Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH:67]1[CH2:72][CH2:71][CH:70]([N:73]2[CH2:78][CH2:77][O:76][CH2:75][CH2:74]2)[CH2:69][CH2:68]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:67]3[CH2:72][CH2:71][CH:70]([N:73]4[CH2:78][CH2:77][O:76][CH2:75][CH2:74]4)[CH2:69][CH2:68]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn(CC(=O)N2CCC(N3CCOCC3)CC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (2 mL) was added HATU (100 mg, 0.26 mmol), DIEA (85 mg, 0.66 mmol), and 4-(piperidin-4-yl)morpholine hydrochloride (67 mg, 0.32 mmol). The resulting solution was stirred at room temperature overnight. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)): Column, XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mM NH4CO3 and MeCN (20.0% MeCN up to 35.0% in 8 min); Detector, 254/220. This resulted in 28.3 mg (21%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[4-(morpholin-4-yl)piperidin-1-yl]-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid. LCMS (Method 20) [M+H]+=615.2, RT=1.84 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.24-5.21 (m, 2H), 4.42-4.31 (m, 1H), 4.02-3.95 (m, 1H), 3.55 (t, 4H, J=4.5 Hz), 3.16-3.02 (m, 1H), 2.78-2.64 (m, 1H), 2.49-2.45 (m, 5H), 1.90-1.76 (m, 2H), 1.54-1.21 (m, 2H).
Reaction SMILES: C(OC)(=O)[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:36]=[CH:35][C:24](C(OCC2C=CC=CC=2)=O)=[CH:23][CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C=O)C.C(Cl)Cl>[C:6]([NH:20][C:21]1[CH:36]=[CH:35][CH:24]=[CH:23][CH:22]=1)(=[O:8])[C:5]1[CH:4]=[CH:3][CH:2]=[CH:10][CH:9]=1
Reactant: Nc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 134.8 %

Procedure:
A solution of mono-methyl terephthalate (4.00 g, 22 mmol) in ethyl acetate (25 mL) and DMF (0.1 mL) was cooled in an ice bath and treated with oxalyl chloride (11 mL, 2N in CH2Cl2, 22 mmol) over 30 minutes. After stirring 2 hours at room temperature the solvent was removed on a rotary evaporator and the residue dissolved in CH2Cl2 (20 mL) and added to a solution of benzyl 4-aminobenzoate (5.00 g, 22 mmol) in CH2Cl2 (25 mL) and triethylamine (4.3 mL, 31 mmol) at −60° C. The reaction mixture was warmed to room temperature for 1 hour and then partitioned between water and ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered, and evaporated. The residue was recrystallized from t-butyl methyl ether to give 5.85 g of compound 8.
Reaction SMILES: [CH2:1]([C:4]1([CH3:22])[C:8]2[N:9]=[C:10]([Cl:19])[N:11]=[C:12]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:7]=2[N:6]([CH3:20])[C:5]1=[O:21])[CH:2]=C.C[N+]1([O-])CC[O:27]CC1.S([O-])([O-])=O.[Na+].[Na+].I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O.C(O)CCC>[Cl:19][C:10]1[N:11]=[C:12]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:7]2[N:6]([CH3:20])[C:5](=[O:21])[C:4]([CH2:1][CH:2]=[O:27])([CH3:22])[C:8]=2[N:9]=1
Reactant: C=CCC1(C)C(=O)N(C)c2c(N3CCOCC3)nc(Cl)nc21
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: C1CCOC1
Product: CN1C(=O)C(C)(CC=O)c2nc(Cl)nc(N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a stirred solution of 7-allyl-2-chloro-5,7-dimethyl-4-morpholino-5H-pyrrolo[3,2-d]pyrimidin-6(7H)-one (80.0 mg, 0.25 mmol) in anhydrous THF (3.0 m) and water (1.0 mL) cooled to 0° C. was added N-methylmorpholine N-oxide (34.8 mg, 0.29 mmol), followed by 2.5% osmium tetraoxide in tent-butanol. (0.033 mL, 0.025 mmol). The reaction mixture was stirred at ambient temperature under N2 for 16 h. Sodium sulfite (312.4 mg, 2.48 mmol) was then added, and the reaction mixture was stirred at RT for 20 min. The reaction mixture was diluted with water and then extracted with ethyl acetate (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude intermediate was then diluted with anhydrous THF (3.0 mL) and water (1.0). Sodium periodate (79.5 mg, 0.372 mmol) was added, and the reaction mixture was sonicated for 1 minute and then stirred at RT for 2 days. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 80.4 mg (99%) of 2-(2-chloro-5,7-dimethyl-4-morpholino-6-oxo-6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)acetaldehyde. MS(ESI) m/z: 325.1 [M+1]−.
