Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16](=O)[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(S(O)(=O)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([CH:13]2[CH2:14][CH2:15][N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH2:11][CH2:12]2)=[N:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Reactant: NCc1ccccc1
Agent: O=S(=O)(O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)N1CCC(C(=NCc2ccccc2)c2ccc(F)cc2)CC1
Reaction time: 134.5 h
Yield: 77.1 %

Procedure:
A mixture of 10.32 g (0.0297 mol) of N-benzenesulfonyl-4-(p-fluorobenzoyl)piperidine, 5.4 g (0.0505 mol) of benzylamine and 0.5 g (0.0032 mol) of benzenesulfonic acid in 500 mL of toluene was heated at reflux. Water was removed from the reaction mixture with a Dean-Stark trap. After 134.5 h, the solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The CH2Cl2 solution was dried (MgSO4), the volume was reduced to 100 mL, and 200 mL of ether was added. A precipitate was collected to give 10.0 g (77.1%) of the title compound as a white crystalline solid, mp 153°-155°C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[O:14]=[C:15]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C@@H:31]([C:42](O)=[O:43])[CH2:32][C:33]3[CH:38]=[C:37]([Br:39])[C:36]([OH:40])=[C:35]([Br:41])[CH:34]=3)=[O:29])[CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[CH:45]=[CH:46][CH:47]=[CH:48][C:17]=2[NH:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[O:14]=[C:15]1[N:21]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C@H:31]([CH2:32][C:33]3[CH:34]=[C:35]([Br:41])[C:36]([OH:40])=[C:37]([Br:39])[CH:38]=3)[C:42]([N:11]3[CH2:12][CH2:13][CH:8]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:9][CH2:10]3)=[O:43])=[O:29])[CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[CH:45]=[CH:46][CH:47]=[CH:48][C:17]=2[NH:16]1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: O=C(O)[C@@H](Cc1cc(Br)c(O)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Br)c(O)c(Br)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere 55 mg (0.30 mmol) 1-methyl-4-piperidin-4-yl-piperazine was added to a solution of 151 mg (0.25 mmol) of (R)-1-carboxy-2-(3,5-dibromo-4-hydroxy-phenyl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 104 mg (0.27 mmol) HATU and 47 μL (0.27 mmol) ethyldiisopropylamine in 5 mL DMF and the reaction mixture was stirred for 3 h at RT. The reaction solution was evaporated down i.vac. and the residue was purified by chromatography (silica gel, DCM/MeOH/NH3 80:20:2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[S:23].C(N(CC)CC)C>C1COCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[C:12]2[NH:14][C:22](=[S:23])[NH:15][C:11]2=[N:10][C:9]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1cnccc1-c1cc2[nH]c(=S)[nH]c2nc1-c1cccnc1
Reaction time: 6 h
Yield: 88.3 %

Procedure:
A solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 2 g, 7.11 mmol), 1,1′-thiocarbonyldiimidazole (2.54 g, 14.22 mmol) and triethylamine (2 mL, 14.22 mmol) in THF (30 mL) was heated at 80° C. in a sealed tube. After 6 hours, the mixture was cooled and the solid was filtered, washed with NH4Cl aq. and water and dried to give the title compound (2.03 g, 88%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:12]=[C:11](SC)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:27]([O-:32])(O[O-])(=O)=[O:28].[K+].[K+].O.[C:36](#N)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=2)[N:12]=[C:11]([S:27]([CH3:36])(=[O:32])=[O:28])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#N
Reactant: CSc1nc(OCc2ccccc2)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1nc(OCc2ccccc2)cc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
4-Benzyloxy-2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (100 mg) and potassium peroxymonosulfate (490 mg) were stirred at room temperature in acetonitrile (2 ml) and water (200 μl) for 20 hours. The reaction mixture was diluted with ethyl acetate (40 ml) and washed with water (40 ml). Organics were separated, dried over sodium sulphate, and solvent evaporated under reduced pressure to yield product 4-benzyloxy-2-methanesulfonyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (93 mg). 1H NMR (CDCl3): δ 8.28 (s, 1H), 8.25 (d, 1H), 7.80 (d, 1H), 7.68 (t, 1H), 7.48 (d, 2H), 7.41 (m, 3H), 7.32 (s, 1H), 5.59 (s, 2H), 3.40 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.Cl[CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[CH:7][N:6]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
A mixture of 5-hydroxy-2-methylpyridine (8.46 g), 4-chloromethyl-5-methyl-2-phenyloxazole (15.20 g), potassium carbonate (15.98 g) and N,N-dimethylformamide (200 ml) was stirred at 80° C. for 3 hours, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain 2-methyl-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (19.68 g, yield 96%) as pale yellow crystals from the fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). This was recrystallized from acetone-hexane. Melting point: 103–104° C.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:16][O-].[Na+].C=O.[BH4-].[Na+]>CO>[CH3:16][NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]=1
Reactant: C[O-]
Reactant: CCCCCCC#Cc1cccc(N)c1
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCC#Cc1cccc(NC)c1
Temperature: 0 °C
Yield: 64 %

