Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:15])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.CC[O-].[Na+].Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: ClCc1ccccn1
Reactant: N#Cc1c(-c2ccco2)nc(N)[nH]c1=S
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(SCc2ccccn2)nc(N)nc1-c1ccco1
Reaction time: 16 h
Yield: 72 %

Procedure:
To a stirred solution of 200 mg (0.92 mmol) 2-amino-4-furan-2-yl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile in 10 ml ethanol were added 0.69 (1.84 mmol) sodium ethylate solution (2.67M in ethanol) and 117 mg (0.92 mmol) 2-(chloromethyl)pyridine hydrochloride and stirring continued for 16 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was triturated in ether to afford 205 mg (72%) 2-amino-4-furan-2-yl-6-(pyridin-2-ylmethylsulfanyl)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 310 (M+H+, 100).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.O>C(#N)C>[N:29]1([CH2:28][CH2:27][NH:26][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NCCN1CCCCC1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1NCCN1CCCCC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (200 mg, 0.775 mmol) in acetonitrile (5 mL) was added potassium carbonate (214 mg, 1.55 mmol) and 1-(2-aminoethyl)piperidine (119 mg, 0.93 mmol), and this was heated to reflux for 3 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (266 mg, 94% yield) as yellow crystals.
Reaction SMILES: [H-].[Na+].[C:3](OC)(=[O:5])[CH3:4].[CH3:8][C:9]1([CH3:16])[C@@H:14]2[C@H:10]1[CH2:11][C:12](=[O:15])[CH2:13]2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[C:3]([CH:13]1[C:12](=[O:15])[CH2:11][CH:10]2[CH:14]1[C:9]2([CH3:16])[CH3:8])(=[O:5])[CH3:4]
Reactant: COC(C)=O
Reactant: CC1(C)[C@@H]2CC(=O)C[C@@H]21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)C1C(=O)CC2C1C2(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 147.4 %

Procedure:
To a suspension of NaH (873 mg 55% dispersion in mineral oil, 20 mmol, washed with dioxane prior to use) in dioxane (15 mL) is added methyl acetate (2.22 g, 30 mmol). The suspension is stirred for 5 min at rt and a solution of (1S,5R)-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (1.24 g, 10 mmol) in dioxane (5 mL) is added. The reaction mixture is stirred at 65° C. overnight. The mixture is poured onto cold 10% aq. citric acid solution (75 mL) and extracted with DCM (3×75 mL). The organic extracts are washed with water, dried over MgSO4 and evaporated to give crude racemic (1R, 2R, 5R)-2-acetyl-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (2.45 g, contains dioxane) as a dark yellow liquid. 1H NMR (CDCl3): δ 2.61 (dd, J=7.3, 19.6 Hz, 1H), 2.34-2.20 (m, 1H), 2.01 (s, 3H), 1.72 (d, J=8.2 HZ, 1H), 1.40-1.20 (m, 2H), 1.09 (s, 3H), 0.81 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C:13](=[O:27])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:28])[N:6]=1)[CH2:3][CH3:4].Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[NH:36][CH:37]=[N:38][C:31]=12.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:38]1[C:31]2[C:32](=[N:33][CH:34]=[CH:35][C:30]=2[NH:1][C@H:2]([C:5]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([F:26])([F:24])[F:25])[CH:16]=3)[C:13](=[O:27])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[F:28])[N:6]=2)[CH2:3][CH3:4])[NH:36][CH:37]=1
Reactant: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Reactant: Clc1ccnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CC[C@H](Nc1ccnc2[nH]cnc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
Under nitrogen, to (S)-2-(1-aminopropyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (40 mg, 0.10 mmol, 1.0 equiv) in t-BuOH (0.5 mL) at 23° C. is added 7-chloro-3H-imidazo[4,5-b]pyridine (23 mg, 0.15 mmol, 1.5 equiv) and diisopropylethylamine (63 μL, 0.36 mmol, 4.0 equiv). After stirring for 48 hr at 120° C. in a sealed tube, the reaction mixture is concentrated in vacuo and the residue is purified by preparative TLC eluting with CH2Cl2/MeOH to afford the title compound (Compound 12A).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:5])#[N:2].N12CCN(CC1)CC2.CO/[CH:24]=[CH:25]/[C:26](=O)[CH2:27][CH3:28]>COCCO.Cl.C(OCC)(=O)C>[CH2:27]([C:26]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[C:4](=[O:5])[C:3]([C:1]#[N:2])=[CH:24][CH:25]=1)[CH3:28]
Reactant: N#CCC(=O)Nc1ccc(F)cc1
Reactant: CCC(=O)/C=C/OC
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COCCO
Product: CCc1ccc(C#N)c(=O)n1-c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 16 %

