Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33]>C(Cl)Cl.O>[CH2:35]([O:34][C:32]([N:3]1[CH2:4][CH:5]2[C:1]([C:7]3[CH:8]=[CH:9][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:11][CH:12]=3)([CH2:6]2)[CH2:2]1)=[O:33])[CH:36]=[CH2:37]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Reactant: C=CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CCOC(=O)N1CC2CC2(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)C1
Yield: 49.2 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (100 mg, 0.28 mmol) in dry DCM (5 mL) were added triethylamine (0.16 mL, 1.12 mmol) and allyl chloroformate (0.05 mL, 0.42 mmol) at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.3:9.7 MeOH:CHCl3) to provide the title compound (55 mg, 50%) as white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]1=[O:33].C[Sn]([N:38]=[N+:39]=[N-:40])(C)C>C1(C)C=CC=CC=1>[NH:38]1[C:27]([CH2:26][CH2:25][CH2:24][S:23][C:9]2[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]3[C:6]=2[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:33])[N:4]3[CH2:29][CH:30]([CH3:31])[CH3:32])=[N:28][N:40]=[N:39]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC#N)n(Cc3cccc4ccccc34)cc21
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCc3nnn[nH]3)n(Cc3cccc4ccccc34)cc21
Yield: 28 %

Procedure:
The compound of Example 18, 4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1 H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanenitrile (98 mg) was dissolved in toluene (20 ml) and trimethyltin azide (100 mg) was added. The solution was heated under reflux for 110 hours, then the solvent was evaporated and the residue was chromatographed, eluting with ethanol:dichloromethan(1:19), to give the title compound (30 mg).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:29]=1[NH2:30].C(=O)([O-])[O-].[Na+].[Na+].ClC1C=CC=CC=1Cl>[Cu]I.C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:27][C:28]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:29]=1[NH:30][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C(Nc1ccc(Cl)c2c1C(=O)c1ccccc1C2=O)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: Clc1ccccc1Cl
Product: O=C(Nc1ccc(Nc2ccc([N+](=O)[O-])cc2Cl)c2c1C(=O)c1ccccc1C2=O)c1ccccc1
Reaction time: 7 h

Procedure:
36.15 parts of 1-chloro-4-benzoylaminoanthraquinone, 21.6 parts of 2-chloro-4-nitroaniline and 10 parts of sodium carbonate are stirred in 400 parts of o-dichlorobenzene. A solution of 0.4 part of copper-(I) iodide in 5 parts of pyridine, and 25 parts of toluene, are added and the mixture is heated to the boil -- 160° to 165°. The water liberated is distilled off azeotropically and the toluene is recirculated. After a reaction time of 45 minutes, the reaction product begins to precipitate. The mixture is stirred for 7 hours at 160°-165° and is then allowed to cool. The precipitate is filtered off, washed with o-dichlorobenzene, acetone and hot water, and extracted by boiling with dilute hydrochloric acid. 34.4 parts of 1-(2'-chloro-4'-nitroanilino)-4-benzoylaminoanthraquinone are obtained in the form of a dark powder. The colorant bulk-dyes PES in claret-colored shades of good fastness properties.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([NH:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[OH:29])[CH3:21])=[O:19])=[CH:16][C:15]=1[O:32][CH3:33])=[O:12].[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>ClCCl.C(Cl)(Cl)Cl>[C:34]([O:29][C:23]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=1[N:20]([CH3:21])[C:18](=[O:19])[C:17]1[CH:30]=[CH:31][C:14]([NH:13][C:11]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[NH2:1])=[O:12])=[C:15]([O:32][CH3:33])[CH:16]=1)(=[O:36])[CH3:35]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2O)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OC(C)=O)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Reaction time: 4 h
Yield: 97.2 %

Procedure:
A mixture of 4-(2-amino-3-nitrophenyl)carbonylamino-N-(2-hydroxy-4-methylphenyl)-3-methoxy-N-methylbenzamide (400 mg), acetic anhydride (90.7 mg) and triethylamine (89.9 mg) in dichloromethane (20 ml) was stirred in an ice bath for 4 hours. The mixture was diluted with chloroform and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give N-(2-acetoxy-4-methylphenyl)-4-(2-amino-3-nitrophenyl)carbonylamino-3-methoxy-N-methylbenzamide (425 mg).
Reaction SMILES: BrCC([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:11]1([NH2:18])C=CC=C[C:12]=1[NH2:17].C([O-])(=O)C.[Na+]>C(O)C>[N:17]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:18]=[CH:11][CH:12]=1
Reactant: Nc1ccccc1N
Reactant: O=C(CBr)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc2nccnc2c1
Reaction time: 8 h

