Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][NH:8][CH2:9][C:10]1[S:14][C:13]([NH:15][C:16]([N:18]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:17])=[N:12][CH:11]=1)(C)(C)C.Cl>C(Cl)Cl.C(OCC)C>[CH:25]1([N:18]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16](=[O:17])[NH:15][C:13]2[S:14][C:10]([CH2:9][NH:8][CH2:7][C:6]([OH:31])=[O:5])=[CH:11][N:12]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)CNCc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)CNCc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 76 %

Procedure:
{[2-(3,3-Dicyclohexyl-ureido)-thiazol-5-ylmethyl]-amino}-acetic acid tert-butyl ester (14 mg, 0.03 mmol) was dissolved in methylene chloride. Hydrogen chloride (100 μL, 4N in dioxane) was added and the reaction was stirred at ambient temperature until no ester could be detected. The reaction was diluted with diethyl ether and concentrated. The resulting residue was dissolved in a minimum amount of methylene chloride, precipitated with diethyl ether and decanted. This was repeated to afford 9 mg (69%) of the desired compound. HPLC-MS: m/z 395 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[N:25]1.C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN1CCCC1=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:33]([C:26]5[C:27]6[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=6)[NH:24][N:25]=5)=[O:34])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1n[nH]c2ccccc12
Yield: 67.9 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.484 mmol), 1H-indazole-3-carboxylic acid (94 mg, 0.581 mmol), oxalyl chloride (84 μL, 0.969 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (5 mL) and N-methylpyrrolidone (5 mL) as starting materials and in the same manner as in Example 412, the title compound (149 mg, 68%) was obtained as a white powder.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([NH2:14])=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[CH:15]([NH2:17])=O>>[NH:12]1[C:13]2=[C:5]3[C:6]([CH:7]=[CH:8][C:9]2=[CH:10][NH:11]1)=[N:14][CH:15]=[N:17][C:3]3=[O:4]
Reactant: COC(=O)c1c(N)ccc2cn[nH]c12
Reactant: NC=O
Product: O=c1ncnc2ccc3c[nH][nH]c3c12

Procedure:
6-Amino-1H-indazole-7-carboxylic acid methyl ester (formula 14, obtained according to Example IV) (1.35 g, 7.0 m-mol) was heated with formamide (4.2 ml) at 140° for a period of 4 hours and again at 180° for a period of 1.5 hours. The product that formed on cooling was collected and washed with a small amount of cold water to yield 555 mg of the formula 2 target compound. Additional amounts of the target compound were obtained by working-up the mother liquor. The cumulative product yield was 965 mg (74%), m.p. 325°-327° (decomp.); ir (KBr): 1570, 1620, 1685 cm-1 (aromatic, C=C, C=N, CO); pmr (DMSO-d6): δ 7.45 and 8.22 (2 d, 2, J=9 Hz, H4 and H5), 8.30 and 8.32 (2s, 2, H3 and H7), 13.44 (broad m, 2, D2O-exchangeable N1 --H and N8 --H); ms (70 eV): m/e 186 (100%, M+), 158 (16%, M+--CO).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21].[NH2:26][C:27]1[C:31]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:30][NH:29][N:28]=1>>[F:1][C:2]([F:25])([F:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:14]([F:17])([F:16])[F:15])[N:28]3[N:29]=[CH:30][C:31]([C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[C:27]3[N:26]=2)=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21]
Reactant: Nc1n[nH]cc1-c1cccnc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(OCC(F)(F)F)c(C(F)(F)F)c1
Product: FC(F)(F)COc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)cc1C(F)(F)F
Yield: 68.7 %