Procedure:
To a solution of 3-(oct-1-ynyl)aniline (1.34 g, 6.67 mmol) in MeOH (35 mL) was added NaOMe (25% wt. in MeOH, 7.7 mL), followed by paraformaldehyde (1.0 g, 33.3 mmol). The resulting mixture was refluxed 2 h under argon. After cooling to 0° C., NaBH4 (1.27 g, 33.4 mmol) was added and the mixture was refluxed for 90 min. The reaction mixture was then cooled to rt, quenched with ice and extracted with dichloromethane (50 mL+30 mL). The combined extracts were washed with H2O and brine and dried (Na2SO4). Flash chromatography (eluent: EtOAc/Hex=1:10 to 1:6) gave N-methyl-3-(oct-1-ynyl)aniline as a light yellow oil (920 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 7.10 (t, 1H, J=7.8 Hz), 6.77 (d, 1H, J=7.2 Hz), 6.66 (s, 1H), 6.55 (d, 1H, J=8.4 Hz), 3.80 (s, br, 1H, NH), 2.84 (s, 3H), 2.40 (t, 3H, J=7.0 Hz), 1.61 (quint, 2H, J=7.4 Hz), 1.46 (quint, 2H, J=6.8 Hz), 1.38-1.25 (m, 4H), 0.92 (t, 3H, J=6.6 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([O-:17])=[O:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>CO>[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)([O-:17])=[O:16]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2cccc([N+](=O)[O-])c2)CC1
Temperature: 30 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a mixture of tert-butyl N-(piperidin-4-yl)carbamate (25 g, 125 mmol, 1.0 eq) and 3-nitrobenzaldehyde (19 g, 125 mmol, 1.0 eq) in MeOH (500 mL) were added NaBH(OAc)3 (53 g, 250 mmol, 2.0 eq) and acetic acid (1 mL). Then the resulting mixture was stirred at 30° C. overnight. LC-MS indicated complete conversion. The solvent was removed under vaccum and the residue was purified by column chromatography (DCM:MeOH=15:1), to provide tert-butyl N-{1-(3-nitrobenzyl)piperidin-4-yl}carbamate (32 g, 76%) as a white solid.
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=1)C.C(C1C=CC(OCC[O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][N:38]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=CC=1)(=O)CCC>>[NH2:17][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][N:38]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])=[CH:12][CH:11]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCC(N)c1ccc(OCCN(CC)CC)cc1
Reactant: CCCC(=O)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Product: CCCC(N)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 25 except that (2-(2-(2-(4-butyrylphenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester (44) was used instead of 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-one (21). This produced the crude product which was purified by flash silica gel column chromatography, eluting with ethyl acetate, to give 45 (730 mg, 73%) as a clear oil: MS (ES+) m/z 497.3 (M+H)+.
Reaction SMILES: [C:1]1([PH+:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:25][Br:26]>C1(C)C=CC=CC=1>[Br-:26].[CH3:33][O:32][C:28]1[CH:27]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[C:29]=1[O:30][CH3:31])[CH2:25][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(CBr)cc(OC)c1OC
Solvent: Cc1ccccc1
Product: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Product: [Br-]
Reaction time: 24 h

