Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]OC(=O)OC.N12CCCN=C1CCCCC2>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: COC(=O)OC
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cl)cccc1Cl
Yield: 85.8 %

Procedure:
2,6-Dichlorobenzoic acid (5.00 g, 26.2 mmol) was diluted in dimethylcarbonate (44 mL, 530 mmol). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (3.91 mL, 26.2 mmol) was added last. The reacted was refluxed for 2 days. Upon cooling, the solution was diluted with ethyl acetate and water. The aqueous layer was removed and the organic layer was washed with water, 2N HCl (2×'s), sat. NaHCO3 (2×'s), and twice with water. The organic layer was dried over sodium sulfate, filtered, and concentrated to yield 4.61 g (86%) of the desired compound as a clear oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[N:38]=[C:39]=[O:40])([CH3:28])[CH3:27]>>[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[C:30]=1[NH:38][C:39](=[O:40])[N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:16][CH:17]=1)([CH3:27])[CH3:28]
Reactant: CCCCCCCCc1ccc(NCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCCCCCCCc1ccc(N(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 6.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-nitrophenyl)methyl](4-octylphenyl)amine (2.6 g) and 2,6-diisopropylphenyl isocyanate (1.55 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-nitrophenyl)methyl]-N-(4-octylphenyl)urea (0.27 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C@H:14]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:13][C@@H:12]1[CH3:33])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42].[OH-].[K+]>ClCCl.O>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[C@H:14]([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:13][C@@H:12]1[CH3:33])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: COc1cc2c(cc1OC)N(C(=O)OCc1ccccc1)[C@@H](C)C[C@H]2NCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N(Cc1ccccc1)[C@@H]1C[C@H](C)N(C(=O)OCc2ccccc2)c2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of cis-4-benzylamino-6,7-dimethyoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (Example 2B) (150 mg, 0.34 mmol) in anhydrous dichloromethane (5 mL) were added pyridine (0.20 mL, 2.3 mmol) and ethyl chloroformate (0.16 mL, 1.7 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was then poured into water (20 mL), and aqueous 2N KOH (10 mL) was added. The solution was stirred for 30 min, then the mixture was extracted with ether (3×25 mL). The organic phases were combined and washed with 1N HCl (3×10 mL) and then a saturated sodium bicarbonate solution (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 190 mg of crude product. Purification by silica gel chromatography using 0-40% ethyl acetate/hexanes as eluent afforded the desired final product (146 mg, 83%): MS m/z 519 (M+ +1), 537 (M+ +19), 340 (M+ -178); 1H NMR (CDCl3) δ 6.99 (C8, s, 1H), 6.42 (C5, s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]([OH:30])=O)[CH:23]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Cl.[OH:32][CH:33]1[CH2:36][NH:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)[CH2:11][CH2:12][C:13]1[N:14]=[C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([N:35]4[CH2:36][CH:33]([OH:32])[CH2:34]4)=[O:30])[CH:23]=3)[NH:19][C:16]2=[N:17][CH:18]=1
Reactant: OC1CNC1
Reactant: COc1cc(CCc2cnc3[nH]c(-c4ccnc(C(=O)O)c4)cc3n2)cc(OC)c1
Agent: Cl
Product: COc1cc(CCc2cnc3[nH]c(-c4ccnc(C(=O)N5CC(O)C5)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedure analogous to those described for the synthesis of Example 73, Step 3 starting from 4-{2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazin-6-yl}pyridine-2-carboxylic acid and 3-hydroxyazetidine hydrochloride (from Oakwood). LCMS calculated for C25H26N5O4 (M+H)+: m/z=460.2. Found 460.2.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][C:13]=2[CH2:25][S:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:8]=[C:7]([Cl:32])[CH:6]=1.[OH-].[Li+].Cl>C1COCC1.O.CO>[Cl:32][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][C:13]=2[CH2:25][S:26][CH2:27][C:28]([F:30])([F:31])[F:29])[CH:8]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Oc2ccc(NC(=O)C(C)(C)C)cc2CSCC(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)C(=O)Nc1ccc(Oc2cc(Cl)cc(CC(=O)O)c2)c(CSCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To {3-chloro-5-[4-(2,2-dimethyl-propionylamino)-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester (0.038 g, 0.08 mmol) in THF:H2O:MeOH (2:1:2; 2 mL) was added 1N aqueous lithium hydroxide, and the mixture was stirred at room temperature overnight. The mixture was acidified to pH 5 with 10% aqueous HCl, and extracted with EtOAc. The crude material was purified by preparative HPLC to give the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([OH:36])([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[C:14]=3[CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Br:38][CH2:39][CH2:40][CH2:41]O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11](=[O:37])[O:12][C:13]([O:36][CH2:41][CH2:40][CH2:39][Br:38])([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[C:14]=3[CH2:15][C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(C2(O)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Reactant: OCCCBr
Solvent: ClCCl
Product: COc1ccc(C2(OCCCBr)OC(=O)C(c3ccc4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Reaction time: 48 h