Reaction SMILES: O[CH:2]1[CH:7]([CH2:8][CH2:9][O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][N:4]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:3]1.C(N(CC)CC)C.[C:39](Cl)(=[O:42])[CH2:40][CH3:41].O>C(Cl)Cl>[C:39]([C@H:2]1[C@H:7]([CH2:8][CH2:9][O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5][N:4]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:3]1)(=[O:42])[CH2:40][CH3:41]
Reactant: OC1CN(Cc2ccc(F)cc2)CCC1CCOC(c1ccccc1)c1ccccc1
Reactant: CCC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)[C@@H]1CN(Cc2ccc(F)cc2)CC[C@H]1CCOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 61 mg 3-hydroxy-4-[2-(diphenylmethoxy)ethyl]-1-[(4-fluorophenyl)methyl]piperidine (0.15 mmol) and 21 mg triethylamine (0.23 mmol, 1.5 equiv) in 2 mL CH2Cl2 cooled in an ice bath was added dropwise 18 mg propionyl chloride (0.19 mmol, 1.3 equiv) and the reaction was allowed to warm to RT. After 1 hr, the same quantities of triethylamine and propionyl chloride were added. After 1 hr, H2O was added and the organic layer was separated, dried (MgSO4) and evaporated. The remaining residue was chromatographed (SiO2; CH2Cl2/MeOH) to yield the title compound as the free base (53 mg, 77%). 1H NMR (CdCl3 ∂ 1.1 (3H, t, J=8.1 Hz), 1.26-1.95 (7H, m), 2.26 (2H, q, J=7.2 and 7.5 Hz), 2.71 (1H, d, J=11.7 Hz), 3.02 (1H, d, J=10.5 Hz), 3.41-3.52 (4H, m), 4.67 (1H, t, J=9.6 Hz), 5.31 (1H, s), 6.98 (2H, t, J=9.3 Hz), 7.2-7.4 (12H, m). This was then reacted in a mixture of 2 mL 50% EtOH/Et2O with oxalic acid dihydrate (15.4 mg, 1.1 equiv) to furnish the title compound. mp ° C. Elemental analysis calculated for C32H36NO7F-0.5H2O: C, 67.43; H, 6.41; N, 2.46. Found: C, 67.34; H, 6.43; N, 2.44.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:14][CH2:13]1)[CH:7]=O)([O-:3])=[O:2].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26]C1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][N:24]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:14][CH2:13]1)([O-:3])=[O:2]
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cc(CN2CCCC2)ccc1N1CCC(CN2CCCC2)CC1

Procedure:
Prepared from the product of Example 64 and piperidine.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]2[N:22]=[C:23]([NH2:25])[CH:24]=[C:18]2[CH2:17]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCOCC1>[Br:8][C:6]1[CH:7]=[C:2]([NH:25][C:23]2[CH:24]=[C:18]3[CH2:17][N:16]([CH2:15][CH2:14][CH2:13][O:12][CH3:11])[CH2:21][CH2:20][N:19]3[N:22]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: COCCCN1CCn2nc(N)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: COCCCN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 42.1 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 3,5-dibromo-1-methylpyridin-2(1H)-one (320 mg, 1.2 mmol), 309b (250 mg, 1.2 mmol), tris(dibenzylideneacetone) dipalladium(0) (55 mg, 0.060 mmol), xantphos (70 mg, 0.12 mmol), cesium carbonate (782 mg, 2.4 mmol), and 1,4-dioxane (20 mL). The system was subjected to three cycles of vacuum/argon flush and heated at 100° C. for 5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 309c (200 mg, 42%) as yellow solid. MS-ESI: [M+H]+ 396.2
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:11][C:12]1[CH:35]=[CH:34][C:15]2[O:16][C:17]3[CH:33]=[CH:32][CH:31]=[CH:30][C:18]=3[CH2:19][CH2:20][N:21]([C:25](OCC)=O)[CH2:22][CH2:23][O:24][C:14]=2[CH:13]=1.[OH-].[Na+]>C(OCC)C.O1CCCC1>[Cl:11][C:12]1[CH:35]=[CH:34][C:15]2[O:16][C:17]3[CH:33]=[CH:32][CH:31]=[CH:30][C:18]=3[CH2:19][CH2:20][N:21]([CH3:25])[CH2:22][CH2:23][O:24][C:14]=2[CH:13]=1
