Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([C:8]#[N:9])=[CH:5][CH2:4][CH2:3]1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>CN(C=O)C>[Si:15]([O:1][CH:2]1[CH2:7][C:6]([C:8]#[N:9])=[CH:5][CH2:4][CH2:3]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CC1=CCCC(O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC=C(C#N)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-Hydroxycyclohex-1-ene-1-carbonitrile (500 mg, 4.06 mmol) was dissolved in anhydrous DMF (5.1 mL) and then cooled to 0° C. Imidazole (276 mg, 4.06 mmol) and TBS-Cl (612 mg, 4.06 mmol) were added and the reaction mixture was allowed to stir at 0° C. for 2 hours. The reaction mixture was partitioned between water and DCM. The organic layer was collected and the aqueous layer was again extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100%, EtOAc/hexanes) to afford the title compound. LRMS (ESI) calc'd for C13H23NOSi [M+H]+: 238. Found: 238.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25]([OH:27])=O)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(Cl)CCl.[F:32][C:33]1[CH:34]=[C:35]([CH2:39][NH2:40])[CH:36]=[N:37][CH:38]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:32][C:33]1[CH:34]=[C:35]([CH2:39][NH:40][C:25]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]=2[CH:22]([CH3:24])[CH3:23])=[O:27])[CH:36]=[N:37][CH:38]=1
Reactant: NCc1cncc(F)c1
Reactant: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)c1ccc2c(C(=O)NCc3cncc(F)c3)c(C(C)C)n(Cc3ccccn3)c2c1

Procedure:
Following General Procedure E, 6-(ethoxycarbonyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 40, 150 mg, 0.41 mmol) in CH2Cl2 (25 ml) was added EDC (236 mg, 0.82 mmol) and DMAP (75 mg, 0.60 mmol), followed by (5-fluoropyridin-3-yl)methanamine (94 mg, 0.82 mmol). The crude material was purified by chromatography on silica gel (0→80% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[N:6]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[N:17]=[C:5]2[NH:4][CH2:3]1.Cl.Cl.[NH2:20]C[C@H](N)C.Cl.Cl.NC[C@@H](N)C>>[CH3:1][C@H:2]1[N:6]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[C:9]([NH2:20])[C:8]=3[N:17]=[C:5]2[NH:4][CH2:3]1
Reactant: C[C@@H]1CNc2nc3cnc4ccccc4c3n21
Reactant: C[C@@H](N)CN
Agent: C[C@H](N)CN
Agent: Cl
Product: C[C@@H]1CNc2nc3c(N)nc4ccccc4c3n21

Procedure:
The methods described in Parts A through C of Example 23 were used to prepare (10R)-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline with (R)-(−)-1,2-diaminopropane dihydrochloride used in lieu of (S)-(−)-1,2-diaminopropane dihydrochloride in Part A. The methods described in Parts A through D of Example 27 were used to convert (10R)-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline to the title compound, which was obtained as a white solid, m.p. 272-274° C.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH2:14][N:15]3[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)=[CH:12][N:13]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH2:14][N:15]3[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)=[CH:12][N:13]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2ncc(Cn3cc([N+](=O)[O-])cn3)s2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2ncc(Cn3cc(N)cn3)s2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(2-methyl-[1,3]dioxolan-2-yl)-5-(4-nitro-pyrazol-1-ylmethyl)-thiazole (460 mg, 1.55 mmol), iron powder (263 mg, 4.66 mmol) and NH4Cl (419 mg, 7.76 mmol) in a mixture of EtOH (3.0 mL) and water (1.5 mL) was stirred at 75° C. for 60 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by 1N NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a red oil. TLC: rf (19:1 CH2Cl2-MeOH)=0.20. LC-MS-conditions 02: tR=0.54 min; [M+H]+=266.93.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:36]([O:43][CH2:44][C@H:45]1[O:50][CH2:49][CH2:48][N:47]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53](B3OC(C)(C)C(C)(C)O3)[CH:52]=2)[CH2:46]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[OH-].[Na+]>COCCOC.C(Cl)Cl.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13]([C:55]4[CH:54]=[CH:53][CH:52]=[C:51]([N:47]5[CH2:48][CH2:49][O:50][C@H:45]([CH2:44][O:43][CH2:36][C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[CH2:46]5)[CH:56]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cccc(N3CCO[C@H](COCc4ccccc4)C3)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCO[C@H](COCc7ccccc7)C6)c5)nc43)cc2)CCC1
Temperature: 160 °C
Yield: 48.3 %