Procedure:
Reaction of 1-(4-trifluoroethoxy-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (191 mg, 0.5 mmol), prepared from 4-trifluoroethoxy-3-trifluoromethyl -acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (174 mg, 69%). MS (ISP) 507.5 [(M+H)+]; mp 181° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[N:23]([CH3:29])[CH2:22]4)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[O:28])[N:23]([CH3:29])[CH2:22]4)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)CN(C)C4=O)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccc4c(c3)CN(C)C4=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-methyl-1-oxoisoindolin-5-yl)benzo[d]thiazol-6-yl)acetate (36 mg, 0.064 mmol) dissolved in THF/MeOH (1.25 mL/1.25 mL) and 2N NaOH (0.160 mL) was heated at 50° C. for 2 h and the crude was purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the title compound. LCMS-ESI+: calc'd for C29H27ClN2O4S: 535.1 (M+H+); found: 535.2 (M+H+). 1H NMR (400 MHz, DMSO-d6): δ 8.22 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.65-7.51 (m, 4H), 5.03 (s, 1H), 4.46 (s, 2H), 3.03 (s, 3H), 2.48 (s, 3H), 0.83 (s, 9H).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([NH:17][CH2:18][CH2:19][OH:20])[C:11]([CH3:21])=[C:10]([CH3:22])[N:9]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([NH:17][CH2:18][CH2:19][O:20][C:23](=[O:25])[CH3:24])[C:11]([CH3:21])=[C:10]([CH3:22])[N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCO)c1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 95.6 %

Procedure:
Pyridine (1.0 mL, 12 mmol) and 4-dimethylaminopyridine (DMAP) (0.005 g, 0.04 mmol) was added to a solution of 2-(2-chloro-5,6-dimethyl-3-nitropyridin-4-ylamino)ethanol (0.50 g, 2.0 mmol) in anhydrous dichloromethane (4.5 mL). Under a nitrogen atmosphere, acetic anhydride (0.8 mL, 8 mmol) was added, and the yellow solution was stirred at room temperature for 1.3 hours. The volatiles were removed under reduced pressure, and the residual yellow oil was dissolved in dichloromethane. The solution was washed with aqueous sodium bicarbonate, water, and brine, and then dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 0.55 g of acetic acid 2-(2-chloro-5,6-dimethyl-3-nitropyridin-4-ylamino)ethyl ester as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:11])([CH:8]([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][NH:20][C:21]([C:23]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:25][N:24]=1)=[O:22].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[CH3:19][NH:20][C:21]([C:23]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([C:5](=[O:7])/[CH:4]=[CH:3]/[C:2]([F:1])([F:11])[CH:8]([F:10])[F:9])[CH2:31][CH2:30]2)[CH:26]=[CH:25][N:24]=1)=[O:22]
Reactant: O=C(O)/C=C/C(F)(F)C(F)F
Reactant: CNC(=O)c1cc(N2CCNCC2)ccn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(N2CCN(C(=O)/C=C/C(F)(F)C(F)F)CC2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(E)-4,4,5,5-tetrafluoropent-2-enoic acid (19 mg, 0.11 mmol) was dissolved in DCM (1 ml), oxalyl chloride was added (9 μl, 0.11 mmol) followed by a drop of DMF. The mixture was stirred for 10 minutes at room temperature. N-methyl-4-piperazin-1-yl-pyridine-2-carboxamide hydrochloride (25.6 mg, 0.1 mmol) was dissolved in DMF (0.5 ml), the mixtures were combined, diisopropylethylamine (75 μl, 0.4 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness under reduced pressure, the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 20.2 mg (0.054 mmol, 54%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:7][CH2:6]2.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:19][C:20]([F:28])([F:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:7][CH2:6]2
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(CCl)ccc21
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NC1CCc2cc(COc3ccccc3C(F)(F)F)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
A mixture of N-(5-(chloromethyl)-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (30 mg, 0.104 mmol), 2-(trifluoromethyl)phenol (16.90 mg, 0.104 mmol), and potassium carbonate (28.8 mg, 0.208 mmol) in N,N-dimethylformamide (1 mL) was stirred at 60° C. overnight. The reaction mixture was partitioned between aq. sat. NaHCO3 (4 mL) and DCM (4 mL), filtered over a phase separator, and the organic phase was concentrated by blow down. Purification by flash chromatography (0-60% EtOAc in Heptane) and freeze drying from acetonitrile/water gave the title compound as a white solid (24 mg, 55.7%). MS (ESI): m/z [M−H]− 412.0.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15]O)[O:12][C@@H:11]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:50]I>C(#N)C.CCOCC>[I:50][CH2:15][CH2:14][C@H:13]1[O:12][C@@H:11]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:10][C@@H:9]1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CCO)O2)c(=O)[nH]c1=O
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CCI)O2)c(=O)[nH]c1=O
Reaction time: 0.75 h
Yield: 90 %

