Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:24][C@H:25]([C:28]([OH:30])=[O:29])[CH2:26][SH:27]>C(O)C.O1CCOCC1>[N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[NH:24][CH:25]([C:28]([OH:30])=[O:29])[CH2:26][S:27]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1
Reactant: N[C@@H](CS)C(=O)O
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)C1CSC(c2ccc(-c3ccc(-n4ccc5ccccc54)cc3)cc2)N1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
A solution of 4′-Indol-1-yl-biphenyl-4-carbaldehyde (500 mg, 1.68 mmol) and L-cysteine (150 mg, 1.26 mmol) in ethanol (5 mL) and dioxan (5 mL) was stirred at 50° C. for 16 hours, cooled to room temperature and concentrated in vacuo. Trituration with diethyl ether gave the title compound as a beige solid (302 mg, 45%): mp. 135-137° C. (dec). Rf 0.10 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz) δ 7.82 (4H, m, Ar—H), 7.65 (6H, m, Ar—H), 7.52 (1H, d, J=8 Hz, Ar—H), 7.10-7.24 (2H, m, Ar—H), 6.74 (1H, s, Ar—H), 5.77 and 5.58 (both 0.5H, s, H-2, 1:1 diastereomers), 4.21 and 3.92 (both 0.5H, m, H-4, 1:1 diastereomers), 3.10-3.38 (2H, m, 2×H-5); ESI-LCMS e/z calcd for C24H20N2O2S: 400.500, found 401 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:10]([OH:25])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34].N1C=CN=C1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CO.C1COCC1.O.C(OCC)(=O)C.CCCCCC>[C:1]([NH:8][C@@H:9]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@@H:10]([O:25][Si:37]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1cccc(C#N)c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1cccc(C#N)c1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
Analogously to Example 1j), 1.4 g (3.2 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(m-cyanophenylmethyl)-hexanoic acid in 20 ml of DMF are silylated with 2.2 g (14.6 mmol) of tert-butyldimethylchlorosilane and 1.8 g (26 mmol) of imidazole. Hydrolysis of the silyl ester function with 2.6 g of potassium carbonate in 55 ml of methanol/THF/water 8:1:2, followed by column chromatography (SiO2, ethyl acetate/hexane 1:1), yields the title compound: TLC Rf (A)=0.39; tRet (I)=19.8 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:8]([NH:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:32][CH2:33]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)N1CCN(c2nc(-c3cccc(F)c3)cs2)CC1
Temperature: 70 °C
Reaction time: 72 h
Yield: 28.1 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (226 mg, 0.835 mmol), 4-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (92.7 ml, 28.1%) as a solid. mp 176-177° C.
Reaction SMILES: Cl.[F:2][C:3]([F:20])([F:19])[CH2:4][NH:5][C:6]([C:8]1[S:9][C:10]([CH:14]2OCC[O:15]2)=[CH:11][C:12]=1[CH3:13])=[O:7]>CC(C)=O>[F:20][C:3]([F:2])([F:19])[CH2:4][NH:5][C:6]([C:8]1[S:9][C:10]([CH:14]=[O:15])=[CH:11][C:12]=1[CH3:13])=[O:7]
Reactant: Cc1cc(C2OCCO2)sc1C(=O)NCC(F)(F)F
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(C=O)sc1C(=O)NCC(F)(F)F
Reaction time: 4 h
Yield: 51.2 %