Procedure:
To a solution of 2-cyano-N-(4-fluorophenyl)acetamide (1.7 g, 10.6 mmol) in dimethyleneglycol monomethylether (20 mL) were added 1,4-diazabicyclo[2.2.2]octane (1.2 g, 10.6 mmol) and (1E)-1-methoxypent-1-en-3-one (1.82 g, 15.9 mmol), and the mixture was stirred at 120° C. for 12 hr. The reaction mixture was diluted with 1N hydrochloric acid and ethyl acetate, and extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=50/50→100/0) to give a white solid. The white solid was washed with ethyl acetate to give the title compound (410 mg, 16%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)[CH2:20][C:21](=[O:23])C.C1OC1>C(O)C>[OH:23][CH2:21][CH2:20][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]1
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Reactant: CC(=O)CC(C)C
Solvent: C1CO1
Solvent: CCO
Product: CCOC(=O)C1(c2ccccc2)CCN(CCO)CC1
Temperature: 60 °C

Procedure:
A mixture of 9.9 parts of ethyl 4-phenyl-4-piperidinecarboxylate, 41.8 parts of 4-methyl-2-pentanone, 4.3 parts of ethylene oxide and 79.2 parts of ethanol is heated in a sealed citric bottle at about 60° C for 7 days. The resulting solution is cooled, the solvent is evaporated under reduced pressure and the residual material is partitioned between diluted NaOH and ether. The ether layer is then separated and extracted with diluted HCl. The acid layer is then made alkaline with aqueous sodium hydroxide and the resulting mixture is extracted with ether. The ether layer is dried over sodium sulfate and potassium carbonate and evaporated in vacuum. The residue is crystallized from ether-n-pentane to give ethyl 1-(2-hydroxyethyl)-4-phenyl-4-piperidinecarboxylate, melting at about 91.5°-93° C.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][O:24][CH3:25])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1.[CH3:53][C:54]1[CH:59]=[C:58]([CH3:60])[N:57]2[N:61]=[C:62]([CH:64]=O)[N:63]=[C:56]2[N:55]=1.C(C1NC(C=O)=C(C)N=1)C>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][O:24][CH3:25])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:64][C:62]3[N:63]=[C:56]4[N:55]=[C:54]([CH3:53])[CH:59]=[C:58]([CH3:60])[N:57]4[N:61]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Product: COCc1cc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)ccc1O

Procedure:
The title compound was prepared analogously to Example A(97) where 6-Cyclopentyl-6-[2-(4-hydroxy-3-methoxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione (Example A(194)) was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile and 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde in that example. 1H NMR (400 MHz, DMSO-d6): δ 1.5-2.0 (m, 11H) 2.46-2.75 (m, 11H), 3.25 (s, 3H), 3.73 (d, J=16 Hz, 1H), 3.80 (d, J=16 Hz, 1H), 4.32 (s, 2H), 6.70 (d, J=8 Hz, 1H), 6.94-7.04 (m, 3H), 9.20 (s, 1H). Anal. Calcd. For C28H34N4O5.1.5H2O: C, 63.02; H, 6.99; N, 10.50. Found: C, 63.92; H, 6.74; N, 10.42. MS (ESI): 507.2 (M+H)+.
Reaction SMILES: CS(C)=O.C[O:6][C:7]1[CH:16]=[C:15]2[C:10](C(Cl)=CC=N2)=[CH:9][C:8]=1C(N)=O.[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](NC1CC1)=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:21][C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](=[O:31])[O:6][C:7]1[CH:16]=[CH:15][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Nc1ccc(O)cc1Cl)NC1CC1
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1ccc(O)cc1Cl)Oc1ccccc1
Temperature: 70 °C
Reaction time: 23 h
Yield: 142.4 %

