Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: C1CCCNCC1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCCCCC4)cc3c2)cc1)N1CCOCC1

Procedure:
The product from Example 23D and azepane were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.73 (d, J=8.1, 2H), 7.56 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.77 (s, 1H), 3.3-3.8 (m, 16H), 1.6-2.1 (m, 8H); MS (DCI) m/z 433 (M+H)+;
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]1[N:27]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][C:36]2([O:44][CH2:43][CH2:42][O:41]2)[CH2:35]3)[C:28]([OH:31])=[N:29][N:30]=1)C1C=CC=CC=1>CCOC(C)=O.CCCCCC.[Pd]>[CH2:37]1[C:38]2[C:34](=[CH:33][C:32]([N:27]3[C:28]([OH:31])=[N:29][N:30]=[C:26]3[C:10]3[CH:11]=[C:12]([CH:23]([CH3:25])[CH3:24])[C:13]([OH:15])=[CH:14][C:9]=3[OH:8])=[CH:40][CH:39]=2)[CH2:35][C:36]21[O:41][CH2:42][CH2:43][O:44]2
Reactant: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(c2)CC2(C3)OCCO2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)c1cc(-c2nnc(O)n2-c2ccc3c(c2)CC2(C3)OCCO2)c(O)cc1O
Yield: 97.2 %

Procedure:
5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-(1′,3′-dihydro-spiro[[1,3]dioxolane-2,2′-inden]-5′-yl)-4H-[1,2,4]triazol-3-ol (550 mg, 0.93 mmol) was subsequently hydrodebensylated using Pd/C (10%, dry, 100 mg) and H2 in THF/MeOH (1/1, 25 mL) at 1 atm at r.t. for 2 h. The reaction mixture was filtered through a pad of celite and the mother liquid was concentrated. It was again filtered through a pad of silica gel and the filtrate was concentrated to give the title compound as a white solid (370 mg, 97%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[C:12](=[O:15])[CH2:13]Br.[S-:16][C:17]#[N:18].[NH4+].C(=O)(O)[O-].[Na+]>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[C:12](=[O:15])[CH2:13][S:16][C:17]#[N:18]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Product: N#CSCC(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(2,3,4,5,6-pentafluorophenyl)-2-bromo-1-ethanone 5.00 g, ammonium thiocyanate 1.58 g and acetonitrile 100 mL was stirred at 25° C. for one hour. To the reaction mixtures was added aqueous saturated sodium bicarbonate solution and the mixtures were extracted with ethyl acetate. The organic layers were washed with aqueous saturated sodium bicarbonate solution and were dried over anhydrous sodium sulfate. The resulting mixtures were concentrated under reduced pressure to give 1-(2,3,4,5,6-pentafluorophenyl)-2-thiocyanato-1-ethanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.Cl.[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=O)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:30][CH2:31][O:32][C:33]2[CH:41]=[CH:40][C:36]([CH2:37][NH:9][C:7]3[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[CH:10]3[CH2:19][CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=4)[CH2:11]3)=[CH:35][CH:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCCC3)cc1)C2
Yield: 94.4 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (700 mg) and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride (960 mg) according to an analogous synthetic method to Example 152, the title compound (1.2 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH:5]=[O:6])C.CC1C=CC(S([CH2:18][N+:19]#[C-:20])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:3][C:4]([C:5]1[O:6][CH:20]=[N:19][CH:18]=1)=[O:7]
Reactant: CCOC(=O)C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cnco1
Yield: 621.6 %

Procedure:
To a solution of glyoxylic acid ethyl ester (50% w/w in toluene) (4 mL, 2 mmol) and Tosmic (3.86 g, 2 mmol) in MeOH (60 mL) was added K2CO3 (5.6 g, 4 mmol) and the mixture was stirred at reflux for 7 h. The solvent was then evaporated and 100 mL of water was added. This solution was saturated with sodium chloride and extracted with diethyl ether. The organic layer was washed with brine, dried (MgSO4) filtered and concentrated to give 1.58 g (60%) of oxazole-5-carboxylic acid methyl ester as white solid. m.p.=35-50° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Br[CH2:13][C:14]([C:16]([F:19])([F:18])[F:17])=[O:15].C(=O)(O)[O-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH3:7][C:5]1[O:6][CH2:13][C:14]([OH:15])([C:16]([F:19])([F:18])[F:17])[C:4]=1[C:3]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(C)OCC1(O)C(F)(F)F
Reaction time: 18 h
Yield: 65.9 %

Procedure:
A solution of 18.8 g of sodium hydride in 175 ml of ethanol was added over 3 hours into a mixture of 51 g of ethyl acetoacetate, 74.8 g of 1-bromo-3,3,3-trifluoroacetone and 200 ml of toluene while maintaining a temperature below +10° C. The mixture was stirred for 18 hours and an aqueous sodium bicarbonate solution was added. The mixture was stirred and extracted with isopropyl ether. The extract was dried and the solvent was evaporated to obtain 62 g of the expected product with a boiling point of 64°-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:20]3[CH2:21][CH:22]([C:24]([O:26]CC)=O)[CH2:23][CH:12]2[CH2:13][C:14]2([CH2:19]3)[O:18][CH2:17][CH2:16][O:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:29][CH2:30][Mg+].[Br-]>CCOCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:12]3[CH2:23][CH:22]([C:24]4([OH:26])[CH2:30][CH2:29]4)[CH2:21][CH:20]2[CH2:19][C:14]2([CH2:13]3)[O:15][CH2:16][CH2:17][O:18]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CC2CC3(CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1)OCCO3
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)N1C2CC(C3(O)CC3)CC1CC1(C2)OCCO1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
Ethyl 9-[(4-chlorophenyl)sulfonyl]spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolane]-7-carboxylate (50) (395 mg, 0.918 mmol) was dissolved in Et2O (2 mL) and the resulting solution was cooled to −78° C. Ti(O-i-Pr)4 was added followed by EtMgBr dropwise over 10 minutes. The reaction mixture was warmed to room temperature and stirred for 18 h. The resulting solution was diluted with EtOAc and washed with saturated aqueous NH4Cl. The organic phase was dried (Na2SO4), filtered, and concentrated to give 1-{9-[(4-chlorophenyl)sulfonyl]spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolan]-7-yl}cyclopropanol (55). MS (ESI) 414.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)(Cl)Cl.ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)c2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.6 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid (5.2 g) and 4-nitrophenol (3.14 g) in 30 mL of carbon tetrachloride and 10 mL of dichloromethane was treated with 1.3-dicyclohexylcarbodiimide (3.8 g). The mixture was stirred at room temperature for 2 days. After the usual work up. the ester was crystallized from ether-hexane to yield 4.14 g of (E,E)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid 4-nitrophenyl ester, mP 113°-115° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](O)[C:3]=1[C:9]([F:12])([F:11])[F:10].O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ncnc(O)c1C(F)(F)F
Product: Nc1ncnc(Cl)c1C(F)(F)F
Temperature: 100 °C
Reaction time: 1 h

Procedure:
The mixture of 6-amino-5-(trifluoromethyl)pyrimidin-4-ol (N-4) (300 mg, 1.66 mmol) in POCl3 (8 mL) in a pressure vessel is stirred at 100° C. for 1 h. The mixture is allowed to cool to RT and concentrated in vacuo. The residue is taken up in water (20 mL), basified with saturated NaHCO3 aqueous solution to pH=9 and then extracted with DCM (30 mL×3). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the desired product, 6-chloro-5-(trifluoromethyl)pyrimidin-4-amine (N-5) as a yellow solid.