Procedure:
To 100 mL dichloromethane was added 3-Benzo[1,3]-dioxol-5-yl-5-hydroxy-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 5.0 g (9.87 mmol), giving a suspension. 1-Bromo-3-propanol 3.07 g (22.15 mmol) was added, and the mixture was purged with anhydrous HCl gas until saturated. After 48 hours at room temperature, the mixture was evaporated in vacuo and the residue was suspended in ethyl ether. The ether suspension was washed exhaustively with 0.5 N NaOH, followed by water and saturated sodium chloride solution. The ether phase was dried over anhydrous magnesium sulfate, filtered, and diluted with hexane, giving a solid. Filter and dry in vacuo, giving a white solid, 4.79 g. The product was identified by 1H NMR, MS [M--H]+ =628, 629 Da.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH2:21][F:22])([CH2:19][F:20])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][C:6]=12.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.N1C=CC=CC=1>C(O)C>[F:18][C:12]([F:17])([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:19][F:20])([CH2:21][F:22])[C@@H:2]([OH:1])[C@H:7]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:6]=2[CH:8]=1)[C:13]([F:15])([F:16])[F:14]
Reactant: FCC1(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc2C2OC21
Reactant: Oc1ccccn1
Solvent: CCO
Solvent: c1ccncc1
Product: O[C@H]1[C@H](Oc2ccccn2)c2cc(C(F)(F)C(F)(F)F)ccc2OC1(CF)CF
Yield: 20.3 %

Procedure:
A mixture of 0.42 g of 3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran, 0.21 g of 2-hydroxypyridine, 0.11 g of pyridine and 4 ml of ethanol was refluxed for 3 hours and the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain from the first eluted fraction 0.11 g of oily trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-4-(2-pyridyloxy)-2H-1-benzopyran-3-ol represented by the following formula.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:13][CH:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH:3]=1.[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[N:34]=[C:35]=[O:36]>>[NH2:17][C:15](=[O:16])[CH:14]([CH3:18])[CH2:13][C:9]1[CH:8]=[C:7]([N:6]2[C:2]([NH:1][C:35]([NH:34][C:28]3[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=3[Cl:26])=[O:36])=[CH:3][C:4]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:5]2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(Cc1cccc(-n2nc(-c3ccccc3F)cc2N)c1)C(N)=O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Product: CC(Cc1cccc(-n2nc(-c3ccccc3F)cc2NC(=O)Nc2cccc(Cl)c2Cl)c1)C(N)=O
Yield: 17.9 %