Procedure:
To a solution of 3'-O-t-butyldimethylsilyl-5'-deoxy-5'-hydroxymethyl thymidine prepared according to the method of Example 5 (0.3 g, 0.9 mmol) in dry acetonitrile (5 ml) and ether (3.4 ml) were added 3 eq of triphenyl phosphine (0.7 g, 2.8 mmol), 4 eq of imidazole (0.3 g, 3.7 mmol) and 2.2 eq of iodine (0.5 g, 2.8 mmol). The reaction mixture was stirred for 45 min and the solvent was evaporated. Ethyl acetate was added to the residue and the residue washed with water, saturated sodium chloride and dried with sodium sulfate. The title compound was purified by flash chromatography using a 30-50% gradient of ethyl acetate in hexane. The yield was 90%.
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].C(O)CCO.[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1.[OH-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[Br:1][C:2]1[N:3]=[N:4][C:5]([C:35]2[CH:36]=[CH:37][S:33][CH:34]=2)=[CH:6][CH:7]=1
Reactant: OB(O)c1ccsc1
Reactant: Brc1ccc(Br)nn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: OCCCO
Solvent: C1COCCO1
Product: Brc1ccc(-c2ccsc2)nn1

Procedure:
A mixture of 3,6-dibromo-pyridazine (8.45 g, 35.5 mmol), palladacycle (0.66 g, 0.71 mmol), palladium acetate (0.16 g, 0.71 mmol), tri-tert-butylphosphine (0.35 ml, 1.42 mmol), aqueous potassium carbonate (2 M, 107 mmol), 1,3-propanediol (7.7 ml, 107 mmol) and 1,4-dioxane (100 ml) was stirred at reflux for 1 hour. 3-Thienyl boronic acid (5.0 g, 39.0 mmol) was added and the mixture was stirred at reflux for 7 days. Aqueous sodium hydroxide (50 ml, 1M) was added and the mixture was extracted with ethyl acetate (2×100 ml). Chromatography on silica gel with ethyl acetate:petroleum (1:3) as solvent gave the title compound. Yield 1.5 g (18%).
Reaction SMILES: C[OH:2].O.[Si]([O:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([F:50])=[C:17]([CH:23]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[N:48]=[C:47]([CH3:49])[O:46][N:45]=3)=[CH:40][CH:39]=2)[C:24]2[NH:28][C:27](=[O:29])[N:26]([C:30]3[C:31](=[O:36])[NH:32][CH:33]=[CH:34][N:35]=3)[N:25]=2)[CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)(C(C)(C)C)(C)C>[Fe].C(O)(=O)C>[C:47]([OH:2])(=[O:46])[CH3:49].[F:50][C:16]1[C:15]([O:14][CH2:13][CH2:12][OH:11])=[CH:20][C:19]([O:21][CH3:22])=[CH:18][C:17]=1[CH:23]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([NH2:48])=[NH:45])=[CH:40][CH:39]=1)[C:24]1[NH:28][C:27](=[O:29])[N:26]([C:30]2[C:31](=[O:36])[NH:32][CH:33]=[CH:34][N:35]=2)[N:25]=1
Reactant: COc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncc[nH]c3=O)c(=O)[nH]2)c1
Reactant: CO
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncc[nH]c3=O)c(=O)[nH]2)c1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
Iron powder (55 mg) was added to 4.5 ml of a methanol:water:acetic acid=1:1:1 mixed solvent solution containing 34 mg of 3-(3-{{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-1-yl)-1H-pyrazin-2-one. The mixture was stirred at 65° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was filtered and then purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-[5-oxo-1-(3-oxo-3,4-dihydropyrazin-2-yl)-4,5-dihydro-1H-[1,2,4]triazol-3-yl]methyl}amino)benzamidine acetate (5.9 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[C:5]([Cl:24])=[CH:4][N:3]=1.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]2[N:30]([CH3:36])[C:31](=[O:35])[CH2:32][CH2:33][CH2:34][C:28]=2[CH:27]=1.Cl>COC(O)C.O1CCOCC1>[Cl:24][C:5]1[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])=[N:7][C:2]([NH:25][C:26]2[CH:38]=[CH:37][C:29]3[N:30]([CH3:36])[C:31](=[O:35])[CH2:32][CH2:33][CH2:34][C:28]=3[CH:27]=2)=[N:3][CH:4]=1
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Reactant: NC(=O)c1cc(N2CCCCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: COC(C)O
Agent: Cl
Solvent: C1COCCO1
Product: CN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCCCC5)cc4C(N)=O)n3)ccc21
Temperature: 120 °C
Yield: 21.1 %

