnight, the reaction was neutralized with 1 N hydrochloric acid (0.053 mL) and the solvent evaporated. The residue was purified by preparative hplc to give Example 25 as a floculant white solid (3.5 mg). 1H NMR (DMSO) δ: 2.75 (m, 2H), 2.15 (m, 2H), 2.5 (m, 2H), 3.1 (m, 1H), 3.75 (m, 2H), 7.45-7.55 (m, 3H), 7.72-7.96 (m, 6H), 8.08 (s, 1H), 11.3 (s, 1H); m/e=444 (M+H+).
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][N:22]2[CH2:26][CH:27]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=3)[CH2:28][N:15]([CH2:16][CH2:17][CH2:18][N:19]([CH2:39][C:40]([O:42]CC3C=CC=CC=3)=[O:41])[CH2:20][CH2:21]2)[CH2:14][CH2:13]1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][N:22]2[CH2:26][CH:27]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([NH2:36])=[CH:34][CH:35]=3)[CH2:28][N:15]([CH2:16][CH2:17][CH2:18][N:19]([CH2:39][C:40]([OH:42])=[O:41])[CH2:20][CH2:21]2)[CH2:14][CH2:13]1)([OH:10])=[O:8]
Reactant: O=C(CN1CCCN2CCN(CC(=O)OCc3ccccc3)CCCN(CC1)CC(Cc1ccc([N+](=O)[O-])cc1)C2)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CC2CN3CCCN(CC(=O)O)CCN(CCCN(CC(=O)O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.9 %

Procedure:
10% Pd/C (1.19 g) was added to a solution of compound 30 (3.97 g, 5.91 mmol) in ethanol (100 mL). The resulting mixture was stirred under H2 (g) atmosphere at room temperature for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 mL). The combined filtrate was evaporated in vacuo to give an oily residue which was triturated with Et2O to provide an off-white solid 28 (2.67 g, 98% yield).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][CH:38]=1)[C:12]([NH:14][CH:15]([C:17]1[N:22]=[N:21][C:20]([NH:23][C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)=[N:19][CH:18]=1)[CH3:16])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>ClCCCl.CN(C)C=O>[CH3:16][C:15]1[N:14]=[C:12]([C:11]2[CH:10]=[C:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:38]=[CH:37][CH:36]=2)[N:22]2[C:17]=1[CH:18]=[N:19][C:20]([NH:23][C:24]1[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=1)=[N:21]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(C(=O)c4ccccc4)c3)nn2)cc(OC)c1OC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(C(=O)c5ccccc5)c4)n3n2)cc(OC)c1OC
Temperature: 50 °C
Yield: 9 %

Procedure:
To a solution of 3-benzoyl-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 28) (95 mg, 0.18 mmol) in 1,2-dichloroethane was added catalytic dimethylformamide (3 drops) and thionyl chloride (0.36 mL, 5.0 mmol). The mixture was heated at 50° C. for 14 hours. After cooling to room temperature the mixture was concentrated under vacuum. The resulting solid was taken up in a mixture of dichloromethane and methanol, then concentrated ammonium hydroxide was added until the solution was basic. The solution was then concentrated under vacuum and purified by reverse-phase HPLC to give (3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)-amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)(phenyl)-methanone (8 mg) as a yellow solid. 1H NMR (DMSO-d6): δ9.63 (s, 1H), 9.26 (s, 1H), 8.80 (d, J=7.87 Hz, 1H), 8.61 (s, 1H), 7.74-7.80 (m, 3H), 7.63 (t, J=7.69 Hz, 2H), 7.68 (t, J=7.69 Hz, 2H), 7.05 (s, 2H), 3.68 (s, 6H), 3.62 (s, 3H), 2.52 (s, 3H). MS m/z 495 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][NH2:13].Cl>C(O)C.O>[OH2:5].[ClH:1].[CH3:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:13][CH3:12])[N:10]=1.[CH3:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:13][CH3:12])[N:10]=1.[OH2:5]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CN
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNc1nc(C)ccc1C(=O)O
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-6-methylnicotinic acid (25.00 g) and 33% methylamine in ethanol (100 ml) was heated in a pressure vessel at 100° C. for 18 hours. The mixture was cooled, diluted with water (200 ml) and acidified to pH 2-3 with concentrated hydrochloric acid. The mixture was cooled in an ice bath and filtered to give 6-methyl-2-methylaminonicotinic acid hemihydrochloride hydrate, m.p. 195°-197° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]1[CH3:15].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]1[CH3:15]
Reactant: OCc1ccc(F)cc1
Reactant: Cc1ccc(C)n1-c1ccc(I)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A solution of 1-(2-fluoro-4-iodo-phenyl)-2,5-dimethyl-1H-pyrrole (33.18 g, 105 mmol), 4-fluorobenzylalcohol (26.6 g, 211 mmol), cesium carbonate (68.6 g, 211 mmol), cuprous iodide (2.0 g, 11 mmol) and 1,10-phenanthroline (3.8 g, 21 mmol) in toluene (52 mL) was heated at 100° C. in an autoclave for 48 h. After cooling to room temperature, the mixture was filtered and poured into sodium hydroxide (1N). The resulting mixture was extracted with toluene and the organic extracts washed with brine, dried and evaporated. The residue was triturated with boiling hexane to leave the title compound (24.7 g, 75%) as a light brown solid. MS: m/e 314.1 (M++H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[C:19](O)(=[O:30])[CH2:20][C:21]1[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:23](O)=[O:24].CO>C(O)C>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([N:1]3[C:19](=[O:30])[CH2:20][C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:24])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: CCO
Solvent: CO
Product: O=C1Cc2ccccc2C(=O)N1C1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C

Procedure:
4-Amino-1-[2-(indol-3-yl)ethyl]piperidine (2.43 g, 0.01 mol) and homophthalic acid (1.80 g, 0.01 mol) were heated at 160° (external temperature) for 3 hours then cooled to room temperature, giving a glass. This was dissolved in refluxing methanol and a small quantity of ethanol then cooled at 5° C. overnight. The title compound was deposited as a tacky solid which was collected and dried (0.82 g, 21.2%). The hydrochloride was formed by treatment of the base overnight with ethereal HCl, m.p. 186°-188°.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[C:5]=12.[C:11]1([Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:6]2([OH:10])[CH2:7][CH2:8][CH2:9][N:4]3[CH:3]=[N:2][CH:1]=[C:5]23)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCCn2cncc21
Product: OC1(c2ccccc2)CCCn2cncc21

Procedure:
In analogy to Example 3a 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] and phenylmagnesium bromide solution [100-58-3] (1M in tetrahydrofuran) are reacted. The title compound is obtained as a beige solid. Rt=4.10 (Gradient I).