Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([SH:8])=[N:5][N:4]=1.[H-].[Na+].Cl[C:12]1[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][N:17]=1>CN(C=O)C.C1C=CC=CC=1>[CH3:1][S:2][C:3]1[S:7][C:6]([S:8][C:12]2[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][N:17]=2)=[N:5][N:4]=1
Reactant: CSc1nnc(S)s1
Reactant: N#Cc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nnc(Sc2nccnc2C#N)s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(methylthio)-1,3,4-thiadiazole-2-thiol (821 mg, 5.0 mmol) in DMF and benzene (10 ml, 1/1) was added NaH (60% dispersion in mineral oil, 220 mg, 5.5 mmol) slowly at 0° C. under nitrogen atmosphere. The resulting suspension was stirred at 0° C. for 15 minutes and then to the mixture was added 3-chloropyrazine-2-carbonitrile (698 mg, 5.0 mmol). The reaction was stirred at 80° C. for 4 hr. The reaction was then cooled to room temperature and quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water, brine and dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography on silica gel to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:19][C:20]([CH3:26])([CH3:25])[C:21]([NH:23][NH2:24])=[O:22]>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:24]/[NH:23][C:21](=[O:22])[C:20]([CH3:26])([CH3:25])[CH3:19])/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Reactant: CC(C)(C)C(=O)NN
Product: CCCCCN1C(=O)/C(=N\NC(=O)C(C)(C)C)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 2,2-Dimethylpropionic acid hydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.36 to 1.39 (m, 13H), 1.69-1.75 (m, 2H), 3.70 (t, 2H), 3.87 (s, 3H), 6.42 (d, 1H), 6.62 (dd, 1H), 7.74 (d, 2H), 13.34 (br s, 1H).
Reaction SMILES: O1C=CC=C1.[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8].C([O-])(=O)C.[Na+].C(CC(=O)C)(=O)C.C(O)(=O)CC.O=O.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH:37]=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([O:10][C:6]([CH:7]=[CH:8][C:36]1[O:32][C:33]([CH:37]=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][CH:35]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)C=Cc1ccco1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: c1ccoc1
Solvent: CC(=O)CC(C)=O
Solvent: CCC(=O)O
Product: CCOC(=O)C=Cc1ccc(C=CC(=O)OCC)o1

Procedure:
In a flask, 3 mmol of furan, 1.5 mmol of ethyl acrylate, 0.1 mmol of palladium(II) acetate, 0.02 mmol of H7PMo8V4O40, 0.08 mmol of sodium acetate, 0.1 mmol of acetylacetone, and 5 ml of propionic acid were placed and were stirred at a constant temperature of 50° C. in an atmosphere of oxygen gas at 1 atm (0.1 MPa) for 3 hours. The resulting reaction mixture was analyzed by gas chromatography to find that ethyl 3-(2-furyl)acrylate and 2,5-bis(2-ethoxycarbonylethenyl)furan were produced in yields of 51%0 and 18%, respectively.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(=O)C1C=CC=NC=1.Cl.[CH3:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CCOCC>[CH:1]1[C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:15]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCC
Reactant: [Li]CCCC
Agent: Cl
Agent: O=Cc1cccnc1
Solvent: CCOCC
Product: c1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
36.1 ml (57.75 mmol) of 1.6 M n-butyllithium in hexane are added dropwise, under argon, to a stirred solution of 16.1 g (55 mmol) of 2-bromo-6-napthyl methyl ketone ethylene acetal in 120 ml of absolute ether at -70° C. The mixture is then allowed to reach 0° C. and is stirred for one hour. Then, at -30° C., 6.19 g (57.75 mmol, 5.45 ml) of nicotinaldehyde in 15 ml of absolute ether are added dropwise. The mixture is subsequently allowed to reach room temperature within one hour, and is stirred for a further hour. After acidification to pH 1 with 2 N HCl the mixture is stirred overnight. After separation of the phases, the aqueous phase is extracted once with ether, the ether phase is discarded, and the aqueous phase is neutralized with sodium bicarbonate solution, which is then extracted with ethyl acetate. After drying and evaporation, the residue is recrystallized from isopropanol. 9.2 g (60%) of 2-acetyl-6-(1-hydroxy-1-(3-pyridyl) methyl(naphthalene are obtained. Melting point 157°-9° C.
Reaction SMILES: [OH:1][CH:2]([CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:23])[N:10](COC(=O)C(C)(C)C)[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25].N>CO>[OH:1][CH:2]([CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:23])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC(O)CN1CCCC1
Agent: N
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCC(O)CN1CCCC1
Yield: 95.7 %

