Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])[CH2:13][C:7]=3[C:6]=2[CH:21]=1.[O:22]1[CH:26]=[CH:25][C:24]([C:27]([Cl:29])=[O:28])=[CH:23]1>>[ClH:29].[CH2:15]([N:14]([CH2:18][CH2:19][CH3:20])[CH:12]1[CH2:11][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:27]([C:24]4[CH:25]=[CH:26][O:22][CH:23]=4)=[O:28])=[CH:21][C:6]=3[C:7]=2[CH2:13]1)[CH2:16][CH3:17]
Reactant: CCCN(CCC)C1CCc2oc3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccoc1
Product: CCCN(CCC)C1CCc2oc3ccc(NC(=O)c4ccoc4)cc3c2C1
Product: Cl
Yield: 76.7 %

Procedure:
Beginning with 0.072 gm (0.20 mMol) 8-amino-1,2,3,4-tetrahydro-2-dipropylaminodibenzofuran and 0.026 gm (0.20 mMol) furan-3-carbonyl chloride, 0.064 gm (84%) of the title compound were recovered as a white foam by the procedure described in Example 17.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[C:9]([O:13][C:14]([NH:16][C:17]1([C:24]([OH:26])=[O:25])[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[C:9]([O:13][C:14]([NH:16][C:17]1([C:24]([O:26][CH3:1])=[O:25])[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC(=O)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.90 g potassium carbonate and 1.30 ml methyl iodide are added to 4.65 g 1-tert.-butoxycarbonylamino-4-oxo-cyclohexanecarboxylic acid in 45 ml N,N-dimethylformamide and the reaction mixture is stirred for three hours at ambient temperature. Then the solvent is distilled off using the rotary evaporator and the residue is divided between 10% potassium carbonate solution and diethyl ether. The aqueous phase is separated off and extracted with diethyl ether and the combined organic phases are washed with saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. A colourless oil is left, which slowly crystallises.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH2:21]([O:28][C:29]1[C:30]([CH3:46])=[C:31]2[C:36](=[C:37]([CH3:40])[C:38]=1[CH3:39])[O:35][C@@:34]([CH3:45])([CH2:41][C:42]([OH:44])=[O:43])[CH2:33][CH2:32]2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([O:28][C:29]1[C:30]([CH3:46])=[C:31]2[C:36](=[C:37]([CH3:40])[C:38]=1[CH3:39])[O:35][C:34]([CH3:45])([CH2:41][C:42]([OH:44])=[O:43])[CH2:33][CH2:32]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@](C)(CC(=O)O)O2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC(=O)O)O2

Procedure:
To a solution of 11.0 g. of diisopropylamine in 50 ml. of anhydrous tetrahydrofuran at 0° was added 50 ml. of 2N butyllithium solution. To the resultant solution of lithium diisopropylamide was added a solution of 3.54 g. of (R)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetic acid in 25 ml. of tetrahydrofuran. The resulting mixture was heated at 50° for 4 hours, acidified with 2N HCI and extracted with ether. The ether solutions were washed with brine, dried (Na2SO4) and stripped of solvent to give (±)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetic acid, αD25= ± 0°, m.p. 130° -133°.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]4[O:26][CH2:25][O:24][C:21]=4[CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(OC(N1CCNCC1)=O)(C)(C)C.[F:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]=C=O)=[CH:50][CH:49]=1>C(Cl)Cl.C(N(CC)CC)C>[F:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]4[C:18](=[CH:19][C:20]5[O:26][CH2:25][O:24][C:21]=5[CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:50][CH:49]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc3cc4c(cc23)OCO4)CC1
Reactant: O=C=Nc1ccc(F)cc1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2ccnc3cc4c(cc23)OCO4)CC1

