Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH3:8].C([Li])CCC.CN([CH:17]=[O:18])C.Cl>C1COCC1.O>[CH2:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH:17]=[O:18])[CH3:8]
Reactant: CCc1ccsc1Br
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccsc1C=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of 3-ethyl-thiophene (12.14 g, 54.4 mmol) in acetonitrile (60 mL) is cooled to 10° C. before a solution of N-bromo-succinimide (9.31 g, 52.3 mmol) in acetonitrile (90 mL) is added dropwise. The reaction is slightly exothermic. The mixture is stirred and warmed to rt. Another portion of N-bromo-succinimide (2.0 g, 11.2 mmol) dissolved in acetonitrile (40 mL) is added dropwise. Stirring is continued for 2 h before a third portion of N-bromo-succinimide (0.5 g, 2.81 mmol) dissolved in acetonitrile (10 mL) is added. After additional 1 and 2 h, a further portion of N-bromo-succinimide (0.75 g, 4.21 mmol, and 500 mg, 2.81 mmol, respectively) is added. Stirring is continued for another hour before the solvent is evaporated. The residue is dissolved in DCM, washed twice with 2 M aq. NaOH followed by brine, dried over MgSO4, filtered and concentrated. The crude product is purified by distillation at 180° C./50 mbar to give 2-bromo-3-ethyl-thiophene (11.0 g) as a colourless liquid; LC-MS*: tR=0.92 min. 1H NMR (CDCl3): δ 1.22 (t, J=7.5 Hz, 3H), 2.62 (q, J=7.8 Hz, 2H), 6.85 (d, J=5.5 Hz, 1H), 7.22 (d, J=5.8 Hz, 1H) b) A solution of 2-bromo-3-ethyl-thiophene (1.00 g, 5.23 mmol) in THF (25 mL) is cooled to −75° C. before n-butyl lithium (3.6 mL of a 1.6 M solution in THF) is added. The mixture is stirred at −75° C. for 1 h. DMF (765 mg, 10.5 mmol) is added and stirring is continued at −75° C. for 2 h. The mixture is warmed to 10° C., treated with 1 N aq. HCl (5 mL), diluted with water and extracted with EA (3×50 mL). The organic extracts are washed with water (30 mL) followed by brine (30 mL), combined, dried over MgSO4, filtered and concentrated to give crude 3-ethyl-thiophene-2-carbaldehyde (650 mg) as a yellow oil; LC-MS*: tR=0.78 min, 1H NMR (CDCl3): δ 1.34 (t, J=7.5 Hz, 3H), 3.03 (q, J=7.5 Hz, 2H), 7.06 (d, J=5.0 Hz, 1H), 7.67 (d, J=5.0 Hz, 1H), 10.08 (s, 1H). c) The title compound is prepared in analogy to the procedures described in the literature (G. Constantino et al., II Farmaco 59 (2004), 93-99; A. J. Carpenter et al., Tetrahedron 41 (1985) 3803-3812) starting from the above 3-ethyl-thiophene-2-carbaldehyde; LC-MS*: tR=0.15 min, [M−1]−=183.16; 1H NMR (D6-DMSO): δ1.24 (t, J=7.5 Hz, 3H), 3.00 (q, J=7.5 Hz, 2H), 7.72 (s, 1H), 10.11 (s, 1H).
Reaction SMILES: [NH2:1][C:2](=[C:12](C(OC)=O)[C:13]([O:15][CH3:16])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[OH-].[K+]>CO.O>[NH2:1][C:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[CH:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(C(=O)OC)=C(N)c1cccc([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C=C(N)c1cccc([N+](=O)[O-])c1
Yield: 52.8 %

Procedure:
A mixture of dimethyl (α-amino-3-nitrobenzylidene)malonate (120 g) and potassium hydroxide in a mixture of methanol (1.2 l) and water(120 ml) was refluxed for 8 hours. The reaction mixture was concentrated under reduced pressure to a volume of 200 ml. The resulting crystals were collected by filtration and recrystallized from methanol to give methyl 3-amino-3-(3-nitrophenyl)acrylate (50.2 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[N:12]=[C:13]([S:22][CH3:23])[N:14]=[N:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[S:24]1[CH:28]=[CH:27][C:26]2[C:29]([NH2:33])=[CH:30][CH:31]=[CH:32][C:25]1=2>C1COCC1>[S:24]1[CH:28]=[CH:27][C:26]2[C:29]([NH:33][C:11]3[N:12]=[C:13]([S:22][CH3:23])[N:14]=[N:15][C:16]=3[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:30][CH:31]=[CH:32][C:25]1=2
Reactant: Nc1cccc2sccc12
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(SC)nc1Nc1cccc2sccc12
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
Diisopropylethylamine (0.10 ml) was added to a solution of ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (70 mg) and benzo[b]thiophen-4-amine (70 mg) in THF (1 ml), and the reaction solution was stirred at room temperature for 35 minutes. The solvent was evaporated under vacuum, and then the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain ethyl 5-(benzo[b]thiophen-4-ylamino)-3-(methylthio)-1,2,4-triazine-6-carboxylate as a white solid.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][C:8]2=[O:24])=[CH:3][CH:2]=1.[Br:26]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:25][C:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:11][CH:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)[CH2:9][C:8]2=[O:24])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(C)cc3)C2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(CBr)cc3)C2)cc1
Yield: 56.8 %