Procedure:
A solution of triphenylphosphonium (4.2 g) in toluene (10 mL) was added to a stirred solution of 3,4,5-trimethoxybenzyl bromide (4.0 g) in toluene (15 mL) and stirring was continued for 24 hours. The phosphonium bromide that separated (8.0 g, 99%) was collected and dried under vacuum, mp 223-4 (lit 222°-23° C.).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1([C:13]([OH:15])=[O:14])[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2.[CH3:16]O>>[ClH:3].[NH2:5][C:6]1([C:13]([O:15][CH3:16])=[O:14])[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2
Reactant: NC1(C(=O)O)CC2CCC1C2
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)C1(N)CC2CCC1C2
Product: Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92 %

Procedure:
To 25 mL of methanol at 0° C. was added thionyl chloride (2.4 mL, 32 mmol). After stirring at 0° C. for 5 min, 2-amino-2-norbornanecarboxylic acid (1.0 g, 6.4 mmol) was added in one portion, and the mixture was heated at reflux for 16 h. The mixture was concentrated to give the product (1.2 g, 92%) as a white solid.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)(=O)=O.[C-:35]#[N:36].[Na+]>CS(C)=O>[CH3:33][Si:31]([CH3:34])([CH3:32])[CH2:30][CH2:29][O:28][CH2:27][N:24]1[C:20]2[N:21]=[CH:22][N:23]=[C:18]([C:16]3[CH:15]=[N:14][N:13]([C@@H:10]4[CH2:11][CH2:12][C@H:7]([CH2:6][C:35]#[N:36])[CH2:8][CH2:9]4)[CH:17]=3)[C:19]=2[CH:26]=[CH:25]1
Reactant: [C-]#N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](COS(C)(=O)=O)CC4)c3)ncnc21
Agent: [Na+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CC#N)CC4)c3)ncnc21
Temperature: 60 °C
Reaction time: 24 h

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl methanesulfonate (0.10 g, 0.00020 mol) and sodium cyanide (0.050 g, 0.0010 mol) and DMSO (1.0 mL) were mixed. The mixture was stirred at 60° C. for 24 hours, at which time LCMS analysis showed most of the starting material had been consumed. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)+: 437, 1H NMR (CDCl3): δ 8.90 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.43 (m, 1H), 3.60 (m, 2H), 2.45 (d, 2H, J=7.6 Hz), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][CH3:18])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][CH3:18])[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:19])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c2c(c1)B(O)OC2CC(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
To a solution of (1-hydroxy-6-methoxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.85 g, 3.22 mmol) in THF (7 mL) was added a solution of LiOH (0.385 g, 16.1 mmol) in water (7 mL) at 0° C. The resulting mixture was stirred at room temperature for 1.5 hours then acidified to pH 2 using dilute hydrochloric acid. The mixture was concentrated to remove THF and the white precipitate collected and washed with water to give pure product as a white powder (0.571 g, 75.1%); mp 157-158° C. 1HNMR (400 MHz, DMSO-d δ 9.10 (s, 1H), 7.02 (d, J=2.34 Hz, 1H), 6.83 (d, J=1.76 Hz, 1H), 5.42 (dd, J=9.67, 2.64 Hz, 1H), 3.73 (s, 3H), 3.01 (dd, J=15.38, 2.49 Hz, 1H), 2.24 (s, 3H), 2.03 (dd, 1H). MS (ESI) m/z=235 [M−H]−.
Reaction SMILES: [Li:1][CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.C[C:13]1[CH:21]=[CH:20][C:19](C)=[C:18]2[C:14]=1[CH:15]=CC2.[Br-]>C1COCC1.O>[CH3:19][C:20]1[CH:21]=[CH:13][C:14]([CH3:18])=[C:15]2[C:5]=1[CH:4]=[CH:3][CH:2]2[Li:1]
Reactant: [Li]CCCC
Reactant: Cc1ccc(C)c2c1C=CC2
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: [Li]C1C=Cc2c(C)ccc(C)c21
Reaction time: 2 h