Procedure:
7-(2-Hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7.8 g) was stirred for 48 hours in a solution of methanol saturated with ammonia (200 ml). The solvent was evaporated and the solid obtained was washed with ether (2×) and ether/dichloromethane (95:5, 2×100 ml) to give the 7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (5.5 g).
Reaction SMILES: [O:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](F)=[CH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:10][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[CH:2][O:1][C:9]2=3)=[CH:15][CH:14]=1)#[N:12]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: OC1CNCc2ccoc21
Product: N#Cc1ccc(OC2CNCc3ccoc32)c2ccccc12

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 33) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-cyano-1-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O.[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][N:28]([C:31]2[C:36]([Cl:37])=[CH:35][C:34](Br)=[CH:33][N:32]=2)[C:29]=1[CH3:30])=[O:24])[CH3:21]>O>[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][N:28]([C:31]2[C:36]([Cl:37])=[CH:35][C:34]([CH:1]3[CH2:3][CH2:2]3)=[CH:33][N:32]=2)[C:29]=1[CH3:30])=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cnn(-c2ncc(Br)cc2Cl)c1C
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(-c2ncc(C3CC3)cc2Cl)c1C
Temperature: 100 °C
Reaction time: 6 h
Yield: 26.3 %

Procedure:
Cyclopropylboronic acid (269 mg), tripotassium phosphate (1.61 g) and 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (124 mg) were added to a N,N-dimethylformamide solution (15 ml) of 1-(5-bromo-3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.03 g) described in Reference Example 44(2), and the mixture was stirred at 100° C. for six hours. The reaction solution was cooled to room temperature, diluted with water, filtered through Celite and the filtrate was extracted with ethyl acetate three times. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(3-chloro-5-cyclopropylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (240 mg) as a pale yellow solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=1[O:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29].Cl.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[OH:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=1[O:26][C:27]([F:31])([F:32])[CH:28]([F:29])[F:30]
Reactant: CCOC(=O)C(Cc1ccc(Cl)c(OC(F)(F)C(F)F)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(Cl)c(OC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution of zinc chloride (4.0 g, 29.3 mmol) in diethyl ether (100 ml) was added sodium borohydride (2.22 g, 58.6 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off, and a solution of ethyl 2-((4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-3-(4-fluorophenyl)-3-oxopropionate (6.60 g, 14.6 mmol) in diethyl ether (50 ml) was added to the filtrate. The mixture was stirred at room temperature for 30 min. and 1N hydrochloric acid was added to the reaction solution under ice-cooling to quench the reaction. Then, water (200 ml) was added and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl(2RS,3RS)-2-((4-chloro-3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)-3-(4-fluorophenyl)-3-hydroxypropionate (5.85 g, 88%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27](I)=[C:4]2[N:3]=1.[F:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][C:34](B1OC(C)(C)C(C)(C)O1)=[CH:33]2.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>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].O.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:34]3[CH:35]=[N:36][C:37]4[C:32]([CH:33]=3)=[CH:31][C:30]([F:29])=[CH:39][CH:38]=4)=[C:4]2[N:3]=1
Reactant: CC1(C)OB(c2cnc3ccc(F)cc3c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(I)cnn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Temperature: 40 °C
Yield: 73 %

Procedure:
To 5-chloro-3-iodo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (example 19, step 1, 2.50 g, 4.52 mmol) was added 6-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (2.05 g, 4.52 mmol), K2CO3 (1.87 g, 13.56 mmol), PdCl2(dppf).CH2Cl2 (0.37 g, 0.45 mmol), dioxane (36 mL) and H2O (9 mL). The resulting mixture was heated at 40° C. for 16 hours, at which time LC/MS analysis confirmed full consumption of starting material. On cooling, H2O (20 mL) and CH2Cl2 (50 mL) were used to transfer the reaction mixture to a separatory funnel. Brine (30 mL) was added and organics were extracted with CH2Cl2 (4×50 mL), dried (Na2SO4) and concentrated in vacuo to give a black oil. Gradient column chromatography on silica eluting with 10% to 30% EtOAc/hexanes gave 5-chloro-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine as a light yellow solid (1.89 g, 3.30 mmol, 73%). LC/MS: 3.22 mins, m/z=574.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[N:9]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>O1CCCC1>[O:13]=[C:12]1[N:8]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:19](=[O:20])[N:9]2[CH:10]=[C:11]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)c1cnn(-c2ccccc2N)c1O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn2c(=O)[nH]c3ccccc3n2c1=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
24.7 g 1-(2-aminophenyl)-5-hydroxy-1H-pyrazole-4-carboxylic acid, ethyl ester and 16.2 g 1,1'-carbonyl-bis-[1H-imidazole] are dissolved in 300 ml tetrahydrofuran and stirred for 8 hours at room temperature and one hour at 90° C. The solid residue, after distilling off the solvent, is recrystallized from dimethylformamide to yield 21 g of 5,6-dihydro-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]-benzotriazine-2-carboxylic acid, ethyl ester having a melting point of 269°-271° C.; white-yellow crystals.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.CC1(C)[O:40][C:39](=O)[CH:38]([C:42]2[CH:46]=[CH:45][S:44][CH:43]=2)[C:37](=[O:47])[O:36]1>O1CCCC1>[C:37]([CH:38]([C:42]1[CH:46]=[CH:45][S:44][CH:43]=1)[C:39]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:40])([OH:47])=[O:36]
Reactant: CC1(C)OC(=O)C(c2ccsc2)C(=O)O1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: C1CCOC1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)O)c3ccsc3)[C@H]2SC1