Procedure:
To a magnetically stirred solution of the appropriate alpha-bromoacetophenone (1 eq) in 200 ml of ethanol was added the appropriate 1,2-phenylenediamine (2.4 eq), followed by addition of solid sodium acetate (3 eq). The resultant solution was warmed to reflux and stirred overnight with an air atmosphere. The product formed precipitates, and so the reaction was vacuum filtered, and the solids washed with 50 ml cold ethanol followed by washing with 50 ml 0.1 N HCl. The product was carried on without further purification.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:42]2[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=2[F:49])[S:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.O1CCOCC1.O>O1CCOCC1>[F:49][C:43]1[CH:44]=[CH:45][C:46]([F:48])=[CH:47][C:42]=1[C:23]1[S:22][C:21]([CH2:20][CH2:19][OH:18])([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3ccccc3)sc2C1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (prepared according to Example 26, Steps A-D; 0.090 g, 0.113 mmol) in 1 mL of 1,4-dioxane was added 4M HCl/dioxane (1 mL). The mixture was stirred at room temperature for 16 hours then treated with 4M HCl/dioxane (2 mL) and stirred for a further 3 hours. Water (1 mL) was added and the mixture was stirred for 16 hours then concentrated and dried in vacuo. The residue was triturated with diethyl ether, filtered, washed with ether and dried in vacuo to afford the desired product as an orange/yellow solid, 0.023 g, 38%. MS ESI (+) m/z 459 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.59 (m, 1H), 7.46 (m, 2H), 7.33 (m, 3H), 7.07 (m, 2H), 4.12 (m, 1H), 3.95 (m, 1H), 3.87 (m, 2H), 3.65 (m, 2H), 3.05 (m, 2H), 2.84 (m, 1H), 2.43 (m, 2H) ppm.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]#N)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3]C=1.C(OC([C:31]1C2C(=CC=CC=2)C=C[N:32]=1)(C)C)(=O)C1C=CC=CC=1>>[CH:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:31]#[N:32])[C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#Cc1cccc2c(-c3ccccc3)nccc12
Reactant: CC(C)(OC(=O)c1ccccc1)c1nccc2ccccc12
Product: N#CCc1cccc2c(C3CCCC3)nccc12

Procedure:
1-Cyclopentylisoquinoline (obtained from 1-cyano-2-benzoyl-1,2-dihydroisoquinoline and cyclopentyl bromide) and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to obtain 1-cyclopentyl-5-dichloroacetylaminomethylisoquinoline having a melting point of 151.0° to 152.3° C. The product was successively reacted in the same way as in steps (c), (d), (e), and (f) of Example 18 to afford 1-cyclopentylisoquinoline-5-acetonitrile having a melting point of 99.4° to 100.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][Cl:28]>CS(C)=O>[Cl:28][CH2:27][CH2:26][CH2:25][C:11]([S:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]#[N:13]
Reactant: COc1ccc(C(C#N)Sc2ccc(C)cc2)cc1OC
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C(C#N)(CCCCl)Sc2ccc(C)cc2)cc1OC
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2.39 g of 3,4-dimethoxy-α[(4-methylphenyl)thio]benzeneacetonitrile in 21 mL of dimethyl sulfoxide, under an argon atmosphere with stirring, is added 0.336 g of 60% sodium hydride in oil. This mixture is stirred for 1.5 hours. To the resulting solution is added 1.32 g of 1-bromo-3-chloropropane and this reaction mixture is stirred for 3 hours and is next poured into 100 mL of ice water. This mixture is twice extracted with diethyl ether and the combined organic extracts dried with magnesium sulfate. The organic solution is filtered, and concentrated in vacuo to give the desired compound as a golden oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH2:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[NH2:15][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:7]=[C:6]([CH2:5][C:4]3[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:37])[F:38])[CH:29]=4)=[O:36])[CH:25]=[CH:24][CH:23]=3)[C:14]=12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Cc2nn(Cc3ccccc3)c3ncnc(N)c23)c1
Product: Nc1ncnc2c1c(Cc1cccc(NC(=O)Nc3cccc(C(F)(F)F)c3)c1)nn2Cc1ccccc1