Procedure:
Methyl 4-[1-(4-tolyl)-2-pyrrolidon-4-yl]methoxybenzoate (3.00 g) and N-bromosuccinimide (1.81 g) are suspended in carbon tetrachloride (50 ml), and thereto is added benzoyl peroxide (0.21 g) and the mixture is stirred under refluxing for 5 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate (60 ml), washed successively with aqueous sodium hydrogen carbonate solution and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily product is subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform/n-hexane [1:1 (v/v)]to give the desired product (2.10 g).
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[N:10]=1)C1C=CC=CC=1.[CH2:30]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[CH:40][C:39]=1[F:47])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([NH:15][C:14]2[C:9]([OH:8])=[N:10][C:11]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:21])=[N:12][CH:13]=2)=[O:43])=[CH:40][C:39]=1[F:47])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: C[C@@H](COc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1)NC(=O)OC(C)(C)C
Product: C[C@@H](COc1ncc(NC(=O)c2ccc(OCc3ccccc3)c(F)c2)c(O)n1)NC(=O)OC(C)(C)C

Procedure:
Using tert-butyl ((2S)-1-((4-(benzyloxy)-5-nitropyrimidin-2-yl)oxy)propan-2-yl)carbamate and 4-(benzyloxy)-3-fluorobenzoic acid, and in the same manner as in Step A of Example 4, Step D of Example 83 and Step B of Example 123, the title compound was obtained.
Reaction SMILES: C(Cl)(Cl)Cl.C(N(CC)CC)C.[CH2:12]([O:28][C:29]1[CH:30]=[C:31]([C:35]2[N:39]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:38]=[C:37]([OH:46])[CH:36]=2)[CH:32]=[CH:33][CH:34]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[C:47](Cl)(=[O:57])[O:48][CH2:49][CH:50]([CH2:55][CH3:56])[CH2:51][CH2:52][CH2:53][CH3:54]>O>[CH2:55]([CH:50]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:49][O:48][C:47]([O:46][C:37]1[CH:36]=[C:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:30]=2)[N:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:38]=1)=[O:57])[CH3:56]
Reactant: CCCCCCCCCCCCCCCCOc1cccc(-c2cc(O)nn2-c2ccccc2)c1
Reactant: CCCCC(CC)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCOc1cccc(-c2cc(OC(=O)OCC(CC)CCCC)nn2-c2ccccc2)c1
Temperature: 25 °C

Procedure:
50 ml of chloroform and 1.9 ml (0.014 mol) of triethylamine were added and dissolved in 5.3 g (0.011 mol) of 5-(3-hexadecyloxyphenyl)-3-hydroxy-1-phenylpyrazole and stirred at 25° C. To this was dropwise added 2.3 g (0.012 mol) of 2-ethylhexyl chlorocarbonate. After stirring for 30 minutes, cold water was added to the reaction mixture for liquid separation, and the chloroform layer separated was washed two times with 50 ml of cold water and then dried with Glauber's salt. After the Glauber's salt was filtrated out, the chloroform was distilled out, and the remaining precipitate was purified by column chromatography. The product was oily. Yield: 5.7 g, 82%.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.[CH3:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1>C[Si](N[Si](C)(C)C)(C)C>[CH3:1][Si:2]([C:12]1[NH:11][C:10](=[O:13])[N:9]([Si:2]([CH3:5])([CH3:4])[CH3:1])[C:8](=[O:14])[C:7]=1[CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: Cc1c([Si](C)(C)C)[nH]c(=O)n([Si](C)(C)C)c1=O