Procedure:
A mixture of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50.0 mg, 0.101 mmol), (2S)-2-[(benzyloxy)methyl]-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (82.4 mg, 0.204 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.21 mg, 0.0102 mmol), and 2M NaOH aq. (0.150 mL, 0.310) in DME (2 mL) was heated at 160° C. for 2 hours under microwave irradiation. After cooling to room temperature, the mixture was diluted with DCM and filtered through a Celite pad. The combined filtrate and washings were concentrated. The residue was purified by silica gel column chromatography (CHCl3/MeOH=98:2) and PTLC (CHCl3/MeOH=9:1) to afford desired product (36.0 mg, 47.9%) as pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([O:32][CH3:33])[C:30]=1[OH:31])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]#[CH:16])=[CH:9][C:8]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=1)=O.[O-:34][C:35]#[N:36].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([O:32][CH3:33])[C:30]=1[OH:31])[CH2:5][N:6]1[C:7]2[C:8](=[CH:9][C:10]([O:13][CH2:14][C:15]#[CH:16])=[CH:11][CH:12]=2)[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[N:36][C:35]1=[O:34]
Reactant: N#C[O-]
Reactant: C#CCOc1ccc(NCc2cc(Cl)c(O)c(OC)c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cc(Cl)c(O)c(OC)c1
Reaction time: 12 h

Procedure:
To a mixture of 43.1 mg (0.093 mmol) of [2-(3-Chloro-4-hydroxy-5-methoxy-benzyl-amino)-5-prop-2-ynyloxy-phenyl]-(4-isopropyl-phenyl)-methanone in 1 ml of acetic acid is added 12.1 mg (0.186 mmol) of sodium cyanate. After siring for 12 h at r.t. the solvent is removed in vacuo and the residue partitioned between saturated NaHCO3 solution and ethyl acetate. The organic layer is separated and the aqueous phase extracted twice with ethyl acetate. The combined organic extracts are dried (Na2SO4) and evaporated in vacuo. Flash chromatography (SiO2, hexane/ethyl acetate) affords the title compound as an amorphous yellow solid.
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][C:16](O)=[O:17])[C:10]2=[O:34])[CH:4]=1)#[N:2].C([N:37](CC)CC)C.ClC(OCC)=O.[NH4+].[OH-]>C1COCC1.CCOC(C)=O>[C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][C:16]([NH2:37])=[O:17])[C:10]2=[O:34])[CH:4]=1)#[N:2]
Reactant: CCN(CC)CC
Reactant: COc1ccc2ccc(S(=O)(=O)N(CC(=O)O)[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(S(=O)(=O)N(CC(N)=O)[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 2-[[1-(5-cyanothiophene-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-(7-methoxynaphthalene-2-sulfonyl)amino]acetic acid (0.40 g, 0.80 mmol) in 6 mL of THF at -15° C. is added triethyl amine (0.10 g, 0.96 mmol) and ethyl chloroformate (0.09 g, 0.84 mmol). The solution is stirred for 1 hour. After this time, NH4OH (0.07 mL, 0.90 mmol) is added and the solution is allowed to warm to ambient temperatures. After 16 hours, the solution is diluted with EtOAc. The solution is washed with 1 N HCl, sat. NaHCO3 and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The title compound (0.28 g, 0.56 mmol) is obtained as a white foam.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH3:40])[CH:13]=[C:14]([NH:16][C:17]([C:19]3[N:20]([CH3:39])[CH:21]=[C:22]([NH:24][C:25]([C:27]4[N:28]([CH3:38])[CH:29]=[C:30]([NH:32][C:33](=[O:37])[C:34]([Br:36])=[CH2:35])[CH:31]=4)=[O:26])[CH:23]=3)=[O:18])[CH:15]=2)=[O:10])[CH:5]=[C:4]1[C:41]([NH:43][CH2:44][CH2:45][C:46](N)=[NH:47])=[O:42].C1(=O)OC(=O)CC1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:2][N:3]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH3:40])[CH:13]=[C:14]([NH:16][C:17]([C:19]3[N:20]([CH3:39])[CH:21]=[C:22]([NH:24][C:25]([C:27]4[N:28]([CH3:38])[CH:29]=[C:30]([NH:32][C:33](=[O:37])[C:34]([Br:36])=[CH2:35])[CH:31]=4)=[O:26])[CH:23]=3)=[O:18])[CH:15]=2)=[O:10])[CH:5]=[C:4]1[C:41]([NH:43][CH2:44][CH2:45][C:46]#[N:47])=[O:42]
Reactant: C=C(Br)C(=O)Nc1cc(C(=O)Nc2cc(C(=O)Nc3cc(C(=O)Nc4cc(C(=O)NCCC(=N)N)n(C)c4)n(C)c3)n(C)c2)n(C)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Product: C=C(Br)C(=O)Nc1cc(C(=O)Nc2cc(C(=O)Nc3cc(C(=O)Nc4cc(C(=O)NCCC#N)n(C)c4)n(C)c3)n(C)c2)n(C)c1
Temperature: 60 °C
Yield: 46.2 %