Procedure:
4-Chloro-6,7-methylenedioxyquinoline [obtained from 3,4-methylendioxyaniline following the protocol of Krogstad et. al. (De, D., Byers L. D., Krogstad, D. J. J. Heterocyclic Chem. 1997, 34, 315; 1H NMR ([D]6-DMSO), δ 6.28 (s, 2H), 7.45 (s, 1H), 7.50 (s, 1H), 7.65 (d, 1H), 8.62 (d, 1H)) (0.50 g, 2.4 mmol) and 1-tert-butoxycarbonylpiperazine (1.8 g, 9.6 mmol) are reacted according to method A yielding 391 mg of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-6,7-methylenedioxy quinoline. After cleaving the Boc group with trifluoroacetic acid (1.5 mL) in CH2Cl2 (1.5 mL), the piperazine is treated with 4-fluorophenylisocyanate (86 μL) and triethylamine (0.245 mL) according to method C yielding the title product.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:13]([C:12]([F:11])([F:21])[F:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:9]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1cc(I)ccc1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2cc(I)ccc2OC1C(F)(F)F
Temperature: 70 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
A mixture of 5-iodosalicylaldehyde (16.2 g, 65.3 mmol), ethyl 4,4,4-trifluorocrotonate (22.4 g, 133 mmol) and triethylamine (50 ml, 395 mmol)were combined, stirred at 70° C. for 8 h and then heated at reflux for 48 h. The solution was poured into ethyl acetate (300 mL) and washed with 1N hydrochloric acid (3×200 mL). The aqueous layers were combined and extracted with ethyl acetate (1×100 mL). The combined ethyl acetate extracts were washed with saturated ammonium chloride (2×200 mL), dried over magnesium sulfate and concentrated in vacuo yielding a dark red oil. This oil was purified by flash chromatography using ethyl acetate-hexanes (3:7) yielding a red oil. Crystallization of this oil from hexanes yielded the title compound as light red crystals (8.3 g, 31%): mp 105-106° C. 1H NMR (CDCl3/300 MHz) 7.63 (s, 1H), 7.58 (dd, 2H, J=8.6, J=2.1 Hz, 7.54 (d, 1H, J=2.1 Hz), 6.77 (d, 1H, J=8.6 Hz), 5.70 (q, 1H, J=6.7 Hz), 4.20-4.38 (m 2H), 1.35 (t, 3H, J=7.2 Hz). ESHRMS 415.9926 (M+NH4+ Calc'd 396.9746).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH:44]([N:47]([CH:51]([CH3:53])[CH3:52])[CH2:48][CH2:49][NH2:50])([CH3:46])[CH3:45]>C(Cl)(Cl)Cl.O>[CH:44]([N:47]([CH:51]([CH3:53])[CH3:52])[CH2:48][CH2:49][NH:50][C:36]([NH:20][C:19]1[CH:21]=[C:22]([CH3:23])[C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[CH3:24])=[O:42])([CH3:46])[CH3:45]
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)N(CCN)C(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)NCCN(C(C)C)C(C)C)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diisopropyl-1,2-ethanediamine (68 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (63 mg, yield 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C:16]1[C:25]([CH3:26])=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[CH3:27].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([NH:15][C:16]2[C:17]([CH3:27])=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][C:25]=2[CH3:26])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(O)c1cc(Cl)nc2ccccc12
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(Cl)nc3ccccc23)c(C)c1
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 960.3 %

Procedure:
To a solution of 2-chloroquinoline-4-carboxylic acid (5.00 g, 0.0024 mol) in CH2Cl2 (50 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (3.88 g, 0.02167 mol, see preparation 12) and N,N-diisopropylethylamine (12.5 ml, 0.07225 mol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 31.0 ml, 0.048 mol) is added via syringe and heated at 40° C. After 5 hours, the reaction mixture is diluted with water and extracted with dichloromethane. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes. After purification the solid is triturated with 20% diethyl ether in pentane and dried to give the title compound as a white solid (8.50 g, 96%). Mass spectrum (m/z): 369.1 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[C:11]([CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16])(=O)[CH3:12]>C(O)C>[NH2:4][C:3]1[C:14]([C:15](=[O:16])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]([CH3:12])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CC(N)c1ccccc1
Reactant: CC(=O)CC(=O)Nc1ccccc1
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)c(N)c1C(=O)Nc1ccccc1

