Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:18]([CH3:19])=[C:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[C:39]4[C:34](=[CH:35][C:36]([O:40][CH3:41])=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)=[C:25]([F:42])[CH:24]=2)=[O:21])[C:16](=[O:43])[N:15]1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O.CCO.NN.C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:3][CH2:12][CH2:13][N:14]1[C:18]([CH3:19])=[C:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[C:39]4[C:34](=[CH:35][C:36]([O:40][CH3:41])=[CH:37][CH:38]=4)[N:33]=[CH:32][CH:31]=3)=[C:25]([F:42])[CH:24]=2)=[O:21])[C:16](=[O:43])[N:15]1[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CCN5C(=O)c6ccccc6C5=O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CCN)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 50 °C
Yield: 82.1 %

Procedure:
To a solution of 1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.20 g, 0.30 mmol) in 1:1 H2O/EtOH was added hydrazine (0.049 g, 1.5 mmol). The reaction was heated to 50° C. for 8 hours and then cooled to RT. The reaction mixture was then diluted with 20 mL of satd. NaHCO3 aq. solution and 60 mL of EtOAc. The organic phase was separated and washed with 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was washed with 20% hexane in EtOAc to give the title compound as a light yellow solid (0.13 g, 81% yield).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.ClS([N:10]=[C:11]=O)(=O)=O.[CH3:13][N:14](C=O)C.[OH-].[Na+]>C(#N)C.CCOC(C)=O>[NH:1]1[CH:5]=[C:4]([C:13]#[N:14])[CH:3]=[C:2]1[C:11]#[N:10]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: c1cc[nH]c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1c[nH]c(C#N)c1
Temperature: 25 °C
Yield: 73.2 %

Procedure:
To a solution of ACN (15 mL) was added pyrrole (1.03 mL, 14.9 mmol) which was cooled in an ice/salt bath. Chlorosulfonyl isocyanate (2.73 mL, 31.3 mmol) was diluted in ACN (5 mL) and then added to the reaction dropwise over the following 30 min. The ice/salt bath was removed and the solution was allowed to warm to rt over the next 1.5 h. The solution was then cooled in an ice/salt bath and DMF (5.00 mL, 65.0 mmol) was slowly added via an addition funnel. The solution was allowed to slowly warm to rt over 17 h. The solution was cooled in an ice/salt bath and aq 1N NaOH (50 mL) was added followed by EtOAc (50 mL). The solution was transferred to a separatory funnel, and the organic layer was isolated and the aqueous layer was back extracted with EtOAc (2×). The collected organic was washed with aq saturated NaHCO3 followed by H2O (100 mL). The aqueous layers were back extracted with EtOAc (2×50 mL). The combined organic layers were collected, dried (MgSO4), concentrated onto silica gel, and purified by column chromatography (9:1 v/v CH2Cl2-EtOAc) to afford 1.28 g of the above compound as a white solid (10.9 mmol, yield 73%). 1H-NMR (DMSO-d6) δ 13.29 (br s, 1H), 8.00 (s, 1H), 7.49 (s, 1H); LCMS RT=1.65 min.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:18]([CH:19]([CH3:21])[CH3:20])[C:17]([CH:22]=[O:23])=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C1N=C(C2[N:41](C(C)C)[C:40]([C:45]([C:47]3SC=[CH:50][CH:51]=3)=O)=NC=2)C=CN=1)C1C=CC=CC=1>>[NH:1]([C:8]1[N:13]=[C:12]([C:14]2[N:18]([CH:19]([CH3:20])[CH3:21])[C:17]([C:22]([C:47]3[CH:45]=[CH:40][N:41]=[CH:50][CH:51]=3)=[O:23])=[N:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Reactant: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C(=O)c1cccs1
Product: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C(=O)c1ccncc1