Procedure:
Using general method A, 3-(3-(5-amino-3-(2-fluorophenyl)-1H-pyrazol-1-yl)phenyl)-2-methylpropanamide (0.1225 g, 0.362 mmol, 1.00 eq) was combined with 2,3-dichlorophenyl isocyanate (0.102 g, 0.543 mmol, 1.50 eq) to yield 34.2 mg (18%) of pure 1-(1-(3-(3-amino-2-methyl-3-oxopropyl)phenyl)-3-(2-fluorophenyl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea. 1H NMR (DMSO-d6): δ 9.40 (s, 1H), 8.89 (s, 1H), 8.11-8.08 (s, 1H), 8.02-7.98 (m, 1H), 7.53-7.39 (m, 4H), 7.36-7.26 (m, 6H), 6.92-6.91 (m, 1H), 6.76 (brs, 1H), 3.00-2.93 (m, 1H), 2.65-2.57 (m, 2H), 1.03-1.02 (m, 3H); MS (ESI) m/z: 526.0 (M+H), 528.0 (M+2+H+).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[S:19][C:18]([CH3:20])=[N:17][CH:16]=2)[N:3]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[I:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH2:14][C:15]2[S:19][C:18]([CH3:20])=[N:17][CH:16]=2)[N:3]=1
Reactant: Cc1ncc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ncc(Cn2nc(I)c3c(N)cccc32)s1
Temperature: 85 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 5-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-2-methylthiazole (332 mg, 0.830 mmol) in EtOH/water (4:1, 10 mL) was added iron powder (463 mg, 8.30 mmol) and ammonium chloride (44.4 mg, 0.83 mmol). The resulting mixture was heated at 85° C. with vigorous magnetic stirring for three hours. The mixture was cooled to ambient temperature, concentrated, and EtOAc (40 mL) and triethylamine (10 mL) were added. The resulting mixture was heated at 85° C. for 20 minutes, then cooled to 45° C., filtered through a Celite plug, and the plug was rinsed with MeOH (30 mL). The combined organic filtrates were concentrated, the residue was extracted with DCM (3×30 mL), the combined organic extracts dried over sodium sulfate, filtered and concentrated to afford the desired product (307 mg).
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][CH:26]3[CH2:28][O:27]3)[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C)C=O.C(OCC)(=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][CH:26]([OH:27])[CH2:28][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[N:9]=2)[CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(Nc1cn(CC2CO2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cn(CC(O)CN2CCOCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(oxiran-2-ylmethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL), DIEA (67 mg, 0.518 mmol) and morpholine (14 mg, 0.161 mmol) was added at room temperature. The resulting solution was stirred at 60° C. overnight, cooled, diluted with 30 mL of ethyl acetate, washed with 2×10 mL of water and 2×10 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (95/5). This resulted in 50 mg of crude product, which was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min; 254 nm to obtain 40 mg (67%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-hydroxy-3-(morpholin-4-yl)propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 35) [M+H]+=548.2, RT=2.28 min. 1H-NMR (300 MHz, DMSO-d6): δ (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5, 7.2 Hz), 8.68-8.67 (m, 2H), 8.34 (s, 1H), 7.65 (d, 1H, J=2.7 Hz), 7.61 (s, 1H), 7.44 (d, 1H, J=8.7 Hz), 7.27 (dd, 1H, J=4.2, 6.9 Hz), 7.00 (t, 1H, J=73.5 Hz), 4.99 (d, 1H, J=4.5 Hz), 4.31-4.28 (m, 1H), 4.13-4.07 (m, 2H), 3.56 (t, 4H, J=4.5 Hz), 2.42 (t, 4H, J=4.5 Hz), 2.32 (d, 2H, J=4.8 Hz).
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[C:25]([C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH:30]5[CH2:34][O:35]C)=[O:28])[S:26][C:19]=34)=[CH:16][C:11]=2[O:10][C:9]=1[CH3:37])=[O:7])[CH:2]([CH3:4])[CH3:3].B(Br)(Br)Br>>[CH2:1]([NH:5][C:6]([C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[C:25]([C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH:30]5[CH2:34][OH:35])=[O:28])[S:26][C:19]=34)=[CH:16][C:11]=2[O:10][C:9]=1[CH3:37])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: COCC1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)NCC(C)C)c(C)oc4c3)c2s1
Agent: BrB(Br)Br
Product: Cc1oc2cc(Oc3ccnc4cc(C(=O)N5CCCC5CO)sc34)ccc2c1C(=O)NCC(C)C

Procedure:
This material was prepared from 2-methyl-6-[2-(2-methoxymethyl-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-benzofuran-3-carboxylic acid isobutyl amide 85 by treatment with BBr3 in a manner as previously described for example 1d. 1H NMR (CD3CN) δ8.52 (1H, d, J=5.5 Hz), 7.89 (1H, s), 7.81 (1H, d, J=8.5 Hz), 7.42 (1H, d, J=2.1 Hz), 7.20 (1H, dd, J=8.5, 2.1 Hz), 6.78 (1H, m), 6.71 (1H, d, J=5.3 Hz), 4.29 (1H, m), 3.94-3.63 (4H, m), 3.22 (2H, t, J=6.4 Hz), 2.65 (3H, s), 2.22-1.95 (4H, m), 0.98 (6H, d, J=6.8 Hz).
Reaction SMILES: [O-]CC.[Na+].C(O)C.[C:8]([O:11][CH2:12][CH3:13])(=[O:10])[CH3:9].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=O)C>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:8](=[O:10])[CH2:9][C:17](=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:13]
Reactant: CCOC(=O)c1ccccn1
Reactant: CCOC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccccn1
Temperature: 90 °C
Yield: 91 %