Procedure:
To 3-(3-aminobenzyl)-1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine, molar equivalents of 3-(trifluoromethyl)phenyl isocyanate (Sigma-Aldrich) were added drop wise in ice-cold CH2Cl2. The reaction proceeded until completion as judged by TLC, was concentrated in vacuo, resuspended in 50:50 H20-CH3CN, and purified on a C18 column in CH3CN/H20/0.1% TFA (1-100% gradient) to yield final Cmpd BB6 1-(3-((4-amino-1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methyl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (ESI-MS m/z [M+H]+ found 518.4, calculated 518.2).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:19][CH:20]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-n-Butyl-4-chloroimidazole-5-carboxaldehyde (6.34 g, 34.0 mmol, 1 eq.), 4-bromomethyl-2'-cyanobiphenyl (9.25 g, 34.0 mmol, 1 eq.), potassium carbonate (5.17 g, 37.4 mmol, 1.1 eq.) and DMF (100 mL) were mixed and stirred at 25° C. overnight. The solids were filtered and the filtrate evaporated. The residue was chromatographed over silica gel in 9:1 to 1:1 hexane/ethyl acetate and crystallized from methylcyclohexane/n-butyl chloride yielding 9.70 g of a solid; m.p. 96.0°-97.0° C. NMR (CDCl3): δ9.78 (s, 1H); 7.83-7.40 (m, 6H); 7.19 (d, 2H, J=9 Hz); 5.63 (s, 2H); 2.71 (t, 2H, J=7 Hz); 1.72 (t of t, 2H, J=7,7 Hz); 1.38 (t of q, 2H, J=7,7 Hz); 0.90 (t, 3 H, J=7 Hz). Anal calcd. for C22H20ClN3O: C, 69.93; H, 5.34; N, 11.12. Found: C, 69.64; H, 5.37; N, 11.21.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH2:8][CH2:9][S:10]([C:13]1[CH:18]=C(C)[CH:16]=[C:15]([C:20](=[O:37])[N:21]([C:23]2[N:24]=[N:25][C:26]([Cl:36])=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH3:22])[CH:14]=1)(=[O:12])=[O:11])(C)(C)C.C1(OC)C=CC=CC=1.[F:47][C:48]([F:53])([F:52])[C:49](O)=O>ClCCl>[Cl:36][C:26]1[N:25]=[N:24][C:23]([N:21]([CH3:22])[C:20]([C:15]2[CH:14]=[C:13]([S:10]([CH2:9][CH2:8][CH2:7][C:6]([OH:38])=[O:5])(=[O:12])=[O:11])[CH:18]=[C:49]([C:48]([F:53])([F:52])[F:47])[CH:16]=2)=[O:37])=[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:27]=1
Reactant: Cc1cc(C(=O)N(C)c2nnc(Cl)cc2-c2ccccc2C)cc(S(=O)(=O)CCCC(=O)OC(C)(C)C)c1
Reactant: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)CCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-{3-[(6-chloro-4-o-tolyl-pyridazin-3-yl)-methyl-carbamoyl]-5-methyl-benzenesulfonyl}-butyric acid tert-butyl ester (0.055 g, 89.9 μmol) in dichloromethane (1.5 mL) were added anisole (10.7 mg, 10.8 μL, 98.8 μmol) and trifluoroacetic acid (512 mg, 346 μL, 4.49 mmol) and the light yellow solution was stirred at room temperature for 3.5 hours. The reaction mixture was evaporated to dryness and the residue treated with toluene and again completely evaporated. The product was purified by preparative HPLC (Gemini NX column) using a gradient of methanol:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless foam (0.037 g; 74%). MS (ESI+): m/z=556.09 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[N:8]=[C:9]([O:29][CH2:30][CH3:31])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:24][CH:25]5[CH2:27][O:26]5)=[C:18]([CH3:28])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH:34]([C:37]1[NH:38][C:39]([SH:42])=[N:40][N:41]=1)([CH3:36])[CH3:35]>CN(C)C=O>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[N:8]=[C:9]([O:29][CH2:30][CH3:31])[C:10]3[N:15]=[C:14]([C:16]4[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:24][CH:25]([OH:26])[CH2:27][S:42][C:39]5[NH:38][C:37]([CH:34]([CH3:36])[CH3:35])=[N:41][N:40]=5)=[C:18]([CH3:28])[CH:17]=4)[O:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1nnc(S)[nH]1
Reactant: CCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC4CO4)c(C)c3)nc12
Solvent: CN(C)C=O
Product: CCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(O)CSc4nnc(C(C)C)[nH]4)c(C)c3)nc12
Yield: 22.7 %