Procedure:
HCl (2N, 4 ml) is added to a solution of 5-[1,3]dioxolan-2-yl-3-methyl-thiophene-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (450 mg) in acetone (10 ml). After 4 hours at 50° C. and one night at room temperature, the reaction is quenched with water. The reaction mixture is extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 5-formyl-3-methyl-thiophene-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide (196 mg) as a yellowish oil. MS (HPLC/MS): 252 (MH+). Retention time: 2.54 min.
Reaction SMILES: CN(C=O)C.[CH3:6][C:7]1([CH3:33])[C:19]2[O:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15]=2[C:14](=[O:24])[C:13]2[C:8]1=[CH:9][C:10](OS(C(F)(F)F)(=O)=O)=[CH:11][CH:12]=2.[CH3:34][C:35]1([CH3:42])[O:39][CH:38]([CH:40]=[CH2:41])[CH2:37][O:36]1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:34][C:35]1([CH3:42])[O:39][CH:38](/[CH:40]=[CH:41]/[C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][CH:11]=2)[C:14](=[O:24])[C:15]2[C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[O:18][C:19]=2[C:7]3([CH3:33])[CH3:6])[CH2:37][O:36]1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1oc1ccccc21
Reactant: C=CC1COC(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OCC(/C=C/c2ccc3c(c2)C(C)(C)c2oc4ccccc4c2C3=O)O1
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To the DMF solution (4 ml) of trifluoro-methanesulfonic acid 6,6-dimethyl-11-oxo-6,11-dihydro-benzo[b]naphtho[2,3-d]furan-8-yl ester (300 mg), 2,2-dimethyl-4-vinyl-[1,3]dioxolane (469 mg) and PdCl2(PPh3)2 (103 mg), sodium hydrocarbonate (184 mg) was added, and the mixture was stirred at 100° C. overnight under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (130 mg, 46%).
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([N:19]1[CH2:23][CH2:22][CH:21](O)[CH2:20]1)[CH3:18].O>CN(C=O)C>[CH2:17]([N:19]1[CH2:23][CH2:22][CH:21]([O:8][C:7](=[O:9])[C@:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)([OH:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:20]1)[CH3:18]
Reactant: CCN1CCC(O)C1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC(OC(=O)[C@](O)(c2ccccc2)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
0.655 g (0.00297 mol) of (2R)-2-Cyclopentyl-2-hydroxy-2-phenylacetic acid were dissolved in 8 ml of dry DMF. To this solution 0.580 g (0.0036 mol) of 1,1′-carbonildiimidazol were added and the mixture was stirred at room temperature for 1 h. After this time, the mixture obtained was added to a suspension (cooled at 0° C.) of 1-ethylpyrrolidin-3-ol (0.390 ml g, 0.0033 mol) and HNa (0.078 g, 0.0033 mol) in 4 ml of dry DMF. After stirring 15 h at room temperature the reaction mixture was treated with water and extracted three times with Et2O. The organic layers were combined, washed with water and dried. The residue was purified by silica gel column chromatography (eluent: CHCl3 plus isopropanol 0%→5%) to obtain 610 mg (65%) of the title product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[C:14][C:15]2[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[CH:17][N:16]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].O.[OH-].[Li+]>CO>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]#[C:14][C:15]2[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][N:16]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccnc(C#Cc2cc(OC)c(OC)c(OC)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C#Cc2cc(C(=O)O)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 2-(3,4,5-trimethoxyphenylethynyl)pyridine-4-carboxylate (1.40 g) was suspended in methanol (100 mL), to the suspension lithium hydroxide hydrate (189 mg) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue and the resultant mixture was neutralized with 1 M hydrochloric acid. After the reaction mixture was cooled with ice, crystals precipitated were collected by filtration to obtain the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:37][NH:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:47]=[N:48][CH:49]=[N:50][CH:51]=2)=[CH:42][CH:41]=1>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:38]([CH3:37])[CH2:39][C:40]3[CH:41]=[CH:42][C:43]([C:46]4[CH:51]=[N:50][CH:49]=[N:48][CH:47]=4)=[CH:44][CH:45]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNCc1ccc(-c2cncnc2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(-c4cncnc4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (75 mg, 0.21 mmol), CDI (41 mg, 0.25 mmol) and N-methyl-1-[4-(pyrimidin-5-yl)phenyl]methanamine (42 mg, 0.21 mmol) in THF (4.5 mL) and DMF (0.6 mL). The crude product was purified using prep method A.
Reaction SMILES: Cl.[N:2]1([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O.ON1C2C=CC=CC=2N=N1.[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30].Cl.CN(C)CCCN=C=NCC.C(=O)([O-])[O-].[Na+].[Na+]>O.C(#N)C.C1(C)C=CC=CC=1>[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:2]3[CH2:3][CH2:4][O:5][CH2:6][CH2:7]3)=[CH:17][CH:16]=2)=[O:15])[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Reactant: CC(C)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: CC(C)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Temperature: 22.5 °C
Reaction time: 0.08 h