Procedure:
The title compound was prepared by the procedure of Example 6 from 2-anilino-4-(2-formyl-1 -isopropylimidazol-5-yl)pyrimidine (Example 10) and N-methoxy-N-methyl 4-pyridinecarboxamide (Method 7). NMR (CDCl3): 1.55-1.75 (m, 10H), 5.56-5.72 (sept, 1H), 6.98 (d, 1H), 7.10 (t, 1H), 7.20 (br s, 1H), 7.30-7.40 (m, 2H), 7.55 (s, 1H) (7.60 (d, 2H), 7.90-7.94 (m, 2H), 8.51 (d, 1H), 8.78-8.82 (m, 2 H); m/z 385.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:17](C(OC(C)(C)C)=O)[NH:18][C:19](OC(C)(C)C)=O)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:33][O:34][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:44]C(O)=O>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:19]([CH3:44])=[N:18][N:17]=3)[C:11]=2[CH:10]=[C:9]1[CH2:33][OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(CO[Si](C)(C)C(C)(C)C)n2Cc2ccccc2)n1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc2ccc3c(cc(CO)n3Cc3ccccc3)n12

Procedure:
di-tert-Butyl 1-[1-benzyl-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (0.20 g, 0.34 mmol, from Step 4) in AcOH (2.7 mL) was heated in the microwave to a temperature of 180° C. for 5 minutes. Acetic acid was removed in vacuo and the residue was then stirred with NaOH (69 mg, 1.7 mmol) in THF (2.0 mL) and water (2 mL) for 20 minutes. The product was purified by preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (38 mg, 38%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][CH:7]=1)(=[O:5])=[O:4].[NH2:17]OS(O)(=O)=O>CN(C=O)C>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[N:8]([NH2:17])[CH:7]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1c[nH]c2ccc(F)cc12
Reactant: NOS(=O)(=O)O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1cn(N)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
A solution of 5-fluoro-1H-indole-3-sulfonic acid dimethylamide (1.24 g) in dry DMF (50 mL) is cooled to 0° C. and treated portion wise with 60% MaH oil dispersion (3.07 g). The mixture is stirred at 0° C. for 30 min. Hydroxylamine-O-sulfonic acid (2.9 g) is added portion wise and the mixture is warmed to rt and stirred for 5 h. The reaction mixture is poured onto ice/water and extracted with EtOAc. The organic layer is separated, washed water and brine, dried (MgSO4) filtered and concentrated in vacuo. The residue is triturated with ether. The solid is collected by filteration to afford 1-amino-5-fluoro-1H-indole-3-sulfonic acid dimethylamide (0.53 g, 41%). MS: 258 (M+H).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:15]([O:19]CC)OCC)=[N:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.[C:29](=[O:31])=[O:30]>CCOCC>[CH:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[C:5]2[CH:22]=[CH:23][C:2]([C:29]([OH:31])=[O:30])=[CH:3][C:4]=2[O:8][N:7]=1)=[O:19]
Reactant: CCOC(OCC)c1ccccc1-c1noc2cc(Br)ccc12
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccccc1-c1noc2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-bromo-3-(2-(diethoxymethyl)phenyl)benzo[d]isoxazole (Compound 5) (50 g) in dry ether (330 mL) under nitrogen at −78° C. was added a 2.5M solution of n-butyl lithium in hexanes (55.8 mL) was added dropwise and stirring continued at −78° C. for 45 min. The thick brown suspension was transferred via cannula to a mechanically stirred mixture of solid carbon dioxide pellets in ether (250 mL, under nitrogen and cooled in acetone/dry ice bath) and the resulting reaction mix topped up with further carbon dioxide pellets and left stirring in cold bath under nitrogen whilst warming to room temperature overnight. The reaction was quenched with 2N HCl (100 mL) and the ether removed under reduced pressure and ethanol (300 mL) added. The resultant yellow suspension was stirred on at 60° C. for 15 min, then cooled to room temperature and stirred in ice bath for 30 min and resulting yellow solid isolated by filtration and dried in vacuum oven at 45° C. to give the title product (29.76 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.C1COCC1.[Pd]>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[N:16][CH:17]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(OCc3ccccc3)cc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Yield: 67.5 %

Procedure:
To a solution of 2-(4-Benzyloxy-phenyl)-5-trifluoromethyl-pyridine (2.55 g) in ethanol (100 mL) and THF (25 mL) is added Pd/C (5%, 0.253 g), the mixture is stirred under 60 psi of hydrogen overnight. The catalyst is filtered off, concentration of the filtrate gave the title compound (1.25 g, 67.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[C:26]([BH3-])#N.[Na+].C=O>CO.C(O)(=O)C>[NH3:6].[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][NH:10][C:11]1[NH:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:26]
Reactant: [BH3-]C#N
Reactant: O=c1cc(NCCCNCc2ccc(Cl)c(Cl)c2)[nH]c2ccccc12
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCCNc1cc(=O)c2ccccc2[nH]1)Cc1ccc(Cl)c(Cl)c1
Product: N
Reaction time: 4 h
Yield: 197.6 %