Procedure:
To a solution of 350 mg of 3-[1-methyl-4[1-methyl-4[1-methyl-4-[1-methyl-4-(α-bromoacrylamido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride (prepared as reported in WO 90/11277) in 20 ml of DMF, were added 120 mg of succinic anhydride and 165 mg of K2CO3. The solution was heated at 60° C. for 3 hours then the solvent evaporated under reduced pressure and the crude residue was purified by flash chromatography (methylene chloride/methanol: 95/5) to yield 150 mg of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=1)[C:14](OC)=[O:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(C)C)(C)C>C(O)(C)C>[CH2:1]([N:8]1[CH2:9][C:10](=[O:11])[NH:12][C@H:13]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2)[C:14]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1ccc(C)c(C)c1)NC(=O)CNCc1ccccc1
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: Cc1ccc(C[C@H]2NC(=O)CN(Cc3ccccc3)C2=O)cc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
A mixture of methyl (2R)-2-[(2-benzylaminoacetyl)amino]-3-(3,4-dimethylphenyl)propionate (2.5 g) and acetic acid (0.2 ml) in isopropyl alcohol (8.8 ml) was stirred for 5 hours under reflux. After being cooled to room temperature, isopropyl ether was added to the mixture. The resulting precipitates were collected by filtration and washed with isopropyl ether to give colorless crystals of (3R)-1-benzyl-3-(3,4-dimethylbenzyl)-2,5-piperazinedione (1.26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([OH:20])=[C:13]([Cl:19])[C:14]=3[Cl:18])[C:9]2=[O:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C([O:31][C:32](=[O:35])[CH2:33]Br)C.[OH-].[Na+].Cl>CN(C)C=O.O>[O:21]=[C:9]1[C:10]2[C:15](=[C:14]([Cl:18])[C:13]([Cl:19])=[C:12]([O:20][CH2:33][C:32]([OH:35])=[O:31])[CH:11]=2)[C:16](=[O:17])[C:8]1([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: CC1(c2ccc(Cl)cc2)C(=O)c2cc(O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2ccc(Cl)cc2)C(=O)c2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 80 °C

Procedure:
A stirred mixture of 2-(p-chlorophenyl)-2-methyl-4,5-dichloro-6-hydroxyindan-1,3-dione (3.06 g., 0.00863 mole), potassium carbonate (2.26 g., 0.0163 mole) and ethylbromoacetate (2.72 g., 0.0163 mole) in dimethylformamide (50 ml.) is warmed at 55°-60°C. for two hours, then treated with water (50 ml.)-10N sodium hydroxide solution (2.5 ml., 0.025 mole) and heated at 80°C. for 1 hour. The reaction mixture is added slowly to water (500 ml.)-12N hydrochloric acid (10 ml.) to precipitate [1,3-dioxo-2-(p-chlorophenyl)-2-methyl-4,5-dichloro-6-indanyloxy]acetic acid.
Reaction SMILES: Cl.C([O:4][C:5](=O)[CH:6]([NH2:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])C.[NH3:27]>CO>[NH2:25][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:5]([NH2:27])=[O:4]
Reactant: CCCCCCCCCCCCCCCCCCC(N)C(=O)OCC
Reactant: N
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCC(N)C(N)=O
Temperature: 60 °C
Reaction time: 65 h
Yield: 93 %

Procedure:
A slurry of ethyl-2-aminoeicosanoate hydrochloride prepared as in Example 28B (74.2 g, 0.189 mol) in anhydrous methanol (500 ml) was saturated with anhydrous ammonia at 0° C. The resulting mixture was sealed in a pressure bottle and heated to 60° C., resulting in a pressure of 40 psi. After 65 h at 60° C., the crystalline mixture was cooled to -20° C. and the solid was filtered to give 57.6 g (93%) of the product as off-white plates: mp 103-4° C.; 1H NMR (CDCl3) δ 0.88 (t, J=6.5 Hz, 3 H), 1.37 (m, 35 H), 1.82 (m, 1 H), 3.67 (m, 1 H), 5.30 (br s, 1 H), 7.09 (br s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:11])([Cl:10])[Cl:9])=[CH:4][N:3]=1.[Cl:12]Cl>>[Cl:1][C:2]1[C:7]([Cl:12])=[CH:6][C:5]([C:8]([Cl:9])([Cl:10])[Cl:11])=[CH:4][N:3]=1
Reactant: ClCl
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cn1
Product: Clc1cc(C(Cl)(Cl)Cl)cnc1Cl