Procedure:
Trimethylchlorosilane (4 ml) was added to a suspension of 5-methyluracil (thymine) (5 g) in hexamethylsilazane (20 ml) followed by refluxing for 5 hours. The resulting ammonium chloride was removed by filtration and the filtrate was evaporated to give bis(trimethylsilyl)-5-methyluracil as oil. To a solution of the oil in dry dichloromethane (10 ml) was added 2-methyl-1,3-dioxolane (15 ml) and then was added dropwise stannic chloride (5 ml). After allowing the mixture to stand at room temperature overnight, it was treated as in Example 10 to give 4.6 g of crystalline 1-[α-(2-hydroxyethoxy)-ethyl]-5-methyluracil.
Reaction SMILES: [Li]CCCC.N#N.Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[N:10]=1.CC1C[CH2:21][NH:20][C:19](=O)[CH2:18]1.[CH2:24]1C[O:27][CH2:26][CH2:25]1>>[Br:15][C:11]1[N:10]=[C:9]([C:26]2([OH:27])[CH2:25][CH2:24][N:20]([CH3:21])[CH2:19][CH2:18]2)[CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cccc(Br)n1
Reactant: C1CCOC1
Reactant: CC1CCNC(=O)C1
Agent: N#N
Agent: [Li]CCCC
Product: CN1CCC(O)(c2cccc(Br)n2)CC1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1.07 M n-BuLi (36.4 mL) and dry THF (200 mL) chilled to −70° C. under a blanket of N2 was added 2,6-dibromopyridine (10 g, 38.9 mmol)in 50 mL of dry THF slowly to maintain a temperature less than −69° C. Stirred at −70° C. for 20 min. Added 4-methylpiperidone (4.8 mL, 38.9 mmol) and stirred the mixture at −70° C. for 1 h. Quenched with saturated NaHCO3 and extracted with EtOAc. Washed the organic layer with brine, dried (MgSO4) and concentrated in vacuo to give 6-bromo-1′-methyl-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol as a light-yellow solid. MS m/z: 272.3 (M+H). Calc'd for C11H15BrN2O-271.15.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH:15]1([C:18]2[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=2)[NH2:21])[CH2:17][CH2:16]1.[NH:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[CH:33][C:28]=2[N:27]=[CH:26]1>>[NH:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34][NH:1][C:4]3[C:5]4[CH:6]=[CH:7][C:8]([NH:21][C:20]5[CH:22]=[CH:23][CH:24]=[C:18]([CH:15]6[CH2:17][CH2:16]6)[CH:19]=5)=[N:9][C:10]=4[CH:11]=[CH:12][CH:13]=3)=[CH:33][C:28]=2[N:27]=[CH:26]1
Reactant: Nc1cccc(C2CC2)c1
Reactant: O=Cc1ccc2[nH]cnc2c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: c1cc(Nc2ccc3c(NCc4ccc5[nH]cnc5c4)cccc3n2)cc(C2CC2)c1

Procedure:
The title compound, MS: m/e=406.5 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 3-cyclopropylaniline and 1H-benzimidazole-5-carbaldehyde as described in example 26.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH:9](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([CH:1]1[CH2:2][CH2:3][C:4](=[O:7])[CH2:5][CH2:6]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:9](=[C:1]1[CH2:2][CH2:3][C:4](=[O:7])[CH2:5][CH2:6]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C(c1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)CC1
Product: O=C1CCC(=Cc2ccccc2)CC1
Product: O=C1CCC(Cc2ccccc2)CC1

Procedure:
4-Benzylcyclohexanone is prepared as follows. Cyclohexane-1,4-dione, ethylene monoketal is reacted with benzylidenetriphenylphosphorane to afford 4-benzylidenecyclohexanone, ethylene ketal, which is catalytically hydrogenated, e.g., using palladium on carbon, to give 4-benzylcyclohexanone, ethylene ketal. Deketalization with mineral acid, e.g., hydrochloric acid in acetone solution, provides 4-benzylcyclohexanone.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:29]([F:32])([F:31])[F:30])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[OH2:36].[OH-:37].[Li+]>O>[NH2:23][C@@:22]([C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[C:13]=2[C:29]([F:31])([F:32])[F:30])[CH:18]=1)([CH3:28])[CH2:26][OH:25].[C:13]([OH:37])([C:29]([F:32])([F:31])[F:30])=[O:36]
Reactant: O
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C(F)(F)F)CC1
Reactant: [OH-]
Agent: [Li+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C(F)(F)F)CC1
Product: O=C(O)C(F)(F)F
Temperature: 80 °C