Procedure:
LiBu is added to the solution in THF and hexane of 4,7-dimethyl-indene. After 2 hours, the bromide dissolved in 20 ml of THF and 10 ml of hexane is added, at −70° C. The mixture is left to rise to room temperature, after 8 hours water is added and the mixture is extracted with ethyl ether. After washing the organic extracts to neutrality and anhydrifying on Na2SO4, the solvent is evaporated. 3.1 g of product are obtained, after purification on a silica gel column using hexane/ethyl acetate as eluant in a ratio of 98/2 (yield=31%).
Reaction SMILES: Cl[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[CH:3][C:4]#[N:5].Cl.[CH2:14]([CH:16]1[CH2:18][CH:17]1[NH2:19])C.[CH3:20]C#N>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:2]([NH:19][CH:17]([CH:16]([CH3:14])[CH3:18])[CH3:20])=[CH:3][C:4]#[N:5]
Reactant: N#CC=C(Cl)c1ccccc1Cl
Reactant: CCC1CC1N
Reactant: CC#N
Agent: Cl
Product: CC(C)C(C)NC(=CC#N)c1ccccc1Cl
Yield: 89 %

Procedure:
To a solution of 3-chloro-3-(2-chlorophenyl)acrylonitrile (1.2 g, 6.05 mmol, 1 eq.) in 15 ml of MeCN was added 2-ethylcyclopropanamine hydrochloride (0.633 g, 7.27 mmol, 1.2 eq.) followed by TEA (0.919 g, 7.08 mmol, 1.5 eq.). The reaction was microwaved (130° C., 2000 s, fixed hold, high absorption) and the solvent evaporated. The residual oil was triturated in ethyl acetate and the white solid removed by filtration. After concentration under vacuum, the residual oil was subjected to column chromatography to give 3-(2-chlorophenyl)-3-[(3-methylbutan-2-yl)amino]acrylonitrile (1.36 g, 89% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=1.C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:24][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the title C compound, [4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-methanol (1.5 g, 5.08 mmol), carbon tetrabromide (2.53 g, 7.62 mmol), and triphenylphosphine (2.0 g, 7.62 mmol) in DCM is stirred at RT overnight. The mixture is then concentrated under vacuum, and chromatographed on a silica gel column using 8% EtOAc in hexane as the eluent to give 4-(4-bromomethyl-phenoxymethyl)-5-methyl-2-phenyl-oxazole as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH3:19][NH2:20].C1COCC1>C1COCC1>[CH3:19][NH:20][C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
A mixture of 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (750 mg, 3.06 mmol), 2.0M Methylamine/THF (2.3 mL, 4.60 mmol) in 50 mL of THF was stirred at room temperature for 6 hr. Then the traction mixture was concentrated to give 1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea. (760 mg, 90% yield). Rt=2.21 min; 277 [M+H].
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[N:11][NH:12][CH:13]=1.CCN(C(C)C)C(C)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.[NH2:36][CH2:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([C:46](=[O:58])[C:47]2[CH:52]=[C:51]([F:53])[CH:50]=[CH:49][C:48]=2[C:54]([F:57])([F:56])[F:55])[CH2:42][CH2:41]1)=[O:39]>C(Cl)Cl.O>[F:53][C:51]1[CH:50]=[CH:49][C:48]([C:54]([F:55])([F:57])[F:56])=[C:47]([CH:52]=1)[C:46]([N:43]1[CH2:42][CH2:41][N:40]([C:38](=[O:39])[CH2:37][NH:36][C:24]([N:12]2[CH:13]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[F:2])[CH:10]=[N:11]2)=[O:26])[CH2:45][CH2:44]1)=[O:58]
Reactant: Fc1ccccc1-c1cn[nH]c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNC(=O)n1cc(-c2ccccc2F)cn1)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A mixture of 4-(2-fluoro-phenyl)-1H-pyrazolehydrochloride salt (prepared by the method described above) (50 mg, 0.25 mmol), DIPEA (85 mg, 0.115 ml, 0.66 mmol) and DCM (1.5 ml) was added to a stirred solution of triphosgene (30 mg, 0.1 mmol) in DCM (2.5 mL) at room temperature. After 30 minutes, to the above solution, a mixture of 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method described above) (102 mg, 0.27 mmol), DIPEA (85 mg, 0.115 ml, 0.66 mmol) and DCM (1.5 ml) was added and the resulting mixture was stirred at room temperature for 1 hr. Cold water was then added and the product was extracted with DCM and the organic layer was washed with 10% HCl solution, saturated sodium bicarbonate solution and brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 59 mg (45% yield) 4-(2-fluoro-phenyl)-pyrazole-1-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 95.23%. 1H NMR (CDCl3): δ 8.6 (t, 1H), 8.0 (m, 2H), 7.8 (m, 1H), 7.6 (t, 1H), 7.3 (m, 1H), 7.2-7.0 (m, 3H), 4.36-4.2 (m, 2H), 4.1-3.8 (m, 1H), 3.8-3.46 (m, 4H), 3.6 (t, 1H), 3.3-3.2 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[C:9]([O:10][C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([Br:18])=[CH:13][C:12]=2[Cl:19])=[CH:8][C:7]([CH3:20])=[N:6][CH:5]=1.O.O.[OH-].[Li+].Cl>O1CCOCC1.ClCCl>[Br:18][C:14]1[C:15]([Cl:17])=[CH:16][C:11]([O:10][C:9]2[C:4]([C:3]([OH:21])=[O:2])=[CH:5][N:6]=[C:7]([CH3:20])[CH:8]=2)=[C:12]([Cl:19])[CH:13]=1
Reactant: COC(=O)c1cnc(C)cc1Oc1cc(Cl)c(Br)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Oc2cc(Cl)c(Br)cc2Cl)c(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
To a solution of 185 mg (0.473 mmol) 4-(4-bromo-2,5-dichloro-phenoxy)-6-methyl-nicotinic acid methyl ester in 3 mL dioxane was added 3 mL water and 30 mg (0.710 mmol) lithium hydroxide monohydrate. The reaction mixture was stirred for 4 hours at room temperature, poured on 30 mL 1M aqueous hydrochloric acid and 30 mL dichloromethane and the layers were separated. The aqueous layer was extracted with 30 mL dichloromethane and the combined organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum to afford 178 mg (100%) of the title compound as a colorless solid. MS (ESI): m/z=377.912 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:7](I)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:17]1(B(O)O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+].O>C1(C)C=CC=CC=1.CCO>[C:1]([C:5]1[NH:9][C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:7]([C:19]2[CH:18]=[CH:17][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(I)c(-c2ccncc2)[nH]1
Reactant: OB(O)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(-c2ccc3ccccc3c2)c(-c2ccncc2)[nH]1

