Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][CH2:13][O-:14].[Na+].[H-].[Na+]>CCO>[CH2:13]([O:14][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)[CH3:12]
Reactant: O=C(O)Cc1ccc(Cl)nc1
Reactant: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(CC(=O)O)cn1
Temperature: 100 °C
Reaction time: 96 h
Yield: 82 %

Procedure:
To a stirred solution of (6-chloro-3-pyridinyl)acetic acid (0.094 g, 0.545 mmol) in EtOH (1.6 mL) was added 3.1 M EtONa in EtOH (0.7 mL, 2.17 mmol) and the reaction mixture was stirred at 100° C. room temperature for 24 hours after which an excess of NaH (60% dispersion in oil) was added together with 1 mL EtOH and heating at 100° C. was continued for 96 h. The solvent was evaporated in vacuo and the residue was taken up into diethyl ether (5 mL). The organic phase was washed with diluted HCl (2×2 mL) and brine (2 mL), dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (0.081 g, 82%) as a pale brown solid, which was used without further purification. 1H NMR (CDCl3): δ 10.06 (br s, 1H), 8.06 (s, 1H), 7.55 (d, J=9.2 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 4.30 (q, J=6.1 Hz, 2H), 3.58 (s, 2H) 1.38 (t, J=8.0, 3H). MS (ESI) (M+H)+=182.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.OS(O)(=O)=O.[C:18]1(C)C=CC=C[CH:19]=1>CCO>[CH2:18]([O:8][C:7](=[O:9])[CH:6]([C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:10])[CH3:19]
Reactant: Cc1ccccc1
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)C(O)c1ccc(Cl)cc1

Procedure:
A solution of 4-chloromandelic acid (12.3 g, 65.9 mmol) in toluene (50 mL), EtOH (16 mL), and concentrated H2SO4 (0.1 mL) was refluxed for 12 hours while removing water using a Dean-Stark trap. The mixture was concentrated in vacuo, diluted with DCM, and washed with dilute aqueous NaHCO3. The separated DCM layer was dried (MgSO4), filtered, and concentrated in vacuo to give (4-chlorophenyl)-hydroxy-acetic acid ethyl ester as a colorless oil (10.0 g) that crystallized upon standing.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([O:4][CH2:5][C:6](O)=[O:7])[CH3:3].C(Cl)(=O)C([Cl:13])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([O:4][CH2:5][C:6]([Cl:13])=[O:7])[CH3:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OCC(=O)O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OCC(=O)Cl
Yield: 52.9 %

Procedure:
To a 3-neck 500 ml round-bottom flask equipped with a magnetic stirrer, reflux condenser and addition funnel was added (1,1-dimethylethoxy)acetic acid (24.00 g, 0.182 moles) and 300 ml of toluene under nitrogen. Oxalyl chloride (46.10 g, 0.363 moles) was then added dropwise and to this mixture was added N,N-dimethylformamide (0.25 g, 0.003 moles). This solution was heated at 30°-40° C. for 5 hours and then concentrated in vacuo to give 14.5 g of the product as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](Cl)[C:3]=1[Cl:11].[Cl-].[NH4+].Cl>COP(OC)(OC)=O.O.[Zn]>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:11])=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: COP(=O)(OC)OC
Product: Clc1cc(Cl)c(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
1.7 g (0.027 gram atom) of zinc dust is introduced into a solution, heated to 80° C., of 5.1 g (0.02 mol) of pentachloropyridine in 35 ml of trimethylphosphate, and there is subsequently added dropwise within 1 hour at 80° to 83° C., with vigorous stirring, a solution of 2.84 g (0.055 mol) of ammonium chloride in 10 ml of water. The reaction mixture is then poured into 250 ml of ice water; 5 ml of concentrated hydrochloric acid is added and stirring is continued for 10 minutes. The mixture obtained is afterwards extracted twice with 100 ml of ether each time; the combined ether extracts are washed with 70 ml of water and dried over sodium sulfate. The ether is evaporated off to leave 4.1 g (93.2% of theory) of crude 2,3,5,6-tetrachloropyridine, m.p. 86° to 88° C., which contains, according to gas-chromatographical analysis, 94.1% of 2,3,5,6-tetrachloropyridine, 2.0% of 2,3,5-trichloropyridine, 2.0% of 2,3,6-trichloropyridine and 2.8% of pentachloropyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[S:13].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:17]1[NH:11][C:12](=[S:13])[NH:14][C:15]1=[O:16]
Reactant: COc1ccccc1C=O
Reactant: O=C1CNC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccccc1C=C1NC(=S)NC1=O
Yield: 85.4 %