Procedure:
To dimethyl sulfoxide (20 mL) were added 7-methoxy-4-chloroquinoline-6-carboxamide (0.983 g), 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea (1.13 g) and cesium carbonate (2.71 g), and the mixture was heated and stirred at 70° C. for 23 hours. The reaction mixture was cooled to room temperature, and water (50 mL) was added, and the resultant crystals were then filtered off to give 1.56 g of the titled compound (yield: 88%).
Reaction SMILES: [C:1]([CH:3]1[CH2:32][CH2:31][N:6]2[C:7]3[C:12]([C:13]([C:14]4[C:15](=[O:30])[O:16][C:17](=O)[C:18]=4[C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]([CH3:28])[CH:20]=4)=[C:5]2[CH2:4]1)=[CH:11][CH:10]=[CH:9][CH:8]=3)#[N:2].C[N:34](C)C=O>N>[C:1]([CH:3]1[CH2:32][CH2:31][N:6]2[C:7]3[C:12]([C:13]([C:14]4[C:15](=[O:30])[NH:34][C:17](=[O:16])[C:18]=4[C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]([CH3:28])[CH:20]=4)=[C:5]2[CH2:4]1)=[CH:11][CH:10]=[CH:9][CH:8]=3)#[N:2]
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(C#N)C4)C(=O)OC2=O)c2ccccc21
Reactant: CN(C)C=O
Agent: N
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(C#N)C4)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 400 mg of 3-[8-cyano-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 12 ml of dimethylformamide and 12 ml of 33% aqueous ammonia was heated to 140° C. for 3 hours. The mixture was cooled and the resulting solid was filtered off and dried to give 275 mg of 3-[8-cyano-6,7,8,9-tetrahydropyrido-[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 312°-313° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:38])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:41][N:40]=[N:39][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:30]3=[O:38])[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(N3Cc4ccccc4C3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-4-methyl-6-(1-oxo-isoindolin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:27])[CH:6]([S:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]O)=[CH:10][CH:9]=1.[CH3:30][S:31]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:37][CH:36]=1)(=[O:33])=[O:32].CS(O)(=O)=O>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][S:17][CH:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:43][C:42](=[O:44])[CH2:41][C:38]3[CH:37]=[CH:36][C:35]([O:34][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:40][CH:39]=3)=[CH:12][CH:13]=2)[C:5]([OH:27])=[O:4])=[CH:21][CH:22]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CCO)cc1)SCCc1ccc(F)cc1
Reactant: CS(=O)(=O)Oc1ccc(CC(=O)O)cc1
Agent: CS(=O)(=O)O
Product: CS(=O)(=O)Oc1ccc(CC(=O)OCCc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-[4-(2-hydroxy-ethyl)-phenyl]-propionic acid 2,2,2-trichloro-ethyl ester (34 mg, 0.072 mmol) and methanesulfonic acid (4-methanesulfonyloxy-phenyl)-acetic acid (15 mg, 0.065 mmol) in the same manner as described for example 1. The crude product was purified by HPLC (yield: 3.0 mg, 8.2%). 1H NMR (400 MHz, CDCl3): δ 7.17-7.24 (m, 4H), 7.00-7.10 (m, 6H), 6.89-6.93 (m, 2H), 4.26 (t, 2H), 3.80 (t, 2H), 3.46-3.50 (dd, 2H), 3.11 (s, 3H), 2.77-2.91 (m, 8H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.S=[C:20]1[CH2:24][S:23][C:22](=[O:25])[NH:21]1>C(O)C>[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1
Reactant: CC(C)[C@@H](N)C(=O)N(C)C
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)[C@@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude product (19.6 g) containing N,N-dimethyl-D-valinamide hydrochloride obtained in B) and triethylamine (44.0 g) in ethanol (150 mL) was added 4-thioxothiazolidin-2-one (14.4 g) at room temperature. The reaction mixture was stirred at room temperature for 3 hr, and the solvent was evaporated under reduced pressure. The obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (4.2 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([CH3:24])=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[F:23])[CH:13]=2)[NH:8][N:7]=1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1.O>[F:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[CH3:24])[NH:8][N:7]=[C:6]2[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1n[nH]c2cc(C)c(-c3ccc(OC)cc3F)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3c(C(=O)O)n[nH]c3cc2C)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.8 %

Procedure:
To a solution of 5-(2-fluoro-4-methoxyphenyl)-6-methyl-1H-indazole-3-carboxylic acid ethyl ester (292 mg, 0.89 mmol) in THF (4 mL) was added a solution of LiOH (298.0 mg, 12.25 mmol) in water (2 mL). The reaction mixture was heated to reflux for 9 hours, and stirred at room temperature for an additional 48 hours. 1N HCl solution was added to acidify the solution to pH 2. White solid formed, which was collected with filtration and dried in a vacuum oven at 50° C. for 4 hours to give the title compound (240 mg, 90% yield) as a solid. MS (ES+) 301.2 (M+H)+. 1H NMR (500 MHz, CD3OD) δ 7.92 (s, 1H), 7.51 (s, 1H), 7.22 (dd, J=8.70, 8.70 Hz, 1H), 6.87 (dd, J=8.42, 2.56 Hz, 1H), 6.81 (dd, J=11.59, 2.56 Hz, 1H), 3.88 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:37][CH2:36][CH:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][N:32]4[CH2:33][CH2:34][CH:35]([NH:38][S:39]([CH3:42])(=[O:40])=[O:41])[CH2:36][CH2:37]4)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: CS(=O)(=O)NC1CCNCC1
Product: CS(=O)(=O)NC1CCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CC1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and N-(piperidin-4-yl)methanesulfonamide (86.5 mg; 0.48 mmol) to give Example 146 as a white solid. 1H NMR: (CDCl3, 400 MHz) δ 8.72 (2H, dd, J=4.5, 1.6 Hz), 8.04 (2H, d, J=8.1 Hz), 7.63-7.52 (2H, m), 7.44-7.33 (5H, m), 7.22-7.15 (1H, m), 4.20 (1H, d, J=7.7 Hz), 3.55 (2H, s), 3.40-3.31 (1H, m), 2.98 (3H, s), 2.82 (2H, d, J=11.4 Hz), 2.16 (2H, t, J=11.3 Hz), 1.99 (2H, d, J=12.5 Hz), 1.66-1.50 (2H, m). LC/MS (Method C): 573 (M+H)+. HPLC (Method F) Rt 3.33 min (Purity: 99.2%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([Br:20])=[CH:9][N:8]=1)(=O)=O.[CH:23]#[C:24][CH:25]([OH:27])[CH3:26].C(N(CC)CC)C.N>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.CN(C)C=O>[CH2:13]([C:11]1[C:10]([Br:20])=[CH:9][N:8]=[C:7]([C:23]#[C:24][CH:25]([OH:27])[CH3:26])[CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#CC(C)O
Reactant: O=S(=O)(Oc1cc(Cc2ccccc2)c(Br)cn1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(O)C#Cc1cc(Cc2ccccc2)c(Br)cn1
Reaction time: 1 h
Yield: 79 %