Procedure:
(R)-4-[6-(trans4-tert-Butylcyclohexyloxy)-5-trifluoromethylnaphthalen-2-yl]-4-methyl-oxazolidin-2-one (0.3341 g, 0.0007433 mol) was dissolved in ethanol (3.00 mL, 0.0514 mol) in a 40 mL capped vial equipped with a magnetic stir bar. 4.2 M Lithium hydroxide, monohydrate in water (3.00 mL) was added and the mixture was heated at 80° C. overnight. HPLC and LCMS analysis showed that the reaction was complete. The solvent was removed under vacuum. Methylene chloride (5 mL) and water (5 mL) were added and the layers were separated. The combined organic layers were concentrated under vacuum and purified by HPLC to give the title compound as a TFA salt in 0.105 g (33% yield). MS: m/z=407.38 [M-NH2]+. 1H NMR (400 MHz, MeOD) δ 0.93 (s, 9 H), 1.10-1.31 (m, 3 H), 1.58 (d, J=12.55 Hz, 2 H), 1.81 (s, 3 H), 1.89-1.98 (m, 2 H), 2.20-2.29 (m, 2 H), 3.82-3.88 (m, 1 H), 3.92-4.00 (m, 1 H), 4.38-4.48 (m, 1 H), 7.40 (d, J=8.78 Hz, 1 H), 7.64 (dd, J=9.04, 2.01 Hz, 1 H), 7.89 (d, J=2.01 Hz, 1 H), 7.93 (d, J=9.04 Hz, 1 H), 8.21 (d, J=9.04 Hz, 1 H)
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]1([C:37]2[NH:41][N:40]=[C:39]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.[NH:50]1[CH2:53][CH:52]([O:54][C:55]2[CH:56]=[C:57]([CH:60]=[CH:61][C:62]=2[CH3:63])[C:58]#[N:59])[CH2:51]1>CN(C=O)C>[C:58]([C:57]1[CH:60]=[CH:61][C:62]([CH3:63])=[C:55]([CH:56]=1)[O:54][CH:52]1[CH2:51][N:50]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:39]2[CH:38]=[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:41][N:40]=2)=[O:43])[CH2:53]1)#[N:59]
Reactant: Cc1ccc(C#N)cc1OC1CNC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)cc1OC1CN(C(=O)CNC(=O)c2cc(-c3ccccc3)[nH]n2)C1
Yield: 22.5 %

Procedure:
DIPEA (193.9 mg, 1.5 mmol) followed by HOBt (53 mg, 0.29 mmol) and EDCI (75 mg, 0.39 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (92 g, 0.37 mmol) in DMF (3 mL) After 2 minutes of stirring, 3-(azetidin-3-yloxy)-4-methyl-benzonitrile hydrochloride (prepared by the method used for the synthesis of Intermediate 71) (84 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC afforded 35 mg (22.5% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[3-(5-cyano-2-methyl-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 416, 92.49%. 1H NMR (300 MHz, DMSO-d6): δ 13.8 (s, 1H), 8.2 (t, 1H), 7.74 (t, 2H), 7.42 (m, 2H), 7.3 (m, 3H), 7.16 (s, 1H), 7.08 (s, 1H), 5.2 (m, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 4.2 (m, 1H), 3.8 (m, 3H).
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].C(O)(=O)C(O)=O.[CH2:30]([NH:34][NH2:35])[CH2:31][CH2:32][CH3:33]>>[CH2:30]([N:34]1[C:2]2[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=2)[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2[OH:13])=[N:35]1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCNN
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Product: CCCCn1nc(-c2ccc(O)cc2O)c2ccc(O)cc21
Yield: 38.9 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.164 g, 2 mmol) and butylhydrazine oxalate (0.178 g, 1.0 mmol) to give 0.058 g of product as a pink solid
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C.[OH-].[Na+]>C1C=CC=CC=1.NCCC(O)=O.O>[C:1](/[C:3](=[CH:9]\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC#N
Agent: NCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)/C(C#N)=C/c1ccccc1
Temperature: 25 °C
Yield: 91.9 %

Procedure:
A mixture containing 4.0 mL (37.6 mmoles) of ethyl cyanoacetate, 3.95 g (37.2 mmoles) of benzaldehyde, 20 mg of β-alanine, and 1.00 mL of glacial acetic acid in 35 mL of benzene was heated at reflux for 3 hours with continuous azeotropic removal of water by means of a Dean-Stark trap. The product was isolated by cooling the mixture to room temperature, pouring it into 75 mL of 2:1 (v/v)1M aqueous NaOH:saturated brine, and extraction with ether. The organic extracts were washed with 75 mL of 2:1 (v/v) 1M aqueous NaOH:saturated brine, 10% aqueous sodium chloride solution, then were dried over anhydrous magnesium sulfate and subsequently filtered. Removal of the ether and benzene by evaporation at reduced pressure afforded 6.88 g (92% yield) of crystalline cyanoester 1: mp 49°-50° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:19]([O-])=O.[Na+].[C:23]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:24][C:25]([CH3:27])=[O:26].C(=O)(O)[O-].[Na+]>Cl.C(O)C.CO>[CH2:30]([O:29][C:23]([C:24](=[N:19][NH:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:25](=[O:26])[CH3:27])=[O:28])[CH3:31]
Reactant: COc1c(N)cccc1-c1cccc(C(=O)O)c1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)C(=NNc1cccc(-c2cccc(C(=O)O)c2)c1OC)C(C)=O