Procedure:
A mixture of 2-methoxybenzaldehyde (2.5 g, 18 mmoles), 2-thiohydantoin (2.0 g, 17 mmoles), sodium acetate (4.0 g, 49 mmoles), acetic anhydride (1/2 ml), and acetic acid (15 ml) is stirred under an inert atmosphere and heated to reflux. After 1 hour the mixture is stirred into water (300 ml), and the precipitate is filtered off, rinsed with water three times and dried. The product is triturated in boiling methanol, filtered off, and dried to afford the pure product (3.4 g), mp 234°-235° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])=[N:6][CH:7]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[Cl:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=4)=[CH:7][N:6]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(Br)cn4)cc3)c(Cl)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(-c5ccc(Cl)cc5)cn4)cc3)c(Cl)cc21
Temperature: 100 °C
Reaction time: 36 h
Yield: 56.4 %

Procedure:
Ethyl 7-(4-(5-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (50 mg, 0.094 mmol), 4-chlorophenylboronic acid (15 mg, 0.094 mmol), Na2CO3 (25 mg, 0.24 mmol) and Pd(PPh3)4 (11 mg, 0.0094 mmol) were placed in a 1 mL vial and diluted with toluene (800 μL) and water (80 μL). The vial was purged with argon, sealed and heated to 100° C. After stirring for 36 hours, the reaction was loaded onto silica gel eluting with 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to yield the desired compound (30 mg, 0.053 mmol, 57% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:28]=1)[CH2:18]2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(N(C)C)=O>[CH:21]12[CH2:22][CH:17]1[CH2:18][N:19]([CH2:23][C:24]1[S:25][C:26]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=3)=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:28]=1)[CH2:20]2
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: Clc1ccc(-c2csc(CN3CC4CC4C3)n2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1ccc(-c2sc(CN3CC4CC4C3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 150 °C
Yield: 22 %

Procedure:
4-bromobenzenesulfonamide (0.37 g, 1.57 mmol) and potassium acetate (0.28 g, 2.87 mmol) were added to a solution of 2-(3-azabicyclo[3.1.0]hexan-3-ylmethyl)-4-(4-chlorophenyl)thiazole (Step-2 of compound 102, 0.42 g, 1.43 mmol) in a DMA (5 ml) in a tube at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Palladium acetate (0.032 g, 0.14 mmol) was then added to the reaction mixture under nitrogen atmosphere and the tube was sealed. The reaction mixture was heated at 150° C. for 20 hrs under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with ethyl acetate (20 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound (0.14 g, 21.4%). MS: m/z 446 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:10]=[CH:11][C:12]2[C:18](=[O:19])[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:15]([CH3:25])[C:13]=2[N:14]=1>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[N:10]=[CH:11][C:12]3[C:18](=[O:19])[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:15]([CH3:25])[C:13]=3[N:14]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cn(C)c2nc(Cl)ncc2c1=O
Solvent: CCO
Product: CCOC(=O)c1cn(C)c2nc(N3CCN(C)CC3)ncc2c1=O
Reaction time: 2 h
Yield: 56.5 %