Procedure:
A solution of 300 mg of 5-(4-chloro-benzyl)-2-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-7-ethoxy-oxazolo[5,4-d]pyrimidine (prepared analogously as described in example 20, step (a)) and 92 mg of 5-isopropyl-4H-[1,2,4]triazole-3-thiol in 3 ml of dimethylformamide was heated for 2 h to 130° C. in a microwave reactor. After removal of the solvent the product was isolated by preparative HPLC (method HPLC1) to yield 89 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:17])[NH:15][NH2:16])=[N:6]1.[NH2:22][C:23](=S)[C:24](OCC)=[O:25].C(N(CC)CC)C>CO>[NH2:22][C:23]1[N:16]=[N:15][C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[F:1])[N:6]=2)=[N:17][C:24]=1[OH:25]
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: CCOC(=O)C(N)=S
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Reaction time: 8 h

Procedure:
2.000 g (7.035 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidohydrazide in 50 ml of methanol were initially introduced and admixed with 0.937 g (7.035 mmol) of ethyl amino(thioxo)acetate, and 1.424 g (14.070 mmol) of triethylamine were admixed and the mixture was heated under reflux for 5 h. The reaction mixture was left to stand overnight, and the precipitate was filtered off with suction, washed with a little ethanol and dried under high vacuum. This gave 1.892 g of the target compound (purity 94%; 75% of theory).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[S:14][C:15](C([O-])=O)=[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=[CH:3]1.[NH4+].Cl>O1CCOCC1.O>[C:18]1([NH:17][C:16]2[C:5]3[CH:4]=[CH:3][C:2](=[O:1])[N:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:6]=3[S:14][CH:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C([O-])c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1ccc2c(Nc3ccccc3)csc2n1-c1ccccc1
Temperature: 70 °C
Yield: 53.6 %

Procedure:
To a solution of the compound of Example 14 (200 mg) in 1,4-dioxan (10 mL) was added 2M HCl(aq) (0.5 mL) and the reaction mixture heated at 70° C. for 1 h. The reaction was diluted with water (30 mL), extracted with EtOAc (3×20 mL) and the EtOAc extracts dried (MgSO4) and concentrated in vacuo. The crude residue was purified by chromatography on silica (0-5% EtOAc in DCM) to give the title compound as a white solid (90 mg). δH (DMSO-d6) 8.21 (1H, bs), 7.96 (1H, d, J 9.6 Hz), 7.63-7.47 (3H, m), 7.43-7.36 (2H, m), 7.25-7.11 (2H, m), 7.10-7.03 (2H, m), 6.82-6.71 (1H, m), 6.46 (1H, d, J 9.6 Hz), 6.44 (1H, s). LCMS (ES+) RT 3.54 minutes, 319 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)[CH:2]=[CH2:3].C(OC(=O)C)(=O)C.N1C=CC=CC=1>COCCOC>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:13](=[O:14])[O:15][C:10](=[O:12])[C:7]2=[N:8][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cnc(C(=O)O)c(C(=O)O)c1
Solvent: COCCOC
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: C=CCc1cnc2c(c1)C(=O)OC2=O