Procedure:
Stir a mixture of sodium ethoxide (360 g, 5.29 mol, 2 eq), toluene (4 L), ethanol (18 mL, 0.265 mol, 0.1 eq) and ethyl acetate (1.04 L, 10.58 mol, 4 eq) in a 22 L flask equipped with a reflux condenser, nitrogen inlet and mechanical stirrer. Stir for 1 h as the mixture warms to 26° C. Add pyridine-2-carboxylic acid ethyl ester (Fluka; 400 g, 2.65 mol, 1 eq) and heat the mixture to reflux (90° C.) for 18 h. Cool the mixture to room temperature. Dilute with toluene (8 L), wash with water (6 L), and separate the layers. Acidify the aqueous layer to pH 5 with glacial acetic acid. Extract with ethyl acetate (2×4 L), dry the combined organic layers (sodium sulfate), filter and concentrate in vacuo to yield the subtitled compound (466 g, 91% yield) as a dark oil in 93% purity by HPLC analysis. MS ES+ m/e 194 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][C:14]2=[CH:19][N+:20]([O-])=O)=[CH:10][CH:9]=1.[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1>[NH2:20][CH2:19][CH:14]1[CH2:15][O:16][CH2:17][CH2:18][N:13]1[CH2:12][C:11]1[CH:23]=[CH:24][C:8]([F:7])=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])C=C1COCCN1Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: NCC1COCCN1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
To THF (200 ml) was added a small amount of lithium aluminum hydride, the solvent was dried, lithium aluminum hydride (2.0 g, 53 mmol) was suspended and the mixture was stirred at room temperature. Crystals of 4-(p-fluorobenzyl)-3-nitromethylidenemorpholine (6.58 g, 26.1 mmol) was added gradually and the mixture was stirred at room temperature. A further amount of lithium aluminum hydride (1.3 g, 34 mmol) was added and the mixture was stirred for one hour. Water (3.3 ml), 40% aqueous NaOH (3.3 ml) and water (10 ml) were added in turn and then potassium carbonate (40 g) was added followed by stirring. The reaction mixture was filtered and distilled off. The residue was dissolved in chloroform, dried over potassium carbonate and then the chloroform was distilled off to give 5.44 g of 3-aminomethy-4-(p-fluorobenzyl)morpholine as an oily substance. Yield=93%.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:27][C@@H:26]([CH2:28][OH:29])[N:8]3[C:9]4[CH:10]=[CH:11][C:12]([O:16][CH:17]5[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]5)=[CH:13][C:14]=4[CH:15]=[C:7]3[C:6]2=[O:30])[CH2:3][CH2:2]1.[CH3:31]I.[H-].[Na+]>>[CH:1]1([CH2:4][N:5]2[CH2:27][C@@H:26]([CH2:28][O:29][CH3:31])[N:8]3[C:9]4[CH:10]=[CH:11][C:12]([O:16][CH:17]5[CH2:18][CH2:19][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH2:22]5)=[CH:13][C:14]=4[CH:15]=[C:7]3[C:6]2=[O:30])[CH2:3][CH2:2]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](CO)CN(CC3CC3)C2=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC[C@@H]1CN(CC2CC2)C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n21
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 17, from (S)-2-cyclopropylmethyl-4-hydroxymethyl-8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 75), methyl iodide and sodium hydride, to give the desired product as a colorless oil (67%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([C:13]([N:15]3[CH2:19][CH2:18][CH:17]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:16]3)=[O:14])[C:9]=2[CH3:25])[CH:5]=[CH:6][CH:7]=1.[C:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])#[CH:27]>N1CCCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:21]([N:20]([CH2:23][CH3:24])[CH:17]1[CH2:18][CH2:19][N:15]([C:13]([C:10]2[C:9]([CH3:25])=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:27]#[C:26][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:3]=3)[NH:12][N:11]=2)=[O:14])[CH2:16]1)[CH3:22]
Reactant: C#C[Si](C)(C)C
Reactant: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(Br)c3)c2C)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(C#C[Si](C)(C)C)c3)c2C)C1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
The synthesis was performed following a procedure of Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel. Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes. Collect. Czech. Chem. Commun. (1999), 64(4), 649-672. A solution of 0.405 g (1.00 mmol) of [5-(3-bromo-phenyl)-4-methyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone in 5 ml piperidine was degassed (argon) and treated with 58 mg (0.05 mmol) Pd(PPh3)4 and 10 mg (0.05 mmol) CuI. The reaction mixture was stirred at 50° C. for 10 min and then slowly (60 min) treated with 0.17 ml (1.20 mmol) of ethynyltrimethylsilane in 5 ml piperidine. After 30 min the bath was slowly (30 min) heated to 80° C. The reaction mixture was stirred at this temperature for 2.5 h and then partitioned between chilled water sat. KHCO3/EtOAc (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (CH2Cl2/MeOH 98:2 to 92:8) yielded 0.27 g (64%) of the title compound as yellow viscous oil. MS: 423.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:35][N:34]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: FC(F)(F)c1ccc(CCl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)cn2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 65 °C
Yield: 55.9 %

Procedure:
A solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (32.4 mg, 0.1 mmol), prepared as described in Example 244, K2CO3 (56 mg, 0.4 mmol), and 2-chloromethyl-5-trifluoromethylpyridine hydrochloride (37 mg, 0.4 mmol) in DMF (0.4 mL) was heated at 65° C. for 2 h. Using a similar procedure as described in Example 247, the crude product was obtained. The crude product was purified by reverse phase HPLC to give the title compound, 7-(4-chlorophenyl)-8-(pyridin-4-yl)-2-((5-(trifluoromethyl)pyridin-2-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (27 mg) as a yellow solid. HPLC RT: 2.78 min; M+H=483; 1H NMR (CDCl3): δ 8.82 (s, 1H), 8.62 (m, 2H), 8.24 (s, 1H), 7.91 (m, 1H), 7.38-7.10 (m, 7H), 5.45 (2H).