Reaction SMILES: [CH:1]([CH:3]([CH2:9][N:10]1[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]1=[O:18])[C:4]([O:6]CC)=O)=O.CCN(CC)CC.[C:26]1([CH2:32][NH:33][NH2:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.Cl>C1(C)C=CC=CC=1>[CH2:32]([N:33]1[C:4](=[O:6])[CH:3]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]2=[O:18])[CH:1]=[N:34]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NNCc1ccccc1
Reactant: CCCC1CC(=O)N(CC(C=O)C(=O)OCC)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCC1CC(=O)N(CC2C=NN(Cc3ccccc3)C2=O)C1
Temperature: 40 °C
Yield: 14 %

Procedure:
In a three neck flask, fitted with a magnetic stirrer, under inert atmosphere, ethyl 2-formyl-3-(2-oxo-4-propylpyrrolidin-1-yl)propanoate x280 (0.9 g) in PhMe (10 ml) is added onto a solution of Et3N (1.6 ml) and PhCH2NHNH2.2HCl (0.75 g, 0.0039 mol.) in PhMe (30 ml) at room temperature. The mixture is heated up to 40° C. for 12 h, cooled down to room temperature, washed with NH4Cl (saturated) and the aqueous layer is acidified to pH 3 by addition of HCl (5 N). After 3 extractions with EtOAc, the organic layers are dried over MgSO4, concentrated in vacuo to afford the crude reaction mixture which is purified by chromatography on silicagel (first purification with CH2Cl2/MeOH/NH4OH 98/018/0.02; second purification with EtOAC/iPrOH 95/5; third purification by preparative reverse phase LC/MS) to afford 2-benzyl-4-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-2,4-dihydro-3H-pyrazol-3-one x281 as a red oil (0.18 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:7][C@H:6]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:3])[CH3:2].[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(N(CC)CC)C>O1CCCC1>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[O:7][C@H:6]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH:32][CH:33]1[CH2:38][CH2:37][N:36]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:35][CH2:34]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(C(C)(C)C)no2)O[C@H]1n1cnc2c(NC3CCNCC3)ncnc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(C(C)(C)C)no2)O[C@H]1n1cnc2c(NC3CCN(S(C)(=O)=O)CC3)ncnc21
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a solution of (2R,3R,4R,5S)-4-(Acetyloxy)-5-[3-(tert-butyl)isoxazol-5-yl]-2-[6-(piperidin-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3-yl acetate (40 mg) in tetrahydrofuran (4 ml) was added methanesulfonyl chloride (0.0088 ml) and triethylamine (0.0212 ml). The reaction mixture was stirred for 16 h at 20° C., and partitioned between ethyl acetate (2×100 ml) and water (100 ml). The organic layers were washed with water (100 ml), dried (MgSO4), and evaporated in vacuo to afford the title compound (36.7 mg) as a colourless gum.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[C:4]([NH:15][CH2:16][C:17]([NH:19][CH:20]2[CH2:23][N:22]([CH:24]3[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]3)[CH2:21]2)=[O:18])=[N:3]1.CC[N:35]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.N>C1COCC1.C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:9]=2)[C:4]([NH:15][CH2:16][C:17]([NH:19][CH:20]2[CH2:21][N:22]([CH:24]3[CH2:29][CH2:28][CH:27]([C:30]([NH2:35])=[O:31])[CH2:26][CH2:25]3)[CH2:23]2)=[O:18])=[N:3]1
Reactant: Cn1nc(NCC(=O)NC2CN(C3CCC(C(=O)O)CC3)C2)c2cc(C(F)(F)F)ccc21
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(C(N)=O)CC3)C2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{3-[2-(1-Methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetylamino]-azetidin-1-yl}-cyclohexane carboxylic acid (as prepared in the previous step, 100 mg, 0.22 mmol), EDCI (Aldrich, 65 mg, 0.33 mmol), HOBt (Aldrich, 45 mg, 0.33 mmol) and ammonia in THF (1N, Aldrich, 0.5 mL) in DCM (5 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel column chromatography using DCM: 7N NH3 in MeOH (10:1) as eluent to give the title compound as white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]([CH2:22][C:23](OCC)=[O:24])[N:14]1[CH2:28][CH2:29][CH3:30]>O>[O:12]=[C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]([CH2:22][C:23]([NH:10][C:9]([NH2:11])=[NH:8])=[O:24])[N:14]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCN1C(=O)c2ccccc2C1CC(=O)OCC