Procedure:
Instead of isolating the 2-chloro-5-(trichloromethyl)-pyridine from this mixture, the above-described mixture is reacted with chlorine according to the conditions of the present invention as described herein to form 2,3-dichloro-5-(trichloromethyl)pyridine. The resulting 2,3-dichloro-5-(trichloromethyl)pyridine is separated from the reaction mixture by distillation, crystal refining, recrystallization from a solvent or a combination thereof.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[OH:7][C:8]([CH2:22][CH2:23][CH3:24])=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:11].IC>CC(C)=O>[CH3:1][CH:9]([C:8](=[O:7])[CH2:22][CH2:23][CH3:24])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=1)=[O:11]
Reactant: CCCC(O)=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCC(=O)C(C)C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
To a stirred suspension of potassium carbonate (596 mg) in acetone (7 mL), was added 3-hydroxy-1-(3-trifluoromethylphenyl)-hex-2-en-1-one (190 mg) followed by iodomethane (0.45 mL). The mixture was heated at reflux for 6 h, cooled to room temperature, and the solvent evaporated at reduced pressure. The resulting oil was dissolved in ethyl acetate (20 mL), washed with water (3×20 mL), dried over sodium sulphate and evaporated at reduced pressure to give the crude product as an oil. Flash silica chromatography afforded 2-methyl-1-(3-trifluoromethylphenyl)-hexane-1,3-dione as an oil (102 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[N:23][CH:24]=4)=[CH:12][CH:13]=3)[C@@:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1.[OH2:32]>C(O)(C(F)(F)F)=O>[NH2:29][C:26]1[O:27][CH2:28][C@@:8]2([N:25]=1)[C:7]1[CH:6]=[C:5]([C:4](=[O:32])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[CH:18]=[CH:17][C:16]=1[O:15][C:14]1[C:9]2=[CH:10][C:11]([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)=[CH:12][CH:13]=1
Reactant: O
Reactant: CC(C)(C)C#Cc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC(=O)c1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 40 °C

Procedure:
(4R)-2′-(3,3-Dimethylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (70 mg, 171 μmol) was dissolved in TFA (1.31 ml) at RT and water (31 μl, 1705 μmol) was added. The mixture then was heated at 40° C. for 1 hr. TFA was removed in a stream of nitrogen and yellow residue was treated with 1.5 ml of 2N ammonia in methanol for 15 min at RT. The solution was concentrated in vacuo, residue was diluted with ethyl acetate (5 ml), the solution was washed with saturated NaHCO3 solution, brine, dried with magnesium sulfate and concentrated to give 1-((4S)-2-amino-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)-3,3-dimethyl-1-butanone.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)O1.Br[C:24]1[C:25]([CH3:36])=[N:26][N:27]([CH2:30][C:31]([O:33]CC)=[O:32])[C:28]=1[CH3:29]>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:36][C:25]1[C:24]([C:9]2[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)=[C:28]([CH3:29])[N:27]([CH2:30][C:31]([OH:33])=[O:32])[N:26]=1
Reactant: CC1(C)OB(c2cc(C(F)(F)F)cc3[nH]ncc23)OC1(C)C
Reactant: CCOC(=O)Cn1nc(C)c(Br)c1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cc1nn(CC(=O)O)c(C)c1-c1cc(C(F)(F)F)cc2[nH]ncc12
Temperature: 140 °C