Procedure:
2-(2,5-dichloro-pyrimidin-4-ylamino)-5-piperidin-1-yl-benzamide (50.1 mg, 0.137 mmol) and 7-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (28.7 mg, 0.151 mmol) were slurried in methoxyethanol (2.0 mL) prior to adding ˜0.2 mL of 4N HCl in dioxane. This mixture was heated at 120° C. for 2 h. After quenching with saturated aqueous NaHCO3 solution (2 mL), the resulting precipitate was collected by filtration, successively washed water (5×2 mL) and ether (2×1 mL) to afford product (15 mg, 21%) as a yellow powder that had the following properties: mp: 295-297° C.; LC/MS (ESI+): 520 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 11.20 (s, 1H), 9.45 (s, 1H), 8.42 (d, J=8.0, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.65 (m, 2H), 7.52 (d, J=8.9, 1H), 7.30 (s, 1H), 7.20 (d, J=8.6, 1H), 7.05 (d, J=9.4, 1H), 3.20 (s, 3H), 3.18 (m, 4H), 2.65-2.20 (series of m, 6H), 1.65 (m, 4H), 1.55 (m, 2H).
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[SH:16].Cl>C1COCC1>[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[S:16][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cn1ccnc1S
Reactant: CC(C)(C)C(=O)OCCl
Agent: Cl
Solvent: C1CCOC1
Product: Cn1ccnc1SCOC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To 1.53 g (0.01 mole) of pivalyloxymethyl chloride dissolved in 30 ml of THF was added 1.14 g (0.01 mole) of 1-methyl-2-mercaptoimidazole. The clear yellow solution that resulted was stirred at room temperature overnight. The solution was concentrated to give a glass which was triturated twice with 100 ml of ether. The suspension was filtered and the residue was dried to give 1.85 g (mp 128°-132°, 67% yield) of the desired product as its hydrochloride. IR (KBr) 2800-2200 cm-1 ; (broad, s) (N+H), 1730 cm-1 (s) (C=O) and 1870 and 1820 cm-1 ; 1H NMR (CDCl3) δ7.60 (broad s, 2, N--CH=CH--N), 5.85 (s, 2, CO2CH2S), 3.57 (s, 3, N--CH3) and 1.18 (s, 9, (CH3)3C).
Reaction SMILES: CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[N:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:23])[CH2:19][C:20]([NH2:22])=O)=[CH:14][CH:13]=1.[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:23])[CH2:19][CH2:20][NH2:22])=[CH:14][CH:13]=1
Reactant: CC(CC(N)=O)c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(CCN)c1ccncc1
Temperature: 25 °C
Yield: 75 %

Procedure:
Next, anhydrous ether (8 ml) was added to lithium aluminum hydride (0.16 g, 4.2 mmol) under a nitrogen atmosphere, and the mixture was stirred under ice-cooling. A solution of 3-(4-pyridyl)butyramide (0.22 g, 1.4 mmol) in anhydrous methylene chloride (8 ml) was added dropwise to the mixture over two minutes, the temperature was raised to room temperature, and the whole was stirred overnight. Ethyl acetate (1 ml) and a 1 N aqueous sodium hydroxide solution (20 ml) were added to the reaction mixture, and the whole was extracted with chloroform (50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 0.15° g (75%) of the titled compound as a pale yellow oily matter.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13]([NH:21]C(=O)C)([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)([NH2:21])[CH3:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)NC(C)(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(N)(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Yield: 55.7 %