Procedure:
2-[3-(3,4-Dichlorobenzylamino)prop-1-ylamino]-1H-quinolin-4-one (0.026 g, 0.07 mmol) was dissolved in methanol (2 ml) and acetic acid (0.05 ml). This was cooled in an ice bath and treated sequentially with sodium cyanoborohydride (6.3 mg, 0.1 mmol) in methanol (0.4 ml) and formaldehyde (3.7% in water/methanol, 0.057 ml, 0.07 mmol) then stirred for 4 h. The reaction mixture was purified by chromatography on a SCX cartridge, eluting with methanol and then 0.2M NH3 in methanol to give the title compound as a pale pink solid (0.027 g, 99%); δH (CD3OD) 1.7-1.9 (2H, m), 2.16 (3H, s), 2.43 (2H, t), 3.25-3.35 (2H, m), 3.43 (2H, s), 5.57 (1H, s), 7.1-7.6 (6H, m), and 8.03 (1H, d); MS (ES+) 390, 392 (45, 30%, MH+) and 201 (100).
Reaction SMILES: [OH-].[Li+].[OH:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C@H:13]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[C:30]4[C:25](=[N:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=4)[N:24](S(C4C=CC(C)=CC=4)(=O)=O)[CH:23]=3)[C:19]([C:45]#[N:46])=[CH:18][N:17]=2)[CH3:14])[CH2:9][CH2:8]1)=[O:6]>O1CCCC1>[OH:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C@H:13]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[C:30]4[C:25](=[N:26][CH:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=4)[NH:24][CH:23]=3)[C:19]([C:45]#[N:46])=[CH:18][N:17]=2)[CH3:14])[CH2:9][CH2:8]1)=[O:6]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCN(C(=O)CO)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](Nc1ncc(C#N)c(-c2c[nH]c3ncc(C(F)(F)F)cc23)n1)C1CCN(C(=O)CO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
1M solution of lithium hydroxide (382.5 μl, 0.38 mmol) was added to a solution of 2-((R)-1-(1-(2-hydroxyacetyl)piperidin-4-yl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (80 mg, 0.128 mmol) in tetrahydrofuran (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The crude mixture was concentrated to dryness and redissolved in ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion) to afford the title compound as a white solid (30 mg, 50% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].N1C=CC=CC=1>>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:18])[CH3:17]
Reactant: CN(CCCCCCO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCCCCN(C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 210 g (1.01 mol) of N-(6-hydroxyhexyl)-N-methylaniline, 112 g (1.10 mol) of acetic anhydride, and 86 g (1.1 mol) of pyridine was heated at reflux with stirring for 2 hours. After cooling, the solution was poured onto 500 g of ice and extracted with ethyl acetate (4×300 mL). The combined extracts were dried (MgSO4) and the solvent was removed at reduced pressure. The residue was distilled in vacuo, collecting the fraction boiling at 130° C. (0.01 mm). Yield: 231 g (93%) of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1ccc(OC)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccc(OC)cc1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(4-methoxyphenyl)acetate hydrochloride (prepared by the Bucherer Modification of the Strecker procedure as described in J. P. Greenstein et al., “The Chemistry of Amino Acids”, Vol. 1, p. 698, Wiley, New York (1961)), the title compound was prepared as a solid (mp=170-174° C.). The reaction was monitored by tlc (Rf=0.1 in 98:2 CHCl3/MeOH) and the product was purified by silica gel chromatography using 98:2 CHCl3/MeOH as the eluent.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH:12]=[O:13])[NH:8][C:7]=1[CH3:14])=[O:5])C.[OH-].[K+].Cl>CO.O>[CH:12]([C:9]1[NH:8][C:7]([CH3:14])=[C:6]([C:4]([OH:5])=[O:3])[C:10]=1[CH3:11])=[O:13]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(C=O)c(C)c1C(=O)O
Temperature: 25 °C
Yield: 95.7 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid which formed was collected by filtration, washed with water and dried in a vacuum oven overnight to give 1.6 g (93%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([Cl:7])=[O:6].[Cl:12]Cl>[Fe](Cl)(Cl)Cl>[Cl:12][C:3]1[C:2]([CH3:1])=[CH:10][C:9]([CH3:11])=[CH:8][C:4]=1[C:5]([Cl:7])=[O:6]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: ClCl
Agent: Cl[Fe](Cl)Cl
Product: Cc1cc(C)c(Cl)c(C(=O)Cl)c1
Yield: 64.8 %

