Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>CO.[Pd]>[NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[CH2:3][O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)COC(C)(C)C

Procedure:
6.3 g of Z-Ser(tBu)-Asn-Leu-OMe are dissolved in 600 ml of methanol and hydrogenated in the presence of 1.2 g of palladium-charcoal (10 % Pd). After 1.25 hours the catalyst is filtered off and the solution evaporated to dryness in vacuo at 30°C bath temperature. The crystalline tripeptide derivative thereupon obtained shows Rf = 0.11 on thin layer chromatography on silica gel plates in the system chloroform-methanol (90:10).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([C:7]([N:9]=[C:10]=[O:11])=[O:8])=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(OCC)C.C(#N)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:13]=[CH:12][C:6]([C:7]([NH:9][C:10]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:11])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Cl)cc1
Solvent: CC#N
Solvent: CCOCC
Product: O=C(NC(=O)c1ccc(C(F)(F)F)cc1)Nc1ccc(Cl)cc1

Procedure:
To a stirred solution of 1.08 g of 4-trifluoromethylbenzoylisocyanate in 5 ml of dry diethylether is added a solution of 0.64 g of 4-chloroaniline in 50 ml of acetonitrile. A precipitate is immediately formed. The precipitate is sucked off and washed with acetonitrile. The title compound is obtained a yield of 1.1 g; melting point 260° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([NH:21][C:22]([NH:24][C:25]2[N:29]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)[N:28]=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)=[O:23])=[CH:13][CH:12]=1.[CH3:41][O:42][CH2:43][CH2:44][O:45][CH2:46][C:47](Cl)=[O:48]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:37]([C:27]1[CH:26]=[C:25]([NH:24][C:22](=[O:23])[NH:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([O:10][CH2:9][CH2:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][C:47](=[O:48])[CH2:46][O:45][CH2:44][CH2:43][O:42][CH3:41])=[CH:12][CH:13]=2)[N:29]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)[N:28]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccncc3N)c3ccccc23)cc1
Reactant: COCCOCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCCOCC(=O)Nc1cnccc1CCOc1ccc(NC(=O)Nc2cc(C(C)(C)C)nn2-c2ccc(C)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.2 %

Procedure:
To 1-(4-(2-(3-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate E) (50 mg, 0.094 mmol) and DMAP (5.71 mg, 0.047 mmol) in DCM (3.0 mL) was added 2-(2-methoxyethoxy)acetyl chloride (30 μl, 0.281 mmol) at 0° C. and the reaction mixture stirred at RT for 1.5 hr. The solvent was removed in vacuo and the residue subjected to SCX capture and release eluting with 1% NH3 in MeOH solution. The residue was purified by column chromatography (4.0 g) gradient elution with 0-8% MeOH in DCM and the product fractions concentrated in vacuo to give N-(4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)pyridin-3-yl)-2-(2-methoxyethoxy)acetamide (Example 22) as a light purple solid (35 mg, 56%): m/z 651 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.25 (9H, s), 2.40 (3H, s), 3.26 (5H, m), 3.50 (2H, m), 3.70 (2H, m), 4.15 (2H, s), 4.40 (2H, t), 6.35 (1H, s), 6.98 (1H, d), 7.35 (2H, m), 7.42 (2H, m), 7.50 (3H, m), 7.62 (1H, d), 7.87 (1H, d), 8.07 (1H, dd), 8.36 (1H, d), 8.56 (1H, br s), 8.60 (1H, s), 8.76 (1H, br s), 9.55 (1H, br s.).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5]([O:7]CC)=O.[C:12]([C:15]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[CH:16]=1)(=[O:14])[CH3:13]>O1CCCC1>[F:11][C:4]([F:3])([F:10])[C:5](=[O:7])[CH:13]=[C:12]([OH:14])[C:15]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]=2[CH:16]=1
Reactant: CC(=O)c1ccc2c(ccc3ccccc32)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=C(O)c1ccc2c(ccc3ccccc32)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
To a suspension of sodium hydride (NaH; 0.13 g, 5.4 mmol) in 5 mL of anhydrous tetrahydrofuran (THF) was added ethyl trifluoracetate (CF3COOEt; 0.64 g, 4.5 mmol) under argon. After stirring at 25° C. for 10 minutes, 2-acetylphenanthrene (1 g, 4.5 mmol) in 5 mL of THF was added dropwise to the solution. The mixture became clear and orange-hued within 30 minutes, and after stirring for an additional 2 hours, was concentrated under vacuum. The residue was suspended in water, and extracted with ethyl acetate (15 mL) twice. The organic phase was separated, dried over sodium sulfate, and concentrated to dryness under vacuum to give the product (yellow solid; 1.29 g, 90% yield). The product was used directly without further purification.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32]I)[C@@H:10]1[O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:42]([O:49]CC)([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45]>>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][P:42](=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])[C@@H:10]1[O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1CI
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O[Si](C)(C)C(C)(C)C)OCC
Yield: 83 %