Procedure:
A stirred solution of N-(1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethyl)acetamide (Example 69) (0.04 g, 0.12 mmol) in concentrated HCl (0.07 mL, 3.03 mmol) was heated at 100° C. for 24 hrs in a sealed glass tube. The reaction mixture was then cooled to room temperature and neutralized with 10% NaOH solution (2 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL), and the combined organic layers were concentrated under vacuum. The crude product residue obtained was purified by preparative TLC using eluting solvent as MeOH:CH2Cl2 (3:7) to afford 20 mg (38%) of 1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanamine as a colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (d, 2H, J=5.6 Hz), 7.91-7.88 (m, 2H), 7.70 (s, 1H), 7.51 (d, 2H, J=6.4 Hz), 7.28 (t, 2H, J=8.8 Hz), 2.81 (s, 2H); 1.85 (s, 3H); LC-MS m/z calculated for [M+H]+300.09. found 300.1.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH:15]=O>>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]2[C:3]3[C:4](=[O:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2]=3[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]2=3)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: O=Cc1ccc(F)c(Br)c1
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1ccc(F)c(Br)c1

Procedure:
Reaction of 3-amino-5,5-dimethyl-2-cyclohexen- 1-one with 3-bromo-4-fluorobenzaldehyde in an analogous manner to that described in Example 1 gave 9-(3-bromo-4-fluorophenyl)-3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-1,8(2H,5H)-acridinedione. Crystallization from absolute ethanol gave a pale yellow crystalline solid of melting point 260° C. (decomposition).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[N:8][N:9]([CH2:11][CH2:12][C@@:13]([CH3:23])([S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([O:16]CC)=[O:15])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>O1CCOCC1>[CH:1]1([C:6]2[CH:7]=[N:8][N:9]([CH2:11][CH2:12][C@@:13]([CH3:23])([S:19]([CH3:22])(=[O:20])=[O:21])[C:14]([OH:16])=[O:15])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(C2CCCC2)cn1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@](CCn1cc(C2CCCC2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of ethyl (2R)-4-(4-cyclopentyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoate (100 mg, 0.292 mmol) in dioxane (3 mL) was added a 2M LiOH solution (0.0876 mL, 1.75 mmol, 6 eq). The reaction was allowed to stir overnight at RT. The mixture was then acidified with 1M HCl. The aqueous phase was then extracted with EtOAc, dried (MgSO4), filtered, and concentrated in vacuo to give (2R)-4-(4-cyclopentyl-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (92 mg, 100% yield) which was used without further purification. LC-MS M+H+315.1.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1O.CCN=C=NCCCN(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O.CN(C=O)C>[CH3:28][C:26]1[CH:25]=[CH:24][C:23]2[O:20][C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)=[N:21][C:22]=2[CH:27]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2oc(-c3ccc4c(c3)nc(C)n4C3CCOCC3)nc2c1
Yield: 28.5 %

Procedure:
2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (0.25 g, 0.96 mmol), 2-amino-4-methylphenol (0.13 g, 1.05 mmol), anhydrous DMF (500 mL) and WSC (0.22 g, 1.14 mmol) were stirred for 3 hours at room temperature. After the reaction was complete, water (50 mL) was added, the precipitated crystals were filtered off, and the filter residue was extracted with water/chloroform. After the organic layer was dried over anhydrous sodium sulfate, filtration and concentration gave crystals that were dissolved in toluene (5 mL), to which p-toluenesulfonic acid hydrate (0.43 g, 2.26 mmol) was added and this was stirred at reflux for 2 hours. After the solvent was concentrated at reduced pressure, water (5 mL) was added and the solid obtained was filtered off, and after washing with water, drying at reduced pressure at 50° C. yielded the title compound (95 mg, 28.5% yield) as a light yellow solid.