Reactant: CCOC(=O)N1CCOc2cc(Cl)ccc2Oc2ccccc2CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CCOc2cc(Cl)ccc2Oc2ccccc2CC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3.13 g of aluminum trichloride in 110 ml of diethyl ether was added to a suspension of 1.56 g lithium aluminum hydride in 110 ml of diethyl ether and then cooled to approx. 5° C., after which a solution of 4.27 g of ethyl 3-chloro-7,8,9,10-tetrahydro-6H-dibenzo[b,j][1,4,7]dioxaazacycloundecine-8-carboxylate 92 ml of tetrahydrofuran was slowly added. After 1 h the aluminum complex was decomposed by addition of 21 ml of 1N sodium hydroxide solution. After 30 min stirring the salts were removed with suction and rinsed with dichloromethane. After evaporation of the solvent 3.6 g of crude product was obtained, which was purified by silica chromatography with toluene-ethanol (9:1) to obtain pure 3-chloro-7,8,9,10-tetrahydro-8-methyl-6H-dibenzo[b,j][1,4,7]dioxaazacycloundecine. After conversion into the maleate and recrystallization from ethanol-diethylether 2.6 g (52%) of 3-chloro-7,8,9,10-tetrahydro-8-methyl-6H-dibenzo[b,j][1,4,7]dioxaazacycloundecine (Z)-2-butenedioate (1:1), mp 145°-157° C., was obtained.
Reaction SMILES: [ClH:1].Cl.Cl.C([O:11][C:12]([C:14]1([C:17](=[O:49])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:35]4[CH2:40][CH2:39][CH:38]([N:41]5[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]5)[CH2:37][CH2:36]4)=[O:34])[CH:27]=3)=[CH:21][C:20]=2[F:48])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1>O.C(O)C.[Pd]>[ClH:1].[ClH:1].[ClH:1].[F:48][C:20]1[CH:21]=[C:22]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:42][CH2:43][N:44]([CH3:47])[CH2:45][CH2:46]4)[CH2:37][CH2:36]3)=[O:34])[CH:27]=2)[CH:23]=[CH:24][C:19]=1[NH:18][C:17]([C:14]1([C:12]([OH:13])=[O:11])[CH2:16][CH2:15]1)=[O:49]
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)OCc6ccccc6)CC5)c(F)c4)ccn3)CC2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)O)CC5)c(F)c4)ccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 266.4 %

Procedure:
1-[2-Fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid benzyl ester trihydrochloride (2 g) was dissolved in a mixed solvent of water (4 ml) and ethanol (8 ml), palladium on carbon (100 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (ca. 1 atmospheric pressure) for 5 hours and 10 minutes. The reaction mixture was filtered, and the residue was washed with a mixed solvent of water (1 ml) and ethanol (2 ml). Ethanol (20 ml) was added to the filtrate, which was concentrated. Addition of ethanol (10 ml) to the residue and subsequent concentrate were repeated four times. The mixture was filtered with heating and ethyl acetate (40 ml) was added dropwise with stirring at the same time. After stirring at room temperature for 25 hours and 30 minutes, the crystals were filtered with washing with a mixed solvent of ethanol (2 ml) and ethyl acetate (2 ml) and dried to give the title compound (1.56 g) as a white solid.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[CH2:13]1[O:23][C:22]2[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][C:15]=2[O:14]1>CN(C=O)C.C(Cl)Cl.C(OCC)(=O)C>[O:23]1[C:22]2[CH:21]=[CH:20][C:17]([CH2:18][N:4]3[C:5](=[O:6])[C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=4[S:1]3(=[O:2])=[O:3])=[CH:16][C:15]=2[O:14][CH2:13]1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: ClCc1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
To saccharin (5.0 g, 0.0273 mol) in DMF (10 mL) was added Nail (1.15 g, 60% in oil, 0.0288 mol) with ice bath cooling. After stirring for 10 minutes. a solution of 3,4-methylenedioxybenzyl chloride in methylene chloride, 50% by weight, (10 g, 0.0293 mol) was added and the mixture stirred for 16 hours. The mixture was diluted with ethyl acetate (200 mL) containing 10% methylene chloride and washed with IN HCl (2×100 mL). The organic phase was washed with brine and dried over MgSO4. The mixture was concentrated until crystals were apparent. After standing for 16 hours the product was collected by filtration (4.2 g, 49%);