Procedure:
A 1 L three-necked flask equipped with an air stirrer and thermocouple was charged with 4-(4-morpholinylmethyl)benzoic acid hydrochloride (50 g, 0.194 mol), toluene (400 mL), acetonitrile (100 mL) and 1-hydroxybenzotriazole monohydrate (17.8 g, 0.116 mol). After stirring the resulting off-white slurry at about 20-25° C. for 5 minutes, 1-isopropyl-piperazine (27.4 g, 0.213 mol) was added and the reaction mixture was stirred for 20 minutes. Next, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (44.6 g, 0.233 mol) was added and the reaction mixture was stirred at about 20-25° C. overnight. Water (250 mL) and aqueous saturated sodium carbonate (150 mL) were then added to the stirring suspension and mixed well. The resulting biphasic mixture was allowed to settle. The aqueous phase was discarded and the organic phase was washed with a 50% brine solution (water (150 mL)/brine (150 m L)). The organic phase was dried over anhydrous sodium sulfate, filtered, washed with acetonitrile and concentrated to yield (4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone, as a free base, as a light yellow oil.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([N:12]1[C@@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][C@H:13]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])=O)(C)(C)C.I[Si](C)(C)C>C(Cl)(Cl)Cl>[NH2:8][CH2:9][C:10]([N:12]1[C@@H:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:22][CH2:21][C@H:13]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1[C@@H](c2ccccc2)CC[C@H]1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@H](c2ccccc2)N1C(=O)CN
Yield: 86.1 %

Procedure:
tert-Butyl (2S,5R)-1-(2-aminoacetyl)-5-phenylprolinate may be obtained in a fashion similar to that described in Example 2 A, but starting from 1.22 g of tert-butyl (2S,5R)-1-(2-tert-butoxycarbonylaminoacetyl)-5-phenylprolinate, 0.45 cm3 of iodotrimethylsilane in solution in 30 cm3 of anhydrous chloroform. 0.79 g of tert-butyl (2S,5R)-1-(2-aminoacetyl)-5-phenylprolinate is thus obtained in the form of an oil, used as it is in subsequent syntheses.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:32]
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2ccccc2Cl)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (2-chlorophenyl)acetic acid (35.2 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred at room temperature for overnight. LCMS showed reaction was completed. The reaction was poured into water, off-white solid formed. The solid was filtered to give 3-{1-[(2-chlorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28-3.30 (m, 2H), 3.94 (s, 3H), 4.02 (s, 2H), 4.32 (t, J=8.46 Hz, 2H), 7.31-7.37 (m, 2H), 7.40-7.45 (m, 2H), 7.46-7.49 (m, 1H), 7.53 (s, 1H), 8.15 (d, J=8.34 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:16]2[CH:20]=[CH:19][C:18]([CH3:21])=[N:17]2)[CH:12]=[CH:13][C:14]=1[F:15])C1C=CC=CC=1>CO.[Pd]>[F:15][C:14]1[CH:13]=[CH:12][C:11]([N:16]2[CH:20]=[CH:19][C:18]([CH3:21])=[N:17]2)=[CH:10][C:9]=1[OH:8]
Reactant: Cc1ccn(-c2ccc(F)c(OCc3ccccc3)c2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1ccn(-c2ccc(F)c(O)c2)n1
Yield: 85.8 %

Procedure:
A solution of 1-(3-benzyloxy-4-fluoro-phenyl)-3-methyl-pyrazole (which may be prepared as described in Description 66) (470 mg, 1.66 mmol) in methanol (20 mL) was hydrogenated using an H-Cube with 10% Pd/C (30 mm cartridge) at 50° C. and 1 mL/min flow rate. The eluent was concentrated in vacuo to give 2-fluoro-5-(3-methylpyrazol-1-yl)phenol (D68) (288 mg, 1.4236 mmol, 85.5% yield) as a colourless oil;
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1([C:18]#[N:19])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[I-].[K+]>>[O:23]1[CH2:24][CH2:25][N:20]([CH2:2][CH2:3][CH2:4][C:5]2([C:18]#[N:19])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:21][CH2:22]1
Reactant: C1COCCN1
Reactant: N#CC1(CCCCl)c2ccccc2-c2ccccc21
Agent: [I-]
Agent: [K+]
Product: N#CC1(CCCN2CCOCC2)c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
9-Cyanofluorene was reacted with sodium amide and 1,3-dichloropropane to give 9-(3chloropropyl)-9-cyanofluorene. A solution of 10.0 g. of 9-(3-chloropropyl)-9-cyanofluorene in 200 ml. of morpholine containing 2.0 g. of potassium iodide was stirred at 160° C. for sixteen hours. After cooling the reaction mixture to room temperature, the solution was diluted with 500 ml. of water, and the aqueous mixture was extracted several times with ethylacetate. The organic extracts were combined, washed with water, and the product was extracted therefrom into 0.6 N hydrochloric acid. The aqueous acid layer was separated and made alkaline by the addition of 10 percent sodium hydroxide solution. The alkaline solution was extracted with fresh ethyl acetate, and the extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure provided 9-(3-morpholinopropyl)-9-cyanofluorene.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]([CH3:10])([O-:9])[CH3:8].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].Cl>O>[C:7]([O:9][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])([CH3:10])([CH3:8])[CH3:6]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)Oc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.9 %