Procedure:
A mixture of 7 g of crude 5-allylpyridine-2,3-dicarboxylic acid, 9.8 mL acetic anhydride, and 3.3 mL pyridine in 100 mL dry 1,2-dimethoxyethane is stirred under nitrogen and heated at 65° for 1 hour. After adding an additional 1 mL of acetic anhydride, the reaction is heated for 2 hours at 65°, then at reflux overnight. The reaction mixture is filtered, and the solids are washed with ether and ethyl acetate. The combined filtrates are concentrated in vacuo and reevaporated from xylenes to afford the product as a solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[NH2:5][C:6]1[C:7]([F:30])=[CH:8][C:9]([F:29])=[C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19](F)[C:20]=3[Cl:22])[C:15](=[O:25])[C:14]([C:26]([OH:28])=[O:27])=[CH:13]2)[CH:11]=1>CN(C)C=O>[NH2:5][C:6]1[C:7]([F:30])=[CH:8][C:9]([F:29])=[C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:24])=[C:19]([NH:4][CH:1]4[CH2:3][CH2:2]4)[C:20]=3[Cl:22])[C:15](=[O:25])[C:14]([C:26]([OH:28])=[O:27])=[CH:13]2)[CH:11]=1
Reactant: NC1CC1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: CN(C)C=O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NC4CC4)c(Cl)c32)c(F)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
Cyclopropylamine (50 mg) and 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg) were, added to N,N-dimethylformamide (2 ml), and the mixtures was stirred at 60° C. for 2 hours. After the reaction mixture was cooled back to room temperature, the solvent was, distilled off under reduced pressure. Ethanol was added to the residue, and solids deposited were collected by filtration to obtain the title compound (80 mg) as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:14])[CH2:12]Cl.[OH-:15].[Na+]>O.O1CCOCC1>[CH3:9][O:10][C:11](=[O:14])[CH2:12][N:1]([CH2:12][C:11]([O:10][CH3:9])=[O:15])[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1
Reactant: COC(=O)CCl
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)CN(CC(=O)OC)c1ccc(C)cc1
Temperature: 5 °C

Procedure:
Into a three-neck r.b. flask, fitted with stirring assembly, thermometer, reflux condenser, and a dropping funnel were placed 10.7g (0.1M) p-toluidine, 21.7g (0.2M) methylchloroacetate, 50 ml water, and 80 ml dioxane. The solution was heated to reflux and 32g of an aqueous solution containing 8g (0.2M) sodium hydroxide was added dropwise so as to maintain the charge at a neutral pH. Addition was completed within 11/2 hours. The flask was cooled to 5° C, and the product was poured into a 4 l. beaker. Upon addition of 3 l. of water, a ppt. formed which was discarded. Extraction of the aqueous phase with chloroform and stripping the extract gave 24.6g of light-yellow solid.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[NH2:12][OH:13]>CO.N1C=CC=CC=1>[C:1]1(=[N:12][OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCc2ccccc21
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: ON=C1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
1-Indanone (4.00 g, 30.3 mmol) and hydroxylamine hydrochloride (5.26 g, 75.7 mmol) were dissolved in a mixture of methanol (40 ml) and pyridine (10 ml) and stirred for 3 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the resultant residue was diluted with 1N HCl (100 ml) and extracted three times with methylene chloride. The organic layer was dried over MgSO4 and concentrated in vacuo to provide 4.13 g (93% yield) of the desired 1-indanone oxime as white needles.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][CH:12]2[CH:19]3[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:21][CH:13]2[CH2:14]4)[CH2:18]3)=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C=O)C.CCOCC>[CH3:35][O:34][C:32](=[O:33])[CH2:31][O:1][CH2:2][C:3]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][CH:12]2[CH:19]3[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:21][CH:13]2[CH2:14]4)[CH2:18]3)=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)CBr
Reactant: O=C(OC1C2CC3CC(C2)CC1C3)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)COCC1(c2ccccc2)CCN(C(=O)OC2C3CC4CC(C3)CC2C4)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 130.8 %

Procedure:
To a stirred solution of 2-adamantyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (230 mg, 0.62 mmol) in dry DMF (5 mL) was added 60% NaH in oil (60 mg, 2.5 mmol). The mixture was stirred at rt for 0.5 h and methyl bromoacetate (0.24 mL, 2.5 mmol) was added. The mixture was stirred at 50° C. in an oil bath for 4 h. The mixture was diluted with ether (90 mL), washed with water (3×20 mL), dried over MgSO4 and concentrated to leave an oil (358 mg). This material was purified by column chromatography on silica gel, eluted with an EtOAc in hexanes gradient, followed by prep HPLC to afford the title compound (20 mg, 7%) as an oil. LC-MS Method 2 tR=11.79 min, m/z=442.