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: CCCN1C(=O)c2ccccc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
N-[(3-Oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 3.9 g of potassium tert-butoxide, 3.3 g of guanidinium chloride and 1.8 g of ethyl (3-oxo-2-propyl-2,3-dihydro-1H-isoindol1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 1 hour, followed by addition of 60 cm3 of water. The aqueous phase is extracted with 3 times 50 cm3 of ethyl acetate and is then concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 45° C. The residue is taken up in water, triturated and filtered. The solid is taken up in methanol and the solvent is then evaporated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 45° C. 0.6 g of N-[(3-oxo-2-propyl-2,3-dihydro-1H-isoindol-1-yl)acetyl]-guanidine is thus obtained in the form of a pale yellow cottony solid melting at 229° C. Mass spectrum EI: m/e 274 (M+), m/e 187, m/e 86 (base peak).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[C:21]([C:22]2[S:23]C(C3NC=NN=3)=C(C3C=CC=CC=3)[N:26]=2)=[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]2[N:14]=1.Cl[CH:39]([C:45]([O:47]CC)=O)[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CC(O)C>[OH:47][C:45]1[N:26]=[C:22]([C:21]2[C:13]([CH3:12])=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=23)[S:23][C:39]=1[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: Cc1nn2ccccc2c1-c1nc(-c2ccccc2)c(-c2nnc[nH]2)s1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1O
Temperature: 90 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
A suspension of 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (1.7 g, 7.5 mmol) produced in Example 11-B (v) and diethyl chloromalonate (2.0 g, 11 mmol) in 2-propanol (25 mL) was stirred at 90° C. for 4 hr with heating. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration and dried to give ethyl 4-hydroxy-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxylate (1.45 g, 64%) as a yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].Cl.[NH2:25][CH2:26][CH2:27][S:28]([NH2:31])(=[O:30])=[O:29].C[O-].[Na+]>CCO>[S:28]([CH2:27][CH2:26][NH:25][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4])(=[O:30])(=[O:29])[NH2:31]
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCCS(N)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NS(=O)(=O)CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 140 °C
Yield: 53.8 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.097 mmol), 2-amino-ethanesulfonic acid amide HCl salt (24 mg, 0.19 mmol), and NaOMe (9.9 mg, 0.18 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between 1 M HCl and EtOAc. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 21 mg of the title compound. MS: (+) m/z 403.25 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1I.[CH3:20][C:21]1([CH3:28])[C:25]([CH3:27])([CH3:26])[O:24][BH:23][O:22]1.C(N(CC)CC)C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:5]=[CH:6][C:7]=1[B:23]1[O:24][C:25]([CH3:27])([CH3:26])[C:21]([CH3:28])([CH3:20])[O:22]1
Reactant: CC1(C)OBOC1(C)C