Procedure:
To a suspension of 656.7 mg (2 mmol) of 7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (as prepared in example 9) in 25 ml. of anhydrous tetrahydrofuran there is added 1.6 ml. of bis-trimethylsilylacetamide. The mixture is stirred to give a solution to which there is added at once 452.5 mg (2 mmol) of 2.2-dimethyl-5-(3-thienyl)-1.3-dioxane-4.6-dione as prepared in example 6, the mixture being stirred at 25° C for 8 hours. Tetrahydrofuran is removed under reduced pressure and the residue is taken up with 30 ml. of water, brought to pH 2.5 with 0.5 ml. 6N HCl, stirred for 15 minutes and extracted three times with 25 ml. of ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and filtered over DARCO G60 (a product manufactured and sold by Atlas Chem. Ind.)-charcoal. Most of the solvent is evaporated under reduced pressure and 100 ml. of petroleum ether (50°-70° C) is added thereto. The suspension is stirred for 30 minutes and filtered. The precipitate is washed with 20 ml. of petroleum ether (50°-70° C) and dried over anhydrous P2O5 under reduced pressure to yield DL-7-[α-carboxy-α-(3-thienyl)-acetamido]-3-(1-methyl-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (RIT 3838).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>C(O)(=O)C>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]1[C:1](=[O:7])[CH:2]=[CH:3][C:4]1=[O:6]
Reactant: NCCCCCCO
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: O=C1C=CC(=O)N1CCCCCCO

Procedure:
One mole equivalent of maleic anhydride and one mole equivalent of 6-amino hexanol are dissolved in anhydrous acetic acid and the solution is heated under reflux for eight hours. The acetic acid is distilled off in a rotary evaporator. The residue is dissolved in diethyl ether and washed once with 1 N NaOH, and twice with water. After drying over MgSO4 and evaporating the diethyl ether, the residue is crystallized from isopropyl ether to produce N-(6-hydroxyhexyl) maleimide.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([C:44]([NH:46][CH3:47])=[O:45])[CH2:35][CH2:36][CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([C:44]([NH:46][CH3:47])=[O:45])[CH2:35][CH2:36][CH2:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(CCCC3CCCCC3)C(=O)NC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(N(CCCC3CCCCC3)C(=O)NC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-methylaminocarbonyl-N-(3-cyclohexyl-n-propyl)-amino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(N(CC)C(C)C)(C)C>>[C:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)(=[O:26])[CH2:24][CH3:25]
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1