Procedure:
1.5 g of N-methylpiperazine are added to a stirred suspension of 2 g of 2-chloro-5-oxo-6-carbethoxy-8-methyl-5,8-dihydro-pyrido(2,3-d)pyrimidine in 20 cm3 of absolute ethanol. The reaction takes place with evolution of heat. After standing for 2 hours at room temperature, the solvent is evaporated in vacuo, the residue is taken up in water and the precipitate is filtered off, washed, dried in vacuo and recrystallised from benzene: 1.4 g (58%) of 2-(4'-methyl-piperazino)-5-oxo-6-carbethoxy-8-methyl-5,8-dihydro-pyrido(2,3-d)pyrimidine are obtained.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:25][C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][N:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(OC(C)C)(=O)C>[Cl:25][C:26]1[C:31]([NH:32][CH:21]2[CH2:22][CH2:23][N:18]([C:16]([O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:17])[CH2:19][CH2:20]2)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Nc1cccnc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: O=C(OCc1ccccc1)N1CCC(Nc2cccnc2Cl)CC1

Procedure:
560 mL (7.25 mol) TFA were added dropwise at approx. 15° C. to 930 g (3.99 mol) N-benzyloxy carbonyl-4-piperidone and 466 g (3.63 mol) 2-chloro-3-aminopyridine in 9.5 L isopropyl acetate. 922 g (4.35 mol) sodium triacetoxyborohydride were added batchwise. The mixture was stirred until the reaction was complete. At RT the reaction mixture was combined with 860 mL sodium hydroxide solution (2 mol/L). The organic phase was separated off, washed with 5 L water and evaporated down.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:9]=[CH:10][N:11](C)C)=[N:5][CH:6]=[CH:7][N:8]=1)#[N:2].N[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(O)(=O)C>C(O)C>[N:9]1[C:4]2[C:3](=[N:8][CH:7]=[CH:6][N:5]=2)[C:1]([NH:2][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[N:11][CH:10]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CN(C)C=Nc1nccnc1C#N
Solvent: CC(=O)O
Solvent: CCO
Product: Oc1ccc(CCNc2ncnc3nccnc23)cc1

Procedure:
To a solution of N′-(3-cyanopyrazin-2-yl)-N,N-dimethylformamidine (prepared as in Albert and Ohta, J. Chem. Soc. C 1971, 3727-3730, which is expressly incorporated by reference herein; 2.0 g, 11.4 mmol) in ethyl alcohol (EtOH; 50 mL) was added 4-(2-aminoethyl)-phenol (4.7 g, 34 mmol) and acetic acid (3.9 mL, 4.1 g, 68 mmol). The solution was heated to reflux for 19 h, concentrated in vacuo, and the residue was slurried with H2O and suction filtered. The filter cake was washed with H2O and dried in a vacuum oven (80° C., 0.5 torr) to yield 4-[2-(pteridin-4-ylamino)-ethyl]-phenol (2.7 g) as a white solid: mp>210° C.; 1H NMR (DMSO-d6) δ 9.20 (s, 1H), 9.08 (s, 1H), 8.94 (s, 1H), 8.95 (t, J=6.0 Hz, 1H), 8.82 (s, 1H), 8.64 (s, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.69 (d, J=8.2 Hz, 2H), 3.75 (t, J=6.2 Hz, 2H), 2.85 (t, J=7.6 Hz, 2H); ESIMS m/z 268 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.COB(OC)OC.Br[C:21]([C:23]([F:26])([F:25])[F:24])=[CH2:22].C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C([Li])CCC.O1CCCC1.O.C(OC)(C)(C)C>[Cl:8][C:6]1[CH:7]=[C:2]([C:21]([C:23]([F:26])([F:25])[F:24])=[CH2:22])[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=1
Reactant: C=C(Br)C(F)(F)F
Reactant: FC(F)(F)c1cc(Cl)cc(Br)c1
Agent: COB(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Yield: 54.5 %