Procedure:
650 mg of 4-benzyl-5-bromo-2-pyridyl trifluoromethanesulfonate (Production Example 1), 115 mg of 1-butyne-3-ol, 100 mg of tetrakis(triphenylphosphine)palladium(0), 30 mg of cuprous iodide and 1 ml of triethylamine were mixed with 5 ml of N,N-dimethylformamide, followed by stirring for one hour in an oil bath kept at 60° C. After cooling as it was, aqueous ammonia was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine and then evaporated. The residue was subjected to silica gel column chromatography and eluted with 30% ethyl acetate/hexane, to give 410 mg of the target compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][CH2:6][CH:7]=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C)P(N(C)C)(N(C)C)=O>[C:9]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH2:6][CH2:5][C:1]#[N:2])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: [C-]#N
Reactant: BrCCC=C(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CCCC=C(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 80 %

Procedure:
To a stirred solution of 73.g (1.5 mol) of sodium cyanide in 1 liter of hexamethylphosphoramide at ambient temperature was added over a 1 hour period a solution of 290. g (1 mol) of 4-bromo-1,1-diphenyl-1-butene in 0.5 liters of hexamethylphosphoramide. The mixture was stirred overnight, poured into 2 liters of water and extracted with 3×1 liters of ether. The ether extracts were combined, washed with 3×0.5 liters of Water, 0.5 liters of brine, and dried over sodium sulfate. The resulting crude solid was recrystallized from isopropyl ether to give 190 .g (80%) of 5,5-diphenyl-4-pentenenitrile as a white solid (mp 64°-66° C.) .
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:19])=[O:18])=[CH:13][CH:12]=1>>[CH2:10]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:18])[CH:19]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)[CH3:9]
Reactant: CCc1ccc(C(C)=O)cc1
Reactant: O=Cc1ccccc1
Product: CCc1ccc(C(=O)C=Cc2ccccc2)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from benzaldehyde and 4-ethylacetophenone, 1-(4-ethylphenyl)-3-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:18](Br)[CH:19]1[O:23][CH2:22][CH2:21][CH2:20]1.O>CN1CCCC1=O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([O:1][CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][O:23]2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(O)ccc1C=O
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(OCC2CCCO2)ccc1C=O
Temperature: 80 °C
Reaction time: 22 h
Yield: 62.3 %

Procedure:
In 160 mL of N-methylpyrrolidone was dissolved 24.5 g (161 mmol) of 4-hydroxy-2-methoxybenzaldehyde. To this solution were added 63 g (0.19 mol) of cesium carbonate and 40 g (0.24 mol) of tetrahydrofurfuryl bromide at room temperature and the mixture was stirred at 80° C. for 22 hours. Water (800 mL) was added to the resulting reaction mixture under ice-cooling, and extraction with diethyl ether (500 mL×3 times) was performed. The combined organic layer was washed with water and then with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting crude product was purified on basic alumina (hexane/ethyl acetate=50/50 to 0/100) to give 23.7 g (62% yield) of the title compound as a light yellow powder with the following properties.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]3=2)[CH:10]=[CH:9]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:9]2[CH2:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=32)=[CH:25][CH:24]=1
Reactant: COc1ccc(I)cc1
Reactant: C1=Cc2ccc3ccccc3c2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(C2=Cc3ccc4ccccc4c3C2)cc1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
20 mnl of triethylamine, 3.32 g (20 mmole) of benzindene, 4.68 g (20 mmole) of p-methoxy-phenyl-iodide and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and treated with 100 ml of ethanol. The crystalline precipitate was isolated, washed with ethanol and dried under vacuum to obtain 2.9 g (54%) of the mixture of two isomers.