Procedure:
A solution of (((2S,3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(iodomethyl)tetrahydro-2H-pyran-3-yl)oxy)(tert-butyl)dimethylsilane (4.0 g, 5.8 mmol, 1.0 equiv) in anhydrous triethyl phosphite (40 mL) was heated to 160° C. in a 100 mL sealed tube for 16 hours. The solvent was removed in vacuo and the resulting product was purified by silica gel chromatography, eluting with 30% EtOAc in petroleum ether, to give diethyl (((2S,3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methyl)phosphonate as a pale yellow oil (3.36 g, 83%). 1H NMR (300 MHz, CDCl3) δ 7.37-7.22 (m, 13H), 7.06 (dd, J=6.6, 3.0 Hz, 2H), 4.90-4.72 (m, 3H), 4.67-4.61 (m, 1H), 4.49 (d, J=4.3 Hz, 1H), 4.46 (d, J=2.9 Hz, 1H), 4.40 (d, J=7.1 Hz, 1H), 4.17-4.03 (m, 4H), 3.93-3.85 (m, 1H), 3.77 (d, J=9.9 Hz, 1H), 3.72-3.61 (m, 3H), 3.55-3.47 (m, 1H), 2.27-2.13 (m, 2H), 1.29 (td, J=7.1, 1.2 Hz, 6H), 0.90 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H). ESI (M+1) 699.2; calc for C38H55O8PSi 698.3.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CCCCCC>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: ClCCN1CCCC1
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc2c(c1)CCc1ccccc1C2CCN1CCCC1
Reaction time: 1 h