Procedure:
In a heavy-walled pressure vessel 4-(2-tert-Butyl-5-iodo-3-H-imidazol-4-yl)-pyridine (100 milligrams (hereinafter “mg”), 0.3 mmol) and tetrakis-triphenylphosphine palladium (0) catalyst was dissolved in toluene (2-3 ml) and argon was bubbled through the solution while the other reagents were added: 1-naphthyl boronic acid (86 mg, 0.5 mmol), solid NaHCO3 (84 mg), water (500 uL), EtOH (500 uL). The vessel was sealed and the reaction heated to 100° overnight. The reaction mixture was partitioned between 5% NaHCO3 and EtOAc and extracted several times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was chromatographed on silica gel (chromatotron, eluting with 1-4% MeOH/CH2Cl2) to give the title compound as a yellow solid. (58 mg, 59%). mp 218-220°; MS m/e: 328 [M+H]+, 326 [M−H]−; 1H NMR(400 MHz, CDCl3) δ 9.63(br s, 1H), 8.16(app d, J=4.8 Hz, 2H), 7.92(br d, J=8.3 Hz, 2H), 7.64 (br d, 1H), 7.52 (m, 3H), 7.41 (t, J=6 Hz, 1H), 7.29 (br s, 2H), 1.49 (s, 9H).