Procedure:
A stirred apparatus with gas feed and discharge to an eliminator was initially charged with 100 g (0.593 mol) of 3,5-dimethylbenzoyl chloride together with 0.5 g of iron (III) chloride, and 42 g of chlorine were introduced at 22-28° C. over the course of 3 hours. Fractional distillation gave 78 g of 2-chloro-3,5-dimethylbenzoyl chloride. Boiling range: 113-114° C. at 5 mbar.
Reaction SMILES: [OH:1][CH:2]([C:25]([O:27][CH3:28])=[O:26])[C:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].CS([C:39]1[N:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([CH3:47])[N:40]=1)(=O)=O>CN(C=O)C.O>[CH3:28][O:27][C:25]([CH:2]([O:1][C:39]1[N:44]=[C:43]([O:45][CH3:46])[CH:42]=[C:41]([CH3:47])[N:40]=1)[C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[O:26]
Reactant: COc1cc(C)nc(S(C)(=O)=O)n1
Reactant: COC(=O)C(O)C(OCC(C)(C)C(=O)OC)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Oc1nc(C)cc(OC)n1)C(OCC(C)(C)C(=O)OC)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
10 g (25.9 mmol) of methyl 3-(2-hydroxy-2-methoxycarbonyl-1,1-di-phenylethoxy)-2,2-dimethylpropionate were dissolved in 40 ml of DMF under N2, 1.78 g (13 mmol) of K2CO3 and 5.2 g (25.9 mmol) of 2-methanesulfonyl-4-methoxy-6-methylpyrimidine were added, and the mixture was stirred at 80° C. for 2 h. It was subsequently diluted with 40 ml of H2O and extracted twice with 30 ml of diethyl ether, the organic phase was dried over MgSO4 and concentrated, and the residue was purified by chromatography on silica gel with ethyl acetate/cyclohexane mixtures. Crystallization from diethyl ether/hexane resulted in 11.8 g (90%) of the product as colorless crystals.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[OH-].[Na+].[F:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>CO.COCCOC>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][S:1][C:2]3[NH:3][C:4](=[O:11])[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Reactant: O=c1[nH]c(S)nc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: O=C(c1ccc(F)cc1)c1ccc(CSc2nc3[nH]ccc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
In methanol (65.7 ml) was suspended 2-mercapto-7H-pyrrolo [2,3-d]pyrimidin-4(3H)-one (2.51 g) followed by addition of 1N-sodium hydroxide (15.75 ml) for dissolution. Then, a solution of 4-(4-fluorobenzoyl)benzyl bromide (5.06 g) in DME (15 ml) was added dropwise with ice-cooling. Then, the mixture was stirred at room temperature overnight. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (silica gel; ethyl acetate: hexane=1:4-1:1-ethyl acetate) to provide the title compound (2.43 g).
Reaction SMILES: I.CS[C:4]1[CH2:5][CH2:6][C:7]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]3[CH2:20][CH:9]2[CH2:10][CH2:11]3)[N:8]=1.[NH3:21].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO.O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[NH2:21][C:4]1[CH2:5][CH2:6][C:7]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]3[CH2:20][CH:9]2[CH2:10][CH2:11]3)[N:8]=1
Reactant: N
Reactant: CSC1=NC2(CC1)C1CCC(C1)C2c1ccccc1
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: O
Product: NC1=NC2(CC1)C1CCC(C1)C2c1ccccc1