Procedure:
This compound is prepared starting from 2-amino-2-phenylacetonitrile and α-acetyl-N-phenyl-acetamide, and is obtained with a 73% overall yield, m.p. 271°-73° C. (from ethanol).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[C:32]([O:40][CH2:41][C:42]1[S:43][CH:44]=[C:45](/[CH:47]=[CH:48]/[C:49]2[C:50]([OH:60])=[N:51][N:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:53]=2)[N:46]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:32]([O:40][CH2:41][C:42]1[S:43][CH:44]=[C:45](/[CH:47]=[CH:48]/[C:49]2[C:50]([O:60][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:51][N:52]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:53]=2)[N:46]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(OCc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(COC(=O)c5ccccc5)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.68 g), {4-[(E)-2-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)ethenyl]-1,3-thiazol-2-yl}methyl benzoate hydrochloride (0.73 g), potassium carbonate (0.45 g) and N,N-dimethylformamide (15 mL) was stirred at 90° C. for 10 min. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (10:90-30:70, v/v) to give {4-[(E)-2-(3-{[4-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)-3-methoxybenzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)ethenyl]-1,3-thiazol-2-yl}methyl benzoate as colorless crystals (0.55 g, yield 44%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 116-117° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9](=[O:14])[CH2:10]S(C)=O)=[C:4]([NH:15][CH3:16])[CH:3]=1>C(O)(=O)C.C(O)C.[Zn]>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9](=[O:14])[CH3:10])=[C:4]([NH:15][CH3:16])[CH:3]=1
Reactant: CNc1cc(F)c(F)cc1C(=O)CS(C)=O
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CNc1cc(F)c(F)cc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-[4,5-difluoro-2-(methylamino)phenyl]-2-methylsulphinylethanone (32.4 g) in acetic acid (90 ml) and ethanol (90 ml) was added over a period of 20 minutes to a stirred suspension of zinc dust (50 g) in acetic acid (45 ml) and ethanol (80 ml) at 0° under nitrogen. The mixture was stirred at ambient temperature overnight and then filtered through diatomaceous earth (sold under the trade name CELITE). The filter bed was washed with acetic acid (3×50 ml). The combined filtrate and washings were poured into water (1200 ml) and the mixture was extracted with dichloromethane (3×400 ml). The combined extracts were washed with aqueous sodium carbonate (1M, 2×500 ml) and dried over magnesium sulphate. The solvent was removed by distillation to give the novel compound 4',5'-difluoro-2'-(methylamino)acetophenone, m.p 51°-52°.
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#N)=[C:6]([F:13])[CH:5]=1.C[OH:15]>>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:15])=[O:1])=[C:6]([F:13])[CH:5]=1
Reactant: [OH-]
Reactant: N#CCc1ccc(Br)cc1F
Reactant: CO
Agent: [Na+]
Product: O=C(O)Cc1ccc(Br)cc1F
Temperature: 100 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
NaOH (56.2 mL, 112 mmol) was added to a solution of 2-(4-bromo-2-fluorophenyl)acetonitrile (4.01 g, 18.74 mmol) in MeOH (30 mL). The mixture was stirred at 100° C. for 12 h. The mixture was cooled to rt. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(4-bromo-2-fluorophenyl)acetic acid (4.13 g, 17.72 mmol, 95.0% yield) was used to next step without further purification. TLC (PE/EA=1/1, Rf=0.4): 1H NMR (400 MHz, CDCl3) δ 7.22-7.31 (m, 2H), 7.13 (t, J=8.05 Hz, 1H), 3.67 (s, 2H); ES-LCMS m/z 232.9 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1ccnc(F)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution of 2-fluoro-4-pyridinecarboxylic acid (10 g, 70.9 mmol) in tetrahydrofuran (150 ml) was added 1,1′-carbonylbis-1H-imidazole (12.7 g, 78.0 mmol), and the mixture was heated under reflux for 30 min. The reaction solution was cooled and monoethyl malonate magnesium salt (11.2 g, 39.0 mmol) was added. The mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid (200 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with 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) and recrystallized from hexane to give ethyl 3-(2-fluoro-4-pyridyl)-3-oxopropionate (7.32 g, 49%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.O>ClCCl>[Cl:7][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:10][CH:9]=1
Reactant: O=C(Cl)C1CC1
Reactant: Clc1ccc(CC2CCCN2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)N1CCCC1Cc1ccc(Cl)cc1
Yield: 67.5 %