Procedure:
To a solution of 3′-amino-2′-methoxybiphenyl-3-carboxylic acid (5 g) prepared as in Example 6, in hydrochloric acid (8.5 mL) and methanol (90 mL) was added a solution of sodium nitrite (1.41 g in 400 mL of water) at about 0° C. to about 5° C. under stirring. The reaction mixture was stirred for about 15 minutes at about 5° C. Then ethyl acetoacetate (2.7 g) was added and the reaction mixture was stirred for about 15 minutes at about 0° C. to about 5° C. Solid sodium bicarbonate (15 g) and ethanol (30 mL) was added and the reaction mixture was allowed to warm to about room temperature and stirred for about 2 hours. The mixture was filtered, washed with water (50 mL) and dried under vacuum at about 35° C. to about 40° C. for about 6 hours.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:11]=[C:12]([CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=4)[CH:18]=3)[C:13](O)=[O:14])=[CH:8][CH:7]=[N:6]2)[CH2:3][CH2:2]1.[CH3:26][C:27]1[N:28]=[CH:29][C:30]([CH2:33][NH2:34])=[N:31][CH:32]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]([C:10]3[CH:11]=[C:12]([CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=4)[CH:18]=3)[C:13]([NH:34][CH2:33][C:30]3[CH:29]=[N:28][C:27]([CH3:26])=[CH:32][N:31]=3)=[O:14])=[CH:8][CH:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ccnn3CC3CC3)c2)nc1
Reactant: Cc1cnc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc(-c3ccnn3CC3CC3)c2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.7 %

Procedure:
3-(2-Cyclopropylmethyl-2H-pyrazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid (0.120 g, 0.36 mmol), C-(5-methyl-pyrazin-2-yl)-methylamine (0.044 g, 0.36 mmol), EDCI (0.103 g, 0.54 mmol), HOBt (0.073 g, 0.54 mmol), and NMM (0.183 g, 1.80 mmol) were added to 7 mL of dichloromethane. The reaction mixture was stirred for 48 hours at room temperature, then concentrated under reduced pressure. The residue was purified via flash chromatography (5:1 EtOAc/hexanes) to give 0.14 g of 3-(2-cyclopropylmethyl-2H-pyrazol-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=439.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.[NH:19](/[C:23](/[CH3:29])=[CH:24]\[C:25](OC)=[O:26])[C:20]([CH3:22])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:25](=[O:26])[CH:24]=[C:23]([CH3:29])[N:19]=[C:20]2[CH3:22])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(N2CCCCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCCCC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.7 %

Procedure:
To a solution of 3-fluoro-4-(piperidin-1-yl)aniline (10.00 g, 51 mmol) in anhydrous CH2Cl2 (100 mL) was added trimethylaluminum (155 mL, 155 mmol, 1.0 M in toluene) under N2. The mixture was stirred at rt for 20 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (9.72 g, 62 mmol) in anhydrous CH2Cl2 (20 mL). The reaction mixture was stirred at rt for 5 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a pale yellow solid (11.02 g, 71%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH2:12][CH2:13][C:14]([C:16]2[S:17][C:18]([CH3:27])=[C:19]3[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][C:20]=23)=[O:15])=[CH:7][C:6]=1[CH3:28].CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:11][C:10]1[CH:9]=[C:8]([CH2:12][CH2:13][C:14](=[O:15])[C:16]2[S:17][C:18]([CH3:27])=[C:19]3[CH2:24][C:23]([CH3:25])([CH3:26])[CH2:22][CH2:21][C:20]=23)[CH:7]=[C:6]([CH3:28])[C:5]=1[O:4][CH2:3][CH2:2][O:1][S:39]([CH3:38])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1OCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1OCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
To a solution of 3-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (130 mg, 0.325 mmol) in DCM (10 mL) and DIPEA (0.09 mL, 0.52 mmol) is added methane sulfonylchloride (0.03 mL, 0.39 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 2-{2,6-dimethyl-4-[3-oxo-3-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propyl]-phenoxy}-ethyl ester (165 mg) as a yellow oil; LC-MS: tR=1.17 min, [M+1]+=479.26.