Procedure:
In a solution of 2.60 g of 3-bromo-5-chlorobenzotrifluoride and 1.2 mL of tert-butylmethyl ether in 25 mL of hexane, 6.38 mL of n-butyl lithium (1.6M hexane solution) was added dropwise at −10° C. with stirring, and stirred at the same temperature for 30 minutes. Then, a solution of 1.09 g of trimethoxyborane in 10 mL of tetrahydrofuran was added dropwise. After the completion of the addition dropwise, it was stirred at the same temperature further for 10 minutes and then the temperature was raised to room temperature. Then, in the reaction mixture, 2.60 g of 2-bromo-3,3,3-trifluoropropene, 2.76 g of potassium carbonate, 15 mL of water and 0.0065 g of 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ilidene (1,4-naphthoquinone) palladium (0) dimmer were added, and stirred under nitrogen atmosphere at 60° C. for 6 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off, and the organic phase was collected and the aqueous phase was extracted with 30 mL of ethyl acetate twice. The combined organic phases were washed with water, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with hexane to obtain 1.50 g of the aimed product as orange oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12](OS(C(F)(F)F)(=O)=O)[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:2].[CH3:22][N:23](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[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>[C:22]([C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:23]
Reactant: CCOc1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)OC)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CCOc1cc(C#N)cc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 3-ethoxy-5-trifluoromethanesulfonyloxybenzoate (308 mg, 0.94 mmol), zinc cyanide (165 mg, 1.41 mmol), tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.05 mmol) and DMF (2.0 mL) was stirred in a nitrogen atmosphere at 80° C. for 12 hours. After left cooled, the reaction mixture was diluted with ethyl acetate (30 mL), washed with aqueous 14% ammonia and aqueous saturated sodium chloride solution, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:9]=[C:10]2[C:22](=[O:23])[NH:21][N:20]=[CH:19][C:12]3=[C:13]([CH:17]=[CH2:18])[NH:14][C:15]([CH:16]=1)=[C:11]23)([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.CO>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:9]=[C:10]2[C:22](=[O:23])[NH:21][N:20]=[CH:19][C:12]3=[C:13]([CH2:17][CH3:18])[NH:14][C:15]([CH:16]=1)=[C:11]23)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.8 %

Procedure:
Palladium (10% on activated carbon) (0.23 g, 0.198 mmol) was added to a solution of the title compound of Example 164 (0.65 g, 1.99 mmol) in 1:10 N,N-dimethylformamide:methanol (11 mL). The reaction mixture was purged with H2 and stirred at room temperature under H2 (1 atm.) for 5 hours. The palladium was filtered and the volatile components were removed in vacuo. The resulting residue was dissolved in methanol and loaded onto a silica gel plug. The plug was then loaded onto a silica gel column and eluted with 1.2:1 dichloromethane:ethyl acetate to afford the title compound (0.45 g, 1.37 mmol) as a yellow solid in 69% yield.
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:30]([CH2:33][CH3:34])CC)C>ClCCl>[C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13][NH:30][CH2:33][CH2:34][S:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCl)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 118.8 %

Procedure:
Dissolve 12.7 g (32 mmol) the compound 10 and 10.2 g (32 mmol) the compound 9 into 60 mL dichloromethane. Then add 6.7 mL (48 mmol) triethylamine followed by a heat flow process for two days. After cooling, wash with 60 mL Sodium hydrogen carbonate aqueous solution, and wash again with 60 mL water, take the organic layer. The organic phase is dried by Na2SO4, condensed and then purified by liquid chromatography (SiO2, ethyl acetate: hexane=1:1) to get light yellow oil product 11 (12.9 g, 59.9%).
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].FC(F)(F)C(O)(C)C#CC1C=CC(S(N2CCCC2)(=O)=O)=CC=1>>[CH2:22]([N:3]([CH2:1][CH3:2])[S:4]([C:7]1[CH:8]=[CH:9][C:10](/[CH:13]=[CH:14]/[C:15]([OH:21])([CH3:20])[C:16]([F:17])([F:18])[F:19])=[CH:11][CH:12]=1)(=[O:5])=[O:6])[CH3:23]
Reactant: CCN(CC)S(=O)(=O)c1ccc(C#CC(C)(O)C(F)(F)F)cc1
Agent: CC(O)(C#Cc1ccc(S(=O)(=O)N2CCCC2)cc1)C(F)(F)F
Product: CCN(CC)S(=O)(=O)c1ccc(/C=C/C(C)(O)C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 11, but substituting 1-[4-(N,N-diethylaminosulfonyl)phenyl]-4,4,4-trifluoro-3-hydroxy-3-methylbut-1-yne for the 4,4,4-trifluoro-3-hydroxy-3-methyl-1-[4-(1-pyrrolidinylsulfonyl)phenyl]but-1-yne used therein, the title compound was prepared; mp 112.1°-117.2° C.; MS: m/z=352(M+1). Analysis for C15 H20F3NO3S: Calculated: C, 51.27; H, 5.74; N, 3.99. Found: C, 51.17; H, 5.96; N, 3.87.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]1>C1COCC1>[Cl:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][N:32]([C:35](=[O:37])[CH3:36])[CH2:33][CH2:34]3)[CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)N1CCN(CCCN)CC1
Reactant: Clc1cccc(Nc2nccc(Cl)n2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(CCCNc2ccnc(Nc3cccc(Cl)c3)n2)CC1
Temperature: 25 °C
Yield: 10 %