Procedure:
Add (dropwise, at 0° to 8°) 5.2 g of cyclopropanecarboxylic acid chloride in 10 ml of dichloromethane to 10 g of 2-(4-chlorobenzyl)pyrrolidine and 6.2 g of triethylamine. Stir the thus-prepared reaction mixture for a further 2 hours at 0°. Add water thereto. Separate off the organic phase and extract it with dichloromethane. Combine the organic phases and wash them with dilute hydrochloric acid and sodium carbonate solution. Dry the washed material over sodium sulfate. Evaporate off the solvent from the dried material, and then distil the oily residue to obtain the title compound (8.85 g) in the form of oil (b.p. 135° to 137° at 0.005 mm Hg), which solidifies to a crystalline mass of m.p. 62° to 64°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[N:16][C:17]([CH2:20][NH:21][CH:22]=O)=[CH:18][CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:24].O=P(Cl)(Cl)Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]4[N:16]([CH:22]=[N:21][CH:20]=4)[CH:15]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: Cc1cc(-c2ncccc2-c2ccc(CNC=O)nc2)ccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cc(-c2ncccc2-c2ccc3cncn3c2)ccc1F
Temperature: 25 °C
Yield: 53.8 %

Procedure:
6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine (Compound 269) can be prepared via the reactions shown in the first two steps of Scheme 20: (2′-(4-Fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methanamine (2.18 g) and formic acid (15 mL) were stirred and heated under nitrogen atmosphere at 100° C. After 72 h, the reaction mixture was concentrated and partitioned between CH2Cl2/aq. NaHCO3. Usual work-up and purification by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g and 50-100% EtOAC/hexanes as elutant) provided 630 mg of N-((2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methyl)formamide as an off white solid. N-((2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methyl)formamide (630 mg) and POCl3 (3 mL) were stirred and heated in benzene (20 mL) overnight at 75° C. The reaction mixture was cooled to room temperature and concentrated. Subsequently, ice/water solution was added to the crude residue followed by CH2Cl2 and aq. NaHCO3. Upon allowing the solution warm to room temperature, organic layer was separated, stirred over Na2SO4, filtered and concentrated. Purification of the crude residue by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g and 2-8% MeOH/CH2Cl2 as an eluting solvent) provided 320 mg of 6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]1[C:8]([CH2:9][C:10]#N)=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:5]1.[OH-:25].[Na+].[OH2:27].C(O)C>>[F:1][C:2]([F:24])([F:23])[CH2:3][N:4]1[C:8]([CH2:9][C:10]([OH:27])=[O:25])=[CH:7][C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[N:5]1
Reactant: O
Reactant: [OH-]
Reactant: N#CCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F