Reaction SMILES: C(N1CCOCC1)C.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:24][C@H:25]([C:38]([O:40][CH3:41])=[O:39])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:29][CH:28]=1.Cl.[NH:43]([C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])[C@H:44]([C:48](O)=[O:49])[CH:45]([CH3:47])[CH3:46].ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH:43]([C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])[C@H:44]([C:48]([NH:24][C@H:25]([C:38]([O:40][CH3:41])=[O:39])[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[CH:31][CH:32]=1)=[O:49])[CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
19.5 ml (approx. 150 mmoles) of N-ethylmorpholine and 33 g (160 mmoles) of DCC are added at 0° C. to a solution in 250 ml of dimethylformamide of 43.15 g (150 mmoles) of H-Tyr(But)-OMe.HCl, 37.65 g (150 mmoles) of Z-Val-OH and 20.25 g (150 mmoles) of 1-hydroxybenzotriazole. The mixture is stirred for 1 hour at 0° C. and is allowed to stand overnight at room temperature. The precipitate which has deposited is filtered off. It is rinsed with a little dimethylformamide. The filtrate is introduced into a mixture of 150 ml of saturated NaHCO3 solution and 3,000 ml of water, while stirring. The mixture is cooled to 4° C. and the precipitate is filtered off. It is washed thoroughly with water. While still wet, the product is dissolved in 400 ml of ethyl acetate. Insoluble matter is filtered off and water is separated off in a separating funnel. The ethyl acetate phase is dried over Na2SO4 and concentrated. The residue is triturated with petroleum ether and the product is filtered off. Yield 67 g (92%). Melting point 111°-112°, [α]D21 =-15.9° (c=1, methanol).
Reaction SMILES: C([O:5][CH2:6][C@@H:7]([NH:22][C:23](=[O:36])[C:24]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=1)[CH2:8][CH2:9][N:10]1[CH2:13][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:11]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:12]2[CH2:11][N:10]([CH2:9][CH2:8][C@H:7]([NH:22][C:23](=[O:36])[C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[CH2:6][OH:5])[CH2:13]2)=[CH:16][CH:17]=1
Reactant: COc1cc(C(=O)N[C@@H](CCN2CC(Oc3ccc(F)cc3)C2)COC(C)(C)C)cc(OC)c1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@H](CO)CCN2CC(Oc3ccc(F)cc3)C2)cc(OC)c1OC
Reaction time: 20 h

Procedure:
A solution of N-{(S)-1-tert-butoxymethyl-3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-3,4,5-trimethoxy-benzamide (Example 1, 0.066 g, 0.130 mmol) in dichloromethane (2 ml) is treated with trifluoroacetic acid (0.11 ml, 0.65 mmol) and the reaction mixture stirred for 20 hours. The solvent is evaporated and the residue partitioned between ethylacetate and saturated aqueous NaHCO3. The ethylacetate phase is washed with brine, dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography (elution 100% ethylacetate then 5:95 methanol/dichloromethane) to afford N-{(S)-3-[3-(4-fluorophenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3,4,5-trimethoxy-benzamide [MH]+ 449.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]3[CH:13]([C:14](=[O:17])[NH:15][N:16]=2)[CH2:12]3)[CH:7]=[CH:8][CH:9]=1)([O-])=O.C1CCCCC=1>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]3[CH:13]([C:14](=[O:17])[NH:15][N:16]=2)[CH2:12]3)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1NN=C(c2cccc([N+](=O)[O-])c2)C2CC12
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Nc1cccc(C2=NNC(=O)C3CC23)c1
Yield: 47.9 %

Procedure:
20.4 g (88.2 millimoles) of 2-(m-nitrophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 32b), 300 ml of ethanol, 150 ml of cyclohexene and 4.2 g of 10% strength palladium on charcoal are refluxed for 12 hours. The catalyst is filtered off, the filtrate is concentrated and the residue is recrystallized from ethyl acetate/methanol. 8.5 g (48% of theory) of 2-(m-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as beige crystals, of melting point 192°-193° C.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]#N.CC[O-].[Na+].Cl.[C:13]([O:17][C:18](=[O:26])[NH:19][C:20]1([C:23](=[NH:25])[NH2:24])[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].[NH4+].[Cl-].N>CCO.CCOC(C)=O>[C:13]([O:17][C:18](=[O:26])[NH:19][C:20]1([C:23]2[N:24]=[C:3]([NH2:2])[CH:4]=[CH:5][N:25]=2)[CH2:22][CH2:21]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC1(C(=N)N)CC1