Procedure:
A tetrahydrofuran (THF) solution (20 ml) of potassium tert-butoxide (3.55 g, 31.6 mmol) was cooled in an methanol-ice bath, and 4.2 g of 2,5-difluoronitrobenzene (26.4 mmol) was further added. The mixture was heated to room temperature, stirred for 96 hours, and further stirred at 60° C. for 1 hour. Water (2 ml) and 2N-hydrochloric acid (2 ml) were added to the reaction mixture while cooling with an ice water bath, and subsequently water was added. The resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was then purified using silica gel column chromatography (n-hexane:ethyl acetate=19:1). The purified product was concentrated under reduced pressure to thereby obtain 4.5 g of oily orange 1-tert-butoxy-4-fluoro-2-nitrobenzene (yield: 80%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH3:16])[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1.C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([N:15]([CH3:16])[C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)=[O:27])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CNc1cc(Nc2ccc(F)cc2)ncn1
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(NC(=O)N(C)c2cc(Nc3ccc(F)cc3)ncn2)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of N-(4-fluoro-phenyl)-N′-methyl-pyrimidine-4,6-diamine (2.18 g, 10 mmol), 4-methoxyphenyl isocyanate (1.29 mL, 10 mmol) and dibutyltin diacetate (0.54 mL, 2 mmol) in dry dioxane (20 mL) is shaken for 6 h at 100° C. After addition of a second portion of 4-methoxyphenyl isocyanate (0.9 mL, 7 mmol) stirring is continued at 100° C. for 9 h. The reaction mixture is treated with ethyl acetate and half-saturated Na2CO3 solution. The organic layer is filtered, dried over Na2SO4, evaporated, and the residue purified by flash chromatography (hexane/ethyl acetate). The combined pure fractions are evaporated, the residue is suspended in hot CH3OH and the hot mixture filtered. This procedure is repeated several times. The solid thus obtained is dried in vacuo to afford the title compound.
Reaction SMILES: ClCCCl.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[CH:17]=2)=[CH:9][CH:8]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:16]=3[C:17]=2[C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccccc2)cc1

Procedure:
To 300 ml. of 1,2-dichloroethane maintained at 0° C. were added 6.0 g. (0.022 mole) of 2-(4-methoxyphenyl)-6-methoxybenzothiophene and 3.10 g. (0.022 mole) of benzoyl chloride. The mixture was stirred vigorously, and 3.2 g. (0.024 mole) of aluminum chloride were added in small portions. The resulting red solution was stirred for one hour, and water then was added. The yellow organic layer was separated, washed with 200 ml. of 1N sodium hydroxide and then with 200 ml. of saturated sodium chloride solution. The mixture then was dried over potassium carbonate, and the solvent was evaporated to give a pale yellow solid which was purified by chromatography over silica gel using benzene and 5% ethyl acetate in benzene as eluant. The appropriate fractions gave product as yellow crystals. The product was recrystallized from methanol to obtain 3.5 g. (42 percent) of 2-(4-methoxyphenyl)-3-benozyl-6-methoxybenzothiophene, melting point 110.5°-111° C.
Reaction SMILES: [C:1]1([CH3:35])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH:28]4[O:32]N=[C:30]([O:33][CH3:34])[CH2:29]4)[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.B(O)(O)O.[OH2:40]>CO>[C:1]1([CH3:35])[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([OH:32])[CH2:29][C:30]([O:33][CH3:34])=[O:40])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:5][CH:6]=1
Reactant: COC1=NOC(CCCCN2CCCc3nc(-c4ccc(C)cc4)c(-c4ccc(C)cc4)nc32)C1
Reactant: O
Agent: OB(O)O
Solvent: CO
Product: COC(=O)CC(O)CCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C

Procedure:
A solution of 5-(4-(2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)butyl)-3-methoxy-4,5-dihydroisoxazole (step 2) (94 mg, 0.2 mmol) in MeOH (3 ml) and water (0.2 ml) was treated with boric acid (37.1 mg, 0.600 mmol) followed by Mo(CO)6 (37.0 mg, 0.140 mmol). The resulting mixture was heated at overnight. After cooling to RT, the mixture was concentrated under reduced pressure and diluted with DCM. The organic portion was washed with water and dried by passing through a phase separating column. The solvent was removed under reduced pressure and purification of the crude product by chromatography on silica eluting with 0-60% EtOAc in iso-hexane afforded the titled compound;