Procedure:
In analogy to the procedure described for example 9 c], [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-acetonitrile was treated with sodium hydroxide in water/ethanol 1/1 at 85° C. to give [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-acetic acid as brown crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1COCC1>[CH2:14]([N:3]1[C:2]([CH3:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:5]=[CH:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1[nH]cnc1C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ncn(Cc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
Part A: To a magnetically stirred suspension of ethyl 4-methyl-1H-imidazole-5-carboxylate (15.42 gram, 0.100 mol) in anhydrous THF was slowly added sodium hydride (NaH) (4.88 g of a 60% suspension, 0.120 mol) and the resulting mixture was stirred at room temperature for 30 minutes. Benzyl bromide (13.8 ml, 0.120 mol) was slowly added and the resulting mixture was reacted for 16 hours. Water was added to the mixture. The organic layer was separated from the water layer. The water layer was extracted 3 times with ethylacetate. The organic layer was dried over MgSO4, filtered and thoroughly concentrated to give an oil. The resulting residue was purified (in order to separate the two formed regioisomers) by flash chromatography (diethyl ether/ethyl acetate gradient) to give ethyl N-benzyl-5-methyl-1H-imidazole-4-carboxylate (11.4 gram, 47% yield). 1H-NMR (400 MHz, CDCl3): 1.40 (t, J=7, 3H), 2.45 (s, 3H), 4.37 (q, J=7, 2H), 5.10 (s, 2H), 7.03-7.08 (m, 2H), 7.28-7.38 (m, 3H), 7.48 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].F[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].O.[OH-].[Li+].Cl>O.CS(C)=O>[F:17][C:15]1[CH:14]=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[C:11]([NH:1][C:2]2[S:3][C:4]([CH3:9])=[CH:5][C:6]=2[C:7]#[N:8])[CH:16]=1
Reactant: Cc1cc(C#N)c(N)s1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C#N)c(Nc2cc(F)ccc2[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.3 %

Procedure:
Add 2-amino-5-methyl-thiophene-3-carbonitrile (10.0 g, 72.4 mmol) and 2,4-difluoro-1-nitro-benzene (8.00 mL, 73.0 mmol) to DMSO (130 mL) and stir under nitrogen at ambient temperature. Add lithium hydroxide monohydrate (6.10 g, 145 mmol) in one portion and stir at ambient temperature. After 18 hours, add deionized water (390 mL) dropwise at 10-20° C. Adjust the pH to 7-8 with concentrated HCl (˜6 mL) and stir for 4 hours. Filter the crude product and rinse with 3:1/water: DMSO, then water. Dry at 50° C. to constant weight. Purify by flash chromatography, eluting with methylene chloride to give the title compound 10.3 g (62%): 1H NMR (400 MHz, DMSO-d6) δ 9.83 (bs, 1H), 8.28 (m, 1H), 7.12 (s, 1H), 6.91 (m, 1H), 6.73 (m, 1H), 2.53 (s, 3H). HRMS (ES) exact mass M+H calcd for C12H8FN3O2S 300.0219; found 300.0219.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[NH2:14][C:15]1([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:14][C:15]3([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]3)[NH:7][C:6]=2[CH:8]=1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: NC1(CO)CCCC1
Solvent: CCO
Product: O=S1(=O)N=C(NC2(CO)CCCC2)Nc2cc(Cl)sc21
Yield: 10.7 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (0.5 g, 1.95 mmol) and (1-aminocyclopentyl)-methanol (0.45 g, 3.9 mmol) in ethanol (4 ml) was stirred for 21 h at 120° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue dissolved in 1N sodium hydroxide (40 ml) followed by treatment with decolourising charcoal. After filtration, the clear solution was acidified to pH <2 with 4M hydrochloric acid and the precipitate was filtered off and recrystallised from ethanol and finally purified by chromatography (dichloromethane/methanol (19:1)) to give 70 mg (10%) of the pure title compound; mp 213-214° C.; 1H-NMR (DMSO-d6): δ1.45-2.0 (m, 8H), 3.53 (s, 2H), 5.05 (br s, 1H), 6.82 (br s, 1H) 7.11 (s, 1H), 10.8 (br s, 1H); MS: m/e 335/337 (M+), 317/319 (M—H2O)+.