Procedure:
Prepared according to Method E from 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol), propanoyl chloride (0.105 mL, 1.2 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) to give 0.284 g to the title compound as a white solid, mp 60–61° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:29]=[C:11]3[N:12]=[C:13]([CH3:28])[C:14]([C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24])=[C:15]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.[B]1OC2C(=CC=CC=2)O1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:29]=[C:11]3[N:12]=[C:13]([CH3:28])[C:14]([C@H:22]([OH:27])[C:23]([O:25][CH3:26])=[O:24])=[C:15]([CH:16]4[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C1CCCCC1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [B]1Oc2ccccc2O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C1CCCCC1
Temperature: -35 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a stirred solution of methyl 2-(2-(3-chlorophenyl)-7-cyclohexyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (0.094 g, 0.205 mmol) in toluene (3 mL) was added 1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (0.041 ml, 0.041 mmol) at rt and cooled to −35° C. To this was added dropwise 1M catecholborane/THF (0.288 ml, 0.288 mmol) over 10 min. After stirring 30 min, the reaction mixture was slowly warm to −15° C. over 30 min and diluted with EtOAc (15 mL). Then, the mixture was vigorously stirred with sat Na2CO3 (2 mL) for 45 min. The aq layer separated and org layer washed with sat sat Na2CO3 (2×5 mL), dried (Na2SO4), filtered, concentrated and the resulting yellow residue purified by prep-HPLC to afford (S)-methyl 2-(2-(3-chlorophenyl)-7-cyclohexyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.0705 g, 0.170 mmol, 83% yield) as yellow solid. LCMS (M+H) calcd for C22H25ClN3O3: 414.16. found: 414.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14]OS(C)(=O)=O)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:8].[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C=O)C>[N:21]([CH2:14][C@@H:12]1[O:11][C:10](=[O:20])[N:9]([C:4]2[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=2)[CH2:13]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 72.5 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of (5R)-methanesulfonic acid 3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (5, 290.0 g, 698.8 mmol) in anhydrous DMF (700 mL) was treated with sodium azide (NaN3, 90.84 g, 1.4 mol, 2.0 equiv) at 25° C., and the resulting mixture was subsequently warmed up to 70-75° C. for 6 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was cooled down to room temperature before being treated with H2O (1500 mL) and the resulting mixture was stirred at room temperature for 2 h. The solids were then collected by filtration, washed with H2O (2×500 mL), and dried in vacuo at 40° C. for 24 h to afford the crude, desired (5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-oxazolidin-2-one (1023, 248.0 g, 252.97 g theoretical, 98%) as white powders, which was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1023: 1H NMR. (300 MHz, DMSO-d6) δ 3.67-3.81 (m, 31H), 4.14 (t, 1H, J=5.4 Hz), 4.88-4.94 (m, 1H), 7.22 (dd, 1H, J=2.4, 8.7 Hz), 7.56 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (dd, 1H, J=7.5, 8.7 Hz); LCMS C10H8FIN4O2, LCMS (EI) m/e 363 (M++H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C@@H:12]([CH:16]([CH3:19])[CH2:17][CH3:18])[C:13](Cl)=[O:14]>>[Cl:11][C@@H:12]([CH:16]([CH3:19])[CH2:17][CH3:18])[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:14]
Reactant: CCC(C)[C@H](Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Product: CCC(C)[C@H](Cl)C(=O)Oc1ccc(C(=O)O)cc1

Procedure:
Using p-hydroxybenzoic acid (1.93 g, 14.0 mmol) and (S)-2-chloro-3-methylpentanoylchloride (2.28 g, 13.5 mmol), the reaction was carried out in the same manner as described in Example 4, (1), to give the title compound as white crystals; yield: 2.95 g; mp. 97.0°-100.5° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([I:11])=[C:9]([C:12]([NH:14][CH2:15][CH:16]([O:22]C(=O)C)[CH2:17][O:18]C(=O)C)=[O:13])[C:8]([I:26])=[C:7]([CH2:27][O:28]C(=O)C)[C:6]=1[I:32])(=[O:3])[CH3:2].[OH-].[Na+].Br[CH2:36][CH:37]([OH:40])[CH2:38][OH:39].Cl>CO.O>[C:1]([N:4]([CH2:36][CH:37]([OH:40])[CH2:38][OH:39])[C:5]1[C:10]([I:11])=[C:9]([C:12]([NH:14][CH2:15][CH:16]([OH:22])[CH2:17][OH:18])=[O:13])[C:8]([I:26])=[C:7]([CH2:27][OH:28])[C:6]=1[I:32])(=[O:3])[CH3:2]
Reactant: OCC(O)CBr
Reactant: CC(=O)Nc1c(I)c(COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)N(CC(O)CO)c1c(I)c(CO)c(I)c(C(=O)NCC(O)CO)c1I
Reaction time: 1 h

Procedure:
N-acetyl-3-acetoxymethyl-5-(2,3-diacetoxypropylaminocarbonyl)-2,4,6-triiodoaniline (1.0 g, 1.27 mmol) was suspended in a mixture of methanol (6 ml) and water (30 ml) and pH was adjusted to 12.0 using a 2 M aqueous solution of NaOH. After stirring for 1 h, 1-bromo-2,3-propanediol (0.99 g, 6.4 mmol) was added and the pH was adjusted to 11.6 using a 2 M aqueous solution of HCl. 1-Bromo-2,3-propanediol (0.99 g, 6.4 mmol) was again added after 16 and 18 h and after 24 h, pH was adjusted to 6.5 using a 2 M aqueous solution of HCl. After evaporation, the residue was purified by preparative HPLC. Yield: 0.373 g (40%).