Procedure:
50 mmoles of 5'-methylthio-3-phenyl-spiro[bicyclo[2.2.1]-heptane-2,2'-5-pyrroline] hydriodide are treated with 250 ml of aqueous ammonia at 70° C. andunder a nitrogen pressure of 80 bars for 24 hours. After stripping off the solvent, an oil which slowly solidifies is obtained. After conversion intothe addition salt of fumaric acid, colorless crystals of melting point 242° C. (from methanol/water 1:1) are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:15][C:16]2[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=2)/[CH:19]=[C:20]2/[C:21](=[O:26])[NH:22][C:23](=[O:25])[S:24]/2)=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:1][C:2]1[C:3]([O:15][C:16]2[CH:17]=[C:18]([CH:27]=[CH:28][CH:29]=2)/[CH:19]=[C:20]2/[C:21](=[O:26])[NH:22][C:23](=[O:25])[S:24]/2)=[N:4][CH:5]=[N:6][C:7]=1[O:8][CH:9]1[CH2:10][CH2:11][N:12]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:13][CH2:14]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(Oc2cccc(/C=C3\SC(=O)NC3=O)c2)ncnc1OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(Oc2cccc(/C=C3\SC(=O)NC3=O)c2)ncnc1OC1CCN(S(C)(=O)=O)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a solution Trifluoro acetate salt of (Z)-5-(3-((5-methyl-6-(piperidin-4-yloxy)pyrimidin-4-yl)oxy)benzylidene)thiazolidine-2,4-dione (524 mg, 0.000974 mol) in dichloromethane (20 ml), was added triethyl amine (1.35 ml, 0.00974 mol) followed by methane sulfonyl chloride (0.150 ml, 0.001461 mol) at 0° C. and reaction mixture was stirred for 2 hrs at 30° C. Then reaction mixture was diluted with dichloromethane and washed with water, dried over calcium chloride and evaporated under reduced pressure to collect the crude product. Then the crude product was purified by column chromatography using 1% methanol in chloroform as eluent to yield 300 mg product as white solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][C:12]2[C:16]3[CH:17]=[C:18]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)=[O:27])=[O:10])[CH2:5][CH2:4]1.C(N([CH2:41][CH3:42])CC)C.[C:43](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.CC(C)=O>[ClH:35].[CH3:24][N:23]([CH3:25])[C:21]([C:18]1[CH:19]=[CH:20][C:15]2[O:14][C:13]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)=[O:27])=[C:12]([NH:11][C:9]([C@H:6]3[CH2:7][CH2:8][C@H:3]([NH:2][CH:41]([CH3:42])[CH3:43])[CH2:4][CH2:5]3)=[O:10])[C:16]=2[CH:17]=1)=[O:22]
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N)CC3)c2c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccc(C(=O)N(C)C)cc23)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-3-(4-aminocyclohexylcarbonylamino)-5-dimethylaminocarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride (160 mg) obtained in Example 344 is suspended in dichloromethane (8 ml), and thereto are added successively triethylamine (129 μl), acetone (113 μl), and sodium triacetoxy borohydride (130 mg) under ice-cooling, and the reaction solution is warmed to room temperature, and stirred for 17 hours. Under ice-cooling, to the reaction solution is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed with a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: ethyl acetate, then chloroform/methanol=30/1). The resulting residue is dissolved in ethanol, and thereto is added 4N hydrogen chloride in ethyl acetate. The reaction solution is concentrated and the resulting residue is suspended in diethyl ether. The precipitates are collected by filtration to give the title compound (94 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[CH2:11][CH2:10][CH2:9]2.Cl.[NH2:19][OH:20].CCN(CC)CC>CO.CCOC(C)=O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[N:19][OH:20])[CH2:11][CH2:10][CH2:9]2
Reactant: CN(C)CCOc1ccc2c(c1)CCCC2=O
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)CCOc1ccc2c(c1)CCCC2=NO

Procedure:
A solution of 6-(2-dimethylamino-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.53 g, 2.3 mmol), hydroxylamine hydrochloride (Riedel DeHaen, 0.69 g, 10.0 mmol), and Et3N (Aldrich, 1.4 mL, 10.0 mmol) in MeOH (6 mL) was heated to reflux overnight. The reaction mixture was diluted with EtOAc (70 mL) and washed with 10% Na2CO3, brine. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo to afford the product as an off-white solid. MS (ESI): 249 (M+H)+.