Procedure:
To 4-chloro-N-(3-chlorophenyl)pyrimidin-2-amine (0.5 g, 2.09 mmol) in THF (13 mL) is added DIPEA (0.73 mL, 4.18 mmol) followed by 1-(4-(3-aminopropyl)-piperazin-1-yl)ethanone, 22, (0.77 g, 4.18 mmol). The resulting mixture is refluxed for 12 hours after which the reaction mixture is cooled to room temperature and the solvent removed in vacuo. To the resulting residue is added water (50 mL) and the solution is washed with EtOAc (3×100 mL). The combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue which is obtained is purified over silica (10% MeOH in CH2Cl2) to afford 0.173 g (10% yield) of the desired compound. 1H NMR (DMSO-d6, 300 MHz) δ1.67-1.75 (m, 2H), 1.97 (s, 3H), 2.27-2.40 (m, 6H), 3.37-3.42 (m, 6H), 5.96 (d, J=6.0 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 7.21 (t, J=8.1 Hz, 1H), 7.28 (bs, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.80 (bs, 1H), 8.13 (bs, 1H), 9.19 (s, 1H). MS (ESI, pos. ion) m/z: 389 (M+1). HRMS calcd for C19H25ClN6O, 389.1857 m/z (M+H)+; observed 389.1851 m/z.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CC(=O)O)cc2)=C(C)C1=O
Reactant: C1CSCCN1
Product: COC1=C(OC)C(=O)C(Cc2ccc(CC(=O)N3CCSCC3)cc2)=C(C)C1=O
Yield: 19 %

Procedure:
4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (21 mg, 0.063 mmol) obtained in Example 52 and thiomorpholine (0.0096 ml, 0.095 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (5.1 mg, 0.012 mmol, yield 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]([OH:26])([CH:23]([CH3:25])[CH3:24])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[H-].[Na+].[CH2:29](I)[CH3:30].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:16]([O:26][CH2:29][CH3:30])([CH:23]([CH3:24])[CH3:25])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: CC(C)C(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(Cn1cncn1)(c1ccc(Oc2ccc(Cl)cc2)cc1Cl)C(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 2-[2-chloro-4-(4-chlorophenoxy)phenyl]-3-methyl-1-(1,2,4-triazol-1-yl)butan-2-ol (2.0 g, 10 mmol) in 50 mL of THF was added sodium hydride (350 mg) at room temperature. The reaction mixture was then stirred for 15 min followed by the addition of ethyliodide (2.39 g, 20 mmol) and stirred at 70° C. for 2 days. After another addition of sodium hydride (350 mg) and ethyliodide (2.39 g, 20 mmol), the mixture was stirred at 70° C. for 1 day more. An aq. solution of ammonium chloride was then added, the mixture was extracted with MTBE, dried, evaporated. The crude residue was purified by flash column chromatography on silica gel to give 1-[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-2-ethoxy-3-methyl-butyl]-1,2,4-triazole as a colorless oil (75 mg, 3%; HPLC-MS Rt=1.42 min; masse=420).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@:13]([F:15])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:27](O)=[O:28])=[N:22][CH:23]=[C:24]([Cl:26])[CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:21]3[C:20]([Cl:19])=[CH:25][C:24]([Cl:26])=[CH:23][N:22]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)c2ncc(Cl)cc2Cl)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 3,5-dichloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=429.2 [M+H]+and 431.1 [M+2+H]+.