Procedure:
1.0 g of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene in 25 ml of dry tetrahydrofuran is treated dropwise at -70° with 6.8 ml of an about 1.14M solution of n-butyl lithium in hexane. The mixture is stirred at -70° for 60 minutes. There are subsequently added dropwise thereto at -30° 1.1 g of 2-chloroethylpyrrolidine in 2.5 ml of dry tetrahydrofuran and the mixture is stirred at -30° for 1 hour and at 0° to 5° for 3 hours. After evaporation of the mixture, the residue remaining is dissolved in toluene and washed with water. The organic phase is filtered over 10 g of aluminum oxide (activity grade II, neutral) using toluene for the elution. Crude 1-[2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidine is obtained as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].[O:16](S(C(F)(F)F)(=O)=O)[S:17]([C:20]([F:23])([F:22])[F:21])(=O)=[O:18]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[S:17]([O:8][C:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][C:4](=[O:9])[CH:5]=1)(=[O:18])=[O:16]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1CC(=O)CC(=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1CC(=O)C=C(OS(=O)(=O)C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 5-methylcyclohexane-1,3-dione (1.0 equiv.) in DCM (0.5 M) was added Na2CO3 (1.1 equiv.) and cooled to 0° C. Added Tf2O (1.0 equiv.) in DCM (5.0 M) dropwise over 1 hr at 0° C. under a nitrogen atmosphere. Upon addition, the reaction was stirred for 1 hr at room temperature (dark red solution). The solution was filtered and the filtrate was quenched by careful addition of saturated NaHCO3 with vigorous stirring until pH=7. The solution was transferred to a separatory funnel and the layers were separated. The organic layer was washed with brine, dried with Na2SO4, filtered, concentrated under vacuo and dried under high vacuum for 15 min to yield 5-methyl-3-oxocyclohex-1-enyl trifluoromethanesulfonate as light yellow oil in 78% yield. The triflate decomposes upon storage and should be used immediately for the next reaction. LC/MS=259.1/300.1 (M+H and M+CH3CN); Rt=0.86 min, LC=3.84 min. 1H-NMR (400 MHz, CDCl3) δ ppm: 6.05 (s, 1H), 2.70 (dd, J=17.2, 4.3, 1H), 2.53 (dd, J=16.6, 3.7, 1H), 2.48-2.31 (m, 2H), 2.16 (dd, J=16.4, 11.7, 1H), 1.16 (d, J=5.9, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](OC)=[O:9])=[CH:6][N:5]=[C:4]([Cl:12])[C:3]=1[F:13].O.[NH2:15][NH2:16]>C(O)C>[Cl:12][C:4]1[N:5]=[CH:6][C:7]2[C:8](=[O:9])[NH:15][NH:16][C:2]=2[C:3]=1[F:13]
Reactant: COC(=O)c1cnc(Cl)c(F)c1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH][nH]c2c(F)c(Cl)ncc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Methyl 4,6-dichloro-5-fluoronicotinate (5.0 g, 22.32 mmol) and hydrazine monohydrate (1.7 mL, 22.32 mmol) were dissolved in ethanol (5 mL) and stirred at 80° C. for 1 h. The reaction mixture was filtered, dissolved in MeOH, and HCl (1 N, 0.5 mL) was added. The reaction was stirred at room temperature for 4 h. The reaction mixture was then filtered and washed with water to give 6-chloro-7-fluoro-1H-pyrazolo[4,3-c]pyridin-3(2H)-one, which was carried onto the next step without further purification. MS ESI calc'd. for C6H13ClFN3O [M+1]+ 188. found 188.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=O)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C1CCC(N=C=NC2CCCCC2)CC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:13])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)c1cc2c(Cl)cccc2s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1cc2c(Cl)cccc2s1
Yield: 74.9 %

Procedure:
Stir a mixture of 4-chlorobenzo[b]thiophene-2-carboxylic acid (0.94 g, 4.44 mmol), N,O-dimethylhydroxylamine hydrochloride (0.86 g, 8.87 mmol), DCC (1.1 g, 5.32 mmol) and DIEA (1.43 g, 1.9 mL, 11.08 mmol) in DCM (8 mL) at ambient temperature for 2 hours. Filter the reaction mixture and the filtrate is washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by column chromatography on silica gel eluting with PE: EtOAc (5:1 to 3:1) to afford 4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide as white solid (0.85 g, 75.2%). 1H NMR (400 MHz, CDCl3) δ 8.10-8.02 (m, 2H), 7.61-7.51 (m, 2H), 3.84-3.79 (s, 3H), 3.37-3.35 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O:14]C)(C)(C)[CH3:11]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([NH:1][C:10](=[O:14])[CH3:11])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: COC(C)(C)C
Product: CC(=O)Nc1cc(Cl)ccc1O
Temperature: 22.5 °C
Reaction time: 0.67 h
Yield: 92 %