Reactant: CC(=O)NCC1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)NCC1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A suspension of N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]acetamide 62 (20.0 g, 52.8 mmol) in anhydrous 1,4-dioxane (130 mL) was treated with 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 11.6 mL, 80.0 mmol) and triethylamine (16.0 g, 22.4 mL, 158.4 mmol) at room temperature, and the resulting reaction mixture was degassed three times under a steady stream of argon before being treated with dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (Pd(dppf)2Cl2, 1.32 g, 1.6 mmol, 0.03 equiv) at room temperature. The reaction mixture was then degassed three times again under a steady stream of argon before being heated to reflux for 7 h. When TLC and LCMS showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being treated with water (100 mL) and ethyl acetate (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×50 mL) and saturated aqueous NaCl solution (50 mL), dried over magnesium sulfate (MgSO4), and concentrated in vacuo. The residual brown oil was further dried in vacuo to afford the crude desired N-{3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide 81 (18.8 g, 20.0 g theoretical, 94%) as a brown solid which was of sufficient purity to be used in subsequent reactions.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[S:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:6][CH:5]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH2:22][CH2:21]1.CCN(CC)CC>CC#N>[N:17]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[S:10][C:9]=1[O:8][C:7]1[CH:18]=[CH:19][C:4]([CH2:3][N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])[CH2:24][CH2:25]2)=[CH:5][CH:6]=1
Reactant: O=C1CCCN1C1CCNCC1
Reactant: ClCc1ccc(Oc2nc3cccnc3s2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCCN1C1CCN(Cc2ccc(Oc3nc4cccnc4s3)cc2)CC1
Temperature: 60 °C
Reaction time: 6 h
Yield: 57.1 %

Procedure:
To a solution of 2-[4-(chloromethyl)phenoxy][1,3]thiazolo[5,4-b]pyridine hydrochloride (70 mg, 0.223 mmol) and 1-piperidin-4-yl-pyrrolidin-2-one (64 mg, 0.379 mmol, 1.7 equiv.) in CH3CN (1.3 mL) was added Et3N (110 μL, 0.759 mmol, 3.4 equiv.). The reaction was allowed to stir at 60° C. for 6 h. The solution was cooled to rt, filtered and purified using preparative reverse phase HPLC to afford the desired product as a cream-colored solid (52 mg, 57%). 1H NMR (600 MHz, DMSO-d6): 8.45 (dd, J=4.7, 1.5, 1H), 8.09 (dd, J=8.1, 1.5, 1H), 7.50 (dd, J=8.2, 4.8, 1H), 7.47-7.40 (m, 4H), 3.80-3.69 (m, 1H), 3.52 (s, 2H), 3.35-3.29 (m, 2H), 2.91-2.85 (m, 2H), 2.20 (t, J=8.1, 2H), 2.07-2.00 (m, 2H), 1.94-1.85 (m, 2H), 1.73-1.62 (m, 2H), 1.54-1.48 (m, 2H). MS (ESI): mass calcd. for C22H24N4O2S, 408.16; m/z found, 409.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:8][C:9]([C:12]([OH:14])=O)=[N:10][N:11]=2)[CH:2]=1.[NH2:15][CH2:16][CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[CH:24]=2)=[N:19]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][CH2:16][NH:15][C:12]([C:9]3[NH:10][N:11]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)=[O:14])[N:19]=2)=[CH:24][C:25]=1[CH3:31])#[N:28]
Reactant: O=C(O)C1=NN=C(c2cccnc2)C1
Reactant: Cc1cc(-c2ccn(CCN)n2)ccc1C#N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccn(CCNC(=O)c3cc(-c4cccnc4)n[nH]3)n2)ccc1C#N
Yield: 63.8 %

Procedure:
The title compound was prepared using the method of Example 31 using 5-pyridin-3-yl-4H-pyrazole-3-carboxylic acid (0.46 g; 2.43 mmol), 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-methylbenzonitrile (0.50 g; 2.21 mmol), HOBt (0.45 g; 3.31 mmol), EDCI (0.64 g; 3.31 mmol) and 0.58 ml (3.31 mmol) of DIPEA as starting materials. After workup the product was precipitated out from DCM to give 0.56 g (64%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 3.67-3.76 (m, 2H), 4.33-4.41 (m, 2H), 6.85 (d, 1H), 7.22 (s, 1H), 7.49 (dd, 1H), 7.74-7.82 (m, 2H), 7.83 (d, 1H), 7.88 (broad s, 1H), 8.10-8.18 (m, 1H), 8.44-8.58 (m, 2H), 9.00 (broad s, 1H), 13.82 (s, 1H).