Reactant: CN(C)C=CC#N
Agent: CC[O-]
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2nccc(N)n2)CC1
Reaction time: 1 h
Yield: 46.3 %

Procedure:
3-Dimethylamino-acrylonitrile (0.05 mL, 0.50 mmol) was dissolved in EtOH (1 mL) and NaOEt solution (21 wt % in EtOH, 0.19 mL, 0.50 mmol) was added. This was stirred for 1 h and then (1-Carbamimidoyl-cyclopropyl)-carbamic acid tert-butyl ester hydrochloride (50 mg, 0.25 mmol) was added. The reaction was stirred for 1.5 h at 60° C. and then solid NH4Cl (27 mg, 0.50 mmol) and NH3 (7 M in MeOH, 0.50 mL, 3.5 mmol) were added and stirring was continued at 60° C. for 1 h and then at 100° C. for 17 h. Additional 3-dimethylamino-acrylonitrile (0.1 mL, 0.87 mmol) was added to the reaction and stirring was continued at 100° C. for 22 h. The solvent was removed under a stream of N2 and the residue was directly purified by reversed phase HPLC (20% MeCN/H2O+0.1% TFA) to give a red semisolid that was neutralized by dissolving in EtOAc (5 mL) and washing with saturated aqueous NaHCO3 (2×5 mL). The organic phase was dried with Na2SO4 and concentrated to give 29 mg of the title compound as a red semisolid, m/z 251.44 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10](O)=[O:11])[N:5]=[CH:4][C:3]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27].[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH2:13][CH:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:10]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:11])[N:5]=[CH:4][C:3]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27]
Reactant: O=C(O)C(CC1CCOCC1)n1ncc(Oc2ccccc2Cl)c(Cl)c1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3ccccc3Cl)c(Cl)c2=O)n1

Procedure:
Using the method described in Example 49 from 2-[5-chloro-4-(2-chloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (Intermediate 96) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[5-chloro-4-(2-chloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (354 mg); ES+-HRMS m/e calcd for C25H29N5O5Cl2 [M+H+] 550.1619 found 550.1622. 1H NMR (300 MHz, CDCl3) δ ppm 1.17 (s, 6H), 1.22-1.55 (m, 4H), 1.55-1.77 (m, 2H), 2.10-2.25 (m, 2H), 3.24-3.41 (m, 2H), 3.86-3.96 (m, 2H), 3.98 (s, 2H), 5.75 (t, J=7.5 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H), 7.23-7.26 (m, 1H), 7.29-7.35 (m, 2H), 7.35-7.43 (m, 1H), 7.49 (s, 1H), 7.54 (d, J=7.8 Hz, 1H), 8.74 (br. s., 1H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[CH:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:32][CH2:31]2)=[O:24])=[N:19][CH:20]=1)=[O:14])(C)(C)C>ClCCl>[C:13]([C:15]1[CH:16]=[CH:17][C:18]([CH:21]=[CH:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:31][CH2:32][N:33]([CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:34][CH2:35]2)=[O:24])=[N:19][CH:20]=1)([OH:14])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(C=CC(=O)NCCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C=Cc1ccc(C(=O)O)cn1)NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (6 ml) is cooled to 5° C., and a solution of 0.8 g of N-[3-(5-t-butoxycarbonyl-2-pyridyl)acryloyl]-4-(4-diphenylmethyl-1-piperazinyl)butylamine (the free base of the product of Example 24) in 3 ml of dichloromethane is slowly added below 20° C. The mixture is stirred at room temperature overnight and concentrated. The residue is dissolved in 10 ml of water and washed with diethyl ether. The aqueous solution is adjusted to pH 5 with aqueous ammonium hydroxide and extracted with three 40-ml portions of ethyl acetate. The combined extracts are dried over magnesium sulfate and the solvent is distilled off. The residue is chromatographed on silica gel with chloroform-methanol (10:1) to give the title compound. m.p. 214°-216° C. (recrystallized from methanol)