Procedure:
143.6 g (1 mole) of 2-amino-4-chlorphenol was suspended in 550 ml of methyl t-butyl ether under mild nitrogen purge. The mixture was heated to reflux until the material was dissolved. After 40 minutes, 112.3 g of acetic anhydride was added. After the addition the mixture was cooled to 20-25° C. in one hour. After stirring for an additional hour the mixture was cooled to 0-5° C. under stirring and kept on this temperature for an additional hour. The product was filtered off, washed with 200 ml of methyl t-butyl ether twice and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 92%.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][N:4]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>ClC(Cl)C.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:13][C:14]([S:17](/[N:19]=[CH:9]\[C:6]1[CH:5]=[N:4][C:3]([C:2]([F:12])([F:11])[F:1])=[N:8][CH:7]=1)=[O:18])([CH3:16])[CH3:15]
Reactant: O=Cc1cnc(C(F)(F)F)nc1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(Cl)Cl
Product: CC(C)(C)S(=O)/N=C\c1cnc(C(F)(F)F)nc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
To a solution of 2-(trifluoromethyl)pyrimidine-5-carbaldehyde (27.2 g, 99 mmol) in dichloroethane (250 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (13.3 g, 109.0 mmol) and copper(II) sulfate (31.5 g, 197.0 mmol). The mixture was heated to 50° C. After 18 h, the mixture was cooled to ambient temperature and filtered through a pad of silica gel. The filtered cake was washed with dichloromethane and the filtrate was concentrated to give the title compound (27.3 g). MS 224 [(M+1)−56].
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:15]([CH:19]=1)[C:16](O)=[O:17])[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71]>CN(C=O)C>[CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:15]([CH:19]=1)[C:16]([NH:68][C:69]([CH3:73])([CH3:72])[CH2:70][OH:71])=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(N)CO
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(=O)NC(C)(C)CO)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
To a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-benzoic acid (0.203 mmol, 94.9 mg), HBTU (0.203 mmol, 79.3 mg), diisopropyl ethyl amine (0.34 mmol, 0.0592 mL) in DMF (1 mL) was added 2-amino-2-methyl-propan-1-ol (0.45 mmol, 42.2 mg). It was stirred at room temperature for 20 min. The reaction mixture was partitioned between ethyl acetate (12 mL) and saturated aq. sodium bicarbonate solution (12 mL). The ethyl acetate layer was washed again with saturated aq. sodium bicarbonate solution (2×12 mL) and dried over sodium sulfate. The organic solvents were removed in vacuo to give 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide (87.7 mg).
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:6].[CH3:19]COCC>CC(O)=O>[I:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([O:16][CH3:19])=[O:15])=[CH:9][CH:8]=1)=[O:6]
Reactant: CCOCC
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCI)cc1
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)c1ccc(C(=O)CCCI)cc1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 12.6 g of 4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid, prepared in accordance with Example 3, in 100 mL of Et2O cooled in an ice bath, was added 40 mL of ethereal CH2N2. The mixture was stirred at 0 C. for few minutes, then let stand for 2 hr. A few drops of AcOH were added to decompose excess CH2N2, then the mixture was filtered and stripped to afford 12.6 g (96%) of methyl 4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetate.
Reaction SMILES: [P:1]([OH:9])([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2].[CH2:10]1[O:12][CH2:11]1>>[P:1]([O:9][CH2:10][CH2:11][OH:12])([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOP(=O)(O)OCC
Reactant: C1CO1
Product: CCOP(=O)(OCC)OCCO
Reaction time: 3 h