Procedure:
To a microwave vial were added a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-indazole (0.3 g, 0.961 mmol), ethyl 2-(4-bromo-3,5-dimethyl-1H-pyrazol-1-yl)acetate (0.351 g, 1.346 mmol) and PdCl2(dppf) (0.035 g, 0.048 mmol) in dioxane (10 mL) and aqueous saturated NaHCO3 (3 mL). The resulting light yellow suspension was heated at 140° C. for 45 minutes in a microwave reactor. The reaction mixture was subsequently concentrated and the residue was purified by preparative HPLC, eluting with a gradient of 40-50% acetonitrile (containing 0.035% TFA) in H2O (containing 0.05% TFA) over a period of 6 minutes. Two products were separated. The product-containing fractions were combined and the volatiles removed in vacuo to give the title compound as the major product. ESI-MS m/z [M+H]+ calc'd for C15H13F3N4O2, 339.1. found 339.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:18][CH3:19])[C:9]1=O)=[O:5])[CH3:2].[C:21](P(=O)(OCC)OCC)#[N:22].[C-]#N.[Li+].O>C1COCC1.CN(C=O)C>[C:21]([C:9]1[C:10]2[C:15](=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][C:8]=1[CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])#[N:22]
Reactant: CCOC(=O)CCC1CCc2c(OC)cccc2C1=O
Reactant: CCOP(=O)(C#N)OCC
Agent: [C-]#N
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCC1=C(C#N)c2cccc(OC)c2CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
2-(2-Ethoxycarbonylethyl)-3,4-dihydro-5-methoxy-1(2H)-naphthalenone (1.1 g, 4 mmol), from Step 1, was dissolved in 15 mL of dry THF and cooled to 0° C. Diethyl cyanophosphonate (1.18 mL, 8 mmol), commercially available from Aldrich Chemical Company, was added, followed by 8 mL of a 0.5M solution of lithium cyanide (4 mmol) in DMF. The reaction mixture was stirred at ambient temperature overnight and then poured into water. The aqueous mixture was extracted with three portions of diethyl ether/ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in 100 mL of toluene and 1.1 g of p-toluenesulfonic acid was added. The reaction mixture was heated at reflux for 2 h and allowed to cool to ambient temperature. The toluene solution was poured into 5% aqueous sodium bicarbonate and the aqueous mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with 10% ethyl acetate in hexane to give 0.8 g (70% yield) of the title compound; MS DCI-NH3 M/Z: 286 (M+H)+, 303 (M+NH4)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5](OCC)=[O:6].OC(C(F)(F)F)CC(OCC)=O.[BH4-].[Na+].Cl>CCOCC>[OH:10][CH:3]([CH2:4][CH2:5][OH:6])[C:2]([F:12])([F:11])[F:1]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: CCOC(=O)CC(O)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Solvent: CCOCC
Product: OCCC(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dihydroxy-1,1,1-trifluorobutane (3) is prepared by sequential reduction of ethyl 4,4,4-trifluoroacetoacetate then ethyl 3-hydroxyl-4,4,4-trifluorobutyrate. Any effective reducing agent can be used. Most preferably, the reactions are conducted as follows. To a solution of ethyl 4,4,4-trifluoroacetoacetate (1) (18.4 g, 100 mmol) in ether (200 mL) is added sodium borohydride (NaBH4) (4 g, 105 mmol) in several portions over a period of 30 min at 0°-5° C. The reaction mixture is stirred at 0°-5° C. for 1 hour and at room temperature overnight. Hydrochloric acid (10%, 100 mL) is carefully added and the solid is removed by filtration. The aqueous layer is extracted with ether (150 mL) and the combination is dried over Na2SO4, filtered and evaporated to give 18.0 g clear liquid (98%). The liquid comprises ethyl 3-hydroxy-4,4,4-trifluorobutyrate (2) (M. Tordeux and C. Wakselman, J. Fluorine Chem., 20:301-306 (1982). The solution of the liquid in ether (50 mL) is added to a suspension of lithium aluminum hydride (6 g, 0.157 mol) in ether (50 mL) at 0°-5° C. for 80 minutes. After being stirred overnight at room temperature, 100 mL of 10% HCl is very carefully added to decompose excessive lithium aluminum hydride (LiAlH4). The aqueous residue is extracted by ether or ethyl acetate (2×150 mL) and the combination dried, filtered and evaporated to afford 12.6 g clear liquid of 2,4-dihydroxy-1,1,1-trifluorobutane (FIG. 1, (3)). The above procedure was conducted and a yield of 88% obtained. The boiling point of compound (3) was 51.5°-54.0° C./0.32 mmHg. The structure was verified with 1H Nuclear Magnetic Resonance (1HNMR) as follows: (CDCl3 /TMS): δ8 6.05 (d, J=6.6 Hz, 1H, 2-OH), 4.60 (s, 1H, 4-OH), 4.03 (m, 1H, CH), 3.56 (s, 2H, 4--CH2), 1.59 (m, 2H, 3-CH2) ppm. This compound was previously described by M. Tordeux, et al., J. Fluorine Chem. 20:301-306 (1982).