Procedure:
A 2 liter, 3-necked flask was equipped with a Dewar condenser, gas inlet and stirring bar. 875 grams (5.7 mole) of diethyl hydrogen phosphate was placed into the flask and about 400 grams of ethylene oxide were added over a 4 hour period. When the exotherm slowed, (pot temperature 50° C.) acid number=70. After the exotherm ceased and temperature dropped to 40° C., acid number=about 50. After refluxing of the ethylene oxide at 50° C. for 1 hour, acid number=about 18, after 3 hours at 50° C. acid number=about 7. All the above acid numbers were based on methyl red end point titration. The total yield was 1171 grams. Approximately half of the product was then wipe film distilled at 80° C. and 0.5 millimeter Hg. NMR data showed a compound having the formula: ##STR28## acid number=1.7 to methyl red, 6.7 to PNB HCl acid to methyl red=14.3 to phenolphthalein=16.3 H2O acid number=4.8 to methyl red HCl/H2O acid number=12.6 to methyl red Thus, the compound had the structure ##STR29##
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:33][C:34]#[C:35][CH3:36])[C:4]([C:11]([N:13]([CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[NH:14]C(OC(C)(C)C)=O)=[O:12])=[C:5]([C:7]([O:9]C)=O)[N:6]=1.Cl>C(OCC)(=O)C.O1CCOCC1>[CH2:33]([N:3]1[C:4]2[C:11](=[O:12])[N:13]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[NH:14][C:7](=[O:9])[C:5]=2[N:6]=[C:2]1[Cl:1])[C:34]#[C:35][CH3:36]
Reactant: CC#CCn1c(Cl)nc(C(=O)OC)c1C(=O)N(Cc1ccc2ccccc2n1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC#CCn1c(Cl)nc2c(=O)[nH]n(Cc3ccc4ccccc4n3)c(=O)c21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2.80 g methyl 2-chloro-5-[N′-tert-butoxycarbonyl-N-(quinolin-2-ylmethyl)-hydrazinocarbonyl]-1-(but-2-ynyl)-1H-imidazol-4-carboxylate are dissolved in 50 ml of ethyl acetate. Then 1.5 ml of 4 M hydrochloric acid in dioxane are added, and the solution is stirred for 2 h at 50° C. Then the solution is cooled to ambient temperature, the precipitate formed is separated off, washed with ethyl acetate and diethyl ether and dried in the drying cupboard at 50° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.O([CH2:26][C:27]([F:30])([F:29])[F:28])S(C(F)(F)F)(=O)=O>O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:6]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 103.5 %

Procedure:
A mixture of 4-iodo-pyrazole (582 mg, 3.0 mmole) and cesium carbonate (1.96 g, 6.0 mmole) was stirred with DMF (6 mL) for 5 minutes. Trifluoroethyl triflate (0.52 mL, 870 mg, 3.75 mmole) was added and the reaction was stirred at room temperature for 4.5 hours. The reaction was added to water (60 mL) and extracted with ether (3×25 mL). The combined organic extracts were washed with water (3×20 mL) and with brine; then dried (MgSO4) and evaporated to afford the title compound (857 mg, 89%). 1H-NMR (CDCl3, 500 MHz): δ 4.72 (q, J=8.20, 2H), 7.58 (s, 1H), 7.61 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:17]([NH:1][C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2nc(-c3ccccc3)oc2n1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2nc(-c3ccccc3)oc2n1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 80 mg. of 5-amino-2-phenyloxazolo[5,4-b]pyridine in 1 ml. of pyridine was treated with 0.07 ml. of benzoyl chloride. After standing 1 hour the mixture was diluted with ice-water. The precipitate was collected and recrystallized from methanol to give 5-benzoylamino-2-phenyloxazolo[5,4-b]pyridine, m.p. 191°-192° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][NH2:41]>C1COCC1.CCOC(C)=O>[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][NH:41][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: COCCOCCN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOCCNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 68.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 2-(2-methoxy-ethoxy)-ethylamine [CAS-no. 31576-51-9] (0.244 mg, 2.04 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.160 g, 68%) as a light yellow oil. MS (ISP) 572.2 [(M+H)+].
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([CH2:11][O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:5]=1>CCO.C(#N)C>[Cl:3][C:4]1[N:9]=[C:8]([NH:2][CH3:1])[CH:7]=[C:6]([CH2:11][O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[N:5]=1
Reactant: Clc1cc(COCC2CC2)nc(Cl)n1
Reactant: CN
Solvent: CC#N
Solvent: CCO
Product: CNc1cc(COCC2CC2)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanamine (0.124 mL, 0.99 mmol) in EtOH was added to a solution of 2,4-dichloro-6-((cyclopropylmethoxy)methyl)pyrimidine (77 mg, 0.33 mmol) in acetonitrile (6 mL). The mixture was stirred at 0° C. for 30 minutes. The mixture was concentrated and the residue was purified by preparative HPLC give the title compound, 42 mg (56%).